A Randomized, Multicenter, Double-Blind, Placebo-Controlled Phase 2 Study to Evaluate the Safety and Efficacy of HMI-115 in Women With Moderate to Severe Endometriosis-Associated Pain Over a 12-Week Treatment Period
Phase: PHASE2
Conditions: Endometriosis
Sponsor: Hope Medicine (Nanjing) Co., Ltd

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A Randomized, Multicenter, Double-Blind, Placebo-Controlled Phase 2 Study to Evaluate the 
Safety and Efficacy of HMI-115 in Women with Moderate to Severe Endometriosis-Associated 
Pain Over a 12-Week Treatment Period 
Short Title: 
To evaluate the safety and efficacy of HMI-115 in 
women with moderate to severe endometriosis-
associated pain over a 12-week treatment period 
Compound: 
HMI-115 
Indication: 
Moderate to Severe Endometriosis-Associated Pain 
Study Sponsor: 
Hope Medicine (Nanjing) Co. Ltd. 
Protocol Number: 
HMI-115EM201 
Study Phase: 
Phase 2 
Vision number: 
6.0 
Approval Date: 
April 11, 2024 
Confidentiality Statement 
The confidential information in this document is provided to you as a Principal Investigator or consultant for 
review by you, your staff, and the applicable Ethics Committee. Your acceptance of this document constitutes 
agreement that you will not disclose the information contained herein to others without written authorization 
from the Sponsor. 
NCT05101317

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Amendment summary  
Version 
Date 
Main Changes/ Reasons 
1.0 
April 21, 2021 
Not applicable 
2.0 
August 12, 2021 
Screening Period, Schedule Of 
Activities, Inclusion and Exclusion 
Criteria, Discontinuation of IMP and 
Subject Withdrawal, Definition of 
AESI, Contraceptive Guidance. 
3.0 
November 23, 2021 
Schedule Of Activities, Inclusion 
and Exclusion Criteria, 
Discontinuation of IMP, Subject 
Withdrawal from the Study, window 
period for DXA, Pregnancy, Primary 
and Secondary Efficacy Endpoints 
assessment, Recording and Follow 
up of AE and SAE, Contraceptive 
Guidance. 
3.1 
April 14, 2022 
Coagulation sampling time, study 
region, Inclusion and Exclusion 
Criteria, Rescue Medicines, 
Prohibited Medications, Analyses 
Set, Estimand, Definition of AESI. 
3.2 
April 26, 2022 
Modified the name of CMO 
4.0 
March 03, 2023 
Modified the inclusion criteria and 
exclusion criteria, Prohibited 
Medications, Estimand, Definition of 
AESI, schedule of activity, etc. 
5.0 
September 20, 2023 
Deleted planned part 2 of the study, 
added an interim analysis, revised 
DXA follow-ups, etc. 

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Version 
Date 
Main Changes/ Reasons 
6.0 
April 11, 2024 
Added some notes for the clinical 
operation, added a second interim 
analysis, wording change to avoid 
ambiguity.  

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Date 
Medical Monitor Name and Contact Information: 
Date 

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Table of Contents 
 
Table of Contents ............................................................................................................................ 5 
1 
Protocol Summary .................................................................................................................... 9 
1.1 
Synopsis ............................................................................................................................... 9 
1.2 
Schema ............................................................................................................................... 13 
1.3 
Schedule of Activities (SoA) ............................................................................................. 14 
2 
Introduction............................................................................................................................. 20 
2.1 
Study Rationale ................................................................................................................. 20 
2.2 
Background ....................................................................................................................... 20 
2.3 
Benefit/Risk Assessment ................................................................................................... 23 
3 
Objectives and Endpoints ....................................................................................................... 27 
4 
Study Design ........................................................................................................................... 28 
4.1 
Overall Design ................................................................................................................... 28 
4.2 
Scientific Rationale for Study Design ............................................................................. 29 
4.3 
Justification for Dose ........................................................................................................ 29 
4.4 
End of Study Definition.................................................................................................... 32 
5 
Study Population ..................................................................................................................... 33 
5.1 
Inclusion Criteria.............................................................................................................. 33 
5.2 
Exclusion Criteria ............................................................................................................. 34 
5.3 
Lifestyle Considerations ................................................................................................... 37 
5.4 
Screen Failures .................................................................................................................. 38 
5.5 
Screening and Enrollment Log and Subject Identification Numbers ......................... 38 
6 
Study Intervention .................................................................................................................. 39 
6.1 
Study Intervention(s) Administered ............................................................................... 39 
6.2 
Preparation, Handling, Storage, and Accountability .................................................... 40 
6.3 
Measures to Minimize Bias: Randomization and Blinding .......................................... 41 
6.4 
Study Intervention Compliance ...................................................................................... 41 
6.5 
Concomitant Therapy ...................................................................................................... 41 
6.6 
Dose Modification ............................................................................................................. 45 
6.7 
Intervention After the End of the Study ......................................................................... 45 

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7 
Discontinuation of IMP and Subject Withdrawal ................................................................... 45 
7.1 
Discontinuation of IMP .................................................................................................... 45 
7.2 
Subject Withdrawal from the Study ............................................................................... 46 
7.3 
Study Pauses for Safety Reasons ..................................................................................... 47 
7.4 
Loss of Subjects to Follow-Up ......................................................................................... 48 
8 
Study Assessments and Procedures ........................................................................................ 48 
8.1 
Efficacy Assessments ........................................................................................................ 50 
8.2 
Safety Assessments............................................................................................................ 53 
8.3 
Exploratory Assessments ................................................................................................. 55 
8.4 
Adverse Events and Serious Adverse Events ................................................................. 56 
8.5 
Treatment of Overdose ..................................................................................................... 58 
8.6 
Pharmacokinetics ............................................................................................................. 58 
8.7 
Pharmacodynamics .......................................................................................................... 59 
8.8 
Genetics ............................................................................................................................. 59 
8.9 
Biomarkers ........................................................................................................................ 59 
8.10 Immunogenicity Assessments .......................................................................................... 59 
8.11 Composite Pelvic Signs and Symptoms Score (CPSSS) ................................................ 59 
8.12 Health Economics or Medical Resource Utilization and Health Economics .............. 60 
9 
Statistical Methods.................................................................................................................. 60 
9.1 
Statistical Hypotheses ....................................................................................................... 60 
9.2 
Sample Size Determination .............................................................................................. 60 
9.3 
Populations for Analyses .................................................................................................. 61 
9.4 
Statistical Analyses ........................................................................................................... 62 
9.5 
Interim Analyses ............................................................................................................... 71 
9.6 
Data Monitoring Committee (DMC) .............................................................................. 71 
10 Supporting Documentation and Operational Considerations ................................................. 72 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ..................... 72 
10.2 Appendix 2: Clinical Laboratory Tests........................................................................... 78 
10.3 Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ................................................................................................ 80 
10.4 Appendix 4: Contraceptive Guidance ............................................................................ 90 
10.5 Appendix 5: Washout Intervals ....................................................................................... 92 

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10.6 Appendix 6: Numeric Pain Rating Scale (NRS) ............................................................ 94 
10.7 Appendix 7: Patient Global Impression of Change (PGIC) ......................................... 95 
10.8 Appendix 8: Endometriosis health profile (EHP-5) ...................................................... 96 
10.9 Appendix 9: Composite Pelvic Signs and Symptoms Score (CPSSS) .......................... 97 
10.10 Appendix 10.10 Procedures that allowed to be repeated during screening period .... 98 
10.11 Appendix 11: Abbreviations and Trademarks ................................................................ 99 
11 References............................................................................................................................. 103 
12 Revision History ................................................................................................................... 104 
List of Figures 
Figure 1–1: 
Study Design for Part 1 of the Study .................................................................... 13 
List of Tables 
Table 1-1  SoA for the study ......................................................................................................... 14 
Table 1-2 Intensive PK Subset (N=10 per arm)………………………………………………….18 
Table 1-3 Sparse PK Sampling…………………………………………………………………..19 
Table 2-1. Risk Assessment .......................................................................................................... 23 
Table 3-1. Objectives and Endpoints ............................................................................................ 27 
Table 4-1.  Summary of Simulated PK Parameters (Geometric Mean [90%CI]) after a Single 
Dose Administration of HMI-115 ......................................................................... 30 
Table 4-2. 
Summary of Simulated PK Parameters (Geometric Mean [90%CI]) at Steady-
State for HMI-115 ................................................................................................. 30 
Table 4-3.  Safety Margins for HMI-115 after Subcutaneous Administration Based on AUC 
(mg×h/L) ............................................................................................................... 32 
Table 4-4. 
Safety Margins for HMI-115 after Subcutaneous Administration Based on Cmax 
(mg/L) ................................................................................................................... 32 
Table 6-1.  IMPs Administered .................................................................................................. 39 
Table 6-2.  IMP(s) and Dosing Schedules .................................................................................... 39 
Table 6-3.  Permitted Rescue Medication for Endometriosis-Associated Pain ..................... 43 
Table 6-4.  Prohibited Medications ............................................................................................ 43 

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Table 9-1 
Populations for Analyses....................................................................................... 61 
Table 10-1.  Protocol-Referred Safety Laboratory Assessments .................................................. 78 
 

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1 Protocol Summary 
1.1 Synopsis 
Protocol Title: A Randomized, Multicenter, Double-Blind, Placebo-Controlled Phase 2 Study to 
Evaluate the Safety and Efficacy of HMI-115 in Women with Moderate to Severe 
Endometriosis-Associated Pain Over a 12-Week Treatment Period 
Sponsor Protocol No.: HMI-115EM201 
Study Phase: Phase 2 
Sponsor: Hope Medicine (Nanjing) Co. Ltd 
Rationale: 
A First-in-Human (FiH) study with HMI-115 has already established the safety and tolerability of 
HMI-115 when administered subcutaneously in post-menopausal women aged between 45 to 
65 years in single doses up to 240 mg and multiple doses up to 90 mg once every two weeks (Q2W) 
for 6 weeks.1This study aims to evaluate the safety and efficacy of HMI-115 versus a placebo in 
pre-menopausal women aged 18 to 49 years diagnosed with moderate to severe endometriosis 
associated pain. The study will determine the safety and efficacy of HMI-115 at 60 mg Q2W, 
120 mg Q2W, and 240 mg Q2W.  
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
To study the efficacy of HMI-115 
for 
12 weeks 
compared 
with 
placebo in the management of 
endometriosis-associated pain 
Primary 
Change in dysmenorrhea (DYS) measured by Numeric 
Rating Scale (NRS) from Baseline to Week 12 
Secondary 
To study the safety, tolerability, and 
persistence of efficacy of HMI-115 
compared with placebo 
Secondary 
Efficacy 
1. Change in DYS measured by NRS from Baseline to 
Week 24 
2. Change in non-menstrual pelvic pain (NMPP) 
measured by NRS from Baseline to Week 12 and 24 
3. Change in dyspareunia (DYSP) measured by NRS 
from Baseline to Week 12 and 24  

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Objectives 
Endpoints 
4. Change from Baseline (CFB) in the monthly mean 
Endometriosis Daily Impact Pain Scale for DYS, 
NMPP and DYSP at Week 12 and 24 
5. CFB by visit in permitted rescue medication use 
6. Change in menstrual period heaviness (bleeding) 
from Baseline by visit 
Safety and tolerability 
1. Adverse events (AEs) 
2. CFB by visit in vital signs (blood pressure [BP], 
pulse, body temperature, and respiratory rate [RR]) 
3. CFB by visit in physical examinations 
4. Number and ratio of participants used concomitant 
medication 
5. CFB by visit in twelve-lead electrocardiogram 
(ECG) 
6. CFB by visit in clinical laboratory tests 
(hematology, coagulation, clinical chemistry, 
urinalysis, hormones and CA-125) 
7. CFB in Bone mineral density by Dual energy X-ray 
absorptiometry (DXA) scan after 12 weeks’ 
treatment (at EOT visit) 
8. CFB in transvaginal ultrasound (TVU) index 
(including number and size of ovarian cyst, 
thickness of endometrium) after 12 weeks’ reatment 
(at EOT visit) 
 
Exploratory 
To explore the effect of HMI-115 
on Quality of Life, 
pharmacokinetics (PK), PK-PD 
relationship and immunogenicity 
Other patient-reported outcomes: 
1. Quality of Life assessment with health-related 
quality of life questionnaire (HRQoL) 
(Endometriosis Health Profile-5 [EHP-5]) 
2. Response to Patient Global Impression of Change 
(PGIC) 
PK 
1. Cmax, Cmin, tmax, AUC(0-tau), t1/2 following last dose 

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Objectives 
Endpoints 
2. Accumulation ratio (AR) for both Cmax and AUC 
PK-PD 
Relationship between HMI-115 plasma 
concentration/exposure and pelvic pain score 
measured by NRS (cyclic = DYS, 
non-cyclic = NMPP+DYSP, and average)/side 
effects 
Immunogenicity: 
Anti-drug antibody (ADA)  
Overall Design: This is a Phase 2, multicenter, double-blind, placebo-controlled, randomized 
study to assess the safety and efficacy of HMI-115 subcutaneously administered monoclonal 
antibody versus placebo in pre-menopausal women with moderate to severe endometriosis-
associated pain. The study will comprise of three periods (refer to Figure 1-1): 
1)  A Screening Period of up to 75 days prior to first dose: 
• Screening Visit 1  
• Screening Visit 2 (at least 35 days before V3 to ensure at least 5 weeks baseline pain 
score obtained before randomization) 
2) A Treatment Period (12 weeks). Subjects will be given subcutaneous (s.c.) injections 
Q2W in the study. 
3) A Follow-up Period of 12 weeks 
Number of Subjects: 
152 eligible subjects will be randomly assigned to HMI-115 or placebo and 136 evaluable 
subjects for an estimated total of 34 evaluable subjects per treatment group.  
Intervention Groups and Duration: 
Eligible subjects will be randomized into four arms: placebo, 60 mg, 120 mg, and 240 mg 
HMI-115 in a 1:1:1:1 ratio with 38 subjects/arm. 
Blood samples will be collected to determine PK profile from Day 1 to Day 169. A full PK 
sampling strategy will be followed for a subgroup of 10 subjects per arm (refer to Table 1-2). 
Sparse sampling will be obtained from the rest of the subjects (refer to Table 1-3). Intensive and 

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sparse PK blood sampling will be performed at timepoints specified in Table 2 and Table 3. Plasma 
concentrations of HMI-115 will be determined using a validated enzyme-linked immunosorbent 
assay (ELISA) method. PK parameters will be assessed as described in Section 9.4.9. 
An e-Diary will be dispensed, and training will be provided to subjects at Visit 2 on how to record 
endometriosis associated pain, uterine bleeding, and analgesic medication use for endometriosis 
associated pain on a daily basis. Study related examinations, laboratory assessments and pregnancy 
testing will be performed according to the schedule of activities (SoA) throughout the study (refer 
to Table 1-1 ). 
 Data Monitoring Committee (DMC) will be used for this study. 
 
 

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1.2 Schema 
Figure 1–1: 
Study Design for Part 1 of the Study 
 
 
 

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11. Cervical cytology can be assessed at any time during the Screening period. (Virgins may be exempted per the investigator’s discretion) 
12. DXA scan and Sellar MRI can be assessed at any time during the Screening period. Only subjects who have greater chances of enrollment into the study will undergo 
DXA scan and Sellar MRI. For subjects who are eligible for randomization, the Screening DXA data will be used as baseline. 
13. Subjects who discontinue from IMP prior to week 11 or become pregnant during the study does not require a DXA scan. For more details, including subjects who needs 
further DXA scan after EOT visit, refer to Section 8.2.7. 
14. TVU should be performed during the early proliferative phase of the subject’s menstrual cycle (approximately days 4 through 8). In some circumstances, transrectal or 
transabdominal ultrasound is allowed per the investigator’s discretion. 
15. Viral serology tests include anti-HAV, HBsAg, HBcAb, anti-HCV, HCV RNA (for positive or equivocal anti-HCV), and HIV antigen/anti-HIV (1+2). 
16. Clinical laboratory tests are listed in Section 10.2. Samples of sex hormones (PRL, LH, FSH, estradiol, progesterone, testosterone, DHEAS) will be collected at the 
menses cycle days 1 to 5, and subjects should not take any opioids 2 days prior to blood sampling of PRL.  
17. Blood samples of sex hormones (PRL, LH, FSH, estradiol, progesterone, testosterone, DHEAS) could be taken on a separate day from the scheduled Visit Day to meet the 
menses cycle days 1 to 5.  
18. eGFR will be calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) formula. 
19. 12-ECG can be tested at any time apart from the specified timepoints if the subject feels uncomfortable. If QTc prolongation is found, including repeating PVCs 
confirmed by additional ECG examination at least 30 minutes apart, or QTcF >500 ms, or increase in QTcF interval >60 ms compared to baseline in the absence of 
possible causes other than the IMP, drug can be temporarily stopped to investigate the reason. See Section 7.1 for more details. 
20. Vital signs include blood pressure, tympanic body temperature, pulse, and respiratory rate. Vital signs of subjects will be observed 1 hour after IMP administration on Day 
1 and pre-dose at each visit. 
21. Physical examination: for detailed information, refer to section 8.2.1.  
22. Pelvic examination: for detailed information, refer to section 8.2.3 and 10.9. 
23. e-Diary training will be provided at Visit 2, and e-Diary will be dispensed to record endometriosis associated pain (including NRS and scales for DYS, NMPP and 
DYSP), uterine bleeding, and rescue medication use for endometriosis associated pain on a daily basis from Visit 2 and at approximately the same time every day 
(morning preferred). Must be completed in the morning prior to arrival at the study site for study visits. 
24. e-Diary entries compliance will be assessed and additional training will be provided to subjects who have missed data entry. 
25. Rescue medication and education will be provided to subjects from Visit 2 for rescue use if needed for endometriosis associated pain throughout the study. Refer to table 
6-3 for protocol allowed rescue medication. 
26. All reported AEs to be checked for injection site reaction. 
27. In addition to the listed sampling time, ADA will also be collected at week 17, together with PK sampling (not required for those who discontinued from IMP or withdraw 
from study). 
28. Intensive and sparse PK blood sampling will be performed at timepoints specified inTable 1-2 and Table 1-3. 
 
Note: Blood draws should be performed before vital signs, ECG recordings and physical examinations at visits (can be adjusted according to the condition of the site).  
A certified central laboratory will be utilized to process and provide results for all blood tests. 
          DXA will be analyzed/evaluated centrally by an experienced and qualified imaging vendor. 
Procedures that allowed to be repeated during screening period are listed in section 10

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Table 1-2 
Intensive PK Subset (N=10 per arm) 
WEEK 
STUDY DAY 
TIME (in relation to dosing) 
TIME WINDOW 
hour 
day 
Week 1 
Day 1(first dose) 
Pre-dose 
Pre-dose 
 
Week 1 
Day 3 
+48 h (post-first dose) 
+2 day (post-first dose) 
+/-2 h 
Week 1 
Day 5 
+96 h (post-first dose) 
+4 day (post-first dose) 
+/-2 h 
Week 1 
Day 7 
+144 h (post-first dose) 
+6 day (post-first dose) 
+/-6 h 
Week 2 
Day 11 
+240 h (post-first dose) 
+10 day (post-first dose) 
+/-12 h 
Week 3 
Day 15±3 
Pre-dose 
Pre-dose 
Within 2 h before dosing 
Week 5 
Day 29±3 
Pre-dose 
Pre-dose 
Within 2 h before dosing 
Week 9 
Day 57±3 
Pre-dose 
Pre-dose 
Within 2 h before dosing 
Week 11 
Day 71±3(last dose) 
Pre-dose 
Pre-dose 
Within 2 h before dosing 
Week 11 
Day 73 
+48 h (Post-last dose) 
+2 day (Post-last dose) 
+/-2 h 
Week 11 
Day 75 
+96 h (Post-last dose) 
+4 day (Post-last dose) 
+/-2 h 
Week 11 
Day 77 
+144 h (Post-last dose) 
+6 day (Post-last dose) 
+/-6 h 
Week 12 
Day 81 
+240 h (Post-last dose) 
+10 day (Post-last dose) 
+/-1 day 
Week 13 
Day 85 
+336 h (Post-last dose) 
+14 day (Post-last dose) 
+/-2 days 
Week 17 
Day 113 
+ 1008 h (Post-last dose) 
+42 day (Post-last dose) 
+/-7 days 
Week 19 
Day 127 
+1344 h (Post-last dose) 
+56 day (Post-last dose) 
+/-7 days 
Week 21 
Day 141 
+ 1680 h (Post-last dose) 
+70 day (Post-last dose) 
+/-7 days 
Week 25 
Day 169 
+ 2352 h (Post-last dose) 
+98 day (Post-last dose) 
+/-7 days 
 
 
 
 

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Table 1-3 Sparse PK Sampling  
WEEK 
STUDY DAY 
TIME (in relation to dosing) 
TIME WINDOW 
hour 
day 
Week 1 
Day 1(first dose) 
Pre-dose 
Pre-dose 
 
Week 1 
Day 7 
+144 h (post-first dose) 
+6 (post-first dose) 
+/-2 days 
Week 3 
Day 15±3 
Pre-dose 
Pre-dose 
Within 2 h before dosing 
Week 5 
Day 29±3 
Pre-dose 
Pre-dose 
Within 2 h before dosing 
Week 9 
Day 57±3 
Pre-dose 
Pre-dose 
Within 2 h before dosing 
Week 11 
Day 71±3(last dose) 
Pre-dose 
Pre-dose 
Within 2 h before dosing 
Week 11 
Day 77 
+144 h (post-last dose) 
+6 day (post-last dose) 
+/-2 days 
Week 13 
Day 85 
+336 h (post-last dose) 
+14 day (post-last dose) 
+/-4 days 
Week 17 
Day 113 
+ 1008 h (post-last dose) 
+42 day (post-last dose) 
+/-7 days 
Week 25 
Day 169 
+ 2352 h (Post-last dose) 
+98 day (Post-last dose) 
+/-7 days 
Note: For subjects discontinued from IMP or withdraw from study, no additional PK sampling except for EOT and EOS visits (if possible) is required after IMP discontinuation. 
 

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2 Introduction 
HMI-115 is a highly specific human monoclonal antibody that will be investigated for safety and 
efficacy in pre-menopausal women with moderate to severe endometriosis associated pain. 
2.1 Study Rationale 
A First-in-Human (FiH) study with HMI-115 has already established the safety and tolerability of 
HMI-115 when administered subcutaneously in post-menopausal women aged between 45 to 
65 years in single doses up to 240 mg and multiple doses up to 90 mg once every 2 weeks (Q2W) 
for 6 weeks1. This study aims to evaluate the safety and efficacy of HMI-115 versus a placebo in 
pre-menopausal women aged 18 to 49 years diagnosed with moderate to severe endometriosis 
associated pain. The study will determine the safety and efficacy of HMI-115 at 60 mg Q2W, 
120 mg Q2W, and 240 mg Q2W.  Administration of different doses of HMI-115 together with 
placebo will allow for further evaluation of efficacy and safety of the drug and determine 
appropriate dose for future pivotal studies. 
As a prove-of-concept study, change in dysmenorrhea (DYS) is used as the primary endpoint to 
show the preliminary efficacy of HMI-115 in endometriosis associated pain. Non-menstrual pelvic 
pain (NMPP) is considered as critical endometriosis associated pain, and is used for recruiting 
subjects with Composite Pelvic Signs and Symptoms Score (CPSSS) at least 2 for NMPP and 
evaluating NMPP by NRS as a secondary endpoint. Co-primary endpoints include DYS and NMPP 
would be used in the confirmative studies in future. In addition, a central laboratory will be used 
in this study for blood tests (including hormones). Dual energy X-ray absorptiometry (DXA) scan, 
as a bone mineral density (BMD) monitoring indicator, will be performed with a central reading. 
Transvaginal ultrasound (TVU), mainly to confirm the eligibility for study entry and to assess the 
condition of pelvis after administration of HMI-115, are suggested to be performed by the same 
staff from each site. Sellar MRI with contrast will also be performed locally for excluding subjects 
with pituitary tumor growth. 
This study will not recruit subjects with obvious pre-existing mood disorders such as depression, 
bipolar disorder, besides, HMI-115 has not shown any potential of affecting subjects’ mental state 
based on the mechanism of action, therefore, the mood state assessment by tools will not be 
involved at the current stage. However, if any sign of mental influence of HMI-115 is detected, a 
validated tool such as the Columbia-Suicide Severity Rating Scale will be used in the future studies. 
2.2 Background 
Endometriosis is a gynecological disorder that manifest during the reproductive years of women 
with initial symptoms seen during adolescence. However, these initial symptoms may be very mild 

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leading to the condition being undiagnosed for a long time. The pathophysiology of the disorder 
is yet to be fully understood but the disease is an estrogen dependent inflammatory condition that 
involves the formation of endometrial tissue outside the uterine cavity. 
The prevalence of endometriosis has been reported to be around 10 % of reproductive aged 
women2. In population-based studies, the annual incidence of endometriosis has been reported to 
be 0.1 % to 0.3 %3,4,5,6. Thus, endometriosis is one of the most common gynecologic conditions. 
The symptoms of endometriosis have a tremendous impact on patients' lives, negatively 
influencing quality of life, fertility, emotional well-being, intimate relationships, work life, and 
daily activities.  
As endometriosis is estrogen-dependent, drugs interfering negatively with estradiol-mediated 
signaling such as gonadotropin-releasing hormone (GnRH) agonists and antagonists as well as 
antiestrogens, selective estrogen receptor modulators (SERMs) and aromatase inhibitors proved 
to be effective in human endometriosis. Surgery is another optional treatment method for 
endometriosis but has drawbacks. Because of the characteristics of the disease itself, it is difficult 
to remove all the lesions through surgery, so the recurrence of the disease is very common. Plus, 
there is the risk of surgical complications, which make surgical treatment more challenging. 
According to statistics, the 2-year recurrence rate post-surgery of endometriosis is 21.5%, and 
the 5-year recurrence rate is 40-50%7. Long-term medication treatment is necessary and routine 
practice to prevent relapse post-surgery.  Many available drugs for endometriosis induced 
“amenorrhea” conflicts with patient’ s desire for fertility. Many of these treatments have 
significant side effects and/or precaution (such as hot flushes, bone loss, venous 
thromboembolism, and contraindicated with history of diabetes) or may not provide adequate 
pain relief, leading to non-adherence to long term treatment. Historically, these treatments have 
not been effective at resolving high endometriosis relapse rates. Endometriosis is a chronic 
serious disease with no viable long term treatment options. Therefore, there is an unmet medical 
need for a safe and effective long term endometriosis therapy. 
It had reported that prolactin (PRL) and its receptors are overexpressed in endometriotic tissue. 
There is evidence that systemic hyperprolactinemia can cause endometriosis in women. Systemic 
administration of bromocriptine reduces serum PRL level, and vaginal application of 
bromocriptine alleviates pain and menstrual bleeding in women with interna endometriosis. 
Prolactin signalling may be involved in the pathophysiology of endometriosis by (a) systemic 
hyperprolactinemia (b) disease-associated organ-specific overexpression or constitutively active 
mutations of the prolactin receptors (PRLR) or (c) local hyperprolactinemia via autocrine or 
paracrine mechanism (refer to the Investigator’s Brochure [IB]). PRLR antagonists provide new 
insight to resolve unmet medical needs in the treatment of endometriosis. 

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In mammals (including humans), the PRLR is widely distributed. PRLR antagonists may act in 
many different tissues, its safety needs to be evaluated. But according to Newey et al. who reported 
the first loss-of-function mutation of the PRLR in family hyperprolactinemia (i.e., excess of 
circulating PRL) in 2013, one should expect that drug mediated down-regulation of systemic 
PRLR-signaling in patients should exert no major interference with any physiological function 
other than female fertility8.  
The possible advantage of PRLR antagonists includes absence of side effects of drugs interfering 
negatively with estradiol-mediated signaling, no restriction of the targeted population, and non-
proliferative action on the breast epithelium as opposed to estrogens and progestins. Of interest, 
PRLR antagonists prevented/reversed PRL effects involving TRPV1 which are considered as 
potential targets in the treatment of inflammatory pain. It has potential to relieve pain and opioid-
induced hyperalgesia (OIH) in female selectively by limiting PRL/PRLR-S signaling 
pharmacologically9,10. 
BAY1158061 is a highly specific human monoclonal antibody that was developed by Bayer 
HealthCare AG to treat endometriosis. This product was acquired by Hope Medicine (Nanjing) 
Co., Ltd and its parent company Hope Medicine Inc., and is now known by the name HMI-115. 
HMI-115 binds to the extracellular domain of the PRLR leading to diminished PRLR signaling. 
In a PRL driven murine endometriosis interna model, the parental lead antibody and HMI-115 in 
the murine IgG2a format showed full efficacy in treating interna endometriosis. In the FiH study 
that aimed at establishing the safety and tolerability of HMI-115 in single doses up to 240 mg and 
cumulative doses up to 270 mg (3×90 mg) in healthy post-menopausal female subjects, HMI-115 
was well tolerated in all doses.1 No significant impact of HMI-115 on the sex hormone levels (e.g., 
estrogen) have been observed. The FiH study showed a favorable safety profile and full efficacy 
was observed in preclinical studies thereby providing a new approach to resolve unmet medical 
needs in the treatment of endometriosis. 
Pharmacokinetic (PK) evaluation of HMI-115 demonstrated that the drug reached peak plasma 
concentration approximately 4 to 11 days after administration of 7.5 mg to 240 mg subcutaneously. 
Following repeated dosing and an accumulation index of approximately 2, a more than dose 
proportional increase in the main PK parameters was observed. Pharmacodynamic (PD) evaluation 
of HMI-115 demonstrated no effect on the circadian rhythm of PRL secretion.1 
HMI-115 was well tolerated in FiH studies and animal studies. In post-menopausal women, no 
specific adverse events (AE) patterns or clinically significant effects on the vital signs, ECG or 
laboratory parameters were observed. As a fertility and early embryonic study in female 

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Cynomolgus monkeys demonstrated that weekly administration of HMI-115 at doses up to 
50 mg/kg prior to mating, throughout mating and post-mating/early gestation did not affect the 
mating success and had no influence on pregnancy outcome, this study will further evaluate the 
safety and efficacy of HMI-115 in pre-menopausal women with endometriosis related pain. 
A detailed description of the chemistry, non-clinical pharmacology and toxicology data for 
HMI-115 is provided in the most updated version of IB. 
2.3 Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of HMI-115 may be found in the IB of HMI-115. 
2.3.1 
Risk Assessment 
Table 2-1. Risk Assessment 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
HMI-115 
Non-clinical Risks 
Pituitary gland function 
(endocrinology) 
Nonclinical - toxicology studies in 
monkeys demonstrated HMI-115 to 
elevate PRL levels which may 
influence other hormone levels. 
In the 26-week toxicity study in 
male and female cynomolgus 
monkeys treated with 24 and 100 
mg/kg of HMI-115 weekly, no 
HMI-115 related changes were 
noted in hormone detection 
(testosterone, estradiol and 
progesterone) throughout the study.  
 
 
In the FiH study, the hormone TSH, 
cortisol, somatotropin, FSH, LH, 
and estradiol were evaluated and no 
significant changes observed in the 
doses tested. The hormonal levels 
will be monitored in this study as 
higher doses of HMI-115 will be 
administered. The impact of 
treatment with HMI-115 on other 
hormones remains to be 
investigated further 
Non-Clinical Risk 
Mammary gland function 
Toxicology studies in Cynomolgus 
monkeys showed a minimal 
reversible atrophy of the mammary 
gland 
Changes in mammary gland 
function is reversed after a dosing-
free period. Treatment 
contraindicated during pregnancy 
and lactation and in women with 
abnormal clinical findings during 
mammography 

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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
Clinical Risk 
Immune function 
Neutropenia was reported in one 
subject in the Phase 1 study (subject 
already had a neutrophil count that 
was lower than the lower limit of 
normal [LLN] prior to enrollment) 
Careful monitoring of subjects for 
any ongoing, subclinical infection 
and exclusion of patients with 
existing immunosuppression. 
Non-Clinical Risk 
Cardiovascular system 
Slight increase in single ectopic 
ventricular heart beats in 
Cynomolgus monkey at highest 
tested dose (At the No Observed 
Adverse Effect Level (NOAEL) in 
the cardiovascular safety study 
there is an 11-fold safety margin for 
the 240 mg Q2W dose based on 
Cmax). 
Monitoring of electrocardiographic 
parameters through ECG 
measurements. 
 
Clinical Risk 
PRLR blockade may induce PRL 
over secretion.  Whether it affects 
secretion of other sex hormones and 
dopamine through the 
Hypothalamic-Pituitary axis 
feedback is unknown. Considering 
PRLR is blocked, PRL effect on 
other hormones is very likely to be 
minimized. 
Increased PRL may cause disorder 
in the secretion of other sex 
hormones and dopamine and further 
induce conditions such as 
galactorrhea, change in menstrual 
cycles with oligo- or amenorrhea, 
hirsutism, acne, change in mood, 
etc.  
However, considering the blockade 
of PRLR by HMI-115, the above 
conditions are very unlikely to be 
induced by HMI-115. 
Collect galactorrhea, change in 
menstrual cycles with oligo- or 
amenorrhea, Hirsutism, Acne, 
change in mood, etc., as adverse 
event of special interests (AESIs). 
Refer to Section 10.3.1. 
Non-Clinical Risk 
Bone cell metabolism 
Loss of bone mineral density in 
PRLR knock-out mice.  
Biomarkers of bone 
formation/resorption (CTX-1; t-
P1PNP, PTH) and bone mineral 
densitometry were investigated in 
GLP-toxicity studies that involved 
administration of HMI-115 in 
Cynomolgus monkeys and no 
adverse impact was identified 
Monitoring by CTX, P1NP, BSAP 
and DXA scan. Refer to Section 
8.2.7 for details on DXA scan. 
Study Procedures 
HMI-115 will be administered by 
injection through s.c. route in the 
study. The subjects will receive 
Application site reaction such as 
swelling, hematoma, and pain. 
Repeated s.c. injections may cause 
Local tolerability studies and 
HMI-115’s low to medium 
immunogenicity indicate s.c. route 
of administration does not cause 

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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
injections of HMI-115 (60 mg to 
240 mg) or placebo.  
inconvenience to subjects and make 
injection site assessments difficult. 
However, according to 26-week 
toxicity study in male and female 
cynomolgus monkeys, there were 
minimal or mild non-adverse 
microscopic findings (subcutaneous 
and/or intramuscular mixed cell 
inflammation) in the injection sites. 
any site reaction that is outside 
normal range. However, due to 
repeated s.c. injections over 12 
weeks in the study, injection sites 
need to be sufficiently apart from 
each other to allow for injection site 
assessments. 
2.3.1.1 
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 
There is currently an outbreak of respiratory disease (COVID-19) caused by a novel severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2). The countermeasures initiated by national 
and local governments worldwide and the recommendations issued by the health authorities have 
impacted current and new clinical studies. As the threat of pandemic burden including new 
outbreaks, locally or globally, will impact the further conduct of clinical studies, appropriate risk 
assessments and mitigation measures will need to be taken into consideration in all clinical 
studies to protect subjects, site staff and society as a whole. 
Both European Medicines Agency (EMA)11 and United States Food and Drug Administration 
(USFDA)12 have issued new guidelines that aim to provide recommendations for the conduct of 
clinical studies of medical products during COVID-19 pandemic. Since the pandemic situation is 
evolving, guidelines, recommendations, national laws and local restrictions may change at a 
rapid pace.  
Appropriate measures have been implemented into this protocol to conduct the study. 
Risk Assessment for COVID-19 Pandemic 
HMI-115 is not believed to cause immune suppression. Therefore, risk of the subjects to 
COVID-19 will be similar to the general population. However, the risk of exposure to infected 
people cannot be completely excluded as the subjects may be exposed to public areas (e.g., 
commute to the site) and have additional human contact (e.g., with site staff and other subjects of 
the clinical study). 
Measures to mitigate the additional risks caused by COVID-19 include: 
• This study will start enrolling only when both the Sponsor and Contract research organization 
(CRO) agree that it is safe to start the study. 

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• Current national laws and local recommendations to prevent further spread of COVID-19 
will be strictly adhered to. 
• Subjects will be closely monitored for any signs and symptoms of COVID-19, including 
fever, dry cough, dyspnea, sore throat and fatigue throughout the study. Once clinical signs of 
infection are reported by subjects, the Investigator needs to determine whether samples can 
be collected, and safety data can be recorded on site. If not, AE and concomitant medications 
will be obtained via phone calls. Daily tympanic body temperature measurements during 
in-house stay and outpatient visits will be implemented. 
• The IMP will not be administered to subjects upon identification of any signs of COVID-19 
infection. 
• Confirmation of COVID-19 infection by optional laboratory assessment will be conducted 
based on Investigator’s discretion and/or local requirements and/or policy. 
• The probability of virus transmission will be controlled as much as possible by: 
o Advising subjects to adhere to local requirements for reduction of the public exposure 
while ambulatory. 
o All subjects are contacted by phone one day prior to every visit for assessing COVID-19 
symptoms and signs and are asked not to attend the site in case of suspected infection 
reported. If applicable, subjects will be referred to the local health care system for 
further follow up and treatment. 
o Physical distancing and person-to-person contact restrictions will be applied during on-
site visits. 
o Where physical distancing is not possible, personal protective equipment (PPE) will be 
used by study subject (surgical face mask, gloves) and staff (for example, but not limited 
to masks, gloves, protectors, medical suits) if deemed appropriate by the Investigators 
and site staff and guided by local requirements. 
The measures may be adjusted according to local laws and/or policy. 
2.3.2 
Benefit Assessment 
HMI-115 may have the potential benefit of relieving moderate to severe pain caused by 
endometriosis and improve the Health-related Quality of life (HRQoL) of patients with 
endometriosis. For details on dose justification  of this study, refer to Section 4.3. Clear criteria for 
subject selection and close monitoring of identified potential risks and subject discontinuation have 
been implemented in this protocol to avoid undue risks to the subjects. An independent data 
monitoring committee (DMC) will regularly review all safety data to ensure the well-being of all 
subjects.  

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2.3.3 
Overall Benefit: Risk Conclusion 
Considering the measures taken to minimize risk to subjects participating in this study, the 
potential risks identified in association with HMI-115 are justified by the anticipated benefits that 
may be afforded to subjects with endometriosis associated pain. 
3 Objectives and Endpoints 
Table 3-1. Objectives and Endpoints 
Objectives 
Endpoints  
Primary 
To study the efficacy of HMI-115 
for 12 weeks compared with 
placebo in the management of 
endometriosis associated pain 
Primary 
Change in dysmenorrhea (DYS) measured by Numeric 
Rating Scale (NRS) from Baseline to Week 12 
Secondary 
To study the safety, tolerability, and 
persistence of efficacy of HMI-115 
compared with placebo 
Secondary 
Efficacy 
1. Change in DYS measured by NRS from Baseline to 
Week 24 
2. Change in non-menstrual pelvic pain (NMPP) 
measured by NRS from Baseline to Week 12 and 24  
3. Change in dyspareunia (DYSP) measured by NRS 
from Baseline to Week 12 and 24 
4. Change from Baseline (CFB) in the monthly mean 
Endometriosis Daily Impact Pain Scale for DYS, 
NMPP and DYSP at Week 12 and 24 
5. CFB by visit in permitted rescue medication use. 
6. Change in menstrual period heaviness (bleeding) 
from Baseline by visit 
Safety and tolerability 
1. Adverse events (AEs) 
2. CFB by visit in vital signs (blood pressure [BP], 
pulse, body temperature, and respiratory rate [RR]) 
3. CFB by visit in physical examinations 
4. Number and ratio of paticipants used concomitant 
medication 
5. CFB by visit in twelve-lead electrocardiogram (ECG) 

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Objectives 
Endpoints  
6. CFB by visit in clinical laboratory tests (hematology, 
coagulation, clinical chemistry, urinalysis, hormones 
and CA-125) 
7. CFB in bone mineral density by Dual energy X-ray 
absorptiometry (DXA) scan after 12 weeks’ 
treatment (at EOT vist) 
8. CFB in transvaginal ultrasound (TVU) index 
(including number and size of ovarian cyst, thickness 
of endometrium) after 12 weeks’ treatment (at EOT 
visit) 
Exploratory 
To explore the effect of HMI-115 
on Quality of Life, 
pharmacokinetics (PK), PK-PD 
relationship, and immunogenicity 
Other patient-reported outcomes: 
1. Quality of Life assessment with health-related quality 
of life questionnaire (HRQoL) (Endometriosis Health 
Profile-5 [EHP-5]) 
2. Response to Patient Global Impression of Change 
(PGIC)  
PK 
1. Cmax, Cmin, tmax, AUC(0-tau), t1/2 following last dose 
2. Accumulation ratio (AR) for both Cmax and AUC 
PK-PD 
Relationship between HMI-115 plasma 
concentration/exposure and pelvic pain score 
measured by NRS (cyclic = DYS, 
non-cyclic = NMPP+DYSP, and average)/side effects 
Immunogenicity: 
Anti-drug antibody (ADA) 
4 Study Design 
4.1 Overall Design 
This is a Phase 2, multicenter, double-blind, placebo-controlled, randomized study to assess the 
safety and efficacy of HMI-115 subcutaneously administered monoclonal antibody versus placebo 
in pre-menopausal women with moderate to severe endometriosis-associated pain. The planned 
study regions include China, the United States of America (USA) and European countries. 
The study will comprise of three periods (refer to Figure 1-1): 

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1.  Screening Period of up to 75 days prior to first dose 
• Screening Visit 1  
• Screening Visit 2 (at least 35 days before V3 to ensure at least 5 weeks baseline 
pain score obtained before randomization) 
2. Treatment Period (12 weeks). Subjects will be given subcutaneous (s.c.) injections Q2W in 
the study.   
3. Follow-up Period of 12 weeks 
Eligible subjects will be randomized into four arms: placebo, 60 mg, 120 mg, and 240 mg 
HMI-115 in a 1:1:1:1 ratio with 38 subjects/arm. 
Blood samples will be collected to determine PK profile from Day 1 to Day 169. A full PK 
sampling strategy will be followed for a subgroup of 10 subjects per arm (refer to Table1-2). Sparse 
sampling will be obtained from the rest of the subjects (refer to Table1-3). Plasma concentrations 
of HMI-115 will be determined using a validated enzyme-linked immunosorbent assay (ELISA) 
method. PK parameters will be assessed as described in Section 9.4.9. 
An e-Diary will be dispensed, and training will be provided to subjects at the Visit 2 on how to 
record endometriosis-associated pain, uterine bleeding, and rescue medication use for 
endometriosis-associated pain on a daily basis. Study-related examinations, laboratory 
assessments and pregnancy testing will be performed according to the SoA throughout the study 
(refer to Table 1-1 ). 
 Note: Environmental sanitization procedures will be implemented in the study site and where 
study procedures are conducted. The study design and associated safety measures are deemed 
appropriate for conduct during COVID-19 pandemic. 
4.2 Scientific Rationale for Study Design 
Evaluation of different doses of HMI-115 together with placebo will allow for further evaluation 
of efficacy and safety of the drug. A parallel design is preferable due to the long half-life of 
HMI-115, i.e., 6 doses over 12 weeks will be administered to reach steady state.  
4.3 Justification for Dose 
4.3.1 
PK Modeling and Simulation of HMI-115 
To date, a multi-center, randomized, double-blind, placebo controlled, first-in-human study to 
investigate the safety, tolerability, and pharmacokinetics of HMI-115 following single and 

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repeated subcutaneous administration to healthy postmenopausal women was completed in 
Germany.  
In summary, escalating subcutaneous single doses of 0.75 mg - 240 mg of HMI-115 and 
subcutaneous multiple doses (up to three administrations) of 30 mg - 90 mg of HMI-115 given 
every other week (Q2W) were well tolerated in healthy postmenopausal women.  
To predict the steady-state PK exposure of HMI-115 in humans at dosing regimens higher than 
90 mg Q2W, modeling and simulations were conducted using a population PK model developed 
based on PK data from repeat doses (30 mg Q2W, 60 mg Q4W and 90 mg Q2W) FIH study in 
post-menopausal women.   
The predicted Cmax, Ctrough and AUC after a single dose administration of 240 and 480 mg are 
shown in Table 4-1. Following a 240 mg Q2W dosing regimen. The average steady state Cmax, 
and AUC (0-τ) were predicted to be 36.6 mg/L and 11,008 mg·h/L, respectively. Following a 480 
mg Q2W dosing regimen, the average steady state Cmax and AUC(0-τ) were predicted to be 74.3 
mg/L and 22,377 mg·h/L, respectively (Table 4-2). 
Table 4-1.  Summary of Simulated PK Parameters (Geometric Mean [90%CI]) after a 
Single Dose Administration of HMI-115 
Doses 
AUCtau (mg·h/L) 
Cmax (mg/L) 
Ctrough (mg/L) 
240 mg 
3475 [2099-5760] 
12.4 [7.57-20.4] 
9.76 [5.63-16.7] 
480 mg 
7015 [4259-11583] 
25.0 [15.3-40.9] 
19.9 [11.6-33.9] 
Table 4-2. Summary of Simulated PK Parameters (Geometric Mean [90%CI]) at Steady-
State for HMI-115 
Doses 
AUCtau,ss (mg·h/L) 
Cmax,ss (mg/L) 
Ctrough,ss (mg/L) 
240 mg Q2W 
11008 [5310-23073] 
36.6 [18.5-73.8] 
27.3 [12.0-61.4] 
480 mg Q2W 
22377 [10858-46682] 
74.3 [37.7-149] 
55.6 [24.7-124] 
* Calculated for tau=2W for direct comparison; ss = steady state 
4.3.2 
Prediction of Efficacious Dosing Regimens of HMI-115 
A significant reduction in interna endometriosis score (full response in all animals) was observed 
when animals were treated with the BAY 1158063 which is HMI-115 in the murine IgG2a 
format (closely related to HMI-115 with similar properties) at the dose of 30 mg/kg once weekly 
for 7 weeks (refer to IB). Exposure to the drug in mice was not measured in the study, however, 
the extrapolation of exposure based on the Ctrough of 70mg/L observed after 65 mg/kg single dose 
treatment on mice, translates into a Ctrough of 35 mg/L at 30mg/kg dosage. Corrected for species 

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differences in potency, which is 3.8 calculated from the IC50 between mice vs human 
(4.2nM/1.1nM) based on cellular proliferation assay performed on Ba/F3 cells transfected with 
human, mice and monkey PRLR, and assuming similar tissue distribution between mice and 
human, it is anticipated that a Ctrough,ss above 10 mg/L is needed in humans to achieve maximum 
effect (response in all subjects). Based on PK simulations, a dose of 240 mg Q2W would be 
needed for all subjects to reach Ctrough,ss at 12 mg/L.  
Similarly, a partial reduction of the interna endometriosis score was observed in mice treated 
with 10 mg/kg weekly for seven weeks. Thus, the dose in human most likely to produce a similar 
exposure as that in mice treated with 10 mg/kg after correction by differences in drug potency, 
and assuming similar tissue distribution between mice and human, it is anticipated that minimum 
effective dose is 60 mg Q2W. Therefore, the doses of 60 mg Q2W as minimum effective dose 
and 240 mg Q2W as maximum effective are proposed. 
4.3.3 
Estimated Safety Margins for HMI-115 
HMI-115 was well tolerated in 13-week repeat-dose toxicity studies in mice and Cynomolgus 
monkeys. No signs of systemic toxicity were observed after repeated once weekly s.c. 
administrations at doses up to 400 mg/kg (mice) and 100 mg/kg (monkeys) over a period of 
13-week. Thus, the high dose was considered the No Observed Adverse Effect Level (NOAEL) 
in these studies. The exposure at the NOAEL the end of the treatment period was used to 
calculate the safety margins along with the estimated exposure at the anticipated human dose of 
240 mg and 480 mg given Q2W. 

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Table 4-3.  Safety Margins for HMI-115 after Subcutaneous Administration Based on AUC 
(mg×h/L) 
Species/Sex 
NOAEL 
(mg/kg/day) 
Duration  
of Dosing 
AUC(0–168) 
(mg⋅h/L) 
Safety  
Margin 
(240 mg Q2W)a 
Safety  
Margin 
(480Q2W)b 
Mouse/Male 
400 
13 weeks 
390000 
35 
17.4 
Mouse/Female 
400 
13 weeks 
150000 
14 
6.7 
Monkey/Female 
100 
13 weeks 
181000 
16 
8.1 
a,b  Estimated exposures at 240 mg Q2W (AUCt,ss of 11008 mg·h/L) or 480 mg Q2W (AUCt,ss of 22377 mg·h/L) 
were used to calculate margins 
Table 4-4. Safety Margins for HMI-115 after Subcutaneous Administration Based on Cmax 
(mg/L) 
Species/Sex 
NOAEL 
(mg/kg/day) 
Duration  
of Dosing 
Cmax 
(mg/L) 
Safety  
Margin 
(240 mg Q2W)a 
Safety  
Margin 
(480Q2W)b 
Mouse/Male 
400 
13 weeks 
3160 
86 
43 
Mouse/Female 
400 
13 weeks 
2360 
64 
32 
Monkey/Female 
100 
13 weeks 
1540 
42 
21 
a,b  Estimated exposures at 240 mg Q2W (Cmax of 36.597 mg/L) or 480 mg Q2W (Cmax of 74.297mg/L) were used to 
calculate margins 
The predicted steady state HMI-115 exposures are well below the NOAEL values (Cmax=1,540 
mg/L and AUC(0-168h)=181,000 mg·h/L) reported in a 13-week GLP toxicology study in the most 
sensitive studied species, the Cynomolgus monkey, suggesting that the repeated dose regimens 
(240/480 mg Q2W) are appropriate with sufficient safety coverage with respect to both AUC(0-tau) 
and Cmax (Table 4-3 and Table 4-4).  
Thus, the available nonclinical safety data are considered to provide adequate support for the 
proposed Phase 2 study in patients with endometriosis. 
4.4 End of Study Definition 
A subject is considered to have completed the study if she has completed all phases of the study 
including the last scheduled procedure (follow-up at Week 25 for safety and to cover 5 half-
lives) as shown in the SoA. 
The end of the study is defined as the date of the last visit of the last subject in the study or last 
scheduled procedure shown in the SoA for the last subject in the study globally. 

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5 Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
The study population will consist of subjects with moderate to severe endometriosis-associated 
pain. Subjects must be able to provide written consent and meet all the inclusion criteria and 
none of the exclusion criteria. 
5.1 Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the following criteria apply: 
1. Pre-menopausal female subjects, between 18 and 49 years of age, inclusive, at the time of 
signing informed consent. 
2. Subject must have a clinical diagnosis of endometriosis (laparoscopy or laparotomy) as 
documented by medical records within 10 years before screening.  
3. Subject must have a Composite Pelvic Signs and Symptoms Score (CPSSS, refer to Section 
8.11 and 10.9) total score of ≥ 6 at screening with a score of at least 2 for DYS and at least 2 
for NMPP. 
4. Subject must have reported at Baseline at least 2 days of “moderate” or “severe” pain for 
DYS and NMPP, with NRS score of at least 4 (where 0 represents absence of pain and 10 
indicates unbearable pain, refer to Section 8.1.3 and 10.6). 
5. Mammography or contrast-enhanced breast MRI performed within the last 12 months prior 
to randomization without clinically significant abnormal findings in subjects aged 40 and 
over only (subject with BI-RADS Classification 1 – 3 is eligible for randomization). 
6. Subject must have at least two consecutive regular menstrual cycle (i.e. 21 to 35 days in 
duration) prior to Day 1. 
7. Subject agrees to use required (nonhormonal) birth control methods during the entire length 
of participation in the study (refer to Section 10.4) and agrees to avoid pregnancy from 
signing the informed consent until 3 months after the last dose. 
8. Subject must agree to use only those rescue analgesics (i.e. not prophylaxis) permitted by the 
protocol during the Screening, Treatment and Posttreatment follow-up Periods for her 
endometriosis-associated pain. (refer to Section 6.5.1). 

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9. In the Investigator’s opinion, subject is able to understand the nature of the study and any 
risk involved in participation in this study and is willing to cooperate and comply with the 
protocol restrictions and requirements, including transvaginal ultrasound (TVU). 
10. Subject agrees not to participate in another interventional study while participating in the 
present study. 
11. Subject who is willing to limit alcohol consumption during the study to no more than 
approximately one alcoholic drink or equivalent [beer (354 mL/12 ounces), wine (118 mL/4 
ounces), or distilled spirits (29.5 mL/1 ounce)] per day. 
5.2 Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply 
1. Subject with confirmed SARS-CoV-2 infection, within 2 weeks prior to Screening or 
randomization. 
2. Subject who had severe course of COVID-19 (extracorporeal membrane oxygenation 
[ECMO], mechanically ventilated). 
3. Subject is pregnant or breastfeeding or is planning a pregnancy during the study period or is 
less than 6 months post-partum or 3 months post-abortion at the time of entry into the 
Screening Period or pregnancy before randomization. 
4. Subject has an intra-uterine device (IUD) (refer to Section 10.5). 
5. Subject has chronic pelvic pain that is not caused by endometriosis (e.g., interstitial cystitis, 
irritable bowel syndrome) or has any other chronic pain syndrome (e.g., fibromyalgia, chronic 
back pain, myofascial pain syndrome, chronic headaches) that requires chronic analgesic or 
other chronic therapy, which would interfere with the assessment of endometriosis-related 
pain. 
6. Subject has clinically significant gynecologic conditions other than endometriosis, including 
but not limited to: 
a. Ovarian cyst>5 cm (except confirmed endometrioma) that persists on repeat TVU;   
b. Single fibroid ≥ 4 cm or multiple (> 4) fibroids that measure ≥2 cm or symptomatic 
submucosal fibroid of any size on screening TVU; 
c. Any ovarian tumors or pelvic masses of unclear etiology requiring further diagnostic 
procedures; 
d. Acute or chronic endometritis 
7.   Subject has a current history of undiagnosed abnormal genital bleeding. 

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8. Subject has history of hysterectomy and/or bilateral oophorectomy. 
9. Subject has had surgery for endometriosis within the 4 weeks prior to entry into the 
Screening Period. 
10. Subject plans to schedule elective surgery during the study execution. 
11. Subject has known any history of anterior pituitary, posterior pituitary or hypothalamic 
dysfunction, including but not limited to prolactinomas, hypogonadism, growth hormone 
deficiency.  
12. Subject has a current history of hyperthyroidism or uncontrolled hypothyroidism. 
13. Subjects with past or present pituitary tumor growth as confirmed by a sellar magnetic 
resonance imaging (MRI) with contrast at screening period or has contraindications to 
contrast used in MRI. 
14. Subjects with immunocompromised status (e.g, congenital immune deficiency syndrome, or 
currently under immunosuppressive therapy, etc.). 
15. Subjects with a personal or family history of Multiple Endocrine Neoplasia syndrome type 1 
(MEN1). 
16. Subject has previous history of a severe, life-threatening or other significant sensitivity to any 
opioids or non-steroidal anti-inflammatory drugs (NSAIDS) or any contraindication to their 
use such as gastrointestinal ulcer or bleeding. 
17. Subject with known hypersensitivity to any of the IMP ingredients. 
18. Subject has a positive result on the screening urine drug screen and/or per the investigator’s 
discretion, has had a history of drug or alcohol abuse or dependence within the last year. 
19. Subject has, in the Investigator’s opinion, uncontrolled hypertension (systolic blood pressure 
[SBP] > 159 mmHg, diastolic blood pressure [DBP] > 99 mmHg) at Screening Period. 
20. Subject has an estimated glomerular filtration rate (eGFR) of < 60mL/min/1.73 m2 (using the 
Chronic Kidney Disease Epidemiology Collaboration [CKD EPI] formula) at Screening 
Period. 
21. Subject is currently participating in or has participated in an interventional clinical study with 
an investigational compound or device within 90 days prior to the start of Screening Period 
or 5 half-lives, whichever is longer. If a subject has participated in an investigational study 
with hormonal treatment, the minimal washout period applies as given in Section 10.5 also 
need to refer. 

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22. Subject has used medications such as hormones, analgesics, medications associated with 
bone loss, products that affect PRL levels, etc. within specific time window before Screening 
(refer to Section 10.5). 
23. Subject with current or past use of any of the following drugs to treat osteoporosis:  
a. Bisphosphonates, Denosumab, Teriparatide, Abaloparatide, Romosozumab and Calcitonin. 
b. Strontium or Fluoride (other than for dental indication). 
c. Selective estrogen receptor modulators: Raloxifene, Bazedoxifene, Lasofoxifene, 
Clomifene, Tamoxifen, etc 
24. Subject has clinically significantly abnormal laboratory tests at Screening Period, including: 
a. Alanine transaminase (ALT/SGPT), or aspartate aminotransferase (AST/SGOT) ≥200% of 
the upper limit of normal, or total bilirubin (unless known diagnosis of Gilbert’s syndrome) 
≥ 150% of the upper limit of normal range. 
b. Hemoglobin < 10 g/dL, Neutrophil count < 1500 mm3, Platelet count < 100 × 103/mm3. 
25. Subject has cervical cytology collected during the Screening Period shows evidence of 
malignancy or pre-malignant changes. 
26. Subject has clinically significant abnormal ECG, or ECG with QTcF > 450 msec at 
Screening Period. 
27. Subject has a positive Screening test result for hepatitis A virus immunoglobulin M 
(HAV – IgM), hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), 
detected HCV RNA (for positive or equivocal anti-HCV), or positive human 
immunodeficiency virus (HIV) or HIV antibody (HIV Ab). The HIV/HIV Ab results will be 
kept confidential by the study sites. 
28. Subject has a history of active malignancy (with or without systemic chemotherapy), except 
treated basal cell carcinoma of the skin. 
29. Subject is using any systemic corticosteroids for over 14 days within 3 months prior to 
Screening or is likely to require treatment with systemic corticosteroids during the course of 
the study. Over-the-counter and prescription topical, inhaled or intranasal corticosteroids are 
allowed. 
30. Subject has a medical history of confirmed psychiatric disorder (e.g., major depression, post-
traumatic stress disorder, schizophrenia, bipolar disorder) or has a history of suicide attempt 
or epilepsy, for whom it would not be recommended to stop concurrent medication therapy 
or may require medication therapy during study participation (refer to Section 6.5.2 and 10.5 
for prohibited medication and washout period). 

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31. Subject has any of the following conditions within 6 months prior to Screening: 
a. Myocardial infarction, stroke, unstable angina or transient ischemic attack. 
b. Classified as being in New York Heart Association Class III or IV. 
32. Subject has a history of osteoporosis or other metabolic bone disease, or including any one or 
more of the following:  
a. Low bone mass (Z-score ≤ -1.5 on screening DXA scan [lumbar spine, femoral neck or 
total hip BMD]) OR  
b. Body weight greater than 300 pounds or 136 kilograms (due to limits of DXA scanners) 
or any condition that would interfere with obtaining adequate DXA measurements (e.g., 
history of spinal surgery, severe scoliosis, hardware or artifact overlying the region of 
interest, including umbilical ring with refusal to remove) 
c. History of fragility fracture OR  
d. History or presence of an unstable condition that is associated with a decrease in BMD 
(e.g., uncontrolled hyperparathyroidism, anorexia nervosa)  
33. Any other conditions in the investigator’s opinion that prevent the subject from participating. 
34. Subject works in the investigational site or has an immediate family member (e.g. spouse, 
parent/legal guardian, sibling or child) who works in the investigational site or is a staff of 
the Sponsor directly involved with this study. 
Procedures that are allowed to be repeated for screening are listed in section 10.10 
5.3 Lifestyle Considerations 
For the duration of the study, subjects must agree to adhere to local requirements for reduction of 
the public SARS-CoV-2 exposure. This may include, but is not limited to: 
• Practice “social distancing” or similar as defined by their local health authorities and refrain 
from joining large gatherings of people 
• Wear a face mask in enclosed public spaces and/or when using public transportation if 
required by local regulations 
• Wash their hands with soap for at least 20 seconds regularly throughout the day (e.g., every 
time after using the washroom) and immediately after returning from a trip outside their 
home 
• Make every effort to refrain from touching their face unnecessarily 

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• While visiting the study site, physical distancing and person-to-person contact restrictions 
will be applied and explained to subjects. Where physical distancing is not possible subjects 
will be asked to use surgical face masks, gloves and/or face shields if deemed appropriate by 
the Investigator and site staff and guided by local requirements. 
5.3.1 
Prolactin Sampling 
Prior to PRL sampling, the subject must be examined and instructed to avoid PRL influencing 
factors such as emotional/physical stress, high-protein meals, all forms of chest and breast 
stimulation, including sexual activity and impact exercises such as running/jogging (these factors 
should be avoided on the morning prior to blood sampling), or any medication influencing PRL 
levels (refer to Section 6.5.2). 
5.3.2 
Activity 
Subjects will abstain from strenuous exercise for 24 hours before each blood collection for 
clinical laboratory tests. Subjects may participate in light recreational activities during studies 
(e.g., watching television, reading). 
5.4 Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently randomly assigned to the IMP. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure subjects to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, reason for screen failure 
(e.g., eligibility requirements failed), and any serious adverse events (SAEs). 
Individuals who originally do not meet the criteria for participation in this study (screen failure) 
may be rescreened once when Investigator considers the patient to be eligible to be enrolled. 
Rescreened subjects should be assigned a different subject ID and will be considered a new subject. 
5.5 Screening and Enrollment Log and Subject Identification Numbers 
The subject’s enrollment will be recorded in the Screening and Enrollment Log. Upon 
enrollment, each subject will receive a unique subject identification number. A rescreened subject 
will be given a new identification number. 

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6 Study Intervention 
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study subject according to the study protocol. 
In this regard, study interventions in this study include Investigational Medicinal Products (IMPs) 
(HMI-115, placebo) and Non-Investigational Medicinal Products (NIMP) (rescue medications). 
6.1 Study Intervention(s) Administered 
The following study interventions will be administered to the subject: 
Table 6-1.  IMPs Administered  
 
Table 6-2.  IMP(s) and Dosing Schedules 
Arm Name: 
Placebo Q2W 
HMI-115 60 mg Q2W 
HMI-115 120 mg 
Q2W  
HMI-115 240 mg 
Q2W 
Dosing 
schedules 
Placebo: 4mL  
HMI-115 60mg/mL: 
1 mL 
Placebo: 3 mL 
HMI-115 60mg/mL: 
2 mL  
Placebo: 2 mL 
HMI-115 60mg/mL: 
4 mL 
Arm Name: 
Placebo 
 
HMI-115 60 mg 
 
HMI-115 120 mg 
 
HMI-115 240 mg 
 
Intervention Name: 
Placebo 
HMI-115 
HMI-115 
HMI-115 
Type: 
Drug 
Drug 
Drug 
Drug 
Dosage Formulation: 
Lyophilized form 
Lyophilized form  
Lyophilized form  
Lyophilized form 
Unit Dose 
Strength(s): 
NA 
60mg/vial 
60mg/vial 
60mg/vial 
Dosage Levels: 
Placebo Q2W 
60 mg Q2W; 
12 weeks  
(6 treatment cycles) 
120 mg Q2W; 
12 weeks 
(6 treatment cycles) 
240 mg Q2W 
12 weeks  
(6 treatment cycles) 
Route of 
Administration: 
Subcutaneous 
Subcutaneous 
Subcutaneous 
Subcutaneous 
Use: 
Placebo 
Experimental 
Experimental 
Experimental 
Sourcing: 
Provided centrally by the Sponsor 
Packaging and 
Labeling: 
IMP will be provided in vials. Kits containing the vials will be labeled as required per country 
requirement. 

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In general, all subcutaneous injections were in the upper or lower abdomen around the belly 
button, but at least 1 cm away from the belly button itself. 
Repeated injections in the same spot can cause scarring and hardening of subcutaneous tissue, 
and therefore should have been avoided. Each injection should have been at least 2.5 cm apart. 
Different injection sites should be used between visits to in case the occurrence or worsening of 
injection site reactions. 
IMP administration should be performed after blood sampling and vital signs examination during 
each visit. 
Note: For subjects who fail to visit the study site on schedule, subject will be requested to return 
to site and complete the study visit as soon as possible. If the rescheduled visit is within one week 
(i.e., < 7 days) of the next scheduled visit, the schedule of all the subsequent visits will be 
adjusted based on this visit date and dosing will follow the Q2W interval. 
6.2 Preparation, Handling, Storage, and Accountability 
The lyophilized Drug Product must be stored at 2-8°C. Requirements for aseptic operation should 
be followed during IMP preparation. Unless administered immediately, for microbiologic 
consideration, the reconstituted solution should be stored at 2-8°C or room temperature, and 
administered within 4 hours.  
If the solution has been frozen, it must no longer be used for application and should therefore be 
discarded. 
The Investigator or designee must maintain a log to confirm appropriate temperature conditions 
have been maintained during transit for all IMPs received and any discrepancies are reported and 
resolved before use of the IMP. 
Only subjects enrolled in the study may receive the IMP and only authorized site staff may supply 
or administer IMPs. All IMPs must be stored in a secure, environmentally controlled, and 
monitored (manual or automated) area in accordance with the labeled storage conditions with 
access limited to the Investigator and authorized site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is responsible 
for IMP accountability, reconciliation, and record maintenance (e.g., receipt, reconciliation, and 
final disposition records). 

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Further guidance and information for the final disposition of unused IMPs are provided in the 
Study Reference Manual or other specified location. 
6.3 Measures to Minimize Bias: Randomization and Blinding 
All subjects will be centrally randomized using an Interactive Response Technology (IRT). The 
randomization will be stratified with two stratification factors 1) region and 2) participation in 
the intensive PK sampling subset. Each subject will be assigned a unique number (randomization 
number) that encodes the subject’s assignment to different arms of the study. Details of the 
procedure are described in the IRT Manual provided to all sites. IMP will be 
administered/dispensed at the study visits summarized in Section 6. 
6.4 Study Intervention Compliance 
The subjects will receive the study intervention directly from the Investigator or designee, under 
medical supervision. The date and time of each dose administered in the study site will be 
recorded in the source documents and recorded in the electronic case report form (eCRF). The 
IMP to be used and study subject identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the IMP. 
When subjects self-administer rescue medications at home, the type and dosage of rescue 
medication will be assessed at each visit. Compliance will be assessed by direct questioning (for 
e-Diaries) and counting returned rescue medication during the site visits and documented in the 
source documents and eCRF. 
6.5 Concomitant Therapy 
Any medication or vaccine (including vaccines for COVID-19, over-the-counter or prescription 
medicines, vitamins, and/or herbal supplements) that the subject is receiving at the time of 
enrollment or receives during the study must be recorded along with: 
• reason for use 
• dates of administration including start and end dates 
• dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding concomitant or prior 
therapy. 

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No pain medications other than the prescribed pain medication as rescue medication can be taken 
during the study duration. Further details on prohibited medications have been presented in 
section 6.5.2.  
6.5.1 
Rescue Medications 
Protocol specific analgesic rescue medication for endometriosis-associated pain will include four 
equivalent NSAID choices and three equivalent opioid choices. The protocol-allowed analgesic 
rescue medications for endometriosis-associated pain are presented in Table 6-3. Investigators 
will prescribe a specific analgesic rescue medication for subjects at the time of Visit 2, taking 
into consideration the subject's preference and/or historical use of analgesics and the 
investigator's clinical judgement (based on the approved options).  
Investigators are not to suggest or advise subjects on any modifications to their rescue 
medication regimen. Subjects will be instructed to contact the site if a change in their rescue 
analgesic medication is needed, such that appropriate adjustments can be considered. 
Investigators may then prescribe a different analgesic rescue medication (from each medication 
class if necessary) for the subject. Investigators should not prescribe more than one analgesic 
rescue medication from the same medication class at one time. The dosage outlined in Table 6-3 
could be utilized, but all prescribed use of rescue analgesic medication should be according to 
appropriate clinical practice standards and the investigator's clinical judgment.  
It is the investigator’s discretion whether to withdraw a subject due to an analgesic issue. 
Prophylactic use of protocol-specific rescue analgesic medications is not allowed. Use of any 
other analgesic medications for endometriosis-associated pain, including prophylactically, is not 
allowed from Visit 2 through the Follow-up Period.  
Daily use of rescue analgesic medications taken for endometriosis-associated pain will be 
recorded by the subject in the e-Diary from Visit 2 through the Follow-up period including date 
of rescue medication use as well as the name, dosage and total number of the rescue medication 
within a 24-hour period. Detailed information on the rescue medication that will be sourced and 
provided to the subject can be found in the site operation manual. In addition, any pain 
medication taken for pain other than for rescue (such as treatment for toothache etc.) will be 
recorded in eCRF, not in the e-Diary.   
Use of a prohibited medication for treatment of endometriosis-associated pain will be 
documented in the eCRF. If a subject continues to take analgesic(s) other than the protocol-

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If a hormonal emergency contraception is used, the use of the drug and any associated menstrual 
cycle irregularity after the use should be documented.  
If there are medications not listed in the table above that need further clarification, consult the 
Hope Medicine Medical Monitor for suggestions. 
6.6 Dose Modification 
Not applicable. 
6.7 Intervention After the End of the Study 
There will be no study intervention after the end of the study. Subjects could follow the routine 
medical practice. 
7 Discontinuation of IMP and Subject Withdrawal 
7.1 Discontinuation of IMP 
It may be necessary for a subject to permanently discontinue (definitive discontinuation) the IMP. 
If the IMP is definitively discontinued, the subject will remain in the study until Visit 10 to be 
evaluated for safety and efficacy of the IMP. Please refer to Section 10.4 and 8.4.5 for details on 
contraceptive guidance and collection of pregnancy information.  
The Investigator or Medical Monitor (and, if needed, with DMC review) may temporarily hold or 
stop the dosing of IMP to a subject at any time during the study. For subjects that discontinue IMP 
for reasons related to safety, unblinding of the treatment assigned to the subject may be carried out 
if deemed necessary by the Sponsor to assess any potential safety signal or by the Investigator to 
provide adequate medical care to the subject. All details of reasons, therapies that may have been 
subsequently started should be well documented and reviewed.  
Examples of conditions or symptoms that may warrant holding or stopping IMP at the 
Investigator’s and/or Medical Monitor’s discretion include: 
•   Occurrence of a severe or serious AE assessed as related to IMP 
•   Repeating premature ventricular contractions (PVC) confirmed by additional ECG examination 
at least 30 minutes apart, or QTcF interval >500 ms, or increase in QTcF interval >60 ms 
compared to baseline in absence of possible causes other than the IMP 
•   Significant decrease of neutrophils count < 1500 mm3 confirmed by repeat measurement 

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•   Pregnancy 
•   Intolerance of the IMP authorized under this protocol 
•  If in the Investigator’s opinion, continuation with the administration of the IMP would be 
detrimental to the subject’s well-being 
Investigator must notify the Sponsor within one calendar day of being aware of an event that may 
warrant holding or stopping the IMP. If the IMP is held due to safety concerns, approval by the 
Medical Monitor is required prior to resumption of IMP. If the subject meets the holding or 
stopping conditions again after resumption (re-challenge), the IMP will be permanently 
discontinued. 
Unless informed consent is withdrawn, subjects who permanently discontinue IMP during the 
treatment period should attend all subsequent visits up to Visit 10 and complete all procedures 
(except IMP administration related) as outlined in the SoA. 
7.2 Subject Withdrawal from the Study 
The subject may withdraw or may be withdrawn from the study: 
• If they decide to do so, at any time and irrespective of the reason 
• At the specific request of the Sponsor 
Subject discontinuation from IMP or withdrawal from the study should be avoided as much as 
possible. Every attempt should be made to restart IMP if medically appropriate and approved by 
Medical Monitor, irrespective of the duration of holding IMP. 
In the event of withdrawn from the study during the treatment period, if possible, an early 
discontinuation visit (procedures same as Visit 9) needs to be performed as soon as possible and 
an on-site follow-up visit (procedures same as Visit 10) after 12 weeks from the last dose should 
be conducted. If the subject is unwilling to attend the on-site follow-up visit, a follow-up phone 
call should be attempted if the subject agrees, to collect safety information (monitoring AE, 
pregnancy status, concomitant medications) (refer to Section 1.3). 
In the event of withdrawn from the study during the follow-up period, if possible, an on-site follow-
up visit (procedures same as Visit 10) is recommended to complete as soon as possible followed 
by a phone call follow-up at 12 weeks from the last dose to collect safety information (monitoring 
AE, pregnancy status, concomitant medications). If the subject is unwilling to attend an on-site 

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follow-up visit, a phone call follow-up at 12 weeks from the last dose should be attempted if the 
subject agrees (refer to Section 1.3). 
If the subject withdraws informed consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
Note: For subjects discontinued from IMP or withdrawn from study, no additional PK and ADA 
sampling except EOT and EOS visits (if possible) is required after IMP discontinuation. 
Handling of subjects with suspected COVID-19 infection: 
If a subject develops fever or symptoms suspected of being a result of COVID-19 during the study, 
they will be instructed to follow-up with their regular healthcare provider or follow the instructions 
for suspected COVID-19 cases per their local health authority. 
A subject may be withdrawn by the Investigator based on discussion with the Sponsor and Medical 
Monitor under the following circumstance: 
• any confirmed COVID-19 case that warrants withdrawal in the judgment of the 
Investigator or Sponsor to protect the safety of the subject, other study subjects or study 
site staff. 
7.3 Study Pauses for Safety Reasons 
In order to monitor and protect the safety of study subjects, to ensure early insight into any safety 
signal, and for early elimination of any potential safety hazard for an individual subject or a full 
cohort/entire study population, the Medical Monitor will review all AEs from the entries in the 
eCRF on an ongoing basis and SAE reports as received. An independent DMC will be 
established and will review all study data pertaining to subjects’ safety on a regular basis to 
adjudicate the overall safety of the subjects in this study. In addition, the DMC will be notified, 
and a meeting may be called for each case of IMP discontinuation due to an IMP related safety 
reason. 
Study will be paused pending prompt review by DMC if 2 or more subjects experience similar 
SAE or severe AE assessed as related to IMP, or discontinue IMP for safety reasons assessed as 
related to IMP. 
Study will be paused if any of the following assessed as related to IMP occurs, pending prompt 
review of the case(s) by the DMC: death, suicide attempt, serious changes in behavior (such as 

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psychosis or the development of impulse control disorders or addictive behavior), cardiac 
arrhythmia or AEs pertaining to the pituitary gland. 
7.4  Loss of Subjects to Follow-Up 
A subject will be considered lost to follow-up if she repeatedly fails to return for scheduled visits 
and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible (and within the visit window, where one is defined) and counsel the subject on the 
importance of maintaining the assigned visit schedule and ascertain whether or not the 
subject wishes to and/or should continue in the study. 
• In cases in which the subject is deemed lost to follow-up, the Investigator or designee must 
make every effort to regain contact with the subject (where possible, three telephone calls 
and, if necessary, a certified letter to the subject’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the subject’s medical 
record. 
Should the subject continue to be unreachable, she will be considered to have withdrawn from 
the study. 
8 Study Assessments and Procedures 
Study procedures and their timing are summarized in the SoA (Table 1-1). Protocol waivers or 
exemptions are not allowed. 
Adherence to the study design requirements, including those specified in the SoA, is essential and 
required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential subjects meet 
all eligibility criteria. The Investigator will maintain a screening and enrollment log to record 
details of all subjects screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
Procedures conducted as part of the subject’s routine clinical management (e.g., mammography) 
and obtained before signing of the informed consent form (ICF) may be utilized for Screening 

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purposes provided the procedures met the protocol-specified criteria and were performed within 
the time frame defined in the SoA. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. 
Informed Consent 
Informed consent must be documented according to Section 10.1.3. 
Eligibility Criteria 
All inclusion and exclusion criteria will be reviewed by the Investigator or designee to ensure 
that the subject qualifies for the study. 
Subject Identification Card 
All subjects will be given a subject identification card identifying them as subjects in a research 
study. The card will contain study site contact information (including direct telephone numbers) to 
be used in the event of an emergency. The Investigator or qualified designee will provide the 
subject with a subject identification card immediately after the subject provides written informed 
consent. At the time of randomization, site personnel will add the randomization number to the 
subject identification card. 
The subject identification card also contains contact information for the emergency unblinding call 
center so that a healthcare provider can obtain information about IMP in emergency situations 
where the Investigator is not available. 
Demographic information 
The following demographic information will be recorded: 
• Age 
• Ethnic origin 
• Race 
• Height in cm 
• Body weight (in kg) 
Medical history 

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A medical history will be obtained by the Investigator or qualified designee. The medical history 
will collect all active conditions and any condition diagnosed prior to signing informed consent 
that the Investigator considers to be clinically significant. Details regarding the disease for which 
the subject has enrolled in this study will be recorded separately and not listed as medical history. 
Prior and concomitant medications review 
The Investigator or qualified designee will review prior medication use and record prior 
medications taken by the subject within 1 month prior to Screening. For medications related to the 
inclusion/exclusion criteria with specific washout period, refer to Section 10.5 for the time 
requirement.  
The Investigator or qualified designee will record medication, if any, taken by the subject during 
the study through the last visit. Concomitant medications will be recorded until last study visit. 
All reasonable measures will be taken to decrease potential transmission of COVID-19; for 
example, study staff and physicians will wear surgical masks and gloves and/or face shields while 
meeting with subjects and will wash their hands per the Center for Disease Control (CDC)/World 
Health Organization (WHO)/regional health authority guidelines before, between, and after 
meeting each subject. 
8.1 Efficacy Assessments  
8.1.1 
Electronic-Diary (e-Diary) 
All subjects will be administered an e-Diary after adequate training at Visit 2. Subjects are 
required to record uterine bleeding and endometriosis-associated pain every day at around the 
same time for the entire duration of the study. The use of rescue medications for endometriosis-
associated pain will also be recorded. Compliance to e-Diary filling will be assessed as shown in 
the SoA (refer to Section 1.3). Subjects need to return the e-diary devices after the completion of 
study participation or after withdrawal from the study. 
8.1.2 
Evaluation of the need for Rescue Medication 
Subjects will be supplied rescue pain medication (as listed in Table 6-3) that should be used only 
for endometriosis-associated pain throughout the study duration. Assessment will be based on the 
average number of rescue medication consumed by the subject and the percentage of days the 
subject took rescue medication. 

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8.1.3 
Numeric Rating Scale (NRS) for Pain 
NRS pain scale will be used to measure DYS from Baseline to Week 12 and Baseline to Week 24 
with Pain Scale ranging from 0 (no pain) to 10 (severe pain). Subjects will assess in the e-Diary 
their endometriosis-associated pain during the past 24 hours (last calendar day). NMPP and DYSP 
will be also measured using the NRS pain scale from Baseline to Week 12, and Week 24. 
Refer to Section 10.6 for the template. 
8.1.4 
Endometriosis Daily Impact Pain Scale 
Endometriosis Daily Impact Pain Scale will be used to record the mean change every month 
from Baseline to Week 12 and 24 with the Pain scale ranging from 0 (no pain) to 3 (severe pain). 
Based on the subject's response to the question "Did you have your period in the last 24 hours 
(last calendar day)?" in the daily e-Diary, the subject will be asked to assess either their 
dysmenorrhea or non- menstrual pelvic pain as follows: 
Dysmenorrhea (DYS) 
Subjects will be asked to assess their DYS and its impact on their daily activities. Subjects will 
be prompted to "Choose the item that best describes your pain during the last 24 hours (last 
calendar day) when you had your period." 
0        None             No discomfort 
1        Mild              Mild discomfort but I was easily able to do the things I usually do 
2        Moderate      Moderate discomfort or pain. I had some difficulty doing the things I 
usually do 
3        Severe           Severe pain. I had great difficulty doing the things I usually do 
 
Non-Menstrual Pelvic Pain (NMPP) 
Subjects will be asked to assess their NMPP and its impact on their daily activities. Subjects will 
be prompted to "Choose the item that best describes your pain during the last 24 hours (last 
calendar day) without your period." 
0        None             No discomfort 

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1        Mild              Mild discomfort but I was easily able to do the things I usually do 
2        Moderate      Moderate discomfort or pain. I had some difficulty doing the things I 
usually do 
3        Severe           Severe pain. I had great difficulty doing the things I usually do 
 
Dyspareunia (DYSP) 
Subjects will be asked to assess their dyspareunia (described as 'pain during sexual intercourse'). 
Subjects will be prompted to "Choose the item that best describes your pain during sexual 
intercourse during the last 24 hours (last calendar day)." 
Not applicable    I was not sexually active for reasons other than my endometriosis or 
did not have sexually intercourse  
0        None                   No discomfort during sexual intercourse 
1        Mild                    I was able to tolerate the discomfort during sexual intercourse 
2        Moderate            Intercourse was interrupted due to pain 
3        Severe                 I avoided sexual intercourse because of pain 
 
8.1.5 
Uterine Bleeding  
Subjects will be prompted to indicate if they had "Did you have any uterine bleeding in the last 
24 hours (last calendar day)?" Subject will then document the intensity of the bleeding as 
follows: 
0        None              
1        Spotting          A light amount of bleeding noted, no protection or panty shield only 
2        Light              1 to 2 regular tampons or pads required in 24 hours 
3        Medium         3 to 4 regular tampons or pads required in 24 hours 
4        Heavy            More than 4 tampons or pads required in 24 hours 

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8.2 Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
8.2.1 Physical Examinations 
A complete physical examination will include, at a minimum, assessments of General appearance, 
HEENT (head, eyes, ears, nose, throat), Neck (including thyroid), Lung/pulmonary, Chest 
(including breast), Cardiovascular, Abdomen, Back, Neurological, Extremities, Skin and Lymph 
nodes, and will be performed at Visit 1, Visit 9 and Visit 10. Height (cm) and weight (kg) will also 
be measured and recorded at specified period shown in the SoA (refer to Section 1.3). 
A brief physical examination will include, at a minimum, assessments of General appearance, 
HEENT (including extra-ocular movements), Neck, Lung/pulmonary, Breast, Cardiovascular, 
Abdomen, Extremities and Skin, and will be performed at Visit 2, Visit 3, Visit 4, Visit 5, Visit 6, 
Visit 7, and Visit 8. Additional physical examination may be necessary based upon the subjects’ 
complaints. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
8.2.2 Vital Signs 
Vital signs will be assessed from Screening Period to EOT period and during the follow-up visit. 
Tympanic body temperature, pulse rate, respiratory rate, and blood pressure will be assessed. 
Blood pressure and pulse measurements will be assessed with a completely automated device. 
Manual techniques will be used only if an automated device is not available. 
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest (e.g. in a 
sitting position) for the subject in a quiet setting without distractions (e.g., television, cell phones). 
8.2.3 Pelvic examination 
The pelvic examination should specifically document presence or absence of uterine or adnexal 
induration and/or tenderness, with description of tenderness (location, intensity, e.g., mild, 
moderate or severe) if present. The results of pelvic examination will be used for CPSSS. 
8.2.4 Electrocardiograms 
12-lead ECG will be obtained as outlined in the SoA using an ECG machine that automatically 
calculates the heart rate and measures PR, QRS and QT. QT interval will be corrected for heart 
rate using Fridericia’s correction formula (QTcF) and Bazett’s correction formula (QTcB) 
respectively. 

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8.2.5 
 Clinical Safety Laboratory Assessments 
Refer to Section 10.2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency. Blood draw will not exceed 500 mL during the entire study period. 
The Investigator must review the laboratory report, document this review, and record any clinically 
significant abnormal changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless judged 
by the Investigator to be more severe than expected for the subject’s condition. 
All laboratory tests with values considered clinically significant abnormal during participation in 
the study or within 14 days after the last dose of IMP should be repeated until the values return to 
normal or Baseline, or are no longer considered clinically significant by the Investigator or Medical 
Monitor, or subject lost to follow-up or death. 
• If such values do not return to normal/Baseline within a period of time judged reasonable by 
the Investigator, the etiology should be identified, where possible, and the Sponsor notified. 
• All protocol-required laboratory assessments, as defined in Section 10.2, must be conducted in 
accordance with the laboratory manual and the SoA. 
• If laboratory values from laboratory assessments not specified in the protocol and performed 
at the institution’s local laboratory result in the need for a change in subject management or 
are considered clinically significant by the Investigator (e.g., are considered to be an SAE or 
an AE or require dose discontinuation), then the results must be recorded in source document. 
8.2.6 Transvaginal Ultrasound (TVU) Assessments 
Assessments for TVU include, but are not limited to, the following:  
• Endometrial thickness (double layer, mm)  
• Other endometrial findings such as heterogeneity or other abnormality 
• Presence, size and appearance of ovarian cysts or masses 
• Presence, location and size of uterine fibroids 
• Endometriomas 
The Screening TVU may be repeated per protocol (e.g., ovarian cyst criteria) or as clinically 
appropriate. An unscheduled (elective) TVU may also be performed as clinically indicated for 
subject evaluation during the course of the study. 

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8.2.7 Dual Energy X-ray Absorptiometry （DXA） 
DXA results of the lumbar spine, total hip, and femoral neck will be obtained at screening period 
and Visit 9. A central bone density vendor will be used to conduct blinded reads of DXA scans 
and manages the longitudinal quality control of DXA scanners at each imaging center. The data 
from these analyses will be electronically transferred from imaging center to the study database. 
Subject treatment management will be made based on the central review.  
For individual subject, the degree of bone loss that requires a follow-up DXA scan(s) as follows: 
a) Obtain a 6-month post-treatment follow-up DXA scan for subjects with change from pre-
treatment baseline of ≤ -2.0% in the lumbar spine or ≤ - 2.5% total hip, or Z-score ≤ -2.0 (i.e., 
below the expected range for age) at any anatomic site (lumbar spine, total hip, or femoral 
neck). 
b) If the subject does not meet the criteria for adequate recovery on her DXA scan at post-
treatment month 6, refer to a bone specialist (Define adequate recovery as change from pre-
treatment baseline of > -1.5% at the lumbar spine and > -2.0% at the total hip). 
c) Refer to a bone specialist those subjects with Z-score ≤ -2.0 at any anatomic site at post-
treatment month 6 (or on their final DXA scan if they do not follow-up as instructed). 
The window period for EOT visit and post-treatment month 6 DXA scan is ±14 days. 
Subjects who prematurely discontinue IMP treatment prior to week 11 will not have a DXA at 
the EOT visit or in the Post-treatment Follow-up Period. Subjects who become pregnant during 
the study will not have protocol required DXA scans. 
8.3 Exploratory Assessments 
8.3.1 Patient Global Impression of Change (PGIC) Score  
Subjects will score the PGIC as shown in the SoA (refer to Table 1-1). The PGIC questionnaire is 
a self-reported 7-point scale rating a subject’s overall impression of change in their 
endometriosis-associated pain since start of IMP, where 1 = very much improved, 2 = much 
improved, 3 = minimally improved, 4 = not changed, 5 = minimally worse, 6 = much worse, 7 = 
very much worse. 
Refer to Section 10.7 for the template.  

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8.3.2 Endometriosis Health Profile-5 (EHP-5)13 
The EHP-5 is a HRQoL scoring that has a core questionnaire and modular questionnaire with a 
4-point rating scale for each item (0 = never, 1=rarely, 2=sometimes, 3=often, 4 = always).  
Anything that is not applicable to the subject in the questionnaire will be marked not relevant. 
Refer to Section 10.8 for the template. 
8.4 Adverse Events and Serious Adverse Events 
The definitions of AEs and SAEs can be found in Section 10.3. 
8.4.1 Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from the signing of ICF until the end of study participation 
at the time points specified in the SoA (Section 1.3). 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Section 10.3. The Investigator will submit any updated SAE data to the Sponsor within 24 hours 
of it being available. 
Investigators are not obliged to actively seek AEs or SAEs after the end of study participation. 
However, if the Investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event to be reasonably related to IMP or 
study participation, the Investigator must promptly notify the Sponsor. 
8.4.2 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures 
for completing and transmitting SAE reports are provided in Section 10.3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence. 
8.4.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each subject at 
subsequent visits/contacts. All AEs and SAEs will be followed until resolution, stabilization, until 
the event is otherwise explained, or the subject is lost to follow-up (as defined in Section 7.3) or 
death. Further information on follow-up procedures is given in Section 10.3. 

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8.4.4 Regulatory Reporting Requirements for SAE 
Prompt notification (within 24 hours, refer to Section 10.3) by the Investigator to the Sponsor of 
an SAE is essential so that legal obligations and ethical responsibilities toward the safety of 
subjects and the safety of a study intervention under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, Institutional Review Board (IRB) or Independent Ethic Committee 
(IEC), and Investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSAR) according to local regulatory requirements and Sponsor policy and forwarded to 
Investigators as necessary. 
An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAE) from the Sponsor will file it along with the 
IB and will notify the IRB/IEC, if appropriate according to local requirements. 
8.4.5 Pregnancy 
All subjects should follow contraceptive guidance strictly as detailed in Section 10.4. However, 
in the event of pregnancy after start of study visit with relevant consent obtained: 
• Details of all pregnancies in subjects will be collected from the signing of ICF until the end 
of study participation. 
• If a pregnancy is reported, the Investigator should inform the Sponsor (or Sponsor designated 
agent) within 24 hours of learning of the pregnancy and complete the pregnancy report forms 
within 30 days. 
• Investigator will collect pregnancy information on any subject, who becomes pregnant while 
participating in this study. Subject will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the subject and neonate for 
one month after delivery, which will be forwarded to the Sponsor. For live infant births, 
information on the health of the infant will be collected 6 to 12 months after delivery. 
• Any termination of pregnancy will be reported, regardless of fetal status (presence or absence 
of anomalies) or indication for procedure. 
• IMP should be discontinued permanently when pregnancy is identified. 

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Pregnancy alone is not regarded as an AE. Abnormal pregnancy outcomes (e.g., spontaneous 
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered to be 
SAEs. 
Elective abortions without complications should not be handled as AEs, unless the abortion was 
required for treatment of a specific AE. Hospitalization for normal delivery of a healthy newborn 
should not be considered a SAE. 
Any SAE that occurs during pregnancy (including SAEs occurring after last administration of 
IMP) must be recorded on the SAE report form (e.g., maternal serious complications, 
spontaneous or therapeutic abortion, ectopic pregnancy, stillbirth, neonatal death, congenital 
anomaly, or birth defect) and reported within 24 hours in accordance with the procedure for 
reporting SAEs. 
Any SAE occurring as a result of a post-study pregnancy which is considered reasonably related 
to the IMP by the Investigator, will be reported to the Sponsor. While the Investigator is not 
obligated to actively seek this information in former study subjects, he or she may learn of an 
SAE through spontaneous reporting. 
8.5 Treatment of Overdose 
This study is a dose finding study and thus no data is available for treatment of overdose. 
8.6 Pharmacokinetics 
Plasma samples will be collected for measurement of plasma concentrations of HMI-115 at time 
points specified in the SoA (refer to Table1-2, and Table1-3). The timing of sampling may be 
altered during the course of the study based on newly available data (e.g., to obtain data closer to 
the time of peak plasma concentrations) to ensure appropriate monitoring. Instructions for the 
collection and handling of biological samples will be provided by the Sponsor. The actual date 
and time (24-hour clock time) of each sample will be recorded. 
Samples collected for analyses of HMI-115 plasma concentration may also be used to evaluate 
safety or efficacy aspects that address concerns arising during or after the study. 
Subject confidentiality will be maintained. At visits during which samples for the determination 
of plasma concentration of HMI-115 will be taken, 1 blood draw of sufficient volume can be 
used.  

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Plasma samples collected for pharmacokinetics analysis will be retained for up to 5 years 
following study finalization for possible further characterization of pharmacokinetic profile of 
HMI-115 at a specialized laboratory. 
Drug concentration information that may unblind the study will not be reported to study sites or 
blinded personnel until the study has been unblinded. 
8.7 Pharmacodynamics 
Not applicable. 
8.8 Genetics 
Pharmacogenomics will not be evaluated in this study. 
8.9 Biomarkers 
The following biomarkers will be evaluated: Prolactin and CA-125. 
8.10 Immunogenicity Assessments 
To assess the overall immunogenicity potential of HMI-115, subject’s blood will be tested for 
anti-drug antibody (ADA) production: ADA (positive/negative and titer) and neutralizing 
antibodies (NAB) (positive/negative and titer only in subjects with ADA positive result). The 
time points for ADA determinations in blood are provided in SoA with one additional sampling 
point at week 17. All samples for ADA should be collected together with the corresponding PK 
sample. 
Serum samples collected for immunogenicity assessments will be retained for up to 5 years 
following study finalization for possible further characterization of a potential ADA response at 
a specialized laboratory. 
8.11 Composite Pelvic Signs and Symptoms Score (CPSSS) 
The CPSSS is a rating instrument used to assess signs and symptoms of endometriosis. It consists 
of two sections completed by two different individuals. The first section (Section 1) is completed 
based on the subject’s responses regarding DYS, DYSP, and NMPP. The first section should not 
be completed by the subject. This section should also not be completed by the individual who is 
completing the second section of the CPSSS. The second section (Section 2) is completed by the 
investigator based on findings associated with a pelvic examination (i.e., pelvic tenderness and 
induration). In order to avoid bias in his/her assessment, the investigator will not reference the 
subjects' e-Diary data or CPSSS Section 1.  

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Each individual component of the CPSSS will be scored on a scale of 0 to 3 (0 = None; 1 = Mild; 
2 = Moderate; 3 = Severe). For DYSP, the choice of "Not Applicable" applies to subjects not 
sexually active for reasons other than endometriosis pain. Responses of "Not Applicable" for the 
assessment of DYSP will be treated as missing values and will not be included in the 
summaries/analyses. The total CPSSS has a maximum possible value of 15 (total score range: 0 
to 15, lower score indicates less signs and symptoms of endometriosis). 
Refer to Section 10.9 for the template. 
8.12 Health Economics or Medical Resource Utilization and Health 
Economics 
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study. 
9 Statistical Methods 
9.1 Statistical Hypotheses 
The primary objective of the study is to evaluate the efficacy of HMI-115 for 12 weeks 
compared with placebo in the management of endometriosis-associated pain. This objective will 
be addressed by comparing the primary efficacy endpoint between each HMI-115 treatment 
group and placebo. The null hypothesis is that there is no difference in the mean change of DYS 
at Week 12 between each HMI-115 treatment group and placebo. All statistical tests will be two-
sided and a significance level of 0.05 will be used unless otherwise specified. Multiplicity 
adjustment will not be employed with respect to the multiple dose groups in this proof-of-
concept study. A test will be considered significant if the p-value is less than 0.05. Two interim 
analysis is planned. More details of the interim analysis are presented in Section 9.5. 
The objective will also be addressed by obtaining the point and interval estimates of the mean 
CFB to Week 12 in the DYS NRS for each HMI-115 treatment group and placebo.  In addition, 
hypothesis test for a statistically significant trend (upward slope) across HMI-115 doses will be 
performed using the 0.05 significance level. 
9.2 Sample Size Determination 
152 eligible subjects will be randomly assigned to HMI-115 or placebo group and 136 evaluable 
subjects for an estimated total of 34 evaluable subjects per treatment groupA sample size of 34 
evaluable subjects per treatment group is planned. With an assumption that up to 10% of subjects 
may prematurely discontinue the study without providing data for efficacy evaluations, 

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enrollment of approximately 38 subjects per treatment group is planned. With 38 subjects per 
group, there is an 80% power to detect a 1-point difference in the CFB to Week 12 in DYS NRS 
within a treatment group. This is based on the assumption of a standard deviation (SD) of 2.0 and 
a paired t-test at the 0.05 alpha level. This sample size is also expected to provide adequate 
precision in the point estimate and 95% confidence interval (CI) of the CFB for each treatment 
group. 
Because this is a proof-of-concept study, the sample size is planned to provide adequate data to 
evaluate the efficacy and safety of HMI-115 in the dose range studied. It is not based on power 
calculation to demonstrate statistically significant difference versus placebo. However, in the 
context of comparing an HMI-115 treatment group versus placebo (ie, between-group 
comparison), this sample size will provide 80% power to detect a treatment difference of 1.4 
point in the CFB in DYS NRS based on the assumption of SD of 2.0 and a 2-sample t-test at 0.05 
significance level. 
9.3 Populations for Analyses 
For purposes of analysis, the following analysis sets will be used: 
Table 9-1 
Populations for Analyses 
Population (Analysis Set) 
Description 
Enrolled Analysis Set 
All subjects who signed the ICF (including screening failures). 
Full Analysis Set (FAS) 
This analysis set includes all randomized subjects who take at 
least one dose of IMP. For the FAS, subjects are assigned to a 
treatment group based on the randomization schedule, regardless 
of the treatment actually received. FAS will be used for all 
efficacy analyses. 
Per Protocol Analysis Set 
(PPS) 
The PPS comprises a subset of the FAS who do not have protocol 
deviations that could significantly affect the results for the 
primary endpoints. Subjects’ inclusion/exclusion from the PP 
population will be determined and documented prior to the 
database lock and unblinding. PPS will be used for the primary 
and secondary efficacy endpoints. 
Safety Analysis Set 
The Safety Analysis Set consists of all subjects who received at 
least one dose of IMP. Subjects will be analyzed according to the 
IMP they actually received. Safety Analysis Set will be used for 
all safety analyses. 
PK Analysis Set 
The PK analysis set consists of all subjects in the Safety Analysis 
Set with at least one drug concentration value and have no major 
protocol deviation that could significantly impact PK assessment. 

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Immunogenicity analysis 
set 
The immunogenicity analysis set consists of all subjects in the 
Safety Analysis Set with at least one immunogenicity value. 
All protocol deviations will be reviewed and classified regarding how they affect clinical and 
analysis outcomes during the Blinded Data Review Meetings. Subjects may be excluded from 
the PPS and PK Analyses Set. 
The FAS will be the primary analysis set for all efficacy analyses and the PPS will be used to 
demonstrate robustness of results for the primary and secondary efficacy endpoints. 
9.3.1 Variables for Stratification of Randomization 
This study employs a stratified randomization with two stratification factors: 1) region 2) 
participation in the intensive PK sampling subset (Yes, No). These stratification factors will be 
taken into account in the statistical analyses. 
9.4 Statistical Analyses 
A detailed Statistical Analysis Plan (SAP) will be provided in a separate document. The SAP 
will be finalized prior to database lock. Below is a description of planned statistical analyses. 
Further details will be presented in the SAP. 
9.4.1 
General Considerations 
All study data will be summarized by treatment group using descriptive statistics. Unless otherwise 
specified, for continuous data (e.g., age, weight), descriptive statistics will include the number of 
subjects with data to be summarized (n), mean, SD, median, minimum (min) and maximum (max). 
All categorical/qualitative data (e.g., gender, race) will be presented using absolute and relative 
frequency counts and percentages. 
All summaries, statistical analyses, and individual subject data listings described below will be 
completed using Version 9.4 or later of the SAS software (SAS Institute, Inc. Cary, NC). 
9.4.2 
Demographics and Baseline Characteristics  
Demographics and baseline characteristics will be summarized descriptively by treatment group 
for the FAS and the Safety Analysis Set.  

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9.4.3 
Estimand 
The estimand that corresponds to the primary study objective is the treatment effect of HMI-115 
in moderate to severe endometriosis-associated pain in the endometriosis population over 12 
weeks if all subjects continue using HMI-115 and did not use rescue medication.  
The primary estimand is described by the following attributes: 
• 
Treatment conditions: the treatment condition of interest is HMI-115 at 60 mg, 120 mg, 
and 240 mg injected Q2W for 12 weeks. Placebo treatment is the control group. 
• 
Population: the population includes women with moderate to severe endometriosis-
associated pain. As defined in the protocol-specified inclusion/exclusion criteria reflecting the 
target study patient population for approval. 
• 
Endpoint: the primary efficacy endpoint is CFB in DYS measured by NRS at Week 12. 
• 
Intercurrent event (ICE):    
1. 
Premature withdrawal from study treatment: this ICE will be handled using hypothetical 
strategy by assuming subjects who have missing data due to early discontinuation behave 
similarly to other subjects who completed the study in that treatment group.   
Missing average DYS score measured by NRS due to early discontinuation will be imputed by 
reference-based multiple imputation method (jump to reference) under the missing not at random 
(MNAR) framework as if subjects were completed the study.  
2. 
At least 15% increase in average pill count of rescue analgesic medications compared to 
Baseline in the EOT menstrual cycle (definition in Section 9.4.4): this ICE will be handled using 
composite strategy by assuming subjects have no improvement in their pain intensity, and the 
DYS at EOT menstrual cycle will be set as baseline average value (baseline observation carried 
forward, BOCF).  
• 
Population-level summary: the mean change in DYS will be summarized for each 
treatment group with point estimates (least square mean [LSM] with its associated standard error 
[SE]) and 95% CIs. Estimated treatment difference (compared for each HMI-115 treatment 
group against the placebo group) along with corresponding 95% CI will be presented using 
analysis of covariance models (ANCOVA) with treatment, the randomization stratification factor 
of region as the fixed effects and baseline DYS as covariate. 

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Subjects who have missing data due to early discontinuation are assumed to behave similarly to 
other subjects who completed the study. Sensitivity analyses of the same estimand with different 
assumptions will be employed to check the robustness of the primary analysis. These sensitivity 
analyses include mixed-effect model repeated measures (MMRM) method, and the Last 
Observation Carried Forward (LOCF) method will be used.  The details of the sensitivity 
analyses will be included in the statistical analysis plan. 
Because the phase 2 study is the first study of HMI-115 in the endometriosis population in a 12-
week duration, this estimand will allow HMI-115 to evaluate the efficacy of HMI-115 in the 
treatment of moderate to severe endometriosis-associated pain relative to placebo. When the 
results are available, this effect size will be examined for its clinical significance. A definition of 
responder who reaches clinically meaningful improvement as measured by DYS will then be 
defined based on a receiver operating curve (ROC) analysis using PGIC as an anchor. In addition 
to the anchor-based method, the empirical cumulative distribution function (eCDF) method will 
also be used to determine the clinically meaningful improvement. 
9.4.4 
Primary Efficacy Endpoints  
The primary efficacy endpoint is the mean change of DYS measured by NRS from Baseline to 
Week 12. 
Measurement of Baseline: The baseline measurements will be derived from  the  last complete 
menstruation cycle during the Screening Period prior to Day 1.It will be designated as the 
baseline menstrual cycle and is defined as the interval from the first day of the menstruation to 
the day before the first day of the next menstruation.  
Measurement of Week 12: Because the Week 12 (EOT) visit may or may not occur during 
menstruation, the measurement of Week 12 will be defined by the following 2 approaches, 
depending on the scenarios. The objective of these approaches is to capture a complete menstrual 
cycle and designate it as the EOT menstrual cycle. 
• If EOT visit occurs during menstruation, the EOT menstrual cycle is defined as the 
interval that begins from the first day after the end of the previous menstruation to the last 
day of the menstruation during which the EOT visit occurred. It is expected that the end 
of this menstruation may be days after the EOT visit. 
• If EOT visit occurs outside of a menstruation period, the closest menstruation period to 
the EOT visit will be identified. This menstrual period may be before or after the EOT 
visit. In either case, the EOT menstrual cycle will begin at the end of the menstruation 

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period immediately before the closest menstruation period to the last day of the closest 
menstruation period.  
The mean change will be summarized for each treatment group with point estimate and 95% CI 
and will be compared for each HMI-115 treatment group to the placebo group using analysis of 
covariance models (ANCOVA) with treatment, the randomization stratification factor of region 
as the fixed effects and baseline DYS as covariate. In addition, a mixed-effect model repeated 
measures (MMRM) method with treatment, the randomization stratification factor of region, and 
visit as the main effects, and treatment-by-visit interaction will be used as a sensitivity analysis. 
The use of rescue medication will be taken into account in the analysis of the primary endpoints. 
In the ANCOVA analysis, if a subject has at least 15% increase of rescue medication use (in 
terms of medication counts) compared to baseline in the EOT menstrual cycle, the measurement 
for Week 12 will be imputed with the baseline NRS measurement (i.e. assuming no improvement 
from baseline). In the MMRM analysis, if a subject has at least 15% increase of rescue 
medication use at a particular visit compared to baseline, the measurement at that visit will be 
imputed with the baseline NRS measurement. Such subjects will also be considered non-
responders in the PGIC responder analysis for that visit.  The visit window for the MMRM 
analysis will be defined in the SAP. 
In addition to rescue medications, all analgesic medications taken to treat pain other than 
endometriosis-associated pain will be captured as concomitant medications. The pain intensity 
NRS measurement for endometriosis-associated pain in the days when these concomitant pain 
medications are used will be considered unevaluable and will be imputed by the corresponding 
average baseline measurement (i.e. assuming no improvement from baseline on those days).  
To study the dose-response relationship, the CFB to Week 12 will be plotted versus dose. A 
simple linear regression model will be fitted as a function of dose to characterize the dose-
response relationship. In case of lack-of-fit of the simple linear regression model, multivariate or 
non-linear regression models may be explored. 
 
 

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9.4.5 
Secondary Efficacy Endpoints 
Efficacy 
The analysis methods for the secondary endpoints are summarized in the table below. Details of 
model specifications and sample SAS codes will be presented in the SAP. 
Measurement of Week 24: Because the Week 24 (EOS) visit may or may not occur during 
menstruation, the measurement of Week 24 will be defined by the following 2 approaches, 
depending on the scenarios. The objective of these approaches is to capture a complete menstrual 
cycle and designate it as the EOS menstrual cycle. 
• If EOS visit occurs during menstruation, the EOS menstrual cycle is defined as the 
interval that begins from the first day of the previous menstruation to the day before the 
first day of the menstruation during which the EOS visit occurred.  
• If EOS visit occurs outside of a menstruation period, the latest menstruation period prior 
to the EOS visit will be identified.  The EOS menstrual cycle will begin at the end of the 
menstruation period immediately before the latest menstruation period to the end of the 
latest menstruation period.  
Secondary Endpoints 
Analysis Methods 
Change of NMPP measured by NRS from 
Baseline to Week 12 and 24 
ANCOVA and MMRM methods as used for 
the primary endpoint. 
CFB in the monthly mean Endometriosis 
Daily Impact Pain Scale for DYS, NMPP and 
DYSP at Week 12 and 24 
ANCOVA and MMRM methods as used for 
the primary endpoint. 
Change of DYS measured by NRS from 
Baseline to Week 24 
ANCOVA and MMRM methods as used for 
the primary endpoint. 
Change of DYSP measured NRS from 
Baseline to Week 12 and 24 
ANCOVA and MMRM methods as used for 
the primary endpoint. 
CFB by visit in permitted rescue medication 
use 
The number of medication and the percentage 
of days that permitted rescue medication is 
used will be summarized as two separate 
endpoints. Depending on the frequency of use 

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Secondary Endpoints 
Analysis Methods 
of permitted rescue medications, treatment 
comparison may be compared using an 
ANOVA with treatment and region as the 
main effects. 
The correlation between the use of rescue 
medications and the DYS and NMPP NRS 
will be explored by summary statistics and 
graphical presentations. 
Change in menstrual period heaviness 
(bleeding) from Baseline by visit 
The number and percentage of subjects in 
each category will be summarized by 
treatment group for baseline and each visit. 
Descriptive statistics for the percentage of 
days subjects had any uterine bleeding will be 
presented. 
9.4.6 
Handling of Missing Values 
For the analyses using MMRM, missing data will not be imputed. Subjects with missing data 
will not be excluded from the MMRM analysis. The validity of the missing-at-random (MAR) 
assumption for the MMRM model will be assessed when interpreting the analysis results. For 
other analyses, the Last -Observation -Carried -Forward (LOCF) method will be used for post-
baseline measurements. For subjects who prematurely discontinue before Week 12, the available 
observation corresponding to the last post-baseline visit will be carried forward to subsequent 
visits. Only the available observations in follow-up can be carried forward to Week 24. 
9.4.7 
Pooling of Investigator Centers 
Data from all investigator sites will be pooled for analysis. The analyses will not be performed 
by center and will not include adjustment for centers. 
9.4.8 
Safety Analyses 
9.4.8.1 
IMP Exposure 
Duration of exposure to IMP will be summarized descriptively for each treatment group. 

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9.4.8.2 
Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary. Treatment-emergent AEs (TEAE) will be summarized for each treatment group. 
TEAEs are defined as AEs with a start date on or after the first dose of IMP. Frequencies and 
percentages of subjects with TEAEs will be calculated for each treatment group as follows: 
• Any event 
• By system organ class, preferred term and relationship 
• By system organ class, preferred term and maximum severity 
• Any event and by system organ class and preferred term for events resulting in death 
• Any event and by system organ class and preferred term for events resulting in IMP 
discontinuation 
• Any event and by system organ class and preferred term for serious adverse events 
• Events of special interest (refer to Section 10.3.1) 
A listing by treatment group of TEAEs grouped by body system, and preferred term with subject 
ID numbers will be generated. Listings of all treatment-emergent SAEs, AEs leading to death, 
and AEs leading to discontinuation will be generated.  
9.4.8.3 
Vital signs (BP, pulse, body temperature, and RR) 
Vital signs will be summarized descriptively for each treatment group at each visit. The 
within-group changes from baseline to each visit will be summarized and will be tested with a 
paired t-test for continuous measurements. The between-group difference will be compared with 
an ANOVA. Two-sided 95% CI will be constructed for the differences between each of the 
treatment groups and the placebo group in CFB. 
9.4.8.4 
Physical examinations 
Physical examination findings will be summarized by treatment group and body system. 
Frequency counts and percentages will be presented. 
9.4.8.5 
Twelve-lead electrocardiogram (ECG) 
ECG parameters, i.e., heart rate (HR), RR, PR, QRS, QTcF, and QTcB will be summarized 
descriptively for each treatment group at each visit. The within-group changes from baseline to 
each visit will be summarized and will be compared with a paired t-test for continuous 

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measurements. The between-group difference will be compared with an ANOVA. Two-sided 
95% CI will be constructed for the differences between each of the HMI-115 treatment groups 
and the placebo group in CFB. The number and percentage of subjects with other clinically 
significant ECG findings will also be summarized by treatment group at each visit. 
9.4.8.6 
Clinical laboratory tests  
Clinical laboratory test results will be summarized descriptively for each treatment group at each 
visit. The within-group changes from Baseline to each visit will be summarized and will be 
compared with a paired t-test for continuous measurements. The between-group difference will 
be compared with an ANOVA. Two-sided 95% CI will be constructed for the differences 
between each of the treatment groups and the placebo group in CFB. Shift tables for changes 
from Baseline according to the normal minimum and maximum will be provided for each 
laboratory parameter. 
9.4.8.7 
DXA scan 
Bone mineral density data from dual energy X-ray absorptiometry (DXA) scan will be 
summarized descriptively for each treatment group at each visit. The within-group changes from 
baseline to each visit will be summarized and will be compared with a paired t-test for 
continuous measurements. The between-group difference will be compared with an ANOVA. 
Two-sided 95% CI will be constructed for the differences between each of the HMI-115 
treatment groups and the placebo group in CFB. 
9.4.8.8 
TVU Assessments 
TVU data will be summarized descriptively for each treatment group at each visit. Changes from 
baseline in the number and/or size of ovarian cysts, changes in endometrial thickness will be 
summarized. Abnormal findings will be listed and discussed. 
9.4.8.9 
Concomitant Medications 
Concomitant medication usage will be summarized by the number and proportion of subjects in 
each treatment group. The World Health Organization Drug Dictionary (WHO DD) will be used 
to classify prior and concomitant medications by therapeutic class and generic name based on 
Anatomical Therapeutic Chemical Classification System (ATC) code level 3. Subjects will only 
be counted once in each unique ATC Class and generic name if multiple drugs are used by a 
subject. 

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9.4.9 
Exploratory Analyses 
Quality of life: 
Quality of Life will be assessed with the HRQoL (Endometriosis Health Profile-5 [EHP-5]). 
EHP-5 data will be summarized descriptively by treatment group at each visit and will be 
compared using the MMRM and ANCOVA methods as used in for the primary endpoint. 
PGIC: 
The number and percentage of subjects in each PGIC response category will be summarized at 
each visit by treatment group. Statistical comparisons between each HMI-115 treatment group 
and placebo group in mean scores at each visit will be performed using ANOVA with treatment 
group as the fixed effect. 
The percentage of subjects with response of “Much Improved” or “Very Much Improved” will 
be summarized at each visit by treatment group, and comparison will be made between each 
HMI-115 treatment group and placebo group using a chi-square test. 
PK analysis: 
The following parameters will be calculated for the extensive PK subset and will be reported in 
the clinical study report together with listing of sparse sampling: 
• Cmax, Cthrough, tmax, AUC(0-tau), t1/2 following last dose 
• AR for both Cmax and AUC 
Phoenix® WinNonlin® Version 8.2 or later will be used to calculate PK parameters using 
non-compartmental model according to the actual blood collection time. 
The descriptive statistics of plasma concentrations will be made based on scheduled sampling 
time, and individual, average and median concentration-time curves will be separately plotted. 
PK parameters (extensive PK subset) will be summarized in descriptive statistics (mean, median, 
SD, minimum and maximum, coefficient of variation [CV%], geometric mean [GM] and 
geometric coefficient of variation [gCV%]). 
A population pharmacokinetic (popPK) model might be developed using all available PK data. 
The data analysis plan will be described in a separate document from the SAP, and the results 
will be reported separately from the clinical study report. 

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PK-PD relationship: 
An exploratory analysis of the relationship between HMI-115 plasma concentration/exposure 
(Cmax, Ctrough and/or AUC(0-tau)) and pelvic pain score measured by NRS (cyclic, non-cyclic, and 
average) as well as the side effects will be performed. Exposure parameters available for each 
subject from the non-compartmental (NCA) PK analysis or the raw PK data will be compared 
among the three groups of pelvic pain score and values of side effects. Further details will be 
provided in the SAP. In addition, the exposure-response relationship between HMI-115 exposure 
and efficacy and exposure and safety data might be explored by means of population PK-PD 
analyses. If a population PK-PD analysis is performed, the data analysis plan for the population 
PK-PD analyses will be described in a separate document from the SAP, and the results will be 
reported separately from the clinical study report. 
Immunogenicity: 
• Anti-drug antibody (ADA) and Neutralizing antibody (NABs) will be summarized 
descriptively for each group at each visit. 
9.5 Interim Analyses 
In addition to the ongoing safety data monitoring, two unblinded interim analyses of the efficacy 
data are planned. The first interim analysis will be performed after 60 subjects completed Week 
12 visits. The second interim analysis will be performed when 100 subjects completed Week 12 
visits. The objective of the interim analyses is to provide preliminary data for the planning of 
subsequent development activities, and no adjustment of significance level will be employed. 
The statistical hypotheses tests for the final analysis will be performed at the 0.05 level as 
described in Section 9.1.  These interim analyses will be performed following an interim SAP 
and will be conducted by an analysis team that is independent from the study team responsible 
for the study conduct and the final analysis.  
9.6 Data Monitoring Committee (DMC) 
In order to monitor and protect the safety of study subjects, an independent DMC will be 
established to review all study data pertaining to subjects’ safety on regular basis to adjudicate 
the overall safety of the subjects in this study. The DMC will convene to provide 
recommendations on study design and IMP based on review of unblinded safety data. In 
addition, ad-hoc DMC meetings may be called by the Sponsor at any time for review of newly 
identified safety concerns. Refer to the DMC Charter for further details. 

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10 Supporting Documentation and Operational Considerations 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines. 
o Applicable ICH Good Clinical Practice (GCP) Guidelines. 
o Applicable regional and local laws and regulations. 
o Regional subject data protection laws and regulations. 
o USA Federal Regulations, as applicable. 
• The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IEC/IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study subjects. 
• The Investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. 
o Notifying the IRB/IEC of SAE or other significant safety findings as required by 
IRB/IEC procedures. 
o Overall conduct of the study at the site and adherence to requirements of 21 CFR, 
ICH GCP guidelines, the IRB/IEC, and all other applicable local regulations. 
10.1.2 
Financial Disclosure 
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate regulatory authorities. 

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Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study. 
10.1.3 
Informed Consent Process 
The Investigator or his/her representative will explain the nature of the study to the subject or her 
legally authorized representative and answer all questions regarding the study. 
Subjects must be informed that their participation is voluntary. Subjects or their legally authorized 
representatives will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study site. 
The medical record must include a statement that written informed consent was obtained before 
the subject was enrolled in the study and the date the written consent was obtained. The authorized 
person obtaining the informed consent must also sign the ICF. 
Subjects must be re-consented to the most current version of the ICF(s) during their participation 
in the study. A copy of the ICF(s) must be provided to the subject or the subject’s legally authorized 
representative. Subjects who are rescreened are required to sign a new ICF. 
The ICF will contain a separate section (or in some cases a separate ICF for optional samples) that 
addresses the use of remaining mandatory samples for optional exploratory research (if applicable). 
The Investigator or authorized designee will explain to each subject the objectives of the 
exploratory research. Subjects will be told that they are free to refuse to participate and may 
withdraw their specimens at any time and for any reason during the storage period. A separate 
signature will be required to document a subject’s agreement to allow any remaining specimens to 
be used for exploratory research if applicable. Subject who declines to participate will not provide 
this separate signature. 
If a protocol amendment is required, the ICF may need to be revised to reflect the changes to the 
protocol. If the ICF is revised, it must be reviewed and approved by the appropriate IEC/IRB and 
signed by all subjects subsequently enrolled in the study as well as those currently enrolled in the 
study. 
10.1.4 
Data Protection 
Subjects will be assigned a unique identifier by the Sponsor. Any subject records or datasets that 
are transferred to the Sponsor will contain the identifier only; subject names or any information 
which would make the subject identifiable will not be transferred. 

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The subject must be informed that her personal study-related data will be used by the Sponsor in 
accordance with local data protection law. The level of disclosure must also be explained to the 
subject who will be required to give consent for their data to be used as described in the informed 
consent. 
The subject must be informed that her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5 
Committees Structure 
The DMC will consist of two unblinded experts in the fields of gynecology and one independent 
unblind biostatistician. Details refer to DMC charter.   
10.1.6 
Dissemination of Clinical Study Data 
A description of this clinical study will be available on http://www.clinicaltrials.gov as will the 
summary of the main study results when they are available. The clinical study and/or summary of 
main study results may also be available on other websites according to the regulations of the 
countries in which the main study is conducted. 
10.1.7 
Data Quality Assurance 
• All subject data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (e.g., laboratory data). The Investigator 
is responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Monitoring details describing strategies e.g., risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies, methods, responsibilities and 
requirements, including handling of noncompliance issues and monitoring techniques 
(central, remote, or on-site monitoring) are provided in the Monitoring Plan. 
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals (e.g., CROs). 

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• Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of subjects are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
• Records and documents, including signed ICF, pertaining to the conduct of this study must be 
retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor. 
• All data generated by the site personnel will be captured electronically at each study site 
using eCRFs. Data from external sources (such as laboratory data) will be imported into the 
database. Once the eCRF clinical data have been submitted to the central server at the 
independent data center, corrections to the data fields will be captured in an audit trail. The 
reason for change, the name of the person who performed the change, together with the time 
and date will be logged to provide an audit trail. 
• If additional corrections are needed, the responsible monitor or data manager will raise a 
query in the electronic data capture (EDC) application. The appropriate staff at the study site 
will answer queries sent to the Investigator. The name of the staff member responding to the 
query, and time and date stamp will be captured to provide an audit trail. Once all source data 
verification is complete and all queries are closed, the eCRF will be frozen. 
• The specific procedures to be used for data entry and query resolution using the EDC 
system/eCRF will be provided to study sites in a training manual. In addition, site personnel 
will receive training on the EDC system/eCRF. 
10.1.8 
Source Documents 
Source documents provide evidence for the existence of the subject and substantiate the integrity 
of the data collected. Source documents are filed at the Investigator’s site. 
Data entered in the eCRF that are transcribed from source documents must be consistent with the 
source documents or the discrepancies must be explained. The Investigator may need to request 
previous medical records or transfer records, depending on the study. Also, current medical records 
must be available. 
E-Dairy source data will come from electronic device and be interfaced into EDC. 

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10.1.9 
Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of subject. 
The first act of recruitment is the first site open and will be the study start date. 
The Sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies have 
been collected and a study site closure visit has been performed. 
The Investigator may initiate study site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor’s procedures, or GCP guidelines 
• Inadequate recruitment of subjects by the Investigator 
• Discontinuation of further IMP development 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the subject and should assure 
appropriate subject therapy and/or follow-up. 
10.1.10 
Publication Policy 
The data and information generated in this study are the exclusive property of the Sponsor and are 
confidential. Written approval from the Sponsor is required prior to disclosing any information 
related to this study. Publication of the results will be based on appropriate analyses and review of 
the completed data. Authorship will be determined based on ICMJE criteria. Publication of any 
data of this clinical trial without prior Sponsor approval is not permitted. 
10.1.11 
Protocol Approval and Amendment 
Before the start of the study, the study protocol and/or other relevant documents will be approved 
by the IEC/IRB/Competent Authorities, in accordance with local legal requirements. The Sponsor 

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must ensure that all ethical and legal requirements have been met before the first subject is enrolled 
in the study. 
This protocol is to be followed exactly. To alter the protocol, amendments must be written, receive 
approval from the appropriate personnel, and receive IRB/IEC/Competent Authority approval 
prior to implementation (if appropriate). In the US: Following approval, the protocol amendment(s) 
will be submitted to the IND under which the study is being conducted. 
Administrative changes (not affecting the subject benefit/risk ratio) may be made without the need 
for a formal amendment. All amendments will be distributed to all protocol recipients, with 
appropriate instructions. 
10.1.12 
Liability and Insurance 
The Sponsor will take out reasonable third-party liability insurance cover in accordance with all 
legal requirements. The civil liability of the Investigator, the persons instructed by him or her and 
the hospital, practice, or institute in which they are employed and the liability of the Sponsor with 
respect to financial loss due to personal injury and other damage that may arise as a result of the 
carrying out of this study are governed by the applicable law. 
The Sponsor will arrange for subjects participating in this study to be insured against financial loss 
due to personal injury caused by the pharmaceutical products being tested or by medical steps 
taken in the course of the study. 
10.1.12.1 Access to Source Data 
During the study, a monitor will make site visits to review protocol compliance, compare eCRF 
entries and individual subject’s medical records, assess drug accountability, and ensure that the 
study is being conducted according to pertinent regulatory requirements. eCRF entries will be 
verified with source documentation. The review of medical records will be performed in a manner 
to ensure that subject confidentiality is maintained. 
Checking of the eCRF entries for completeness and clarity, and cross-checking with source 
documents, will be required to monitor the progress of the study. Moreover, regulatory authorities 
of certain countries, IRBs, IECs, and/or the Sponsor’s Clinical Quality Assurance Group may wish 
to carry out such source data checks and/or on-site audit inspections. Direct access to source data 
will be required for these inspections and audits; they will be carried out giving due consideration 
to data protection and medical confidentiality. The Investigator assures CRO and the Sponsor of 
the necessary support at all times. 

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Reasonable Possibility: 
After consideration of factors including timing of the event, biologic plausibility, clinical 
judgment, and potential alternative causes, there is sufficient evidence (information) to 
suggest a causal relationship. 
No Reasonable Possibility: 
After consideration of factors including timing of the event, biologic plausibility, clinical 
judgment, and potential alternative causes, there is insufficient evidence (information) to 
suggest a causal relationship. 
• For causality assessments, events assessed as having a reasonable possibility of being 
related to the study intervention will be considered "associated." Events assessed as having 
no reasonable possibility of being related to study intervention will be considered "not 
associated." When the event is causality assessment impossible and cannot rule out 
causality, e.g., insufficient case data, the event will also be considered associated and 
revised if appropriate when accessible. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention administration 
will be considered and investigated. 
• The Investigator will also consult the Investigator’s Brochure and/or Product Information, 
for marketed products, in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred, and the Investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the Investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to Sponsor. 
• The Investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 

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assessment of the event. The Sponsor (or Sponsor’s designated agent) will be responsible for all 
information processing and reporting according to local legal requirements. Where necessary, 
Investigators will inform regulatory authorities in their own countries. 
 

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10.4 Appendix 4: Contraceptive Guidance  
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal, unless 
permanently sterile. All subjects in this study are WOCBP and must follow the contraception 
requirements below. This includes women with tubal infertility from endometriosis. 
Exception: Women who have had a documented bilateral salpingectomy or bilateral tubal 
ligation may participate in the study, but do not have to follow protocol-specified contraception 
requirements. 
Note: Documentation of bilateral salpingectomy can come from the site personnel’s review of 
the subject’s medical records, medical examination, or medical history interview. 
Contraception Requirements 
A woman is eligible to participate in the study if she meets one of the following criteria: 
• Is heterosexually abstinent; 
Note: Sexual abstinence is defined as refraining from heterosexual intercourse during the entire 
period of risk associated with the study intervention. The reliability of sexual abstinence needs to 
be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the 
subject. 
OR 
• Is heterosexually active and agrees to use two forms of the following contraception methods 
consistently and correctly during the protocol-defined time frame in inclusion and exclusion 
criteria: 
o Condoms used with spermicide (cream, spray, foam, gel, suppository, or polymer film) 
or Phexxi 
o Diaphragm used with spermicide (condom may or may not be used) or Phexxi 
o Cervical cap used with spermicide (condom may or may not be used) or Phexxi 
o Vaginal sponge impregnated with spermicide or Phexxi; used with a condom 
Note: Hormonal contraception except for sporadic use of emergency contraception is not 
permitted during the study. Male and female condoms should not be used at the same time. 
OR 
• Has undergone bilateral tubal sterilization or bilateral salpingectomy; 
OR 
• Has a vasectomized partner. 

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Note: Partner must be the sole male sexual partner of the WOCBP and the absence of sperm has 
been confirmed. If not, a two-forms method of contraception must be used. 
Subjects should avoid pregnancy from signing the consent until the completion of the study or 3 
months after the last dose of IMP, whichever is longer. 
Pregnancy Testing: Study subjects should only be included after a negative serum pregnancy 
test at Visit 1 and a negative urine pregnancy at Visit 3. Urine pregnancy testing to be done at 
Visit 3, 5, 7, 9 and 10 through home pregnancy test kit. It will be under the supervision of 
investigators and the results will be recorded in source documents, then collected in EDC. 
 
 

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10.6 Appendix 6: Numeric Pain Rating Scale (NRS) 
 
0             1            2            3           4            5            6            7            8           9          10 
 
 
     No pain           Mild pain                      Moderate pain                         Severe pain 
 
 

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10.7 Appendix 7: Patient Global Impression of Change (PGIC) 
Since I started taking the IMP, my endometriosis related pain has: 
☐ Very much improved 
☐ Much improved 
☐ Minimally improved 
☐ Not changed 
☐ Minimally worse 
☐ Much worse 
☐ Very much worse 
 
 

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10.8 Appendix 8: Endometriosis health profile (EHP-5) 
PART 1: CORE QUESTIONNAIRE 
DURING THE LAST 4 WEEKS, HOW OFTEN, BECAUSE OF YOUR ENDOMETRIOSIS, 
HAVE YOU... 
 
Never 
Rarely Sometimes 
Often 
Always 
1. 
Found it difficult to walk because  
of the pain? 
 
 
 
 
 
 
2. 
Felt as though your symptoms  
are ruling your life? 
 
 
 
 
 
 
3. 
Had mood swings? 
 
 
 
 
 
 
4. 
Felt others do not understand  
what you are going through? 
 
 
 
 
 
 
5. 
Felt your appearance has been 
affected? 
 
 
 
 
 
 
Please verify that you have checked one box for each question. 
PART 2: MODULAR QUESTIONNAIRE 
DURING THE LAST 4 WEEKS, HOW OFTEN, BECAUSE OF YOUR ENDOMETRIOSIS, 
HAVE YOU... 
 
Never 
Rarely Sometimes Often 
Always 
A. 
Been unable to carry out duties at 
work because of the pain? 
If not relevant, please check here 
 
 
   
 
 
 
 
B. 
Found it difficult to look after your 
child/children? 
If not relevant, please check here 
 
 
  
 
 
 
 
C. 
Felt worried about having intercourse 
because of the pain? 
If not relevant, please check here 
 
 
 
 
 
 
 
D. 
Felt the doctor(s) think it is all in your 
mind? 
If not relevant, please check here 
 
 
 
 
 
 
 
E. 
Felt frustrated because treatment is not 
working? 
If not relevant, please check here 
 
 
 
 
 
  
 
F. 
Felt depressed at the possibility of not 
having children/more children? 
If not relevant, please check here 
 
 
 
 
 
 
 
Please verify that you have checked one box for each question. 

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10.9 Appendix 9: Composite Pelvic Signs and Symptoms Score (CPSSS) 
 
 
A. Non-Menstrual Pelvic Pain 
None         0 
Mild           1=Occasional pelvic discomfort 
Moderate  2=Noticeable discomfort for most of the cycle 
Severe       3=Requires strong analgesics. Persists during cycle when not menstruating 
B. Dysmenorrhea 
None         0 
Mild           1=Some loss in work efficiency 
Moderate  2=In bed part of the day, occasional loss of work efficiency 
Severe       3=In bed one or more days, incapacitation 
C. Dyspareunia  
Not Applicable     Not sexually active for reasons other than endometriosis pain 
None         0 
Mild           1=Tolerated discomfort 
Moderate  2=Intercourse painful to the point of causing interdiction 
Severe       3=Avoids intercourse because of pain 
Total Pelvic Pain score (A+B+C) 
None  0           Mild  1-3           Moderate  4-6           Severe  7-9 
D. Pelvic Tenderness 
None        0 
Mild          1=Minimal tenderness on palpation 
Moderate  2= Extensive tenderness on Palpation 
Severe       3=Unable to palpate because of tenderness 
E. Induration 
None         0 
Mild           1=Uterus freely mobile, induration in the cul-de-sac 
Moderate  2=Thickened and indurated adnexa and cul-de-sac, restricted uterine mobility 
Severe       3=Nodular adnexa and cul-de-sac, uterus frequently frozen 
Total Physical Sign Score (D+E) 
None  0           Mild  1-2           Moderate  3-4           Severe  5-6 
Total Symptom and Sign Severity Score (A+B+C+ D+E) 
None  0      Mild  1-2      Moderate  3-5      Severe  6-10      very severe  11-15 

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10.10 Appendix 10.10 Procedures that allowed to be repeated during 
screening period 
Procedures 
Repeat timeframe 
Precautions  
Blood pressure 
Could be repeated once with 
the timeframe of ≤7 days  
For those who the abnormal 
results indicate any ongoing 
or underlying severe disorder 
that require further 
intervention, the repeat 
examinations may not be 
appropriate to perform 
Hematology 
Coagulation  
Clinical Chemistry 
Urinalysis 
eGFR 
ECG 
Urine drug screen 
Could be repeated once upon 
the investigators’ discretion 
 
TVU 
Could be repeated once upon 
the investigators’ discretion  
 
Cervical cytology 
Could be repeated once upon 
the investigators’ discretion 
In the case of an 
unsatisfactory sample only 
Body weight  
Could be repeated once 
before having DXA scan 
It is for the requirement of 
DXA equipment 
Reasons for the repeat should be documented in detail and the investigator should make the final 
decision for the eligibility of the subjects based on the repeat outcome. 
Note: Repeat procedures is not rescreening. Repeat procedures include but not limited to the 
upper items as per the investigator’s discretion. 
 
 

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10.11 Appendix 11: Abbreviations and Trademarks 
ADA 
AE 
AESI 
Anti-Drug Antibody 
Adverse event 
Adverse event of special interest 
ALT 
Alanine transaminase 
ANCOVA 
APTT 
Analysis of covariance 
Activated partial thromboplastin time 
AR 
Accumulation ratio 
AST 
Aspartate transaminase 
ATC 
Anatomical therapeutic chemical classification system 
AUC(0-tau) 
Area under the curve of plasma concentrations vs time for the dosing interval 
BMI 
BMD 
BP 
BUN 
BSAP 
Body mass index 
Bone mineral density 
Blood pressure 
Blood urea nitrogen 
Bone specific alkaline phosphatase 
CI 
Confidence interval 
CFB 
Change from baseline 
COVID-19 
Coronavirus disease 2019 
CRF 
Case report form(s) (paper or electronic as appropriate for this study) 
CKD EPI 
Chronic kidney disease epidemiology 
Cmax 
Maximum concentration 
CPSSS 
Composite pelvic signs and symptoms score 
CRO 
Contract research organization 
Ctrough 
CTX 
Concentration before dosing during multiple dose administration 
C-terminal telopeptide of type 1 collagen 
CV 
Coefficient of variation 
DBP 
Diastolic blood pressure 
DXA 
DHEAS 
Dual energy X-ray absorptiometry 
Dehydroepiandrosterone-sulfate 
DMC 
Data monitoring committee 
DYS 
Dysmenorrhea 
DYSP 
Dyspareunia 
ECG 
ECMO 
Electrocardiogram 
Extracorporeal membrane oxygenation 
eCRF 
Electronic case report form 

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eDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
EHP-5 
Endometriosis health profile-5 
ELISA 
Enzyme-linked immunosorbent assay 
EOT 
End of treatment 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FiH 
FT3 
FT4 
FSH 
First-in-Human 
Free triiodothyronine 
Free thyroxine 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GnRH 
Gonadotropin-releasing hormone 
HAV-IgM 
Hepatitis A Virus Immunoglobulin M 
HBsAg 
Hepatitis B surface antigen 
HBcAb 
Hepatitis B core antibody 
HCV RNA 
hepatitis C virus RNA 
ICE 
Intercurrent event 
ICF 
informed consent form 
IUD 
Intra-uterine device 
HIV 
Human Immunodeficiency Virus 
HIV Ab 
HIV Antibody 
HRQoL 
Health-Related Quality of Life 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
LSM 
least square mean  
MMRM 
Mixed-effect model repeated measures 
MRI 
NAB 
Magnetic Resonance Imaging 
Neutralizing antibody  
NOAEL 
No Observed Adverse Effect Level 
NMPP 
Non-Menstrual Pelvic Pain 
NRS 
Numeric Rating Scales 
NSAIDs 
Non-steroidal anti-inflammatory drugs 

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P1NP 
Procollagen type 1N-terminal propertied 
PD 
Pharmacodynamic(s) 
PGIC 
Patient Global Impression of Change 
PK 
Pharmacokinetic(s) 
POPPK 
Population pharmacokinetics 
PPS 
Per protocol analysis set 
PRL 
Prolactin 
PRLR 
Prolactin receptor 
PVC 
Premature ventricular contraction  
QTc 
QT interval corrected for heart rate 
QTcB 
QT interval corrected for heart rate using Bazett’s correction formula 
QTcF 
QT interval corrected for heart rate using Fridericia’s correction formula 
Q2W 
Once every two weeks 
Q4W 
Once every 4 weeks 
RT-PCR 
Real-time reverse transcriptase polymerase chain reaction 
SARS-
CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SoA 
Schedule of activities 
RNA 
Ribonucleic acid 
SBP 
Systolic blood pressure 
s.c. 
Subcutaneous 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SERM 
Selective estrogen receptor modulators 
SoA 
Schedule of activities 
SS 
Steady state 
SUSAR 
Suspected unexpected serious adverse reaction 
TOC 
Table of contents 
T1/2 
Elimination half-life  
Tmax 
The time to reach maximum (peak) plasma, blood, serum, or other body fluid 
drug concentration 
TVU 
Transvaginal ultrasound 
USA 
United States of America 
V 
Visit 
WHO 
World Health Organization 
WOCBP 
Woman of childbearing potential 

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Declaration of the Investigator 
Title: A Randomized, Multicenter, Double-Blind, Placebo-Controlled Phase 2 Study to Evaluate 
the Safety and Efficacy of HMI-115 in Women with Moderate to severe Endometriosis-
Associated Pain Over a 12-Week Treatment Period. 
All documentation for this study that is supplied to me and that has not been previously published 
will be kept in the strictest confidence. This documentation includes this study protocol, 
Investigator's Brochure, CRFs/ electronic CRF (eCRF), and other scientific data. 
The study will not be commenced without the prior written approval of a properly constituted 
Institutional Review Board (IRB) or Independent Ethic Committee (IEC). No changes will be 
made to the study protocol without the prior written approval of the Sponsor and the IRB or IEC, 
except where necessary to eliminate an immediate hazard to the subjects. 
I have read and understood and agree to abide by all the conditions and instructions contained in 
this protocol. 
Responsible Investigator of the Local Study Center 
 
_____________________________________ 
_____________________ 
Signature 
Date 
_____________________________________                                                                                                       
Name (block letters)  
_____________________________________ 
Title (block letters) 
_____________________________________ 
Institution (block letters) 
 
 

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11 References 
1. Clinical Study Report (PH-39176). BAY 1158061/16288. A multi-center, randomized, double-blind, placebo 
controlled first-in-man study to investigate the safety, tolerability and pharmacokinetics of the monoclonal 
antibody BAY 1158061 following single and repeated subcutaneous administration to healthy postmenopausal 
women. Date of report: 07 August 20107. 
2. Leibson CL, Good AE, Hass SL, Ransom J, Yawn BP, O'Fallon WM, and Melton LJ 3rd. Incidence and 
characterization of diagnosed endometriosis in a geographically defined population. Fertil Steril. 2004;82:314–
21. 
3. Gylfason JT, Kristjansson KA, Sverrisdottir G, Jonsdottir K, Rafnsson V, and Geirsson RT. Pelvic endometriosis 
diagnosed in an entire nation over 20 years. Am J Epidemiol. 2010; 172:237–43. 
4. Ferrero S, Arena E, Morando A, Remorgida V. Prevalence of newly diagnosed endometriosis in women attending 
the general practitioner. Int J Gynaecol Obstet. 2010; 110:203–7.9. 
5. Houston DE, Noller KL, Melton LJ 3rd, Selwyn BJ, and Hardy RJ. Incidence of pelvic endometriosis in Rochester, 
Minnesota, 1970–1979. Am J Epidemiol. 1987; 125:959–69. 
6. Eggert J, Li X, and Sundquist K. Country of birth and hospitalization for pelvic inflammatory disease, ectopic 
pregnancy, endometriosis, and infertility: a nationwide study of 2 million women in Sweden. Fertil Steril. 2008; 
90:1019–25. 
7. Guo S.W. Recurrence of endometriosis and its control. Hum. Reprod. Update. 2009;15:441–461. 
8. Newey PJ, Gorvin CM, Cleland SJ, et al. Mutant prolactin receptor and familial hyperprolactinemia. N Engl J 
Med 2013;369: 2012-20. 
9. Vincent Goffin, Philippe Touraine. The prolactin receptor as a therapeutic target in human diseases: browsing 
new potential indications. Expert Opin. Ther. Targets. 2015; 19(9):1229-44. 
10. Chen Y, Moutal A, Navratilova E, Kopruszinski C, Yue X, Ikegami M, Chow M, Kanazawa I, Bellampalli SS, 
Xie J, Patwardhan A, Rice K, Fields H, Akopian A, Neugebauer V, Dodick D, Khanna R, Porreca F. The prolactin 
receptor long isoform regulates nociceptor sensitization and opioid-induced hyperalgesia selectively in females. 
Sci Transl Med. 2020 Feb 5;12(529):eaay7550. 
11. Guidance on the Management of Clinical Trials during the COVID 19 (Coronavirus) pandemic, EMA, Version 
5 (10/02/2022). Reference the most up-to-date version, see 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/guidanceclinicaltrials_covid19_en.pdf. 
12. FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency, 
August 2021. Reference the most up-to-date version, see https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/fda-guidance-conduct-clinical-trials-medical-products-during-covid-19-public-health-
emergency. 
13. Goshtasebi A, Nematollahzadeh M, Hariri FZ, and Montazeri A. The short form endometriosis health profile 
(EHP-5): translation and validation study of the Iranian version. J. Ovarian Res. 2011;4:1 
 
 

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12 Revision History 
Sections  
Change  
Rationale  
Version 5.0 to 
Version 6.0 
 
 
1.1 Synopsis 
3.Objectives and 
Endpoints 
Safety and tolerability endpoints 7 
from “CFB in Bone mineral density 
by Dual energy X-ray absorptiometry 
(DXA) scan at week 12” to “CFB in 
Bone mineral density by Dual energy 
X-ray absorptiometry (DXA) scan 
after 12 weeks’ treatment (at EOT 
visit)” 
 
 
Safety and tolerability endpoints 8 
from “CFB in transvaginal ultrasound 
(TVU) index (including number and 
size of ovarian cyst, thickness of 
endometrium) at week 12” to “CFB in 
transvaginal ultrasound (TVU) index 
(including number and size of ovarian 
cyst, thickness of endometrium) after 
12 weeks’ reatment (at EOT visit)” 
Keep consistence with the 
Schedule of Activities (SoA) and 
avoid ambiguity 
1.3 Schedule of 
Activities (SoA) 
Note 8 added excptions “Urine drug 
screen includes amphetamine, 
barbiturates (except for sites in 
China), benzodiazepines, 
tetrahydrocannabinol, cocaine, 
methadone, methamphetamine, 
opiates, phencyclidine, and tricyclic 
antidepressants (except for sites in 
China). 
According to the condition in 
different countries. 
 
 
 
 
 

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Added “(Virgins may be exempted 
per the investigator’s discretion)” to 
note 11. 
Added “In some circumstances, 
transrectal or transabdominal 
ultrasound is allowed per the 
investigator’s discretion.” to note 14. 
Added “(can be adjusted according to 
the condition of the site).”  To note 
“Blood draws should be performed 
before vital signs, ECG recordings 
and physical examinations at visits.” 
For ethnical reasons and regular 
clinical operations in different 
countires. 
 
 
 
According to the clinical practice 
of different sites.  
9.5 Interim 
Analyses  
A second interim analysis added. 
“The second interim analysis will be 
performed when 100 subjects 
completed Week 12 visits. The 
objective of the interim analyses is to 
provide preliminary data for the 
planning of subsequent development 
activities, and no adjustment of 
significance level will be employed.” 
“This interim analysis These interim 
analyses will be performed following 
an interim SAP and will be conducted 
by an analysis team that is 
independent from the study team 
responsible for the study conduct and 
the final analysis.” 
According to the sponsor’s 
dicision 
Version 4.0 to 
Version 5.0 
 
 
Sponsor Signatory Changed the names of signatory   
NA 

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1.1 Synopsis 
2.1 Study 
Rationale 
3 Objectives and 
Endpoints 
Removed the part of part 2 in the 
whole protocol. 
The study will have two parts: Part 1 
and Part 2. Part 1 will determine the 
safety and efficacy of HMI 115 at 60 
mg Q2W, 120 mg Q2W, and 240 mg 
Q2W. Only when the safety and 
efficacy have been evaluated by the 
Sponsor in Part 1 of the study will 
eligible subjects (new subjects) be 
admitted to Part 2 of the study. Part 2 
of the study will determine the safety 
and efficacy of HMI 115 at 480 mg 
every 4 weeks (Q4W) and Q2W. 
According to the sponsor’s 
decision. 
Deleted “For Part 1 and Part 2 of the 
Study”in the “Objectives and 
Endpoints” form. 
Keep consistency with the 
removal of Part 2 study. 
Changed the description of the 
secondary endpoints “Safety and 
tolerability”to  
2. CFB by visit in vVital signs (blood 
pressure [BP], pulse, body 
temperature, and respiratory rate 
[RR]) 
3.CFB by visit in pPhysical 
examinations 
4.Number and ratio of participants 
used cConcomitant medication 
5.CFB by visit in tTwelve-lead 
electrocardiogram (ECG) 
6.CFB by visit in cClinical laboratory 
tests (hematology, coagulation, 
clinical chemistry, urinalysis, 
hormones and CA-125) 
7.CFB in Bone mineral density by 
Dual energy X-ray absorptiometry 
(DXA) scan at week 12  
Keep consistency with the 
statements of primary endpoints 

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8.CFB in tTransvaginal ultrasound 
(TVU) index (including nNumber and 
size of oOvarian cyst, thickness of 
endometrium) at week 12   
1.1 Synopsis  
4.1 Study design 
Deleted statements of part 1 and part 
2 in the “Overall Design” section 
Keep consistency with the 
removal of Part 2 study. 
Deleted statements of part 1 and part 
2 in the “Number of Subjects” section 
Keep consistency with the 
removal of Part 2 study. 
Deleted statements of part 1 and part 
2 in the “Intervention Groups and 
Duration” section 
Keep consistency with the 
removal of Part 2 study. 
1.2 Schema 
Deleted Figure 1-2  
Deleted “Part 1” from titile of Figure 
1-1 
Keep consistency with the 
removal of Part 2 study. 
1.3 Schedule of 
Activities (SoA) 
8.6 
Pharmacokinetics 
Deleted Part 1 in “SoA for Part 1 of  
the study” 
Keep consistency with the 
removal of Part 2 study. 
Deleted “Rescue Medication Return 
for count” 
For the clinical practice 
Deleted note 4 and changed the 
numbers of the notes accordingly 
Keep consitency with the 
deletion of Part 2 study 
Deleted Table 1-2, Table 1-5, Table1-
6 and changed the number of the 
other tables accordingly, including in 
note 28 (originally 29) and section 
8.6.  
Keep consitency with the 
deletion of Part 2 study 
1.3 Schedule of 
Activities (SOA ) 
7.2 Subject 
Withdrawal from 
the Study 
Revised the note for PK and ADA 
sampling: “Note: For subjects 
discontinued from IMP or withdrawn 
from study, no additional PK and 
ADA sampling other than except 
regularEOT and EOS visits (if 
possible) areis required after IMP 
discontinuation.” 
For the clinical practice and the 
meaning of PK and ADA 
samples for subjects 
discontinued from IMP or 
withdrawn from study. 
2.3.1 Risk 
Assessment 
HMI-115 will be administered by 
injection through s.c. route in Part 1 
and Part 2 of the study. In Part 1 of 
Keep consistency with the 
removal of Part 2 study. 

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the study, the subjects will receive 
injections of HMI-115 (60 mg to 240 
mg) or placebo. and in Part 2 subject 
will receive injections of HMI 115 
480 mg or placebo. 
2.3.2 Benefit 
Assessment 
Deleted the descriptions for part 1 and 
part 2 “Part 2 of the study will be 
carried out only if limited effect is 
observed at the dose of 240 mg Q2W ” 
Keep consistency with the 
removal of Part 2 study. 
4.2 Scientific 
Rationale for 
Study Design 
Deleted “In addition, data of Part 1 of 
the study will allow for choosing 
appropriate doses for Part 2 of the 
study.” 
Keep consistency with the 
removal of Part 2 study. 
6.1 Study 
Intervention(s) 
Administered 
Deleted the projected dose of part 2 in 
Table 6-1 and deleted the notes for 
part 1 and part 2 in Table 6-1 and 
Table 6-2 
Keep consistency with the 
removal of Part 2 study. 
6.2 Preparation, 
Handling, Storage, 
and 
Accountability 
Added “Requirements for aseptic 
operation should be followed during 
IMP preparation.”  
“the reconstituted solution should be 
stored between 2°C and 8°C…” is 
revised to “the reconstituted solution 
should be stored at 2- 8°C or room 
temperature…”.  
Deleted “If the solution has been 
stored above 25°C, it must no longer 
be used for application and should 
therefore be discarded. 
According to updated 
<Investigational Products 
Preparation and Administration 
Instruction for Clinical Trial 
HMI-115EM201>, Revision 01 
8 Study 
Assessments and 
Procedures 
Deleted Table 2 in“ Study 
procedures and their timing are 
summarized in the SoA (Table 1-1 
and Table 1 2).” 
Keep consistency with the 
removal of Part 2 study. 
8.1 Efficacy 
Assessments (for 
Part 1 and Part 2) 
Deleted “(for Part 1 and Part 2)” in 
the subtitile of this part 
Keep consistency with the 
removal of Part 2 study. 
8.2.7 Dual Energy 
X-ray 
b) If the subject does not meet the 
criteria for adequate recovery on her 
Post treatment DXA may not 
reflect the effect of HMI-115 on 

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Absorptiometry 
（DXA） 
DXA scan at post-treatment month 6, 
refer to a bone specialist perform 
another DXA scan at post-treatment 
month 12 (Define adequate recovery 
as change from pre-treatment baseline 
of > -1.5% at the lumbar spine and > -
2.0% at the total hip). 
c) Refer to a bone specialist those 
subjects with change from pre
treatment baseline in BMD of ≤ 
3.0% at the lumbar spine and/or total 
hip, and/or Z-score ≤ -2.0 at any 
anatomic site at post-treatment month 
12 6 (or on their final DXA scan if 
they do not follow-up as instructed). 
The window period for EOT visit and, 
post-treatment month 6 and month 12 
DXA scan is ±14 days. 
BMD, especially after 12 
months, because after a subject 
leaves the study, she will not be 
prohibited from medications that 
influence her BMD.  
8.3.1 Patient 
Global Impression 
of Change (PGIC) 
Score 
Subjects will score the PGIC as 
shown in the SoA (refer to Table 1-1, 
and Table 1-2). 
Keep consistency with the 
removal of Part 2 study. 
9.1 Statistical 
Hypotheses 
Added “One interim analysis is 
planned. More details of the interim 
analysis are presented in Section 9.5.” 
Introduce the interim analysis. 
9.2 Sample Size 
Determination 
Deleted the paragraph of sample size 
for part 2 and revised “152 eligible 
subjects will be randomly assigned to 
HMI-115 or placebo group and 136 
evaluable subjects for an estimated 
total of 34 evaluable subjects per 
treatment group in Part 1. Sample 
sizes for Part 1 and Part 2 are planned 
separately.” 
Keep consistency with the 
removal of Part 2 study. 
9.4 Statistical 
Analyses 
The SAP will be finalized prior to 
database lock and unblinding of Part 
1. 
Clarify the time for SAP 
finalization. 
9.4.1 General 
Considerations 
All study data will be summarized by 
treatment group using descriptive 
Keep consistency with the 
removal of Part 2 study. 

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statistics for Part 1 and Part 2 of the 
study. 
9.4.3 Estimand 
Deleted “The intercurrent events 
considered include 1) use of rescue 
medication, and 2) missing values 
during the study, and 3) missing 
values due to early discontinuation of 
HMI-115 .” 
Described with more details in 
the following paragraphs. 
9.5 Interim 
Analysis 
Deleted the original statements and 
added the interim analysis. “In 
addition to the ongoing safety data 
monitoring, one unblinded interim 
analysis of the efficacy data is 
planned after 60 subjects completed 
Week 12 visits. The objective of the 
interim analysis is to provide 
preliminary data, and no adjustment 
of significance level will be 
employed. The statistical hypotheses 
tests for the final analysis will be 
performed at the 0.05 level as 
described in Section 9.1.  This interim 
analysis will be performed by an 
analysis team that is independent 
from the study team responsible for 
the study conduct and the final 
analysis.” 
According to the sponsor’s 
decision 
Others 
Corrected typographical errors and 
other minor edits for consistency 
NA 
Version 3.2 to 
Version 4.0 
 
 
1.3 Schedule of 
Activities (SoA) 
Deleted the test for Covid-19 
infection delete footnote 17 and 
accordingly revised other order 
numbers  
According to the global COVID-
19 situation and change in 
exclusion criteria 
Added “for count” after “Rescue 
medication return” 
Clarify the reason for the rescue 
medication return 

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2.3.1 Table 2 1. 
Risk Assessment 
Revised “In the 26-week toxicity 
study in male and female cynomolgus 
monkeys treated with 24 and 100 
mg/kg of HMI-115 weekly, no HMI-
115 related changes were noted in 
hormone detection (testosterone, 
estradiol and progesterone) 
throughout the study.” from 
mitigation strategy to Summary of 
Data/Rationale for Risk. 
Adjust the content to a more 
proper place 
Clarify the source of “minimal 
reversible atrophy of the mammary 
gland”. 
Clarify the source of this risk  
2.3.1.1 Risk 
Assessment for 
COVID-19 
Pandemic 
Modified “Appropriate measures have 
been implemented into this protocol 
to detect COVID 19 disease to 
confirm eligibility of subjects and to 
safely conduct the study.” 
According to the change of the 
exclusion criteria 
Deleted “In addition, subjects will be 
asked if they have been exposure to a 
person who has tested positive for 
SARS CoV 2.” 
According to the change of the 
exclusion criteria 
5.1 Inclusion 
Criteria 
Added“11. 
Subject who is willing 
to limit alcohol consumption during 
the study to no more than 
approximately one alcoholic drink or 
equivalent [beer (354 mL/12 ounces), 
wine (118 mL/4 ounces), or distilled 
spirits (29.5 mL/1 ounce)] per day.” 
According to FDA reviewer’s 
comments  
5.2 Exclusion 
Criteria 
 
Deleted “1. Subject has a positive 
RT-PCR test for SARS-CoV-2 at the 
Screening Visit or prior to 
randomization” 
According to the global COVID-
19 situation 
Modified the criterion 2 from 
“Subject has clinical signs and 
symptoms consistent with SARS-CoV-
2 infection, e.g., fever, dry cough, 
dyspnea, sore throat, fatigue, loss of 
smell or taste, confirmed with positive 
SARS-CoV-2 test result within 4 
weeks prior to Screening or 
randomization.”to“Subject with 
confirmed SARS-CoV-2 infection 
According to the global COVID-
19 situation 

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within 2 weeks prior to Screening or 
randomization.” 
Deleted“4. Recent (within 14 days 
prior to screening or randomization) 
exposure to someone who has COVID-
19 symptoms or positive test result” 
According to the global COVID-
19 situation 
30. Added “has a history of suicide 
attempts or…” 
According to FDA reviewer’s 
comments and recommendations 
5.3.1Prolactin 
Sampling 
Modified this section to “Prior to PRL 
sampling, the subject must be 
examined and instructed  to avoid PRL 
influencing factors such as 
emotional/physical stress, high-protein 
meals, all forms of chest and breast 
stimulation, including sexual activity 
and impact exercises such as 
running/jogging (these factors should 
be avoided on the morning prior to 
blood sampling), or any medication 
influencing PRL levels (refer to 
Section 6.5.2).” 
Clarify the activities which should 
be avoided before prolactin 
sampling and the subject should 
be instructed to avoid these 
activities. 
5.3.3 Alcohol 
Restrictions 
Deleted this section 
Added this criterion to inclusion 
criteria 11. 
 

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6.5.2 Prohibited 
Medications 
10.5 Appendix 5 
Added “Cannabinoids” to the list of 
prohibited medications and added 
washout period in Appendix 5 
 
According to FDA reviewer’s 
comments  
8.2.1 Physical 
Examinations 
Added “(including extra-ocular 
movements)” in the brief physical 
examination of HEENT 
 
According to FDA reviewer’s 
comments  
8.6 
Pharmacokinetics 
Added “Plasma samples collected for 
pharmacokinetics analysis will be 
retained for up to 5 years following 
study finalization for possible further 
characterization of pharmacokinetic 
profile of HMI-115 at a specialized 
laboratory.” 
Clarified the maximum storage 
time of PK samples. 
9.1Statistical 
Hypotheses 
Changed “The null hypothesis is that 
there is no difference between each 
HMI-115 treatment group and 
placebo” to“The null hypothesis is 
that there is no difference in the mean 
change of DYS at Week 12 between 
each HMI-115 treatment group and 
placebo.” 
Make the null hypothesis more 
clear 
9.2 Sample Size 
Determination 
Added “(ie, between-group 
comparison),”in “However, in the 
context of comparing an HMI-115 
treatment group versus placebo (ie, 
between-group comparison), this 
sample size will provide 80% power to 
detect a treatment difference of 1.4 
point in the CFB in DYS NRS based 
on the assumption of SD of 2.0 and a 
2-sample t-test at 0.05 significance 
level.” 
Clarify or expalain to make it 
more clear 
9.3 Table 9-1 
Population for 
Analyses  
The PK analysis set consists of all 
subjects in the Safety Analysis Set 
with at least one drug concentration 
value and adequate data to derive the 
PK parameters. have no major 
protocol deviation that could 
significantly impact PK assessment. 
Clarify the definition of PK 
analysis set  
 

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9.4.2 
Demographics and 
Baseline 
Characteristics 
Deleted “Hypotheses  testing may be 
performed to assess the comparability 
of demographics and baseline 
characteristics among the treatment 
groups.” 
Will not do this test 
9.4.3 Estimand 
Added the primary estimand and 
Intercurrent event(ICE) 
Provide more details of Estimand 
and Intercurrent event 
9.4.4 Primary 
Efficacy Endpoints 
Measurement of Baseline: changed 
from “The baseline measurement is 
defined as the average of the last 5 
weeks (35 calendar days)  during the 
Screening Period prior to Day 1.” to 
“The baseline measurements will be 
derived from the last complete 
menstruation cycle during the 
Screening Period prior to Day 1.It will 
be designated as the baseline menstrual 
cycle and is defined as the interval 
from the first day of the menstruation 
to the day before the first day of the 
next menstruation”and provided the 
two senarios. 
Measurement of Week 12: changed 
from“The Week 12 measurement will 
be the average of  the last 5 weeks 
prior to the  EOT Visit .” to 
“ Because the Week 12 (EOT) visit 
may or may not occur during 
menstruation, the measurement of 
Week 12 will be defined by the 
following 2 approaches, depending on 
the scenarios. The objective of these 
approaches is to capture a complete 
menstrual cycle and designate it as the 
EOT menstrual cycle”and 
accordingly revised related contents 
Make the baseline  and primary 
end point time period more 
reasonable as fixed duration of 
35days may include 1 and a half 
or two halves of menstrual 
bleeding periods to evaluate DYS 
which is the primary endpoint and 
may not reflect of the real pain of 
the subjects 
 

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9.4.4 Primary 
Efficacy Endpoints 
Deleted “The time frame for a visit for 
which the rescue medication use will 
be attributed to is defined as the 5 
weeks (35calendar days) preceding the 
EOT visit for the ANCOVA analysis.” 
According to the change of time 
frame for EOT menstrual cycle 
9.4.5 Secondary 
Efficacy Endpoints 
Added the Measurement of Week 24 
Keep consistency with primary 
endpoints 
9.4.6 Handling of 
Missing Values 
For other analyses, the Last  
Observation  Carried  Forward (LOCF) 
method will be used for post-baseline 
measurements. Added “for post-
baseline measurements.” 
Added “Only the available 
observations in follow-up can be 
carried forward to Week 24.” 
Clarify the method of handling 
missing values 
10.2 Appendix 2: 
Clinical Laboratory 
Tests 
Modified “Protocol-Required Safety 
Laboratory Assessments” to “Protocol-
Referred Safety Laboratory 
Assessments” 
For the convenience of 
implementation in different 
countries 
10.3.1 Definition 
of AE 
Modified from “Change in vision (and 
particularly loss of peripheral vision) 
includes dim, dark, or blurred vision in 
one or both eyes or double vision or 
diminished peripheral vision to both 
sides, etc.” to “Change in vision (and 
particularly loss of peripheral vision) 
includes dim, dark, or blurred vision or 
diminished peripheral vision in one or 
both eyes or double vision or 
diminished peripheral vision on one or 
both sides, etc.” 
According to FDA reviewer’s 
comments 
 

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10.3.3  Recording 
and Follow up of 
AE and SAE 
Deleted “potential exposure” in 
“Adverse event questioning will 
include specific questions regarding 
symptoms of COVID 19: fever, cough, 
dry throat, and difficulty breathing, 
and potential exposure in the past 2 
weeks.” 
Keep consistency with the 
exclusion criteria. 
 
 
 
 
 
 
Revised Assessment of Intensity from 
“Severe: An event that prevents 
normal everyday activities.” to 
“Severe: An event that is 
incapacitating with inability to work or 
do prevents normal everyday 
activities.” 
Wording change to clarify the 
word prevents and definition of 
severe AE. 
10.10 Appendix 10 Added “Repeat procedures include but 
not limited to the upper items as per 
the investigator’s discretion.” to the 
note. 
To make it more flexible 
others 
Corrected typographical errors and 
other minor edits for consistency 
NA 
Version 3.1 to 
Version 3.2 
 
 
Page 3 sponsor 
signature 
Modified the name of CMO 
Corrected the name of CMO 
Version 3.0 to 
Version 3.1 
 
 
1.1 Number of 
Subjects and 9.2 
Sample Size 
Determination  
Change from “Approximately 190 
subjects will be screened to achieve 
152 subjects randomly assigned” to 
“152 eligible subjects will be randomly 
assigned”  
The number of screened subjects 
will depend on the actual situation 
1.3 Schedule of 
Activities (SoA) 
Deleted “Medical history, current 
medical conditions” from Visit 2 
Medical conditions after Visit 1 
will be collected as AEs 
 

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1.3 Schedule of 
Activities (SoA)  
and 8.2.1 Physical 
Examinations 
Replaced “complete physical 
examination” in Visit 3 and Visit 6 
with “brief physical examination” 
Brief physical examination can 
meet the requirement for body 
check during treatment period. 
This is to simplify the procedure.  
1.3 Schedule of 
Activities (SoA) 
and 8.2.7 DXA 
Changed 1.3 annotation 14 to 
“Subjects who discontinue from IMP 
prior to week 11or become pregnant 
during the study does not require a 
DXA scan” and changed the last 
paragraph in 8.2.7 to “Subjects who 
prematurely discontinue IMP treatment 
prior to week 11 will not have a DXA 
at the EOT visit or in the Post-
treatment Follow-up Period. Subjects 
who become pregnant during the study 
will not have protocol required DXA 
scans.” 
Added clarification that pregnant 
subjects will not have DXA. 
1.3 Schedule of 
Activities (SoA) 
and 10.2 Appendix 
2: Clinical 
Laboratory Tests 
Deleted “Samples of coagulation test 
should avoid menstrual period.” from 
SOA annotation 18 and table 10-1. 
No significant difference in 
coagulation results between 
different periods of menstrual 
cycle have been identified by 
studies.  
2.3.1.1 Severe 
acute respiratory 
syndrome 
coronavirus 2 
(SARS-CoV-2) 
Changed “United States Food and 
Drug Administration (USFDA) has 
issued new guidelines” to “Both 
European Medicines Agency (EMA) 
and United States Food and Drug 
Administration (USFDA) have issued 
new guidelines” 
Added European countries as new 
study regions, then added the 
guideline accordingly. 
4.1 Overall 
Design 
Changed from “The planned study 
locations include China and United 
States of America (USA).” to “The 
planned study regions include China, 
the United States of America (USA) 
and European countries.” 
Updated to reflect the current 
study regions and to address the 
U.S. FDA’s comments about 
specifying the regions by which 
your randomization will be 
stratified. 
5.1 Inclusion 
Criteria 
Deleted 11. Subject who is willing to 
limit alcohol consumption during the 
study to no more than approximately 
one alcoholic drink or equivalent (1 
glass is approximately equivalent to: 
beer [354 mL/12 ounces], wine [118 
mL/4 ounces], or distilled spirits [29.5 
mL/1 ounce]) per day. 
Moved it to 5.3.3 lifestyle 
consideration, alcohol restrictions. 
It is more appropriate to 
considerate this requirement as 
subject’s education.  
 

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5.2 Exclusion 
Criteria 
2. Changed to “Subject has clinical 
signs and symptoms consistent with 
SARS-CoV-2 infection; e.g., fever, dry 
cough, dyspnea, sore throat, fatigue, 
loss of smell or taste, confirmed with 
positive SARS-CoV-2 test result 
within 4 weeks prior to Screening or 
any time prior to randomization.” 
To make it clear that the 
restriction is for 4 weeks prior to 
screening or 4 weeks prior to 
randomization to avoid 
misunderstanding.  
5. Changed from “Subject is …or is 
less than 6 months post-partum or 
post-abortion …” to “Subject is … or 
is less than 6 months post-partum or 3 
months post-abortion …”. 
For most post-abortion cases, 3 
months would be enough to cover 
the recovery of patient’s body 
condition. And this is the bottom 
line, the investigators could make 
decision based on the actual 
situation. 
14. Change from “Subject has a 
current history of thyroid dysfunction 
(hyper , or hypothyroidism)” to 
“Subject has a current history of 
hyperthyroidism or uncontrolled 
hypothyroidism”. 
Hypothyroidism can be controlled 
by medication and the patients’ 
thyroid function can remain stable 
for years. Subjects with controlled 
hypothyroidism can still have 
reliable study results. 
16. Added “ (e.g, congenital immune 
deficiency syndrome, or currently 
under immunosuppressive therapy, 
etc.)” behind “Subjects with 
immunocompromised status” 
To give some examples to help 
the investigators to understand the 
requirement better. 
32. Changed to “Subject has a medical 
history of confirmed psychiatric 
disorder (e.g., major depression, post-
traumatic stress disorder, 
schizophrenia, bipolar disorder) , or 
has a history of epilepsy or has suicidal 
attempt, for whom it would not be 
recommended to stop concurrent 
medication therapy or may require 
medication that prohibited during 
study participation (refer to Section 
6.5.2 and 10.5 for prohibited 
medication and washout period)” 
It is not precise to detect suicidal 
attempt without a specific 
instrument. It will be based on the 
investigators’ judgment if the 
subject’s mental status is proper 
for the study. And during the 
study, the subject’s mental status 
will be strictly monitored. 
 
34. Changed Z-score from ≤-2.0 to ≤
-1.5 
To address the U.S. FDA’s 
comments 
 

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6.5.1 Rescue 
Medications 
Table 6-3 
Added “tramadol+ acetaminophen” 
To give investigators and subjects 
more choices and improve the 
subject’s compliance. 
6.5.2 Prohibited 
Medications and 
10.5 Appendix 5: 
Washout Intervals 
Deleted “Thyroxine or Levothyroxine” 
and “Cannabinoids” from table 6-4 and 
Appendix 5 
To keep consistent with revised 
exclusion criterion 14 and 
“Cannabinoids” can be covered 
by urine drug screen 
9.3 Populations for 
Analyses  
Table 9-1 
Added “Immunogenicity analysis set/ 
The immunogenicity analysis set 
consists of all subjects in the Safety 
Analysis Set with at least one 
immunogenicity value.” in the table 
To add an analysis set 
9.4.3Estimand 
Added a paragraph to describe the 
estimand analysis 
To address the U.S. FDA’s 
comments 
9.4.4 Primary 
Efficacy Endpoints 
Added the penultimate paragraph to 
describe how to handle all analgesic 
medications taken to treat pain other 
than endometriosis-associated pain in 
efficacy analysis. 
To address the U.S. FDA’s 
comment about “Capture use of 
all analgesic medications taken to 
treat pain other than 
endometriosis-associated pain 
(EAP) (e.g. migraine). Describe 
how you will handle these 
protocol deviations in your 
efficacy analysis.” 
9.4.5 Secondary 
Efficacy Endpoints 
Added “as two separate endpoints.” To 
the end of “The number of medication 
and the percentage of days that 
permitted rescue medication is used 
will be summarized”   
To address the U.S. FDA’s 
comment about how to determine 
the overall use of rescue 
medication incorporating both 
components 
9.4.8.8 TVU 
Changed the content to “TVU data will 
be summarized descriptively for each 
treatment group at each visit. Changes 
from baseline in the number and/or 
size of ovarian cysts, changes in 
endometrial thickness will be 
summarized. Abnormal findings will be 
listed and discussed.” 
To address the U.S. FDA’s 
comment about “In your final 
clinical study report (CSR), 
include a summary of findings on 
transvaginal ultrasound reporting 
changes from baseline to end of 
study (e.g., change in the number 
and/or size of ovarian cysts, 
changes in endometrial thickness, 
and other abnormal findings).” 
10.3.1 Definition of 
AE  
Changed the definition of “Hirsutism” 
to “Hirsutism is a condition in subjects 
with excessive growth of dark or 
To address the U.S. FDA’s 
comments 
 

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Adverse Events of 
Special Interest 
(AESI) 
coarse hair in a male-like pattern —
face, chest, abdomen and back” 
Changed the definition of 
“Palpitations” to “Palpitations are 
feelings of having a fast-beating, 
fluttering or pounding heart, or single 
forceful or skipped beats that not 
caused by emotional or physical 
stimulus, exercise, other drugs or food, 
and cannot be relieved through rest or 
mental relaxation.” 
Changed the definition of “Change in 
mood or behavior” to “Change in 
mood or behavior includes abnormal 
thought, speech, and behavior after 
IMP administration compared with 
past. Such as mood extremes 
(depression or mania), new or 
worsening symptoms of anxiety or 
depression, and disorganized speech or 
behavior.” 
Changed the definition of “headache” 
to “Constant or severe headache that is 
distinctly different in quality from 
usual headaches and may be worse at 
night or in the early morning, 
including newly happened or 
worsening dull, "pressure-type" 
headaches, sharp or "stabbing" pain. 
They can be localized to a specific area 
or generalized. They can be made 
worse with coughing, sneezing or 
straining.” 
Changed the definition of “Change in 
vision” to “Change in vision (and 
particularly loss of peripheral vision) 
includes dim, dark, or blurred vision in 
one or both eyes or double vision or 
reduced diminished peripheral vision 
to both sides, etc.” 
Version 2.0 to 
Version 3.0 
 
 
 

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1.1, and 3.0 
Objectives and 
Endpoints/Study 
Design 
Change from “Quality of life” to 
“Other patient-reported outcomes” 
Made the title more appropriate 
 
1.3 Schedule of 
Activities 
(SoA) 
Table 1-1 
Annotation 5, deleted “If subjects are 
discontinued from IMP, all visits and 
procedures as outlined in the SoA till 
EOT Visit should be completed. If 
subjects withdraw from the study 
during the treatment period, the EOT 
Visit should be performed as soon as 
possible and sex hormones collection 
is not required for subjects not in 
menses cycle days 1 to 5” 
For subject who early 
discontinued from study without 
withdrawal consent, efforts will 
be made to retain the subject in 
the study until follow-up visit.  
 
 
 
 
 
 
 
Annotation 6, changed from “If the 
subjects withdraw from the study 
during the follow up period, the 
follow-up visit should be performed as 
soon as possible (sex hormones 
collection is not required for subjects 
not in menses cycle days 1 to 5).” to 
“Refer to Section 7.1 and 7.2 for the 
follow-up requirement for subjects 
who discontinue from IMP or 
withdraw from the study.” 
The detail follow-up visit 
arrangement has been updated in 
“Section 7.1 and 7.2” 
 
Annotation 8, added “after collecting 
all testing/examination data at each 
visit (except for Visit3, refer to #22)” 
just after IMP will be administered 
Q2W 
To clarify that IMP administration 
should be the performed after all 
scheduled testing/examination 
completion at each onsite visit 
Annotation 14, Change from “IMP 
discontinuation prior to week 11 does 
not require a DXA scan.” to “Subjects 
who discontinue IMP prior to week 11 
during the study does not require a 
DXA scan. For more details, including 
subjects who needs further DXA scan 
after EOT visit, refer to Section 8.2.7.” 
Added more clarification for 
DXA scan. 
Annotation 16, change from “(for 
positive anti-HCV only), and anti-HIV 
(1+2).” to “(for positive or equivocal 
Revised to reflect central lab 
classification for viral serology 
test 
 

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anti-HCV), and HIV antigen/anti-HIV 
(1+2).” 
Annotation 26,added “and additional 
training will be provided to subjects 
who have missed data entry.” to e-
Diary entries compliance will be 
assessed  
Update to ensure investigators 
will take efforts to maintain 
patient’s compliance for e-Diary 
data entry. 
Annotation 29, added “(not required 
for those who discontinued from IMP 
or withdraw from study).” 
To specify no additional sampling 
other than regular visits are 
required for those who 
discontinued from IMP 
1.3 Schedule of 
Activities 
(SoA) 
Table 1-2 
Updated in accordance with Table 1-1 To keep consist with the previous 
part 
2.2 Background 
Change from “the IB (Version 1.0, 21 
April 2021)” to “the most updated 
version of IB” 
IB have been updated 
2.3.1 Risk 
Assessment 
Table 2-1 
Added 26-week toxicity study result to 
non-clinical risk part 
Added new pre-clinical safety 
data 
4.1 Overall 
Design 
Changed from “The planned study 
locations include China and United 
States of America (USA).” to “The 
planned study locations include China, 
the United States of America (USA) 
and European countries.” 
Updated to reflect the current 
study regions 
5.1 Inclusion 
Criteria 
4. added “with” before NRS score 
To make it clearer for 
understanding 
5.2 
Exclusion 
Criteria 
20. Changed from “Subject is, at the 
time of signing informed consent, a 
user of recreational or illicit drugs or 
has had a recent history (within the last 
year) (e.g., positive urine drug 
screening result) of drug or alcohol 
abuse or dependence.” to “Subject has 
a positive result on the screening urine 
drug screen and/or has had a history of 
drug or alcohol abuse or dependence 
within the last year” 
Rephased sentence to avoid 
misunderstanding 
 

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26. Added “or” to a, in front of 
aspartate aminotransferase 
Changed “Hemoglobin <10mg/dL” to 
“Hemoglobin <10g/dL” 
To avoid misunderstanding 
To correct to a typo 
29. Changed from “(for positive anti
HCV only)” to “(for positive or 
equivocal anti-HCV)” 
Revised to reflect central lab 
classification for viral serology 
test 
32. Changed from “Subject has a 
medical history of psychiatric disorder 
at any time (e.g., depression, 
schizophrenia, bipolar disorder) or has 
a history of epilepsy.” to “Subject has 
a medical history of confirmed 
psychiatric disorder (e.g., major 
depression, post-traumatic stress 
disorder, schizophrenia, bipolar 
disorder), has a history of epilepsy or 
has suicidal attempt, for whom it 
would not be recommended to stop 
concurrent medication therapy or may 
require medication that prohibited 
during study participation (refer to 
Section 6.5.2 and 10.5 for prohibited 
medication and washout period)” 
To clarify and specify the 
definition of psychiatric disorder.  
6.5.2 Prohibited 
Medications 
Added “Medications that covered by 
urine drug screen (if applicable)” to 
table 6-4 
 
Added “If there are medications not 
listed in the table above that need 
further clarification, consult the Hope 
Medicine Medical Monitor for 
suggestions.” at the end of the section 
To exclude the relevant 
medications that may impact pain 
evaluation from study 
participation 
 
Added an instruction to 
investigators for the relevant 
situation 
 
7.1 Discontinuation 
of IMP 
Changed “the subject will remain in 
the study until EOT visit” to “…… 
until Visit 10” 
Changed “should attend all subsequent 
visits up to Visit 9” to “should attend 
all subsequent visits up to Visit 10 and 
complete all procedures (except IMP 
administration related) as outlined 
in the SoA.” 
Updated follow-up period for 
subjects who discontinued from 
IMP, collecting safety 
information during a period that 
could cover 5 half-lives of HMI-
115, further ensure subjects 
safety. 
 

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7.2 
Subject 
Withdrawal from 
the Study 
Changed from “In the event of 
withdrawn from the study during the 
treatment period, if possible, an early 
discontinuation visit (same as Visit 
9)should be conducted (refer to 
Section 1.3).” to “In the event of 
withdrawn from the study during the 
treatment period, if possible, an early 
discontinuation visit (procedures same 
as Visit 9) needs to be performed as 
soon as possible and an on-site follow-
up visit (procedures same as Visit 10) 
after 12 weeks from the last dose 
should be conducted. If the subject is 
unwilling to attend the on-site follow-
up visit, a phone call follow-up should 
be attempted if the subject agrees, to 
collect safety information (monitoring 
AE, pregnancy status, concomitant 
medications) (refer to Section 1.3).”  
 
Added “ In the event of withdrawn 
from the study during the follow-up 
period, if possible, an on-site follow-
up visit (procedures same as Visit 10) 
is recommended to complete as soon 
as possible followed by a phone call 
follow-up at 12 weeks from the last 
dose to collect safety information 
(monitoring AE, pregnancy status, 
concomitant medications). If the 
subject is unwilling to attend an on-site 
follow-up visit, a phone call follow-up 
at 12 weeks from the last dose should 
be attempted if the subject agrees 
(refer to Section 1.3).” 
Updated follow-up period for 
subjects who withdraw from 
study, collecting safety 
information during a period that 
could cover 5 half-lives of HMI-
115, further ensure subjects 
safety. 
Added “and ADA” after “no additional 
PK” 
To specify no additional sampling 
other than regular visits are 
required for those who 
discontinued from IMP 
8.1.1 Electronic-
Diary (e-Diary) 
Added “Subjects need to return the e-
diary devices after the completion of 
Added an instruction for when to 
recall the device 
 

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study participation or after withdrawal 
from the study.” 
8.2.7 Dual Energy 
X-ray 
Absorptiometry 
(DXA) 
Added “The window period for EOT 
visit, post-treatment month 6 and 
month 12 DXA scan is ±14 days.”  
To clarify the time window 
8.4.1 Time Period 
and Frequency for 
Collecting AE and 
SAE Information 
Changed “All AEs and SAEs will be 
collected from the signing of ICF until 
the follow up visit” to “…… until the 
end of study participation” 
This requirement also includes 
those who withdraw from study. 
Change the wording to avoid 
misunderstanding 
8.4.3 Follow-up of 
AEs and SAEs 
Changed “All SAEs” to “All AEs and 
SAEs” 
To clarify all AEs will be 
followed not just SAEs 
8.4.5 Pregnancy 
Changed “Details of all pregnancies in 
subjects will be collected after the start 
of study intervention until the follow
up visit or at EOT visit (in case of 
premature discontinuation of IMP).” to 
“Details of all pregnancies in subjects 
will be collected from signing of ICF 
until the end of study participation” 
Updated follow-up period for 
subjects who withdraw from 
study, collecting safety 
information during a period that 
could cover 5 half-lives of HMI-
115, further ensure subjects 
safety. 
 
 
 
8.10 
Immunogenicity 
Assessments 
Added “with one additional sampling 
point at week 17. All samples for ADA 
should be collected together with the 
corresponding PK sample.” to the first 
paragraph 
To clarify the ADA sampling 
time 
8.11 Composite 
Pelvic Signs and 
Symptoms Score 
(CPSSS) 
Added “e-Diary data or” Infront of 
CPSSS Section 1 
To add an instruction 
9.4.4 Primary 
Efficacy Endpoints 
and 9.4.5 
Secondary Efficacy 
Endpoints 
change from MMRM to ANCOVA as 
the primary analysis method  
To make it more appropriate for 
the analysis of efficacy endpoints 
9.4.8 Exploratory 
Analyses 
Deleted “PK data will be compared 
graphically and statistically” 
Added “and Neutralizing antibody 
(NABs) will be summarized 
descriptively for each group at each 
visit.” to Anti-drug antibody (ADA) 
Specific method will be described 
in SAP 
 
Completed the analysis items 
 

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10.1.8 Source 
Documents 
Added “e-Dairy source data will come 
from electronic device and be 
interfaced into EDC” in the end of this 
section 
To clarify data source for e-Dairy 
10.2 Appendix 2: 
Clinical Laboratory 
Tests 
Added “within 7 days” to SARS-CoV-
2 RT-PCR in front of prior to 
randomization 
To clarify the testing time point 
Added “※Samples of coagulation test 
should avoid menstrual period.” 
Added an instruction for 
coagulation blood sampling 
Added “PRL” in front PK and ADA 
PRL will not provide to 
investigator because of the 
potential risk for unblinding 
Added “High-dose biotin supplements 
(e.g., Vitamin B7 or H and coenzyme 
R and multivitamins) ingestion may 
interfere with some of the above 
laboratory tests and should be avoided 
at least 72 hours prior to blood 
collections.” 
Added requirement to avoid 
influence on lab tests 
10.3.1 Definition of 
AE 
Added “In clinical studies, an AE can 
include an undesirable medical 
condition occurring at any time, 
including screening or follow-up 
periods, even if no study intervention 
has been administered.” 
To clarify the record period of AE 
10.3.3 Recording 
and Follow up of 
AE and SAE 
Added “During the course of the 
study” in front of new or updated 
information will be recorded in the 
originally completed eCRF 
Added “Any AEs that are unresolved 
at last visit in the study are followed up 
by the Investigator for as long as 
medically indicated but without further 
recording in eCRF. For any patient 
with ongoing AE(s)/SAE(s) at the end 
of the study, the Sponsor retains the 
right to request additional information 
if judged necessary.” 
Added details to clarify how AEs 
should be followed 
 

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10.4 Appendix 4: 
Contraceptive 
Guidance 
Added “or Phexxi” to spermicide 
Changed “double barrier” to “two 
forms” 
To cover more choices 
To correct the definition  
Version 1.0 to 
Version 2.0 
 
 
1.1 Synopsis 
Overall 
Design 
4.1 Overall 
Design 
Adjusted screening period from 45 
days to 75 days. 
Added “screening visit 2 (at least 35 
days before V3 to ensure at least 5 
weeks baseline pain score obtained 
before randomization)” 
Remove “Baseline pain scores 
collection (5 weeks)” 
Change PK collecting time from 
“Day1 to Day 141” to “Day 1 to Day 
169” 
To cover 2 complete menstrual 
cycles (21-35 days for a cycle) to 
give all subjects adequate time to 
complete the procedures in 
screening period, including 5 
weeks baseline pain score 
obtained. 
To keep consistent with amended 
PK sample timepoint. 
1.3 SOA Table 1-
1 and Table 1-2 
Adapted the SOA table for the 
rearranged procedures.  
Add “screening V2” and remove 
“baseline V2-V4” in version 1.0 
All amendment per protocol relevant 
to the SOA table is revised 
accordingly 
Since screening period extend to 
75 days, to make operation 
feasible and convenience for 
subjects screening, visit 
frequency and relevant test are 
revised accordingly. 
1.3 SOA Table 1-
4 and Table 1-6 
Added “Day1 pre-dose” sampling 
timepoint to sparse PK sub-group; 
Correct an omission 
1.3 SOA Table 1-
3 to 1-6 
Added “Week 25, Day 169” to 
intensive and sparse PK sampling 
schedules 
To determine HMI-115 fully 
elimination and understand if  
 

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PRL levels return to baseline 
when HMI-115 fully eliminated. 
2.3.1 Risk 
Assessment 
Table 2-1 
 
 
 
Revises the mitigation strategy of 
“clinical risk immune function” to 
“Careful monitoring of subjects for 
any ongoing, subclinical disease 
infection and exclusion of patients 
with existing infection 
immunosuppression”. 
Clarify and specify to monitor 
“infection” and exclude subjects 
with existing 
immunosuppression. 
Clinical risk of “PRLR blockage may 
induce PRL over section”: Revised to 
“Increased PRL may cause disorder 
in the secretion of other sex hormones 
and dopamine and further induce 
conditions such as galactorrhea, 
change in menstrual cycles with 
oligo- or amenorrhea, hirsutism, acne, 
change in mood, etc.  
However, considering the blockade of 
PRLR by HMI-115, the above 
conditions are very unlikely to be 
induced by HMI-115.  
Collect galactorrhea, change in 
menstrual cycles with oligo- or 
amenorrhea, Hirsutism, Acne, change 
in mood, etc., as adverse event of 
special interests (AESIs). Refer to 
Section 10.3.1. 
Add as supplemental instruction 
for PRLR blockade outcome.  
Theoretically, PRLR blockage 
will increase PRL and further 
may increase dopamine, however 
PRLR already has been blocked. 
All listed potential risks are more 
conceptional but need to monitor 
during study period. 
 
“Non-Clinical Risk- Bone cell 
metabolism, mitigation strategy”: 
modified to “Monitoring by CTX, 
Monitor biomarkers of bone 
formation/resorption to 
supplementally assess impact of 
 

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P1NP, BSAP and DXA scan. Refer to 
Section 8.2.7 for details on DXA 
scan.” 
bone cell metabolism on top of 
BMD examination by DXA. No 
BMD impact had been 
demonstrated by 26 weeks 
toxicity study in cynomolgus 
monkey. Added biomarker plus 
DXA will provide evidence of 
no bone metabolism impact by 
HMI-115. 
2.3.1.1 Severe 
acute respiratory 
syndrome 
coronavirus 2 
(SARS-CoV-2) 
Risk Assessment 
for COVID-19 
Pandemic 
Confirmation of COVID-19 infection 
by optional laboratory assessment 
will be conducted based on 
availability (test capacity and 
turnaround time) of approved tests 
and on Investigator’s discretion 
and/or local requirements and/or 
policy 
The measures may be adjusted 
according to local laws and/or policy. 
Considering COVID-19 complex 
and dynamic management policy 
among different countries and 
regions, investigators should 
follow local requirement and 
policy. 
4.1 Overall 
Design 
Delete “conduct at selected sites” for 
intensive PK subjects’ selection 
The subjects in intensive PK 
subset will be subjects who 
consent to perform intensive PK 
from any study sites. 
An e-Diary will be dispensed, and 
training will be provided to subjects 
at the baseline Visit (Visit 2) on how 
to record endometriosis-associated 
pain, uterine bleeding, and analgesic 
rescue medication use for 
endometriosis-associated pain on a 
daily basis 
The baseline visits were 
designed in Protocol version 1.0 
has been removed and replaced 
by screening visit 2, all relevant 
information revised accordingly. 
Rescue analgesic medication will 
be dispensed at Visit 2, clarify it 
is rescue medication to be 
recorded in diary, not all 
 

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analgesic for pain other than 
endometriosis-associated. 
5.1 inclusion 
criteria 
Inclusion criterion #5: add note 
“subject with BI-RADS Classification 
1 – 3 is eligible for randomization” 
To specify normal results 
accepted for enrollment 
Deleted original #6 “Subject has not 
used hormonal therapies or 
medications associated with bone loss 
within the required time periods as 
per Section10.5.” 
Integrated it with exclusion criterion 
#24 
Subject has used medications such as 
hormones, analgesics, medications 
associated with bone loss, products 
that affect PRL levels, etc. within 
specific time window before 
Screening (refer to Section 10.5). 
To make criteria simpler for 
reading 
Change #7 to “Subject agrees to use 
required (nonhormonal) birth control 
methods during the entire length of 
participation in the study (refer to 
Section 10.4) and agrees to avoid 
pregnancy from signing the consent 
until 3 months after the last dose of 
IMP” 
Give timeframe for pregnancy 
prohibition 
after 
treatment 
discontinuation 
5.2 exclusion 
criteria 
Revised #8, remove endometrial 
biopsy 
Subject has clinically significant 
gynecologic condition identified on 
Endometrioma belongs to 
endometriosis and the size can 
vary along with menstrual cycle. 
It could be at the investigators’ 
discretion to eliminate subjects 
 

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Screening TVU or endometrial biopsy 
other than endometriosis, (including 
but not limited to: complex ovarian  
a. cyst >3 cm or simple ovarian 
cyst >5 cm (except confirmed 
endometrioma) that persists on 
repeat TVU; clinically significant 
endometrial pathology; or  
b. single fibroid ≥ 4 cm or multiple 
[> 4] fibroids that measure ≥
2 cm OR or symptomatic 
submucosal fibroid of any size on 
screening TVU  
c. Any ovarian tumors or pelvic 
masses of unclear etiology 
requiring further diagnostic 
procedures  
d. acute or chronic endometritis.  
with endometrioma of any size 
based on safety concerns.  
Endometrial biopsy is 
invasive.HMI-115 does not show 
any potential in increasing the 
risk in the development of 
endometrium malignancy from 
its MOA and previous studies 
data. It is also very unlikely that 
endometrial pathology will be 
deteriorated during short study 
period. If the subject has 
significant abnormality with 
their endometrium, there would 
be signs or symptoms and such 
abnormality could be detected 
through TVU. The subjects can 
seek for medical help whenever 
they find anything abnormal 
during the study period. 
Any ovarian tumors or pelvic 
masses of unclear etiology 
requiring further diagnostic 
procedures should be excluded. 
Revised #13 and #14 
Subject has known any history of 
anterior pituitary, posterior pituitary 
or hypothalamic dysfunction, 
including but not limited to 
hyperprolactinemia prolactinomas, 
hypogonadism, growth hormone 
deficiency.  
Adopted the U.S. FDA 
suggestions 
 

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Subject has a current history of 
thyroid dysfunction (hyper-, or 
hypothyroidism), hypogonadism, 
growth hormone deficiency. 
Deleted original #16 “Subjects has 
family history of breast cancer or 
known breast cancer susceptibility 
gene (BRCA) mutation in her first-
degree relatives.” 
HMI-115 doesn’t have the 
potential to increase the risk of 
breast cancer based on the MOA 
and pre-clinical studies data. 
Measures have been taken to 
exclude subject with exist breast 
tumor from study including 
breast examination, and 
mammography for aged 40 and 
over. 
Removed “family history of 
prolactinomas” in #17 
Prolactinoma is not an inherited 
disorder, and it has been moved 
to integrate with #13 
Added “(e.g., positive urine drug 
screening result)” to #20 
To help with the judgement of 
drug abuse  
Changed DBP in #21 from > 95 
mmHg to > 99 mmHg 
We used  the lower limit for 
stage II hypertension (SBP≥
160mmHg and/or DBP≥100 
mmHg ) from "hypertension 
Prevention and Cure Guideline 
of China" as the reference to 
define subjects with uncontrolled 
hypertension.  
Chang ALT/AST requirement from 
≥150% to ≥200% in #26a.  
To keep consistent among HMI-
115 clinical programs. 
 

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Deleted “white blood cell count < 
2500 mm3” in #26b 
Changed “Papanicolaou test” to 
“cervical cytology” in #27 
Provided more choices for 
different sites to perform this test 
in case Pap is not available in 
some sites. 
Modified #34 
Subject has a history of osteoporosis 
or other metabolic bone disease, or 
including any one or more of the 
following: 
a. Low bone mass (Z-score ≤ -2.0 
on screening DXA scan [lumbar 
spine, femoral neck or total hip 
BMD]) OR  
b. Body weight greater than 300 
pounds or 136 kilograms (due to 
limits of DXA scanners) or 
Subject has any condition that 
would interfere with obtaining 
adequate DXA measurements 
(e.g., history of spinal surgery, 
spinal hardware, severe scoliosis) 
or artifact overlying the region of 
interest, including umbilical ring 
with refusal to remove) 
c. History of fragility fracture OR  
d. History or presence of an unstable 
condition that is associated with a 
decrease in BMD (e.g., 
Adopted the suggestions from 
the U.S. FDA. to ensure the 
availability and reliable of DXA 
result. 
 

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uncontrolled hyperthyroidism, 
uncontrolled 
hyperparathyroidism, anorexia 
nervosa) 
Added “Procedures that allowed to be 
repeated are listed in section 10.10”   
in the end of exclusion criteria section 
To remind the investigators that 
some procedures could be 
repeated to enhance the 
possibility of subject 
recruitment. 
6.1 Study 
Intervention(s) 
Administered 
Added instructions of IMP 
administration under table 6-2 
To guide the injection of IMP to 
mitigate injection site reactions 
6.2 Preparation, 
Handling, Storage, 
and 
Accountability 
Changed storage time from 6 hours to 
4 hours. 
Because microbial growth has in 
some cases been detected by 4 
hours at 2-8°C following 
preparation for administration 
6.5.2 Prohibited 
Medications 
Added “If a hormonal emergency 
contraception is used, the use of the 
drug and any associated menstrual 
cycle irregularity after the use should 
be documented” under table 6-4. 
Adopted the suggestions from 
the U.S. FDA 
7 Discontinuation 
of IMP and 
Subject 
Withdrawal 
Reordered the contents in this section.  
Adjusted the study pauses for safety 
reason (refer to section 7.3) 
To make it easier to read and 
understand. 
Adopted the suggestions from 
the U.S. FDA 
8.1.4 
Endometriosis 
Daily Impact Pain 
Scale 
Added “(last calendar day)” to last 24 
hours 
Add as a supplemental 
instruction 
 

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8.2.1 Physical 
Examinations 
Adjusted the visit numbers for 
physical examinations 
Visit 1, Visit 53, Visit 86, Visit 119 
and Visit 1210 
Adjusted according to the 
adjusted overall procedures 
8.2.3 Pelvic 
examination 
Newly add section 
To specify the pelvic 
examination to be operated and 
recorded by investigators 
8.2.6
 
Transvagina
l Ultrasound 
(TVU) 
Assessments 
Change from “Significant ovarian 
findings on TVU include complex 
ovarian cyst > 3 cm or simple ovarian 
cyst > 5 cm. For the purposes of this 
study, an ovarian cyst whose 
appearance is consistent with an 
endometrioma will be considered to 
be complex” to “The Screening TVU 
may be repeated per protocol (e.g., 
ovarian cyst criteria) or as clinically 
appropriate. An unscheduled 
(elective) TVU may also be performed 
as clinically indicated for subject 
evaluation during the course of the 
study”. 
Modified according to update in 
eligibility criteria section 
8.2.7 Dual energy 
X-ray 
absorptiometry 
（DXA） 
Adjusted monitoring criteria and 
procedure for DXA 
Added “Subjects who prematurely 
discontinue treatment prior to week 
11 will not have a DXA at the EOT 
visit or in the Post-treatment Follow-
up Period” 
Adopt the suggestions from the 
U.S. FDA  
HMI-115 is unlikely to induce 
bone loss from its MOA and 
previous studies data. Treatment 
less than 3 months is very short 
and unlikely to detect any 
changes through DXA. 
 

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8.11 CPSSS 
Delete “from a 28 day recall period” 
To make it more flexible to 
cover longer menses cycle (for 
instance 35 days) 
9.3.1 Variables 
for Stratification 
of Randomization 
This study employs a stratified 
randomization withregion (China, 
United States) being the only two 
stratification factors: 1) region 2) 
participation in the intensive PK 
sampling subset (Yes, No). These 
stratification factors will be taken into 
account in the statistical analyses. 
Add stratum of intensive PK to 
ensure subject in this subset will 
be well distributed by treatment 
arm. 
9.4.3 Primary 
Efficacy 
Endpoints 
Added “The time frame for a visit for 
which the rescue medication use will 
be attributed to is defined as 5 weeks 
(35 calendar days) preceding the 
visit.” 
To clarify the timeframe of 
rescue medication information to 
be collected for analysis 
9.4.7.7 DXA scan 
Change “bone marrow density” to 
“bone mineral density” 
Corrected a typo 
10.1.5
 
Committees 
Structure 
Changed DMC members to “two 
unblinded experts in the fields of 
gynecology and one independent 
unblind biostatistician”. Details see 
DMC charter. 
Remove “The DMC meeting will also 
include an unblinded Sponsor 
clinician and an unblinded Sponsor 
statistician. Unblinded Sponsor 
representatives will be independent of 
the study, and study personnel will 
remain blinded”. 
To make committee member as 
odd for voting and easy to make 
conclusion 
 

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10.2 Appendix 2: 
Clinical 
Laboratory Tests 
Adjusted the contents and some 
sampling requirements: 
Add “CTX, P1NP and BSAP 
(exploratory)” 
Add instruction that testing for 
COVID-19 should follow local 
requirement 
Adjusted according to other parts 
in the protocol 
10.3.1 Definition 
of AE 
Combined original 10.3.3 AESI to 
this part and give specific instruction. 
Adopted the suggestions from 
the U.S. FDA 
Added “Symptoms of dopamine 
withdrawal” 
Adopted the suggestions from 
the U.S.FDA 
10.3.4 Reporting 
of SAE 
Change from 10.3.5 to 10.3.4 
Deleted contacts which will be 
present in study safety management 
plan. 
To make operation flexible, 
revised PV contact information 
as it may be updated during 
study ongoing and different by 
country. 
10.4 Appendix 4 
Delete “and Collection of Pregnancy 
Information” from the headline 
The corresponding contents are 
in section 8.4.5 
Add “Subjects should avoid 
pregnancy from signing the consent 
until the completion of the study or 3 
months after the last dose of IMP, 
whichever is longer.” 
Change descriptions on urine 
pregnancy testing: 
Study subjects should only be 
included after a negative serum 
pregnancy test at Visit 1 and a 
negative urine pregnancy at Visit 3. 
Clarify the timeframe that the 
subjects should avoid being 
pregnant 
Ensure pregnancy test can be 
well performed and well 
documented at site level. 
 

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Urine pregnancy testing to be done 
monthly thereafter at Visit 3, 5, 7, 9 
and 10 through home pregnancy test 
kit. It will be under the supervision of 
investigators and the results will be 
recorded in source documents, then 
collected in EDC. 
10.5 Appendix 5: 
Washout Intervals 
Add “Note: The drugs above should 
not be withdrawn by the investigator 
if used for treatment purposes, but 
rather the washout period may be 
used if the prescriber recommends 
discontinuation of any of these drugs” 
Adopted the suggestions from 
the U.S. FDA 
10.10 Appendix 
10 
Newly added “Procedures that 
allowed to be repeated during 
screening period” 
Specified the procedures that 
could be repeated for screening 
and made it more convenient for 
the investigators to refer