Conditions: Polycystic Ovary Syndrome (PCOS)
Keywords: Acne Hirsutism Menstrual Irregularity Alopecia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 55
Healthy volunteers: no

Brief summary:
This is a Phase 2b double-blind, randomized, parallel-group, placebo-controlled study of MLE4901 versus placebo in women with PCOS.

Detailed description:
Following a Screening/Wash-out Period of up to 12 weeks, an 8-week Lead-in Period (starting with a progestin challenge) will be used to better characterize the study population. A Treatment Period of 28 weeks' duration will follow the Lead-in Period. Then, an 8-week Follow-up Period (i.e., no study drug) will be used to assess the durability of effects of MLE4901. The study duration will be approximately 48 weeks (11 months) per subject

Arms:
arm 1: Plain, round, biconvex, white film-coated tablets that appear identical to MLE4901 tablets arm 2: Plain, round, biconvex, white film-coated tablets administered twice per day

Interventions: intervention 1: MLE4901 intervention 2: Placebo
Intervention descriptions: intervention 1: For 80% of subjects randomized to MLE4901 (n=24/30), the dose is 40 mg twice daily. Six subjects (20%) randomized to higher MLE4901 dose cohorts that were promptly discontinued. intervention 2: Placebo to match active drug

Protocol document:
Prot_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
PRODUCT NAME: MLE4901 
STUDY NUMBER:  MLE4901-101 
A Double-blind, Randomized, Parallel-group, Placebo-controlled Study of 
MLE4901 for the Treatment of Polycystic Ovary Syndrome (PCOS) 
 
 
Study Phase: 2b 
Product Name: MLE4901 
IND Number: 116350 
EudraCT Number: 2016-002179-91 
 
Indication: Polycystic Ovary Syndrome (PCOS) 
 
Sponsor: Millendo Therapeutics, Inc. 
 
Sponsor Medical Contact:  Vivian H. Lin, M.D.   
 
Original Protocol: 
Version 0.0 – 19 May 2016 
Country-specific Protocol Amendment 1/UK: 18 October 2016 
Global Protocol Amendment 1: 16 February 2017 
Global Protocol Amendment 2: 08 March 2017 
 
Confidentiality Statement 
This confidential document is the property of Millendo Therapeutics, Inc. and it is provided 
for the use of the Investigator and other designated personnel solely in connection with the 
conduct of the study described herein.  No information contained herein may be disclosed, 
except as necessary to obtain consent from persons who are considering participation in the 
study, without prior written approval of Millendo Therapeutics, Inc. 
 


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2 
INVESTIGATOR’S AGREEMENT 
 
Study Title:  A Double-blind, Randomized, Parallel-group, Placebo-controlled Study of 
MLE4901 for the Treatment of Polycystic Ovary Syndrome (PCOS) 
This protocol is provided for use by you, your staff and the Institutional Review Board or Ethics 
Committee.  The information contained in this document is confidential and belongs to Millendo 
Therapeutics, Inc.  Except as may be otherwise agreed to in writing, by accepting or reviewing 
these materials, you agree to hold such information in confidence and not to disclose it to others 
(except where required by applicable law) nor use it for unauthorized purposes.  In the event of 
actual or suspected breach of this obligation, Millendo Therapeutics, Inc. must be promptly 
notified. 
STUDY INVESTIGATOR SIGNATURE 
By my signature below, I agree to conduct this clinical study in accordance with applicable 
government regulations or laws and institutional/ethical review and informed consent practices.  
I have read the Investigator’s Brochure and protocol.  I agree to ensure the confidentiality of my 
subjects; however, I agree to make available to Millendo Therapeutics, Inc. or designee the 
subject’s medical and/or research chart specifically for the purposes of this clinical study.  I am 
fully conversant with Good Clinical Practices (GCP) and agree to conduct the clinical study in 
accordance with these principles and the procedures described in this protocol.  I am aware of 
my responsibilities as an Investigator. 
 
Name: 
_________________________________ 
Please print 
 
Title: 
 
 
_________________________________ 
Signature: 
 
_________________________________ 
Date: 
 
_________________________________ 
Address: 
_________________________________ 
 
 
________________________________ 
 
 
_______________________________ 
 




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SYNOPSIS 
Name of Sponsor/Company: 
Millendo Therapeutics, Inc. 
Name of Investigational Product: 
MLE4901 
Title of Study:  
A Double-blind, Randomized, Parallel-group, Placebo-controlled Study of MLE4901 for the Treatment of 
Polycystic Ovary Syndrome (PCOS) 
Study Center(s):  approximately 30 sites in the United States 
Principal Investigator: TBD 
 
Studied Period:  
Estimated date first subject screened:  01AUG2016 
Estimated date last subject completed:  01MAY2018 
Phase of Development:  
2b 
Objectives:  
Primary: To evaluate the efficacy of MLE4901 compared to placebo in improving menstrual regularity in 
women with oligo-/amenorrhea due to PCOS 
Secondary:  
• 
To evaluate the efficacy of MLE4901 compared to placebo during the 28-week Treatment Period in 
improving: 
− 
ovulation regularity 
− 
the Most Bothersome Symptom of PCOS 
− 
hormone levels (including testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), 
LH/FSH, estradiol, progesterone and anti-Müllerian hormone (AMH)) 
− 
clinical signs of hyperandrogenism (hirsutism, acne and alopecia) 
− 
metabolic syndrome-related parameters (including fasting glucose, insulin, lipid panel, blood pressure 
and body mass index (BMI)) 
• 
To determine the durability of MLE4901 effects during the 8-week Follow-up Period 
• 
To explore the impact of MLE4901 on measures of health-related quality of life and work productivity  
• 
To assess the safety and tolerability of MLE4901 
• 
To determine the pharmacokinetic (PK) parameters of MLE4901 and its major metabolite 
• 
To evaluate the PK/PD relationships of MLE4901 
Methodology:  
This is a Phase 2b double-blind, randomized, parallel-group, placebo-controlled study of MLE4901 versus 
placebo in women with PCOS.  Following a Screening/Wash-out Period of up to 12 weeks, an 8-week Lead-in 
Period (starting with a progestin challenge) will be used to better characterize the study population.  A 
Treatment Period of 28 weeks’ duration will follow the Lead-in Period. Then, an 8-week Follow-up Period (i.e., 
no study drug) will be used to assess the durability of effects of MLE4901.  The study duration will be 
approximately 48 weeks (11 months) per subject. A study schematic is shown in Figure 1 below. A detailed 
schedule of study assessments is presented in Appendix 1. 
The Screening Visit will assess the subjects’ preliminary eligibility for the study based on the inclusion and 
exclusion criteria.  In addition, pertinent information will be collected such as past medical history, 
demographic data and prior and current medications.  The Screening Visit will also assess laboratory tests as 
part of study eligibility.  If needed, subjects will undergo a wash-out of medications used to treat symptoms of 
PCOS. Subjects who meet all of the inclusion criteria and none of the exclusion criteria that are assessable 


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during Screening will undergo a transvaginal ultrasound and enter into the Lead-in Period. Note: Subjects do 
not need to wait for Screening/Wash-out hormone results prior to proceeding with the TVU and the Lead-in 
Period. 
The Lead-in Period will last for 8 weeks, with visits every 4 weeks. At the beginning of the Lead-in Period, all 
subjects will undergo a progestin challenge with medroxyprogesterone acetate (MPA) 10 mg orally daily (QD) 
for 5 days. During the Lead-in Period, subjects will use an electronic self-reported daily diary to report 
menstrual bleeding.  In addition, ovulation status will be assessed by having subjects collect urine for 
pregnenediol-3-glucuronide three times per week.  Instructions on proper use of the diary and collection of urine 
samples will be provided at the study site.  Continued study eligibility (including frequency of menstrual 
periods) will be assessed during the Lead-in Period, prior to randomization into the Treatment Period. 
Eligible subjects will enter the 28-week Treatment Period. At Visit T1, additional information will be obtained 
to further characterize each subject’s baseline status (e.g., Most Bothersome Symptom associated with PCOS, 
Polycystic Ovary Syndrome Questionnaire (PCOSQ) domain scores, PCOS Acne Questionnaire, EQ-5D-5L™ 
score, Patient Health Questionnaire-4 (PHQ-4) score, Work Productivity and Activity Impairment: General 
Health (WPAI:GH) domain scores, Ferriman-Gallwey score, Investigator’s Static Global Assessment (ISGA) of 
acne, Savin score, laboratory tests, etc.).  Subjects will be stratified by frequency of self-reported menstrual 
periods (<4/year vs 4-6/year) and by baseline BMI (22 to <35 kg/m2 vs 35 to 45 kg/m2) and randomized 1:1 into 
one of two study arms: MLE4901 40 mg twice daily (BID) or placebo BID.  All tablets used in the study will be 
identical in appearance to maintain double-blind status.  Study drug will be administered orally beginning on 
Day 1 of the Treatment Period.  The first dose of study drug will be given at the study site.  During the 
Treatment Period, subjects will continue to self-report menstrual bleeding and collect thrice-weekly urine 
samples for assessment of ovulation status. Additional study visits will take place 2, 4, 6, 8, 12, 16, 20, 24 and 
28 weeks after initiation of study drug.   
An 8-week Follow-up Period will occur immediately after the Treatment Period, with visits every 4 weeks.  No 
study drug will be administered during this period.  However, subjects will continue to self-report menstrual 
bleeding and collect thrice-weekly urine samples for assessment of ovulation status.  This period will be used to 
assess the durability of effects of MLE4901.  
Figure 1: 
Study Schematic 
 
Number of Subjects (planned):  
Approximately 110 women with PCOS and oligo-/amenorrhea with hyperandrogenism (clinical or biochemical) 
and/or polycystic ovaries 


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Diagnosis and Main Criteria for Inclusion:  
Inclusion Criteria: 
1. Provision of signed and dated informed consent prior to any study-specific procedures 
2. Women 18 to 45 years of age (inclusive) at Screening 
3. Oligo-/amenorrhea defined as ≤6 menstrual cycles per year off of any hormone therapy (may be based on 
subject historical recall) 
4. At least one of the following during Screening: 
• 
Clinical signs of hyperandrogenism, where clinical hyperandrogenism may include hirsutism (defined 
as excessive terminal hair that appears in a male pattern), acne, or androgenic alopecia  
• 
Biochemical hyperandrogenism refers to an elevated serum androgen level (i.e., total, bioavailable or 
free testosterone level ≥ULN) 
• 
Polycystic ovarian morphology, defined as the presence of 12 or more follicles 2-9 mm in diameter 
and/or an increased ovarian volume >10 mL (without a cyst or dominant follicle) in either ovary 
5. Body mass index (BMI) 22 to 45 kg/m2, inclusive 
6. Must be willing to avoid use of all hair removal procedures (e.g., electrolysis, laser hair removal, 
plucking/tweezing, waxing, threading, etc.) and products (e.g., Vaniqa®, Nair™, etc.) during study 
participation in the areas of the scalp, upper lip, chin, chest, back, abdomen, upper arms and thighs 
Note: Shaving is allowed; however, subjects must not shave within 72 hours prior to visits S1, T1 and T7 to 
permit assessment of hair growth 
7. Must be willing to avoid all prescription treatments for acne and not increase the dose or frequency of their 
current non-prescription acne treatment regimen during study participation 
8. Must be willing to avoid the use of all hair growth procedures (e.g., hair transplant) and products (e.g., 
minoxidil (Rogaine®)) during study participation 
9. Must be willing to avoid the use of all of the other prohibited medications (including metformin, oral 
contraceptives, clomiphene, letrozole, spironolactone, finasteride and flutamide) and procedures during 
study participation (Sections 5.12, 5.13 and 5.14) 
10. Permanently surgically sterilized (bilateral salpingectomy or tubal occlusion) >2 years or male partner(s) 
has had a vasectomy >2 years or must consent to use two permitted medically-acceptable methods of 
contraception throughout the study during any sexual intercourse with a male partner.  Permitted medically-
acceptable methods of birth control for this study are defined as use of a male condom plus one of the 
following: spermicide, diaphragm with spermicide, or an intrauterine device that does not contain steroid 
hormones.   
11. Must agree to not attempt to conceive during participation in the study 
Exclusion Criteria: 
1. Menopausal or peri-menopausal, defined for this study as FSH >10 IU/L 
2. Irregular vaginal/menstrual bleeding caused by conditions other than PCOS (e.g., uterine polyps or 
submucosal uterine fibroids) 
3. For women ≥21 years of age, abnormal Papanicolaou (Pap) test during Screening requiring follow-up 
sooner than 1 year after the test (Notes: Results from a Pap test performed within 1 year prior to Screening 
may be used. Women under 21 years of age at Screening do not require a Pap.)  
4. Uncontrolled hypo- or hyperthyroidism, defined as having an abnormal TSH during Screening or Lead-in 
and/or change in thyroid medication dose within the month prior to Screening 
5. Any suspected cause of hirsutism, acne, or alopecia other than PCOS 
6. Post-hysterectomy or endometrial ablation 
7. Post-oophorectomy (unilateral or bilateral) or other ovarian surgery 
8. No menstrual periods during Lead-in (i.e., failed progestin challenge) 
9. Two or more menstrual periods during Lead-in 
10. Use of any of the following medications within 28 days prior to the wash-out visit (for those requiring 
wash-out; See Section 5.12 for additional prohibited medications):  
• 
Metformin or other insulin-sensitizing medications (e.g., rosiglitazone, pioglitazone, etc.)  
• 
Hormonal contraceptives (e.g., birth control pills, hormone-releasing implants, etc. Depo-Provera 
needs to be washed out for 16 weeks.)  
• 
Hormone-releasing intrauterine device  
• 
Anti-androgens (e.g., spironolactone, flutamide, finasteride, etc.)  


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• 
Clomiphene citrate or estrogen modulators such as letrozole  
• 
GnRH modulators such as leuprolide  
Note: Women who received every-3-month progestin challenge and no other hormonal therapy during the 
year prior to Screening and who did not have any menstrual bleeding other than that due to withdrawal 
from progestin challenge may be randomized (if they meet all other inclusion/exclusion criteria) into the <4 
menstrual cycles per year stratum. 
11. Medical requirement for any of the prohibited concomitant medications 
12. Medical history of type 1 or type 2 diabetes mellitus  
13. Uncontrolled hypertension, defined as systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥90 
mmHg 
14. Any history of gastric or small intestinal surgery or any current disease that causes malabsorption 
15. Alcohol or substance abuse (cocaine, amphetamines and/or opioids) within the year prior to Screening 
16. Abnormal laboratory values as per the guidelines listed below or any other clinically significant, 
unexplained laboratory abnormality according to the Investigator: 
• 
ALT or AST >2 times ULN 
• 
Total bilirubin >1.5 times ULN 
• 
Creatinine >1.5 times ULN 
• 
Fasting glucose >126 mg/dL (6.99 mmol/L) 
• 
Hemoglobin A1c >6.5% 
• 
Prolactin >ULN 
• 
17-hydroxyprogesterone >200 ng/dL (6 nmol/L) 
• 
Total testosterone >150 ng/dL (5.21 nmol/L) 
• 
DHEA-S >800 µg/dL (21.6 µmol/L) 
• 
TSH >ULN or <LLN 
17. Currently pregnant or breastfeeding or having conceived or given birth within the 3 months prior to 
Screening 
18. QTc >470 msec on electrocardiogram at Screening or at Visit T1 (subjects with a single QTc >470 msec 
may have 2 additional ECGs taken and the QTcs averaged; if the average QTc is >470 msec then the 
subject is excluded) 
19. History of Gilbert’s syndrome or autoimmune hepatitis 
20. HIV, hepatitis B, or hepatitis C positivity 
21. Any malignancy within the previous 10 years, other than curatively resected basal or squamous cell skin 
cancer 
22. Previous receipt of any amount of MLE4901, AZD4901 or AZD2624 
23. Participation in any study of an investigational drug or device or investigational biological agent within 30 
days (or 5 half-lives of the investigational agent, whichever is longer) prior to Screening 
24. Any other medical or psychiatric condition (e.g., uncontrolled sleep apnea, severe depression, etc.) that, in 
the opinion of the Investigator, is likely to confound the interpretation of the study results or prevent the 
subject from understanding the requirements of or successfully completing the study  
Investigational Product, Dosage and Mode of Administration:  
MLE4901 40 mg tablets for oral administration, twice per day. 
Duration of Treatment:  
Approximately 28 weeks 
Reference Therapy, Dosage and Mode of Administration:  
Placebo matching tablets for oral administration, twice per day. 


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Study Endpoints: 
Primary Efficacy Endpoint:  
• 
The change in the duration of menstrual cycles from Baseline to End-of-Treatment (EoT).   
Note: The Baseline menstrual cycle duration will be measured as the time from the start of the first menstrual 
period after the progestin challenge to the start of the next consecutive menstrual period.  The EoT menstrual 
cycle duration will be the duration between the last two menstrual period start dates during the Treatment Period. 
Key Secondary Efficacy Endpoint:  
• 
The number of menstrual periods during the Treatment Period 
Additional Efficacy Endpoints:  
• 
The duration of menstrual cycles over the Treatment Period 
• 
The change from Baseline in the duration of each menstrual cycle over the Treatment Period 
• 
The change in the ovulation interval from Baseline to EoT 
• 
The number of ovulations during the Treatment Period 
• 
The duration of ovulation intervals over the Treatment Period 
• 
The change from Baseline in the ovulation interval for each ovulation over the Treatment Period 
• 
The time from the start of the last menstrual period prior to randomization to the first menstrual period after 
randomization 
• 
The time to the first normal menstrual cycle duration 
• 
The number of consecutive menstrual cycles of 21-35 days’ duration over the Treatment Period 
• 
The time from the last ovulation prior to randomization (or first dose of MPA, if no ovulation during Lead-
in) to the first ovulation after randomization 
• 
The time to the first normal ovulation interval 
• 
The number of consecutive ovulation intervals of 21-35 days’ duration over the Treatment Period 
• 
The proportion of subjects with at least 4 self-reported menstrual periods over the Treatment Period  
• 
The proportion of subjects having menstrual cycles of 21-35 days’ duration for a continuous 6-month 
period during the Treatment Period 
• 
The proportion of subjects having menstrual bleeding of 2-7 days’ duration for a continuous 6-month 
period during the Treatment Period 
• 
The proportion of subjects with normal menstrual cycles for a continuous 6-month period during the 
Treatment Period 
• 
The change from Baseline in the severity of the subjects’ self-identified Most Bothersome Symptom of 
PCOS 
• 
The change from Baseline in the severity of each symptom of PCOS (oligo-/amenorrhea, hirsutism, acne 
and alopecia)  
• 
The change from Baseline in testosterone (total, free and bioavailable), LH, FSH, LH/FSH, estradiol, 
progesterone and AMH 
• 
The change from Baseline in the modified Ferriman-Gallwey score for hirsutism 
• 
The change from Baseline in the Investigator’s Static Global Assessment of acne score  
• 
The change from Baseline in the Savin score for androgenic alopecia 
• 
The change from Baseline in fasting glucose, insulin, total cholesterol, LDL, HDL and triglycerides 
• 
The change from Baseline in systolic blood pressure, diastolic blood pressure and body mass index 
• 
The duration of menstrual cycles over the Follow-up Period 
• 
The duration of ovulation intervals over the Follow-up Period 
• 
The change from Baseline in the frequency of removal of unwanted hair from the upper lip and chin  
• 
The change from Baseline in the domain scores on the PCOSQ and the PCOS Acne Questionnaire 
• 
The change from Baseline in the score on the EQ-5D-5L health state survey 
• 
The change from Baseline in the domain scores on the Work Productivity and Activity Impairment: 
General Health Questionnaire (WPAI:GH) 


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• 
The change from Baseline in the mean total score, anxiety subscale score and depression subscale score on 
the PHQ-4 
Safety Endpoints: Safety endpoints will include the incidence of treatment-emergent adverse events and 
serious adverse events, as well as changes from baseline in clinical laboratory tests, vital signs, physical 
examinations and ECG parameters. 
Pharmacokinetic Endpoints: 
• 
The Cmax, Tmax, AUC, t1/2 and other PK parameters of MLE4901 and its major metabolite (as appropriate 
and as the data allow) 
• 
The relationship between Cmax and AUC vs. the change in the duration of menstrual cycles from Baseline to 
EoT; other PK/PD relationships may be explored as appropriate and as data allow 


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Statistical Methods: 
A Statistical Analysis Plan that includes a more technical and detailed description of the planned 
statistical analyses will be prepared prior to study unblinding.  
Populations:  
Efficacy – The primary efficacy analyses will include all randomized subjects (Intent-to-Treat; ITT). For 
efficacy analyses, subjects will be included in the treatment group to which they were randomized. Additional 
efficacy analyses will be performed on all subjects who complete at least 16 weeks of treatment (Evaluable 
Population). 
Safety – The Safety Population will include all treated subjects. Safety analyses will be based on the Safety 
Population. For the safety analyses, subjects randomized to the placebo group who receive MLE4901 will be 
included in the treatment group of the study drug that they received. 
Pharmacokinetic – The PK Population will include all subjects with measurable drug concentrations. PK 
analyses will be based on the PK Population. 
Sample size considerations: 
Assuming a study dropout rate of approximately 10-20%, a total of 110 subjects will be randomized in the study 
so that each dose group will have 50 subjects at a 1:1 allocation.  
Sample size considerations were based on a multiple comparison Dunnett intersection test and a 1-sided alpha 
of 0.025.  The standard deviation of change in days between start of menstruation was assumed to be 15 days.  
If the mean change in days between onset of menstruation was assumed to be 0 for the placebo group and 10 
days for at least one active dose group, the study has a power of approximately 80-90% as demonstrated in 
simulations. 
Analysis Methodology: 
Primary endpoint – The change in the duration of menstrual cycles from Baseline to EoT will be analyzed with 
an ANOVA model including treatment and stratification factors following the Dunnett intersection test 
procedure to control for multiple comparison testing.  Should the primary endpoint distribution depart from an 
approximate normal distribution, an appropriate non-parametric test will be utilized such as the Wilcoxon rank-
sum test. 
Key secondary endpoint – The number of menstrual periods during the Treatment Period will be analyzed with 
an ANOVA model including treatment and stratification factors following the Dunnett intersection test 
procedure to control for multiple comparison testing.  Should this key secondary endpoint distribution depart 
from an approximate normal distribution, an appropriate non-parametric test will be utilized such as the 
Wilcoxon rank-sum test.   
Additional efficacy endpoints – No further adjustments for multiple group comparisons, multiple additional 
endpoints or multiple subgroups of interest are planned. 
The ovulation interval duration will be analyzed in a similar manner as the menstrual cycle duration, with the 
exception that the analysis of this endpoint will utilize an ANOVA, instead of an ANCOVA model.  Other 
continuous endpoints will utilize similar ANCOVA or ANOVA model methodology, as appropriate. Responder 
analyses and other categorical analyses will be based on the Cochran-Mantel-Haenszel (CMH) test or Fisher’s 
exact test, as appropriate.  Time-to-event endpoints will be summarized using Kaplan-Meier estimates and 
compared using the log-rank test.  
Exploratory endpoints – Additional efficacy endpoints will be pre-specified in the Statistical Analysis Plan, 
including sensitivity analyses associated with drug compliance and missing data issues. 
Safety endpoints – Adverse events counts (overall, as well as by severity, causality and seriousness) will be 
tabulated by Medical Dictionary for Regulatory Activities (MedDRA) system organ class and preferred term. 
Descriptive statistics and shift tables will be used to summarize continuous laboratory parameters. Counts and 
shift tables will be used for categorical lab parameters. 
PK endpoints – Individual PK parameters will be derived using the WinNonlin software and table summaries 
will be provided using descriptive summary statistics. 
 


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TABLE OF CONTENTS 
SYNOPSIS ......................................................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................11 
LIST OF TABLES .........................................................................................................................17 
LIST OF FIGURES .......................................................................................................................18 
LIST OF ABBREVIATIONS ........................................................................................................19 
1. 
INTRODUCTION ......................................................................................................22 
1.1. 
Background .................................................................................................................22 
1.1.1. 
Preclinical Studies ......................................................................................................23 
1.1.2. 
Clinical Studies ...........................................................................................................23 
1.2. 
Research Hypothesis ...................................................................................................27 
1.3. 
Rationale for Conducting This Study .........................................................................27 
1.4. 
Benefit/Risk and Ethical Assessment .........................................................................28 
2. 
STUDY OBJECTIVES ..............................................................................................29 
2.1. 
Primary Objective .......................................................................................................29 
2.2. 
Secondary Objectives .................................................................................................29 
3. 
INVESTIGATIONAL PLAN .....................................................................................30 
3.1. 
Overall Study Design and Plan ...................................................................................30 
3.1.1. 
Screening Period .........................................................................................................30 
3.1.2. 
Lead-in Period ............................................................................................................30 
3.1.3. 
Treatment Period ........................................................................................................31 
3.1.4. 
Follow-up Period ........................................................................................................31 
3.2. 
Rationale for Study Design and Dose Levels .............................................................32 
3.3. 
Criteria for Study Termination ...................................................................................32 
4. 
STUDY POPULATION SELECTION ......................................................................33 
4.1. 
Study Population .........................................................................................................33 
4.2. 
Inclusion Criteria ........................................................................................................33 
4.3. 
Exclusion Criteria .......................................................................................................34 
5. 
STUDY TREATMENT ..............................................................................................36 
5.1. 
Assignment of Subject Identification Numbers ..........................................................36 
5.2. 
Description of Study Drug ..........................................................................................36 
5.3. 
Study Drug Packaging and Labeling ..........................................................................36 


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5.4. 
Study Drug Storage and Accountability .....................................................................36 
5.5. 
Medroxyprogesterone Acetate ....................................................................................37 
5.6. 
Study Drug Administration.........................................................................................37 
5.7. 
Dose Adjustment Criteria ...........................................................................................37 
5.8. 
Study Drug Compliance .............................................................................................38 
5.9. 
Randomization and Blinding ......................................................................................38 
5.10. 
Study Drug Retention at Study Site ............................................................................38 
5.11. 
Concomitant Medications ...........................................................................................38 
5.12. 
Prohibited Medications ...............................................................................................38 
5.13. 
Prohibited Procedures .................................................................................................39 
5.14. 
Restricted Medications ...............................................................................................39 
6. 
STUDY PROCEDURES ............................................................................................41 
6.1. 
Allowable Variation in Study Visits ...........................................................................41 
6.2. 
Informed Consent .......................................................................................................41 
6.3. 
Eligibility ....................................................................................................................41 
6.4. 
Medical History ..........................................................................................................41 
6.5. 
Prior and/or Concomitant Medication Assessments ...................................................41 
6.6. 
Vital Signs, Height, Weight and Body Mass Index ....................................................42 
6.7. 
Physical Examination .................................................................................................42 
6.8. 
Electrocardiography and Determination of QTc ........................................................42 
6.9. 
Transvaginal Ultrasound .............................................................................................42 
6.10. 
Menstrual Bleeding Diary ...........................................................................................43 
6.11. 
PCOS Most Bothersome Symptom Questionnaire (MBSQ) ......................................43 
6.12. 
Hair Removal Questionnaire (HRQ) ..........................................................................43 
6.13. 
Polycystic Ovary Syndrome Questionnaire (PCOSQ) and PCOS Acne 
Questionnaire ..............................................................................................................43 
6.14. 
EuroQol-5 Dimensions-5 Levels Survey (EQ-5D-5L) ...............................................43 
6.15. 
Patient Health Questionnaire-4 (PHQ-4) ....................................................................44 
6.16. 
Work Productivity and Activity Impairment: General Health Questionnaire 
(WPAI:GH) .................................................................................................................44 
6.17. 
Patient’s Global Impression of Change (PGIC) .........................................................44 
6.18. 
Modified Ferriman-Gallwey Score for Hirsutism ......................................................44 
6.19. 
Investigator’s Static Global Assessment (ISGA) of Acne Score ................................44 


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13 
6.20. 
Savin Scale for Alopecia ............................................................................................44 
6.21. 
Pharmacokinetic Assessments ....................................................................................45 
6.22. 
Pharmacodynamic Assessments .................................................................................46 
6.23. 
Adverse Events, Serious Adverse Events, Pregnancies and Reporting ......................46 
6.23.1. 
Definition of Adverse Event, Adverse Drug Reaction and Unexpected 
Adverse Drug Reaction ...............................................................................................46 
6.23.2. 
Assessing Severity of Adverse Events .......................................................................47 
6.23.3. 
Assessing Relationship to Study Treatment ...............................................................48 
6.23.4. 
Serious Adverse Events ..............................................................................................48 
6.23.4.1. 
Definition of Serious Adverse Event ..........................................................................48 
6.23.4.2. 
Reporting Serious Adverse Events (SAEs) – Procedure for Investigators .................49 
6.23.5. 
Pregnancy Reporting ..................................................................................................50 
6.23.6. 
Regulatory Reporting of Adverse Events ...................................................................51 
6.24. 
Clinical Laboratory Tests ...........................................................................................51 
6.24.1. 
Efficacy Laboratory Tests ...........................................................................................52 
6.24.1.1. 
Urinary Pregnanediol-3-Glucuronide .........................................................................52 
6.24.1.2. 
Serum Hormone Levels ..............................................................................................52 
6.24.1.3. 
Fasting Glucose, Insulin and HbA1c ..........................................................................52 
6.24.1.4. 
Fasting Lipid Panel .....................................................................................................52 
6.24.2. 
Safety Laboratory Tests ..............................................................................................52 
6.24.2.1. 
Liver Function Tests ...................................................................................................53 
6.24.3. 
Sample Collection, Storage and Shipping ..................................................................53 
6.25. 
Blood Sample Collection ............................................................................................53 
6.26. 
Removal of Subjects from the Study ..........................................................................53 
7. 
STUDY ACTIVITIES ................................................................................................55 
7.1. 
Screening/Wash-out Period ........................................................................................55 
7.1.1. 
Screening/Wash-out Period, Visit S1 (Screening)......................................................55 
7.1.2. 
Screening/Wash-out Period, Visit W1 (Wash-out) ....................................................56 
7.2. 
Lead-in Period ............................................................................................................56 
7.2.1. 
Lead-in Period, Visit L1 .............................................................................................56 
7.2.2. 
Lead-in Period, Visit L2 .............................................................................................57 
7.3. 
Treatment Period ........................................................................................................58 
7.3.1. 
Treatment Period, Study Day 1, Visit T1 ...................................................................58 


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7.3.2. 
Treatment Period, Visit T2 .........................................................................................59 
7.3.3. 
Treatment Period, Visit T3 .........................................................................................60 
7.3.4. 
Treatment Period, Visit T3.5 ......................................................................................61 
7.3.5. 
Treatment Period, Visit T4 .........................................................................................61 
7.3.6. 
Treatment Period, Visit T5 .........................................................................................62 
7.3.7. 
Treatment Period, Visit T5.5 ......................................................................................63 
7.3.8. 
Treatment Period, Visit T6 .........................................................................................63 
7.3.9. 
Treatment Period, Visit T6.5 ......................................................................................64 
7.3.10. 
Treatment Period, Visit T7 .........................................................................................64 
7.4. 
Follow-up Period ........................................................................................................65 
7.4.1. 
Follow-up Period, Visit F1 .........................................................................................65 
7.4.2. 
Follow-up Period, Visit F2 .........................................................................................66 
7.5. 
Early Termination Visit ..............................................................................................66 
8. 
QUALITY CONTROL AND ASSURANCE ............................................................67 
9. 
PLANNED STATISTICAL METHODS ...................................................................68 
9.1. 
General Considerations ...............................................................................................68 
9.1.1. 
Sample Size ................................................................................................................68 
9.1.2. 
Randomization and Stratification ...............................................................................68 
9.2. 
Analysis Populations ..................................................................................................68 
9.3. 
Demographics and Baseline Characteristics ...............................................................68 
9.4. 
Efficacy .......................................................................................................................69 
9.4.1. 
Efficacy Endpoints ......................................................................................................69 
9.4.1.1. 
Primary Efficacy Endpoint .........................................................................................69 
9.4.1.2. 
Key Secondary Efficacy Endpoint ..............................................................................69 
9.4.1.3. 
Additional Efficacy Endpoints ...................................................................................69 
9.4.2. 
Efficacy Analysis Methodology .................................................................................70 
9.4.2.1. 
Primary Efficacy Endpoint .........................................................................................70 
9.4.2.2. 
Key Secondary Efficacy Endpoint ..............................................................................70 
9.4.2.3. 
Additional Efficacy Endpoints ...................................................................................70 
9.4.2.4. 
Exploratory Endpoints ................................................................................................71 
9.5. 
Safety ..........................................................................................................................71 
9.5.1. 
Safety Endpoints .........................................................................................................71 
9.5.2. 
Safety Analyses ..........................................................................................................71 


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9.6. 
Pharmacokinetics ........................................................................................................71 
9.6.1. 
Pharmacokinetic Endpoints ........................................................................................71 
9.6.2. 
Pharmacokinetic Analyses ..........................................................................................71 
9.7. 
Interim Analysis ..........................................................................................................71 
10. 
ADMINISTRATIVE CONSIDERATIONS ..............................................................72 
10.1. 
Institutional Review Board (IRB)/Ethics Committee (EC) ........................................72 
10.2. 
Ethical Conduct of the Study ......................................................................................72 
10.3. 
Subject Information and Consent ...............................................................................72 
10.4. 
Subject Confidentiality ...............................................................................................73 
10.5. 
Study Monitoring ........................................................................................................73 
10.6. 
Audits and Inspections ................................................................................................74 
10.7. 
Case Report Forms and Study Records ......................................................................74 
10.8. 
Data Safety Monitoring Board ....................................................................................75 
10.9. 
Protocol Deviations ....................................................................................................75 
10.10. 
Access to Source Documentation ...............................................................................75 
10.11. 
Data Generation and Analysis ....................................................................................76 
10.12. 
Retention of Records ..................................................................................................76 
10.13. 
Financial Disclosure ...................................................................................................76 
10.14. 
Premature Termination of the Study ...........................................................................76 
10.15. 
Clinical Study Report .................................................................................................76 
10.16. 
Subject Insurance and Indemnity ................................................................................76 
10.17. 
Amendments to the Protocol ......................................................................................77 
11. 
LIST OF REFERENCES ............................................................................................78 
12. 
APPENDICES ............................................................................................................80 
APPENDIX 1. STUDY SCHEDULE .........................................................................................81 
APPENDIX 2. PCOS MOST BOTHERSOME SYMPTOM QUESTIONNAIRE ....................85 
APPENDIX 3. HAIR REMOVAL QUESTIONNAIRE ............................................................88 
APPENDIX 4. POLYCYSTIC OVARY SYNDROME QUESTIONNAIRE AND 
PCOS ACNE QUESTIONNAIRE .............................................................................89 
APPENDIX 5. EQ-5D-5L, TABLET VERSION .......................................................................91 
APPENDIX 6. PATIENT’S HEALTH QUESTIONNAIRE-4 ..................................................93 
APPENDIX 7. WORK PRODUCTIVITY AND ACTIVITY IMPAIRMENT 
QUESTIONNAIRE: GENERAL HEALTH V2.0 .....................................................94 


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APPENDIX 8. PATIENT’S GLOBAL IMPRESSION OF CHANGE ......................................95 
APPENDIX 9. DAILY MENSTRUAL DIARY.........................................................................96 
APPENDIX 10. MODIFIED FERRIMAN-GALLWEY HIRSUTISM SCALE ........................97 
APPENDIX 11. INVESTIGATOR’S STATIC GLOBAL ASSESSMENT OF ACNE ............98 
APPENDIX 12. LEEDS REVISED ACNE GRADING SYSTEM ............................................99 
APPENDIX 13. SAVIN SCALE FOR ANDROGENIC ALOPECIA .....................................103 
APPENDIX 14. PROCEDURES FOR EMERGENCY UNBLINDING .................................104 
APPENDIX 15. ALGORITHM FOR THE MANAGEMENT OF SUBJECTS WITH 
TRANSAMINASE (AST OR ALT) ELEVATIONS >3X ULN .............................105 


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LIST OF TABLES 
Table 1: 
Abbreviations ..............................................................................................................19 
Table 2: 
Number (%) of Subjects Who Had at least 1 Adverse Event, by System 
Organ Class (Safety Analysis Set) ..............................................................................26 
Table 3: 
Investigational Product ...............................................................................................36 
Table 4: 
Pharmacokinetic Sampling Time Points .....................................................................45 
Table 5: 
Pharmacokinetic Parameters .......................................................................................45 
Table 6: 
List of Clinical Laboratory Tests ................................................................................51 
Table 7: 
Study Schedule ...........................................................................................................81 
Table 8: 
Evaluation of Follow-up AST and ALT Values .......................................................110 
 


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LIST OF FIGURES 
Figure 1: 
Study Schematic ...........................................................................................................5 
Figure 2: 
Study Schematic .........................................................................................................30 
 


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LIST OF ABBREVIATIONS 
Table 1: 
Abbreviations 
Abbreviation 
Explanation 
17-OHP 
17-hydroxyprogesterone 
AE 
adverse event 
ALB 
albumin 
ALK-P 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
AMH 
anti-Müllerian hormone 
AST 
aspartate aminotransferase 
aPTT 
activated partial thromboplastin time 
ATC 
Anatomical Therapeutic Chemical 
AUC 
area under the plasma concentration-time curve 
AUC0-4h 
area under the plasma concentration-time curve from time zero to 4 hours 
postdose 
AUC0-4h/D 
dose-normalized AUC0-4h 
AUC0-8h 
area under the plasma concentration-time curve from time zero to 8 hours 
postdose 
AUC0-24h 
area under the plasma concentration-time curve from time zero to 24 hours 
postdose 
AUC0-∞ 
area under the plasma concentration-time curve from time zero to infinity 
AUC0-t 
area under the plasma concentration-time curve up to the last quantifiable 
concentration time point (t) 
AUC%extrap 
the percentage of AUC0-∞ extrapolated 
βhCG 
beta human chorionic gonadotropin 
BID 
twice daily 
BMI 
body mass index 
BUN 
blood urea nitrogen 
Cavg 
average concentration 
CFR 
Code of Federal Regulations 
CHO 
Chinese hamster ovary 
CL 
clearance 
CL/F 
oral clearance calculated as dose/AUC0-∞ 
Clast 
last quantifiable plasma concentration 
Cmax 
maximum observed plasma concentration 
Cmax/D 
dose-normalized Cmax 
CMH 
Cochran-Mantel-Haenszel 
CQA 
clinical quality assurance 
CRA 
clinical research associate 
CRO 
clinical research organization 
CSR 
clinical study report 
CYP 
cytochrome P450 


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Abbreviation 
Explanation 
DBP 
diastolic blood pressure 
DHEA-S 
dehydroepiandrosterone sulfate 
DSMB 
Data Safety Monitoring Board 
E2 
estradiol 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EoS 
End-of-Study 
EoT 
End-of-Treatment 
ET 
Early Termination 
EQ-5D-5L 
EuroQol-5 Dimensions-5 Levels Survey 
FSH 
follicle-stimulating hormone 
FT 
free testosterone 
GCP 
Good Clinical Practices 
GnRH 
gonadotropin-releasing hormone 
HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen 
Hct 
hematocrit 
HCV 
hepatitis C virus 
HDL 
high density lipoprotein 
HEENT 
head, eyes, ears, nose and throat 
hERG 
human ether-à-go-go-related gene 
Hgb 
hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
human immunodeficiency virus 
HPG 
hypothalamic-pituitary-gonadal 
HRQ 
Hair Removal Questionnaire 
IC50 
half-maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ISGA 
Investigator’s Static Global Assessment (of acne) 
ITT 
intent-to-treat 
IRB 
institutional review board 
IWRS 
interactive web response system 
KNDy 
kisspeptin-neurokinin-dynorphin neuron system 
λz 
plasma terminal phase rate constant 
LDL 
low density lipoprotein 
LFTs 
liver function tests 
LH 
luteinizing hormone 
LLN 
lower limit of normal 
MBSQ 
PCOS Most Bothersome Symptom Questionnaire 
MedDRA 
Medical Dictionary for Regulatory Activities 
MPA 
medroxyprogesterone acetate 


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Abbreviation 
Explanation 
NK3 
neurokinin-3 
NKB 
neurokinin B 
P 
progesterone 
Pap 
Papanicolaou 
PCOM 
polycystic ovarian morphology 
PCOS 
polycystic ovary syndrome 
PCOSQ 
PCOS Questionnaire 
PD 
pharmacodynamic 
PE 
physical examination 
PGIC 
Patient’s Global Impression of Change 
PHQ-4 
Patient’s Health Questionnaire-4 
PK 
pharmacokinetic 
PT 
prothrombin time 
QD 
once daily 
QT interval 
the time from the start of the Q wave and the end of the T wave 
QTc 
corrected QT interval 
QTcF 
QT interval corrected using the Fridericia method 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvate transaminase 
SHBG 
sex hormone-binding globulin 
SOC 
system organ class 
T 
testosterone 
t1/2 
terminal phase half-life 
T4 
thyroxine 
TBD 
to be determined 
Tmax 
time of maximum plasma concentration 
TMF 
trial master file 
TSH 
thyroid-stimulating hormone 
TT 
total testosterone 
TVU 
transvaginal ultrasound 
ULN 
upper limit of normal 
US 
United States 
Vss 
volume of distribution at steady state 
WBC 
white blood cell 
WHO 
World Health Organization 
WPAI:GH 
Work Productivity and Activity Impairment Questionnaire: General Health 


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1. 
INTRODUCTION 
1.1. 
Background 
Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies in women, 
affecting approximately 5% to 10% of women overall (March 2010).  It is a heterogeneous 
disorder of which the principal clinical features are hyperandrogenism, disturbances of 
menstruation, infertility, metabolic derangement and polycystic ovaries.  Patients exhibit 
excessive amounts or effects of androgenic hormones, resulting in acne, hirsutism and insulin 
resistance, often associated with obesity, type 2 diabetes mellitus and high cholesterol levels.  
The symptoms and severity of the syndrome vary greatly among affected women.  Long-term 
risks in such patients include coronary artery disease and cerebrovascular disease, as well as the 
risk of unopposed estrogen and chronic anovulation: endometrial hyperplasia, dysfunctional 
uterine bleeding and possibly endometrial cancer. 
Expression of the PCOS phenotype appears to be dependent on both genetic and environmental 
factors. Potential etiologies include ovarian hyperresponsiveness to LH and selective insulin 
resistance; reflecting the heterogeneity of the condition, linkage studies have shown possible 
associations with a wide variety of genes, ranging from those encoding proopiomelanocortin to 
steroidogenic enzymes to genes involved in regulation of cell growth. Polycystic ovary 
syndrome (PCOS) is known to be associated with gonadotropin releasing hormone (GnRH) 
hyperpulsatility along with increased luteinizing hormone (LH) pulse amplitude and pulse 
frequency. While gonadotropin-releasing hormone (GnRH) pulsatile release cannot be assessed 
directly in humans, it is believed that peripheral LH pulses are directly related to hypothalamic 
GnRH.  In healthy premenopausal women, GnRH pulses occur approximately once every 90 to 
100 minutes during the follicular stage, with a gradual increase in GnRH pulsatility at mid-cycle 
causing an LH surge and thus ovulation.  In contrast, women with PCOS have GnRH pulses 
approximately once every 60 minutes. This results in an excess of pituitary LH secretion and 
frequently a lack of an LH surge, leading to failure of ovulation. In addition, the excess LH 
results in increased ovarian testosterone production (Clarke 1982, Hall 1998, Knobil 2006, 
Levine 1982, Waldstreicher 1988).  
The symptoms usually related to PCOS, including menstrual irregularities, hirsutism, 
anovulation and acne, can lead to a significant decrease in quality of life, mood disorders 
including depression, marital and social maladjustment and sexual dysfunction (Bazarganipour 
2015, Barnard 2007). Self-ratings of hirsutism have been shown to be significantly associated 
with depression (r=0.14, p<0.05) (Pasch 2016). Given that the population of women with PCOS 
is relatively young, since depression is a co-morbidity, PCOS could also impact work 
productivity and limit activities. 
There are no treatments indicated specifically for PCOS as those available treat only the 
symptoms.  Current symptom-based treatments for PCOS address the effects of the disease, e.g., 
spironolactone, cyproterone acetate and GnRH modulators as anti-androgen therapy; metformin 
for the metabolic derangement; oral contraceptives for normalization of menstruation; and the 
selective estrogen receptor modulator, clomiphene, to induce ovulation.  All of these treatments 
address symptomatology but not pathophysiology and have significant side effects, such as 
menopausal-like adverse events, prevention of pregnancy, inducement of multiple/multi-fetal 


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pregnancies, ovarian hyperstimulation syndrome, gastrointestinal complaints, or lactic acidosis.  
None modify the underlying GnRH pulse generator to modify the disease. 
The GnRH pulse generator is controlled by the kisspeptin-neurokinin-dynorphin (KNDy) neuron 
system.  Kisspeptin and neurokinin have stimulatory effects on the GnRH pulse generator, while 
dynorphin has inhibitory effects (Maeda 2010).  MLE4901 is a high-affinity NK3 receptor 
antagonist.  In both clinical pharmacology studies in healthy volunteers and in a study of 
schizophrenia (mainly in men), a reduction in testosterone and to some degree LH, has been 
observed, suggesting that MLE4901 regulates pituitary LH and gonadal testosterone via 
modulation of GnRH pulsatility. Based on the clinical endocrine changes observed and an 
understanding of its mechanism of action, MLE4901 is now being evaluated for the treatment of 
PCOS.  A treatment that could modulate the GnRH axis could potentially control the symptoms 
of PCOS and restore regular menses and ovulation. 
1.1.1. 
Preclinical Studies 
MLE4901 binds with high affinity to human NK3 receptors, with a dissociation constant of an 
inhibitor of 2 nM versus [125I]His, MePhe7 NKB agonist.  MLE4901 completely blocked agonist 
(senktide)-induced calcium flux in Chinese hamster ovary (CHO) cells stably expressing human 
NK3 receptors with a concentration of drug causing half-maximal inhibitory concentration (IC50) 
of 2.57 nM.  M12 (also referred to as AZ12592232), a metabolite of MLE4901, completely 
blocked agonist (senktide)-induced calcium flux in CHO cells stably expressing human NK3 
receptors with an IC50 value of 9.05 nM. 
The preclinical safety evaluation of MLE4901 includes repeat dose toxicity studies of up to 6 
months in rats and 9 months in dogs, embryofetal development studies in rats and rabbits, an 
assessment of fertility in female rats and in vitro and in vivo genetic toxicology studies. 
MLE4901 was generally well tolerated following repeated oral administration of doses up to 
2000 mg/kg/day in rats for up to 6 months, doses up to 1000 mg/kg/day in dogs for up to 
3 months and doses up to 750 mg/kg/day in dogs for 9 months. At ~1000 times the clinical dose 
(rats) and ~70 times the clinical dose (dogs), reversible increases in liver weights occurred. This 
was found to be associated with diffuse hepatocellular hypertrophy and was judged to be an 
adaptive response. At 100 times the clinical dose, rats showed minimal epithelial hypertrophy of 
the thyroid gland along with changes in T4 and TSH. At 500 times the clinical dose (dogs), 
reversible increases in thyroid gland weights were observed with no histopathological correlates. 
Finally, at 100 times the clinical dose, a 25% inhibition of the human ether-à-go-go-related gene 
(hERG) channel was observed. 
1.1.2. 
Clinical Studies 
The early clinical program conducted with MLE4901 (previously referred to as AZD2624 and 
AZD4901) for the indication of schizophrenia was comprised of 2 single ascending dose studies 
(1 in Japanese volunteers) and 2 multiple ascending dose studies (1 in Japanese volunteers) in 
healthy male volunteers, a relative bioavailability study in healthy male and female volunteers 
and a Phase 2a study in patients with schizophrenia.  One hundred and sixty subjects (6 of whom 
were women) received MLE4901 at doses ranging between 1 and 80 mg (single doses), 30 mg 
twice daily (BID) (multiple dose study), or for up to 28 days at 40 mg once daily (QD).  Both 
suspension and tablets (20-mg strength) were utilized. 


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The early clinical program conducted with MLE4901 for the indication of polycystic ovary 
syndrome was comprised of a double-blinded, randomized, parallel-group Phase 2a study of 3 
doses of MLE4901 (20 mg QD, 20 mg BID and 40 mg BID) and placebo for 28 days in 65 
women with PCOS. 20-mg MLE4901 tablets were utilized.  
Data obtained from the clinical studies to date did not identify any safety or tolerability concerns 
that preclude development of MLE4901 in patients with PCOS. 
Pharmacokinetic (PK) properties have been well investigated in healthy male volunteers.  
MLE4901 was quickly absorbed following oral dosing.  Tmax was approximately 2 hours. The 
elimination half-life for MLE4901 was approximately 7 hours.  Both the area under the 
concentration-time curve (AUC) and maximum observed concentration (Cmax) appeared to be 
dose-proportional for both MLE4901 and its major metabolite, M12.  Renal elimination of 
MLE4901 and M12 was negligible. 
Following multiple dose administration, PK steady state was achieved within 4 days, at which 
the exposure to M12 was approximately 66% of the parent; the accumulation of MLE4901 in the 
plasma was minimal following QD dosing and was greater following BID dosing.  MLE4901 PK 
appeared to be time-independent.  Limited exposure observed in women suggests no difference 
in PK properties between women and men.  Based on limited observations, oral administration of 
MLE4901 suspension or tablets with food (a high fat meal) increased the rate of absorption 
(suspension: 25% increase in Cmax; tablet: 75% increase in Cmax).  To date, there has been no 
clear demonstration of Cmax-related toxicity in humans receiving up to 80 mg of the suspension. 
Cytochrome P450 (CYP) enzymes CYP2C9, CYP3A4 and CYP3A5 in vitro appeared to be 
involved in the metabolism of MLE4901.  MLE4901 exhibited a weak to moderate inhibitory 
effect on CYP3A4/5 with an apparent IC50 of 7.1 and 19.8 μM in midazolam and testosterone 
assays, respectively.  MLE4901 may also have the potential to induce CYP3A4/5 enzymes.  
Clinical drug-drug interaction studies have not yet been performed. 
MLE4901 Treatment of Patients with Schizophrenia 
This was a double-blind, randomized, parallel-group, placebo-controlled, multicenter study 
conducted in adult subjects who were diagnosed with schizophrenia and were symptomatic at 
admission.  A total of 106 subjects, 18 to 65 years of age, were randomized to treatment once 
daily for 28 days with MLE4901 40 mg (N=43; 40 male and 3 female), placebo (N=41; 39 male 
and 2 female), or olanzapine 15 mg (N=22; all male).  Eighty-one subjects completed treatment.  
MLE4901 was administered in the morning as an oral suspension in an oral suspending vehicle.   
A comparison of baseline to end-of-treatment (EoT) values of total testosterone revealed that 6 
subjects in the MLE4901 group, 3 subjects in the olanzapine group and 2 subjects in the placebo 
group had shifted from normal testosterone at baseline to low testosterone below the normal 
range.  The decrease was greater in the MLE4901 and olanzapine groups.  Two male subjects in 
the MLE4901 treatment group had total testosterone values less than 150 ng/dL; no male 
subjects in either the olanzapine or placebo groups had testosterone values less than 150 ng/dL.  
No female subjects in the study had total testosterone values below the normal range of 20 to 76 
ng/dL. 
A total of 6 SAEs were reported in this study population of adult patients with symptomatic 
schizophrenia at admission.  All SAEs were reported as psychotic disorder; 4 events were in the 


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MLE4901 group (9%; all moderate intensity) and 2 events were in the placebo group (5%; 1 
moderate and 1 severe intensity).  Discontinuations due to an AE with onset during treatment 
occurred in both the MLE4901 and placebo groups.  Psychotic disorder led to the discontinuation 
of 3 (7.0%) subjects in the MLE4901 group and 2 (5%) subjects in the placebo group.  There 
were no other significant AEs reported in the study.  The overall incidence of AEs was highest in 
the olanzapine group (82%), followed by the MLE4901 and placebo groups (67% and 66%, 
respectively).  Most AEs were mild to moderate in severity.  The most common AEs reported in 
patients with schizophrenia administered MLE4901 were headache, vomiting, nausea, psychotic 
disorder (i.e., failure of efficacy as MLE4901 did not differentiate from placebo in this study), 
sedation, decreased appetite, somnolence and stomach discomfort. 
MLE4901 Treatment of Women with PCOS 
This was a double-blind, randomized, parallel-group, placebo-controlled Phase 2a study that 
assessed the effects of MLE4901 in women with PCOS.  The study’s 28-day treatment and 
intensive blood sampling regimen (baseline, Day 7 and Day 28) were designed to evaluate the 
onset of action of MLE4901 and to provide preliminary information concerning the durability of 
those effects with daily administration of MLE4901 (20 mg QD, 20 mg BID and 40 mg BID) 
and placebo.  A total of 67 women diagnosed with PCOS were randomized into the study across 
9 study sites.  Of the 65 subjects who received the investigational product, 49 subjects were 
randomized to receive MLE4901 and 16 to receive placebo. 
The study showed that MLE4901 at the 40 mg BID dose decreased LH and free testosterone 
levels and reduced LH pulse frequency, as follows:  
• LH: mean AUC0-8h fell by ~52% (95% CI, 32.73 to 70.36%) between baseline and 
Day 7 in subjects treated with the highest tested dose of MLE4901 (40 mg BID) 
compared to placebo. Less marked reductions were also observed at the lower tested 
doses, but their 90% CIs did not conclusively demonstrate a reduction compared to 
placebo. Post-hoc subset analysis of subjects lacking strong biochemical evidence of 
recent ovulation (progesterone <6 ng/mL throughout the study) further revealed 
marked reduction of LH AUC0-8 on Day 28 of treatment (95% CI, 45.43 to 93.38%). 
• Free testosterone: mean AUC0-8h decreased between baseline and Day 7 by 19% (90% 
CI, 67.75 to 96.59%) in subjects treated with the highest tested dose of MLE4901 (40 
mg BID) compared to placebo. Free testosterone also remained lower on Day 28 in 
this group (16% from baseline versus placebo), but its 90% CI (69.60, 100.38%) did 
not conclusively establish a reduction compared to placebo. Similar results were 
obtained for Cavg. Post-hoc subset analysis of subjects lacking strong biochemical 
evidence of recent ovulation (progesterone <6 ng/mL throughout the study) clearly 
showed a reduction of free testosterone AUC0-8h on Day 7 and Day 28 (~23%) of 
treatment with the highest dose of MLE4901 in comparison to subjects receiving 
placebo (90% CI: 66.10 to 90.49% for Day 7 and 64.95 to 90.04% for Day 28). For 
the subset analysis of Cavg, similar results were obtained.  
• LH pulsatility: a reduction by 3.55 pulses/8 hours (90% CI: -4.85 to -2.25; 95% CI: -
5.10, to -2.00] on Day 7 was observed in subjects receiving the highest dose of 
MLE4901 (40 mg BID) compared to placebo. This decrease was less pronounced in 
subjects receiving lower drug doses, where the 90% CI did not clearly establish a 


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reduction. At Day 28, a reduction in pulse frequency (decrease by 1.19 pulses/8 
hours) was still apparent at the highest dose, but was not conclusively (90% CI: -2.58 
to 0.19) different from placebo. Determination of mean differences in LH pulse 
number in subjects lacking clear biochemical evidence of ovulation (progesterone <6 
ng/mL) more plainly demonstrated a reduction at both 7 (decrease by 3.90 pulses/8 
hours) and 28 days (decrease by 1.89 pulses/8 hours) [90% CI, -5.14 to -2.66 on Day 
7 and -3.22 to -0.56 on Day 28].  
The underlying mechanism of action predicted for NK3 pathway blockade was confirmed, with 
MLE4901 decreasing LH pulsatility.  Lower doses of MLE4901 showed less marked changes 
from placebo. 
The safety profile of multiple-dose administration of MLE4901 in female patients with PCOS in 
this study did not raise any safety concerns.  Of the 49 subjects who received MLE4901, 32 
subjects (65.3%) reported at least 1 AE during the study, compared to 50.0% of subjects who 
received placebo.  Adverse events by system organ class are shown in Table 2.  
Table 2: 
Number (%) of Subjects Who Had at least 1 Adverse Event, by System 
Organ Class (Safety Analysis Set) 
 
Number (%) of Subjects 
 
 
MLE4901 
System Organ Class: 
Placebo 
(N=16) 
20 mg QD 
(N=15) 
20 mg BID 
(N=17) 
40 mg BID 
(N=17) 
 
Total 
MLE4901 
(N=49) 
Subjects with any AE 
8 (50.0%) 
8 (53.3%) 
14 (82.4%) 
10 (58.8%) 
32 (65.3%) 
Nervous System Disorders 
5 (31.3%) 
3 (20.0%) 
5 (29.4%) 
5 (29.4%) 
13 (26.5%) 
Gastrointestinal Disorders 
1 (6.3%) 
4 (26.7%) 
4 (23.5%) 
1 (5.9%) 
9 (18.4%) 
Infections and Infestations 
2 (12.5%) 
4 (26.7%) 
3 (17.6%) 
1 (5.9%) 
8 (16.3%) 
Skin and Subcutaneous Tissue 
Disorders 
0 (0.0%) 
0 (0.0%) 
3 (17.6%) 
1 (5.9%) 
4 (8.2%) 
General Disorders and 
Administration Site Conditions 
1 (6.3%) 
0 (0.0%) 
1 (5.9%) 
2 (11.8%) 
3 (6.1%) 
Injury, Poisoning and 
Procedural Complications 
0 (0.0%) 
1 (6.7%) 
2 (11.8%) 
0 (0.0%) 
3 (6.1%) 
Investigations 
0 (0.0%) 
2 (13.3%) 
0 (0.0%) 
1 (5.9%) 
3 (6.1%) 
Reproductive System and Breast 
Disorders 
2 (12.5%) 
1 (6.7%) 
1 (5.9%) 
0 (0.0%) 
2 (4.1%) 
Musculoskeletal and Connective 
Tissue Disorders 
0 (0.0%) 
1 (6.7%) 
0 (0.0%) 
1 (5.9%) 
2 (4.1%) 
Respiratory, Thoracic and 
Mediastinal Disorders 
0 (0.0%) 
0 (0.0%) 
2 (11.8%) 
0 (0.0%) 
2 (4.1%) 
Ear and Labyrinth Disorders 
0 (0.0%) 
0 (0.0%) 
1 (5.9%) 
0 (0.0%) 
1 (2.0%) 
Eye Disorders 
0 (0.0%) 
1 (6.7%) 
0 (0.0%) 
0 (0.0%) 
1 (2.0%) 


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Number (%) of Subjects 
Renal and Urinary Disorders 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (5.9%) 
1 (2.0%) 
Vascular Disorders 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (5.9%) 
1 (2.0%) 
AE: Adverse event; MedDRA: Medical Dictionary for Regulatory Activities; N: Number of subjects; PT: Preferred 
Term; SOC: System Organ Class 
Number (%) of subjects with AEs, sorted by SOC in decreasing order of frequency (sorted by total number on 
MLE4901).  A subject could have had 1 or more PTs reported under a given SOC. MedDRA version 16.1. 
The most commonly reported AEs in the MLE4901 treatment groups in the study were in the 
system organ classes (SOCs) of nervous system disorders, gastrointestinal disorders and 
infections and infestations.  Headache was the most commonly reported AE in both of the 
MLE4901 and the placebo treatment groups (18.4% and 31.3%, respectively).  Most of the AEs 
observed in this study were mild in intensity, resolved by the end of the study and were deemed 
by the Investigators unrelated to MLE4901. 
Additional information may be found in the Investigator’s Brochure. 
1.2. 
Research Hypothesis 
The study will evaluate the hypothesis that treatment with MLE4901 will result in improvements 
in symptoms associated with PCOS such as menstrual irregularity, hirsutism, acne and alopecia. 
1.3. 
Rationale for Conducting This Study 
The use of MLE4901 in PCOS is based on established literature on the hypothalamic kisspeptin, 
neurokinin B and dynorphin (KNDy) neurons. An NK3 receptor antagonist, MLE4901 is 
expected to decrease LH hyperpulsatility via modulation of GnRH, thereby improving symptoms 
associated with PCOS.  In vitro and in vivo data indicate that NKB, the ligand for the NK3 
receptor, is 1 of 3 generators of GnRH pulsatility (Lehman 2010, Maeda 2010).  
In the previous Phase 2a schizophrenia study, conducted primarily in men, MLE4901 did not 
meet the psychiatric endpoints, but was associated with decreases in testosterone. It was 
hypothesized that this was due to blockade of the effect of NKB through NK3 receptor 
antagonism, decreasing GnRH pulse activity, with the consequent observed effects on LH and 
downstream gonadal hormones. In patients with PCOS, the clinical effect of MLE4901 would be 
to reduce the ‘over-activity’ of the GnRH pulse generator in patients with PCOS, thereby 
normalizing the hormonal axis. 
Based on these results, the 28-day Phase 2a study in PCOS was conducted. In this study, 
MLE4901 at doses of 40 mg BID showed decreases in testosterone, LH and LH pulsatility after 
7 and 28 days of treatment, establishing proof-of-mechanism. Lower doses of MLE4901 showed 
lesser effects on testosterone and LH.   
The current study, with a 28-week Treatment Period and an 8-week Follow-up Period, will be 
conducted to evaluate the efficacy of MLE4901 in improving symptoms of PCOS such as 
menstrual irregularity, hirsutism, acne and alopecia.  


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1.4. 
Benefit/Risk and Ethical Assessment 
In preclinical and clinical studies to date, MLE4901 has been well tolerated.  At very high doses, 
preclinical data indicate potential adaptive change effects on the liver and thyroid, as well as on 
QT interval prolongation. However, these effects occurred at 70-1000 times the clinical dose. 
None of these effects have been observed in the clinical program to date; and subjects’ liver 
function tests (LFTs), ECGs and TSH will be monitored during the study. 
As a disease of premenopausal women, the subjects in the study are necessarily of childbearing 
potential, although PCOS often impairs fertility.  Subjects will be required to use reliable 
contraception throughout the study and must not seek to become pregnant while participating.  
Hormonal contraception is disallowed as it could impact the primary efficacy measurements. 
Polycystic ovary syndrome can result in disruption of menstruation, infertility, virilization, and, 
in the longer term, serious metabolic consequences.  Treatments are available, but only suppress 
symptoms of PCOS with variable effectiveness and do not address the underlying 
pathophysiology.  MLE4901 addresses the underlying biology of PCOS and the previous 28-day 
study of MLE4901 demonstrated improvements in LH pulse frequency and decreases in 
androgen levels. The dose of MLE4901 to be tested in the current study will be 40 mg BID, the 
efficacious dose in the previous Phase 2a study. Notably, the highest dose of 40 mg BID is 140-
2000 times less than the doses tolerated in the long-term rat and dog toxicity studies, providing 
for a significant margin of safety. The current study will help to determine the efficacy of 
MLE4901 in ameliorating symptoms of PCOS. Based on the currently available data, the 
benefit:risk is reasonable and administration of MLE4901 to additional women with PCOS is 
justified. 


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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
• To evaluate the efficacy of MLE4901 compared to placebo in improving menstrual 
regularity in women with oligo-/amenorrhea due to PCOS 
2.2. 
Secondary Objectives 
• To evaluate the efficacy of MLE4901 compared to placebo during the 28-week 
Treatment Period in improving: 
− ovulation regularity 
− the Most Bothersome Symptom of PCOS 
− hormone levels (including testosterone, luteinizing hormone (LH), follicle-
stimulating hormone (FSH), LH/FSH, estradiol, progesterone and anti-Müllerian 
hormone (AMH)) 
− clinical signs of hyperandrogenism (hirsutism, acne and alopecia) 
− metabolic syndrome-related parameters (including fasting glucose, insulin, lipid 
panel, blood pressure and body mass index (BMI)) 
• To determine the durability of MLE4901 effects during the 8-week Follow-up Period 
• To explore the impact of MLE4901 on measures of health-related quality of life and 
work productivity 
• To assess the safety and tolerability of MLE4901 
• To determine the pharmacokinetic (PK) parameters of MLE4901 and its major 
metabolite 
• To evaluate the PK/PD relationships of MLE4901 
 


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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This is a Phase 2b double-blind, randomized, parallel-group, placebo-controlled study of 
MLE4901 versus placebo in women with PCOS.  The study will be conducted at approximately 
30 sites in the US.  
Following a Screening Period of up to 12 weeks, an 8-week Lead-in Period (starting with a 
progestin challenge) will be used to better characterize the study population. A Treatment Period 
of 28 weeks’ duration will follow the Lead-in Period. Then, an 8-week Follow-up Period (i.e., no 
study drug) will be used to assess the durability of effects of MLE4901.  The study duration will 
be approximately 48 weeks (11 months) per subject. A schematic of the study design is presented 
in Figure 2. A detailed schedule of study assessments is presented in Appendix 1. 
Figure 2: 
Study Schematic 
 
3.1.1. 
Screening Period 
The Screening Visit will assess the subjects’ preliminary eligibility for the study based on the 
inclusion and exclusion criteria.  In addition, pertinent information will be collected such as past 
medical history, demographic data and prior and current medications.  The Screening Visit will 
also assess laboratory tests as part of study eligibility.  If needed, subjects will undergo a wash-
out of medications used to treat symptoms of PCOS. Subjects who meet all of the inclusion 
criteria and none of the exclusion criteria that are assessable during Screening will undergo a 
transvaginal ultrasound (TVU) and enter into the Lead-in Period. Note: Subjects do not need to 
wait for Screening/Wash-out hormone results prior to proceeding with the TVU and the Lead-in 
Period. All Screening/Wash-out hormone results should be reviewed and confirmed to be 
inclusionary prior to Randomization. 
3.1.2. 
Lead-in Period 
The Lead-in Period will last for 8 weeks, with visits every 4 weeks. At the beginning of the 
Lead-in Period, all subjects will undergo a progestin challenge with medroxyprogesterone 


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acetate (MPA) 10 mg orally QD for 5 days. During the Lead-in Period, subjects will use an 
electronic self-reported daily diary to report menstrual bleeding.  In addition, ovulation status 
will be assessed by having subjects collect urine for pregnenediol-3-glucuronide three times per 
week.  Instructions on proper use of the diary and collection of urine samples will be provided at 
the study site.  Continued study eligibility (including frequency of menstrual periods) will be 
assessed during the Lead-in Period, prior to randomization into the Treatment Period. 
3.1.3. 
Treatment Period 
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria will enter 
the 28-week Treatment Period.  At Visit T1, additional information will be obtained to further 
characterize each subject’s baseline status (e.g., Most Bothersome Symptom associated with 
PCOS, Polycystic Ovary Syndrome Questionnaire (PCOSQ) domain scores, PCOS Acne 
Questionnaire, EQ-5D-5L score, Patient Health Questionnaire-4 (PHQ-4) score, Work 
Productivity and Activity Impairment: General Health (WPAI:GH) domain scores, Ferriman-
Gallwey score, Investigator’s Static Global Assessment (ISGA) of acne, Savin score, laboratory 
tests, etc.).  Subjects will be stratified by frequency of self-reported menstrual periods (<4/year 
vs 4-6/year) and by baseline BMI (22 to <35 kg/m2 vs 35 to 45 kg/m2) and randomized 1:1 into 
one of two study arms: MLE4901 40 mg BID or placebo BID. 
Note: for subjects not on any hormone therapy during the past year, the number of menstrual 
periods over the past year should be used for stratification. For subjects who were on hormone 
therapy such as oral contraceptive medications during the past year, the number of menstrual 
periods per year prior to commencing hormone therapy should be used for stratification. Women 
who received every-3-month progestin challenge and no other hormonal therapy during the year 
prior to Screening and who did not have any menstrual bleeding other than that due to 
withdrawal from progestin challenge may be randomized (if they meet all other 
inclusion/exclusion criteria) into the <4 menstrual cycles per year stratum. 
All tablets used in the study will be identical in appearance to maintain double-blind status.  
Study drug will be administered orally beginning on Day 1 of the Treatment Period.  The first 
dose of study drug will be given at the study site. During the Treatment Period, subjects will 
continue to self-report menstrual bleeding and collect thrice-weekly urine samples for 
assessment of ovulation status. Additional study visits will take place 2, 4, 6, 8, 12, 16, 20, 24 
and 28 weeks after initiation of study drug to evaluate the subjects for changes in questionnaire 
responses; Investigator assessments of hirsutism, acne and alopecia; and hormone levels. 
3.1.4. 
Follow-up Period 
An 8-week Follow-up Period will occur immediately after the Treatment Period, with visits 
every 4 weeks.  No study drug will be administered during this period.  However, subjects will 
continue to self-report menstrual bleeding and collect thrice-weekly urine samples for 
assessment of ovulation status.  This period will be used to assess the durability of effects of 
MLE4901. 
Throughout the course of the study, safety evaluations will include assessment of AEs, 
concomitant medications, clinical laboratory tests, vital signs, physical examinations and 12-lead 
ECGs. 


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3.2. 
Rationale for Study Design and Dose Levels 
MLE4901 is an NK3 receptor antagonist that has shown to decrease LH and testosterone levels 
in women with PCOS.  This Phase 2b study will assess the ability of MLE4901 at various dose 
levels to restore regularity of menses and correct other symptoms of PCOS in women with oligo-
/amenorrhea due to PCOS. 
The study is randomized in order to minimize any bias in determining which subject receives 
which dose level of MLE4901 or placebo.  The study is double blinded so there is no bias 
introduced by knowledge of the treatment identity received by a subject in reporting the clinical 
findings.  Double blinding also minimizes the bias in assessing treatment response measures that 
could be introduced by the Investigators had they known the treatment identity.  The study is 
placebo-controlled in order to have a comparison group to help determine whether safety 
findings during the study are related to the study drug and also to provide a true control rate for 
the assessment of efficacy.  The 8-week Lead-in Period will allow establishment of baseline data 
on PCOS symptoms.  Previous studies of various treatments for PCOS have been limited by their 
short term treatment duration.  The 28-week Treatment Period will allow adequate time to 
determine the onset and consistency of changes in monthly menstrual cycles, PCOS symptoms, 
hormonal levels and quality of life. Stratification of randomized subjects as having <4 or 4-6 
menstrual cycles/year and as having BMI 22 to <35 or 35 to 45 kg/m2 is based on findings from 
a previous PCOS study (Azziz 2001) that demonstrated that subjects in the highest ovulatory rate 
tertile had a higher baseline menstrual period frequency (5.3 menses/year) than those in the 
lowest tertile (3.3 menses/year); also, the highest ovulatory rate tertile had a mean BMI of 33.3 
kg/m2 compared to 38.7 kg/m2 for the lowest tertile. In addition, 4 menses/year is the benchmark 
for minimizing endometrial hyperplasia and risks associated with endometrial cancer.  
Based on toxicity investigations in preclinical species, previous clinical observations in PK and 
PD responses, expected bioavailability, continuous suppression of testosterone and LH pulse 
frequency and safety demonstrated in a previous MLE4901 study in women with PCOS, the dose 
of 40 mg BID has been selected to evaluate the clinical effects of MLE4901 in women with 
PCOS. 
3.3. 
Criteria for Study Termination 
An unblinded Data Safety Monitoring Board (DSMB) will review pooled and individual subject 
data during the course of the study. In addition, a single occurrence of the following safety 
events will trigger an expedited, ad hoc DSMB meeting to review individual cases in an 
unblinded manner: 
• Hepatic toxicity such as marked elevations in transaminases or simultaneous elevations in 
hepatic transaminases and bilirubin (i.e., Hy’s Law) 
• Severe renal impairment  
• Severe cardiovascular dysfunction such as arrhythmia or valvular dysfunction 
If the DSMB determines that the event is drug-related and a clear safety signal has been 
identified, early termination of the study may occur. 


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4. 
STUDY POPULATION SELECTION 
4.1. 
Study Population 
Approximately 110 subjects (55 per study arm) are planned to participate in this study.  The 
subject population will consist of adult pre-menopausal women with oligo-amenorrhea who meet 
criteria for a diagnosis of PCOS by also having 1) clinical signs of hyperandrogenism and/or 2) 
biochemical hyperandrogenism and/or 3) polycystic ovaries on screening transvaginal ultrasound 
(TVU). 
4.2. 
Inclusion Criteria 
Each subject must meet all of the following criteria to be randomized into this study: 
1. Provision of signed and dated informed consent prior to any study-specific procedures 
2. Women 18 to 45 years of age (inclusive) at Screening 
3. Oligo-/amenorrhea defined as ≤6 menstrual cycles per year off of any hormone therapy (may 
be based on subject historical recall) 
4. At least one of the following during Screening: 
• Clinical signs of hyperandrogenism, where clinical hyperandrogenism may include 
hirsutism (defined as excessive terminal hair that appears in a male pattern), acne, or 
androgenic alopecia 
• Biochemical hyperandrogenism defined as an elevated serum androgen level (i.e., total, 
bioavailable or free testosterone level ≥ULN) 
• Polycystic ovarian morphology, defined as the presence of 12 or more follicles 2-9 mm in 
diameter and/or an increased ovarian volume >10 mL (without a cyst or dominant 
follicle) in either ovary 
5. Body mass index (BMI) 22 to 45 kg/m2, inclusive 
6. Must be willing to avoid use of all hair removal procedures (e.g., electrolysis, laser hair 
removal, plucking/tweezing, waxing, threading, etc.) and products (e.g., Vaniqa®, Nair™, 
etc.) during study participation in the areas of the scalp, upper lip, chin, chest, back, 
abdomen, upper arms and thighs 
Note: Shaving is allowed; however, subjects must not shave within 72 hours prior to visits 
S1, T1 and T7 to permit assessment of hair growth 
7. Must be willing to avoid all prescription treatments for acne and not increase the dose or 
frequency of their current non-prescription acne treatment regimen during study participation 
8. Must be willing to avoid the use of all hair growth procedures (e.g., hair transplant) and 
products (e.g., minoxidil (Rogaine®)) during study participation 
9. Must be willing to avoid the use of all of the other prohibited medications (including 
metformin, oral contraceptives, clomiphene, letrozole, spironolactone, finasteride and 
flutamide) and procedures during study participation (Sections 5.12 , 5.13  and 5.14) 
10. Permanently surgically sterilized (bilateral salpingectomy or tubal occlusion) >2 years or 
male partner(s) has had a vasectomy >2 years or must consent to use two permitted 
medically-acceptable methods of contraception throughout the study during any sexual 
intercourse with a male partner.  Permitted medically-acceptable methods of birth control for 


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this study are defined as use of a male condom plus one of the following: spermicide, 
diaphragm with spermicide, or an intrauterine device that does not contain steroid hormones.   
11. Must agree to not attempt to conceive during participation in the study 
4.3. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from participation in the study: 
1. Menopausal or peri-menopausal, defined for this study as FSH >10 IU/L 
2. Irregular vaginal/menstrual bleeding caused by conditions other than PCOS (e.g., uterine 
polyps or submucosal uterine fibroids) 
3. For women ≥21 years of age, abnormal Papanicolaou (Pap) test during Screening requiring 
follow-up sooner than 1 year after the test (Notes: Results from a Pap test performed within 1 
year prior to Screening may be used. Women under 21 years of age at Screening do not 
require a Pap.)  
4. Uncontrolled hypo- or hyperthyroidism, defined as having an abnormal TSH during 
Screening or Lead-in and/or change in thyroid medication dose within the month prior to 
Screening 
5. Any suspected cause of hirsutism, acne, or alopecia other than PCOS 
6. Post-hysterectomy or endometrial ablation 
7. Post-oophorectomy (unilateral or bilateral) or other ovarian surgery 
8. No menstrual periods during Lead-in (i.e., failed progestin challenge) 
9. Two or more menstrual periods during Lead-in 
10. Use of any of the following medications within 28 days prior to the wash-out visit (for those 
requiring wash-out; see Section 5.12 for additional prohibited medications):  
• Metformin or other insulin-sensitizing medications (e.g., rosiglitazone, pioglitazone, etc.)  
• Hormonal contraceptives (e.g., birth control pills, hormone-releasing implants, etc. Depo-
Provera needs to be washed out for 16 weeks.)  
• Hormone-releasing intrauterine device  
• Anti-androgens (e.g., spironolactone, flutamide, finasteride, etc.)  
• Clomiphene citrate or estrogen modulators such as letrozole  
• GnRH modulators such as leuprolide  
Note: Women who received every-3-month progestin challenge and no other hormonal 
therapy during the year prior to Screening and who did not have any menstrual bleeding 
other than that due to withdrawal from progestin challenge, may be randomized (if they meet 
all other inclusion/exclusion criteria) into the <4 menstrual cycles per year stratum. 
11. Medical requirement for any of the prohibited concomitant medications 
12. Medical history of type 1 or type 2 diabetes mellitus  
13. Uncontrolled hypertension, defined as systolic blood pressure ≥160 mmHg or diastolic blood 
pressure ≥90 mmHg 
14. Any history of gastric or small intestinal surgery or any current disease that causes 
malabsorption 
15. Alcohol or substance abuse (cocaine, amphetamines and/or opioids) within the year prior to 
Screening 
16. Abnormal laboratory values as per the guidelines listed below or any other clinically 
significant, unexplained laboratory abnormality according to the Investigator: 
• ALT or AST >2 times ULN 


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• Total bilirubin >1.5 times ULN 
• Creatinine >1.5 times ULN 
• Fasting glucose >126 mg/dL (6.99 mmol/L) 
• Hemoglobin A1c >6.5% 
• Prolactin >ULN 
• 17-hydroxyprogesterone >200 ng/dL (6 nmol/L) 
• Total testosterone >150 ng/dL (5.21 nmol/L) 
• DHEA-S >800 µg/dL (21.6 µmol/L) 
• TSH >ULN or <LLN 
17. Currently pregnant or breastfeeding or having conceived or given birth within the 3 months 
prior to Screening 
18. QTc >470 msec on electrocardiogram at Screening or at Visit T1 (subjects with a single QTc 
>470 msec may have 2 additional ECGs taken and the QTcs averaged; if the average QTc is 
>470 msec then the subject is excluded) 
19. History of Gilbert’s syndrome or autoimmune hepatitis 
20. HIV, hepatitis B, or hepatitis C positivity 
21. Any malignancy within the previous 10 years, other than curatively resected basal or 
squamous cell skin cancer 
22. Previous receipt of any amount of MLE4901, AZD4901 or AZD2624 
23. Participation in any study of an investigational drug or device or investigational biological 
agent within 30 days (or 5 half-lives of the investigational agent, whichever is longer) prior 
to Screening 
24. Any other medical or psychiatric condition (e.g., uncontrolled sleep apnea, severe depression, 
etc.) that, in the opinion of the Investigator, is likely to confound the interpretation of the 
study results or prevent the subject from understanding the requirements of or successfully 
completing the study 


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5. 
STUDY TREATMENT 
5.1. 
Assignment of Subject Identification Numbers 
Once the subject has signed the ICF at Screening, site personnel will assign a subject 
identification number (ID). The subject ID will include the site number (3 digits) and 3 digit 
subject number, assigned sequentially starting with 001. This number will be utilized to identify 
the subject throughout the study period. Each subject ID will only be assigned to one subject, 
e.g., if a subject is withdrawn from the study early, their subject ID will not be used for a new 
subject. 
5.2. 
Description of Study Drug 
The drug product consists of a white, round, immediate release tablet of MLE4901 40 mg (free 
base) for oral administration. A placebo tablet has been developed to match the appearance of the 
active tablet in size, shape, color and weight. 
Study drug will be supplied as 40 mg tablets that are identical in appearance to the placebo as 
described in Table 3. 
Table 3: 
Investigational Product 
 
Investigational Product 
Product Name: 
MLE4901 
Placebo 
Dosage Form: 
tablet 
tablet 
Unit Dose 
40 mg 
0 mg 
Route of Administration 
Oral 
Oral 
Physical Description 
Plain, round, biconvex, white 
film-coated tablets 
Plain, round, biconvex, white 
film-coated tablets that appear 
identical to MLE4901 tablets 
Manufacturer 
Patheon 
Patheon 
Tests for identity, activity, purity and safety will be performed for the MLE4901 formulation.  A 
certificate of analysis will be provided to the Sponsor prior to drug product shipment.  For more 
information regarding the manufacturer and fill/finish, refer to the most recent version of the 
Investigator’s Brochure.   
5.3. 
Study Drug Packaging and Labeling 
The formulation and bulk packaging of MLE4901 will be conducted according to standard 
procedures.  The drug product will be packaged and labeled by Millendo Therapeutics, Inc.’s 
designated contract packager and labeled according to regulatory requirements. 
5.4. 
Study Drug Storage and Accountability 
Study drug must be kept in a secure location and stored at controlled room temperature at the 
study site within its original container and protected from light.  A daily temperature log for 
monitoring of proper storage conditions must be maintained by the site. 


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Access to study drug must be restricted to designated study personnel only.  Under no 
circumstances should the Investigator or other site personnel supply study product to other 
Investigators or clinics, or allow the supplies to be used other than as directed by this protocol 
without written authorization from Millendo Therapeutics, Inc.  The Investigator (or designee) 
must maintain records of the delivery of the study drug to the study site, the inventory at the 
study site, use for each subject and return of the study drug to a designee of the Sponsor or 
destruction.  Total study site accountability will be conducted at the end of the study and the 
Investigator must explain all discrepancies.  A Site Drug Accountability Log will be supplied by 
Millendo Therapeutics, Inc. or designated CRO.  This log must be kept current and will contain 
information such as: 
• Identification (subject ID) of the subject to whom the study drug was dispensed 
• The dates and lot numbers for the dispensed study drug 
• Initial inventory on receipt of drug at the site 
• Final inventory on completion of the study 
All records and inventory must be available for inspection by the clinical study monitor.  
Additional details on the storage and handling of MLE4901 are provided in the Pharmacy 
Manual. 
5.5. 
Medroxyprogesterone Acetate 
Medroxyprogesterone acetate (MPA), 10 mg orally once per day for 5 days, will be used at the 
beginning of the Lead-in Period for the progestin challenge. MPA tablets must be kept in a 
secure location and stored at the study site under conditions consistent with the label for MPA. 
For further details, see the Pharmacy Manual. 
5.6. 
Study Drug Administration 
Subjects will be randomized to be treated with MLE4901 40 mg BID or placebo BID. Each 
treatment will consist of one tablet (MLE4901 40 mg or placebo) taken orally BID. Each study 
dose will be self-administered by the subject with a nonalcoholic beverage (except grapefruit 
juice). At each Treatment Period visit except T3.5, T5.5, T6.5, and T7, the morning study drug 
dose will be taken at the study site. Plasma for PK analysis will be drawn at Visits T1, T3, T5 
and T7. 
If a subject forgets to take a dose on a given day (e.g., the AM dose was not taken), a “make up” 
dose should not be taken. Study drug may be withheld if needed if, for example, the subject has a 
temporary medical need for a prohibited medication. The Investigator should discuss potential 
events of this nature with the study Medical Monitor and Sponsor prior to the event if at all 
possible. 
5.7. 
Dose Adjustment Criteria 
Study drug doses will not be adjusted during the study. 


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5.8. 
Study Drug Compliance 
The investigational product is to be dispensed by qualified personnel at the study site and only to 
subjects randomized into the study.  Subject compliance with therapy will be assessed by 
reviewing the collected study drug at scheduled study visits and documenting the review on the 
eCRF. If subject compliance with study drug administration is outside of the range of 80-120%, 
then the subject will receive additional instruction on compliance. 
5.9. 
Randomization and Blinding 
All tablets used in the study will be identical in appearance to maintain double-blind status. 
Subjects will administer MLE4901 and/or placebo tablets BID as described in Section 5.6. 
Study drug will be packaged as described in Section 5.3. 
The following personnel will be unblinded as to the exact content of investigational treatments 
(i.e., the randomization code): 
• Personnel analyzing the PK samples 
• CRO statistician and programmers preparing tables for DSMB review 
• DSMB members 
Subjects will be stratified by frequency of self-reported menstrual periods (<4/year vs 4-6/year) 
and by baseline BMI (22 to <35 kg/m2 vs 35 to 45 kg/m2) and randomized 1:1 into one of two 
study arms: MLE4901 40 mg BID or placebo BID.  The randomization list will be kept in a 
secure location until after database lock at the end of the study; however, the treatment 
assignment for an individual subject will be provided if unblinding is necessary for a related 
SAE. The procedures for emergency unblinding are provided in Appendix 14.   
5.10. 
Study Drug Retention at Study Site 
At the time of study close-out, Millendo Therapeutics, Inc. will direct the site regarding the 
disposition of any unused study drug, i.e., whether it is to be destroyed or be returned to the 
Sponsor’s designated location. See Pharmacy Manual. 
5.11. 
Concomitant Medications 
Use of concomitant medications should be kept to a minimum during the study.  However, if 
concomitant medications are considered necessary for the subject’s welfare and are unlikely to 
interfere with the investigational product, they may be given at the discretion of the Investigator.  
During the study, any medication given other than the study drug (including blood transfusions, 
parenteral fluids and premedications) is to be considered a concomitant medication and must be 
documented on the electronic case report form (eCRF).   
5.12. 
Prohibited Medications 
The following medications are prohibited from 28 days prior to the wash-out visit (for those 
requiring wash-out) through the end of the study (including the 8-week Follow-up Period): 
• Metformin, rosiglitazone, or pioglitazone 


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• Hormonal contraceptives (e.g., birth control pills, hormone-releasing implants, etc. 
Depo-Provera needs to be washed out for 16 weeks.) 
• Hormone-releasing intrauterine devices 
• Anti-androgens (e.g., spironolactone, flutamide, finasteride (Propecia®), etc.) 
• Clomiphene citrate or estrogen modulators such as letrozole 
• GnRH modulators such as leuprolide 
The following medications are prohibited from Screening through the end of the study (including 
the 8-week Follow-up Period): 
• Minoxidil (Rogaine®) and any other hair growth products 
• Eflornithine (Vaniqa®) and other depilatory creams (e.g., Nair™) may not be used in 
the areas of the upper lip, chin, chest, back, abdomen, upper arms and thighs 
• Prescription treatments for acne 
• New medications or over-the-counter supplements/therapies used with the intent to 
induce or cause weight loss. Subjects entering the study on a stable regimen of weight 
loss medications, whose weight is documented to have been stable for at least 3 
months, should continue their maintenance medications at the same dose and 
frequency. 
• Moderate to strong inducers of CYP3A4, including bosentan, carbamazepine, 
modafinil, nafcillin, phenytoin, rifampin, St. John's wort 
5.13. 
Prohibited Procedures 
The following procedures are prohibited during the study: 
• Elective hysterectomy, endometrial ablation, or ovarian surgery 
• Any form of intentional weight loss including weight-loss diets or bariatric surgery 
• Hair removal procedures (e.g., electrolysis, laser hair removal, plucking/tweezing, 
waxing, threading, etc.) are prohibited in the areas of the scalp, upper lip, chin, chest, 
back, abdomen, upper arms and thighs. Note: shaving is allowed; however, subjects 
must not shave within 72 hours prior to visits S1 (Screening), T1 (Randomization) and 
T7 (End-of-Treatment) to permit assessment of hair growth. 
• Hair growth procedures (e.g., hair transplant)  
5.14. 
Restricted Medications 
The use of the following medications is restricted as follows: 
• Subjects should not increase the dose or frequency of their Screening non-
prescription acne treatment regimen during the study. Starting a new anti-acne 
therapy or restarting a previously used anti-acne therapy is not allowed. 


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• Anti-lipid medications should remain at the same dose and frequency of use as at 
Screening during the study 
• The following medications are allowed but should be used with caution: 
− Moderate to strong inhibitors of CYP3A4, including: clarithromycin, conivaptan, 
grapefruit juice, itraconazole, aprepitant, ciprofloxacin, crizotinib, diltiazem, 
erythromycin, fluconazole, imatinib, verapamil, ketoconazole (systemic exposure 
only), nefazodone, posaconazole, telithromycin, voriconazole 
− Sensitive CYP3A4 substrates, including: alfentanil, aprepitant, budesonide, 
buspirone, conivaptan, darifenacin, dasatinib, dronedarone, eletriptan, eplerenone, 
everolimus, felodipine, fluticasone (systemic exposure only), lovastatin, 
lurasidone, midazolam, nisoldipine, quetiapine, simvastatin, sirolimus, tolvaptan, 
triazolam, ticagrelor 
• Anti-diabetic medications other than metformin, rosiglitazone, or pioglitazone should 
be limited only to those that are medically necessary 


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6. 
STUDY PROCEDURES 
6.1. 
Allowable Variation in Study Visits 
Visit time points are intended as targets and variations may be made to allow for logistical 
considerations and to accommodate scheduling conflicts.  Unless otherwise specified in this 
protocol, assessments are to be completed within ±3 days of the planned visit date.  The medical 
monitor should be contacted to discuss any visits that will occur greater than ±3 days outside of 
the planned visit schedule. 
6.2. 
Informed Consent 
Prior to any study specific screening evaluations and study participation, written informed 
consent will be obtained from each subject to be involved in the study by using the Institutional 
Review Board or Ethics Committee (IRB/EC)-approved Informed Consent Form (ICF).  
Potential subjects will be informed in detail about the study drug and the nature of the clinical 
investigation with the risks and discomforts to be expected.  The subjects will also be instructed 
that they are free to withdraw their consent and discontinue their participation in the clinical 
study at any time.  The Investigator or qualified designee will verify that the subject has granted 
consent.  Each subject will be given a copy of the signed ICF.  Certified translated ICFs will be 
provided by the Sponsor in those languages required or requested by investigational sites.  
6.3. 
Eligibility 
Review of relevant study inclusion/exclusion criteria will be done at/after the Screening Visit 
and at the start of the Lead-in Period; and a comprehensive review of all inclusion/exclusion 
criteria will be done prior to randomization into the Treatment Period. 
6.4. 
Medical History  
A complete medical history will be obtained at the Screening visit (Visit S1).  The following 
systems will be reviewed:  head, eyes, ears, nose and throat (HEENT), respiratory, 
cardiovascular, gastrointestinal/hepatobiliary (specifically, a history of liver dysfunction or the 
presence of hepatomegaly or splenomegaly), genitourinary/ reproductive, musculoskeletal, 
neurological, psychiatric, endocrine/metabolic, blood/lymphatic, dermatologic and immunologic.  
Past surgeries will also be recorded. 
6.5. 
Prior and/or Concomitant Medication Assessments 
Prior and concomitant medications include any treatments taken from Screening (Visit S1) until 
the end of the study (Visit F2). In addition, any treatments for symptoms of PCOS taken during 
the year prior to Screening should be recorded. Any treatments given during the study other than 
MLE4901, including blood transfusions, parental fluids and herbal preparations, are considered 
concomitant therapy and must be recorded on the eCRF. All prior and concomitant medications 
will be coded using the latest version of the World Health Organization (WHO) Drug Dictionary, 
categorizing them by WHO Anatomical Therapeutic Chemical (ATC) levels 1-4 and drug name. 


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6.6. 
Vital Signs, Height, Weight and Body Mass Index 
Vital signs (oral temperature, systolic and diastolic blood pressure, pulse and respiratory rate) 
and weight will be measured at each study visit.  
Systolic and diastolic blood pressure should be taken in the same arm per subject at each study 
visit after the subject has been sitting for at least 5 minutes. Any clinically necessary deviations 
to this will be documented but do not need to be confirmed with the medical monitor prior to 
occurrence or documented as a protocol deviation. 
Body weight will be obtained at each study visit, using a calibrated scale, after voiding and 
without shoes or outerwear (i.e., coats). Height will be assessed only at Screening. Body mass 
index will be calculated based on body weight and Screening height. 
6.7. 
Physical Examination 
A complete physical examination (PE) will be obtained at Visits S1, T1 and T7. A brief PE will 
be performed at Visits T5 and F2. At all other visits, targeted PEs may be performed as needed 
based on adverse events and positives from review of systems. 
The following systems will be examined for a complete physical examination: HEENT, 
respiratory, cardiovascular, gastrointestinal/hepatobiliary (specifically the presence of 
hepatomegaly or splenomegaly will be assessed), musculoskeletal, neurological and 
dermatologic.  On a brief physical examination, the following systems will be examined: 
respiratory, cardiovascular, gastrointestinal/hepatobiliary and any areas pertinent to any adverse 
events and positives from review of systems. 
A Pap test may be performed as part of the physical examination at Visit S1 if the subject has not 
had one done within the past year. 
6.8. 
Electrocardiography and Determination of QTc 
All subjects will have 12-lead ECGs performed at Visits S1, T1, T5 and T7, prior to study drug 
dosing. The ECG test tracings will be interpreted by usual clinic procedures and ECG findings 
will be recorded on the eCRF. ECGs will be stored for later analysis if needed. 
If the QTc is greater than 470 msec on the Screening (Visit S1) ECG, three consecutive ECGs 
will be obtained and the QTc values corrected by the Fridericia method will be averaged.  If the 
average is greater than 470 msec, the subject will be ineligible for the study. 
For all ECGs, the QT interval will be corrected using the Fridericia method (QTcF = QT/RR0.33). 
During the study, if the QTcF is greater than 470 msec, a repeat 12-lead ECG will be obtained as 
soon as practicable. 
In the event of an abnormal ECG (especially in the setting of an intraventricular conduction 
delay) that makes QTc determination unreliable by standard means, the QT interval will be 
corrected by the method of Rautaharju et al.  
6.9. 
Transvaginal Ultrasound 
TVU will be performed by a trained ultrasonographer during the Screening Period and at Visit 
T7. The number and size of ovarian cysts, ovarian size and endometrial thickness will be 


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assessed. In addition, the ovaries, uterus and adnexae will be assessed for pathology such as the 
presence and size of uterine polyps as well as the presence, size and location of uterine fibroids. 
6.10. 
Menstrual Bleeding Diary  
Subjects will be instructed in the use of the daily electronic diary for recording menstrual 
bleeding at Visit L1. Review of diary entries and reinforcement of instructions if needed will 
occur at each scheduled study visit. From Visit L1 to Visit F2, subjects should enter information 
into the diary every day. The diary entries will be used to evaluate the number and duration of 
menstrual cycles and menstrual bleeding. (Appendix 9) 
6.11. 
PCOS Most Bothersome Symptom Questionnaire (MBSQ) 
The MBSQ will be administered at all study visits to evaluate the subjects’ Most Bothersome 
Symptom of PCOS (Appendix 2). At Visits S1, L1, L2 and T1, subjects will indicate their Most 
Bothersome Symptom of PCOS (oligo-/amenorrhea, hirsutism, acne, alopecia and other) prior to 
study entry. At all scheduled study visits, subjects will indicate the severity of each symptom of 
PCOS (hirsutism, acne, alopecia, irregular menses and other) using a Likert scale.  Changes in 
the questionnaire results will be used to assess the efficacy of MLE4901 in improving symptoms 
of PCOS. 
6.12. 
Hair Removal Questionnaire (HRQ) 
The self-administered HRQ at Visits S1, L1, T1, T5, T6, T7 and F2 will assess how often 
subjects remove unwanted hair from their upper lip and chin. (Appendix 3) 
6.13. 
Polycystic Ovary Syndrome Questionnaire (PCOSQ) and PCOS 
Acne Questionnaire 
The PCOSQ (Appendix 4) is a self-administered questionnaire for measuring health-related 
quality of life in women with PCOS. The PCOSQ has 5 domains: emotions, body hair, weight, 
infertility, and menstrual problems. (Cronin 1998) 
The PCOS Acne Questionnaire (Appendix 4) consists of 4 questions that assess health-related 
quality of life related to acne, scored on a 7-point Likert scale. (Barnard 2007) 
The PCOSQ and the PCOS Acne Questionnaire will be administered to subjects at Visits T1, T5, 
T7 and F2 and used to compare changes in health-related quality of life between treatment 
groups. 
6.14. 
EuroQol-5 Dimensions-5 Levels Survey (EQ-5D-5L) 
The EQ-5D-5L (an example of the English version for the US is provided in Appendix 5) is a 
descriptive system of health-related quality of life states consisting of five dimensions (mobility, 
self-care, usual activities, pain/discomfort, anxiety/depression), each of which can take one of 
five responses. The responses record five levels of severity within a particular EQ-5D dimension. 
(http://www.euroqol.org/about-eq-5d/eq-5d-nomenclature.html) The validated EQ-5D-5L survey 
will be administered to subjects at Visits T1, T5, T7 and F2 and used to compare changes in 
health status between treatment groups.  (http://www.euroqol.org/eq-5d-products/eq-5d-5l.html) 


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6.15. 
Patient Health Questionnaire-4 (PHQ-4) 
The PHQ-4 (Appendix 6) is a validated 4-item self-reporting tool that allows for a brief 
assessment of depression and anxiety. The validated PHQ-4 will be administered to subjects at 
Visits T1, T5, T7 and F2 and used to compare severity of depression and anxiety between 
treatment groups. (Kroenke 2009, Löwe 2010) 
6.16. 
Work Productivity and Activity Impairment: General Health 
Questionnaire (WPAI:GH) 
The WPAI:GH (Appendix 7) is a well-validated instrument to measure impairments in work and 
activities. It measures absenteeism, presenteeism, as well as impairments in unpaid activity 
because of health problems during the past seven days.  
The validated WPAI:GH questionnaire will be administered to subjects at Visits T1, T5, T7 and 
F2 and used to compare changes in work productivity and activity impairment between treatment 
groups. (http://www.reillyassociates.net/WPAI_GH.html)  
6.17. 
Patient’s Global Impression of Change (PGIC) 
The PGIC is administered to subjects at Visit T7 and used to compare assessments of overall 
changes in acne, unwanted hair and PCOS between treatment groups. (Appendix 8) 
6.18. 
Modified Ferriman-Gallwey Score for Hirsutism 
The Primary Investigator (or designee) will assess each subject’s degree of hirsutism using the 
modified Ferriman-Gallwey scale at Visits S1, T1 and T7. The clinician (MD, DO, NP, RN, or 
PA) performing this evaluation should be the same per subject during the course of the study. 
(Appendix 10; Ferriman 1961)  
6.19. 
Investigator’s Static Global Assessment (ISGA) of Acne Score 
The Primary Investigator (or designee) will assess each subject’s degree of acne according to the 
ISGA scale in Appendix 11 at Visits S1, T1 and every subsequent scheduled study visit. The 
clinician (MD, DO, NP, RN, or PA) performing this evaluation should be the same per subject 
during the course of the study.  
Appendix 11 also lists the photographic equivalents for each level of the ISGA scale from the 
Leeds Revised Acne Grading System shown in Appendix 12. (US Food and Drug Administration 
Guidance for Industry: Acne Vulgaris: Developing Drugs for Treatment. September 2005; 
Tazorac® Medical Review 2012, 
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202428Orig1s000MedR.pdf. Table 8, 
p 20; Appendix 12; O’Brien 1998) 
6.20. 
Savin Scale for Alopecia 
The Primary Investigator (or designee) will assess each subject’s degree of alopecia using the 
Savin scale at Visits S1, T1 and T7. The clinician (MD, DO, NP, RN, or PA) performing this 
evaluation should be the same per subject during the course of the study. (Appendix 13; Savin 
1994)  


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6.21. 
Pharmacokinetic Assessments 
Approximately 5 mL of blood will be drawn at each PK sampling time point: 
Table 4: 
Pharmacokinetic Sampling Time Points 
Visit 
Sampling Time Points (Morning Dose Only) 
T1 
0 (within 30 min predose), 1 hr (± 5 min), 2 hr (± 10 min), 
2.5 hr (± 10 min), 3 hr(± 10 min) and 4 hr (± 10 min) 
T3 
0 hr (trough, within 30 min predose) 
T5 
0 hr (trough, within 30 min predose) 
T7 
0 hr (trough) 
Logistic considerations may dictate a deviation from the specified time point; therefore, a 
window is permitted around each sampling time point, as shown in Table 4:  sampling times up 
to and including 1 hour postdose have a window of ± 5 min and subsequent time points have a 
window of ± 10 min. Actual times of sampling and actual dosing times of MLE4901 must be 
recorded on the eCRF.  Specific collection and shipment procedures for PK samples are provided 
in the Laboratory Manual.  All samples will be analyzed using a validated assay at a central 
laboratory. 
PK parameters will be derived using non-compartmental methods employing WinNonlin® 
Phoenix version 6.3 or later (Pharsight Corp., Mountain View, CA). The following PK 
parameters will be estimated for MLE4901 and its major metabolite M12 for T1 as data permit 
and as appropriate: 
Table 5: 
Pharmacokinetic Parameters 
Clast 
The last quantifiable drug concentration in plasma determined directly from 
individual concentration-time data 
Cmax 
The maximum drug concentration in plasma determined directly from 
individual concentration-time data 
Cmax/D 
Dose-normalized Cmax, calculated as the ratio of Cmax to dose 
Tmax 
The observed time to reach maximum concentration 
AUC0-t 
The area under the plasma concentration-time curve from time zero to the 
time of the last quantified concentration, calculated using the linear-up/log-
down trapezoidal rule 
AUC0-4h 
The area under the concentration-time curve from time zero to 4 h after 
dosing, calculated using the linear-up/log-down trapezoidal rule 
AUC0-4h/D 
Dose-normalized AUC0-4h, calculated as the ratio of AUC0-4h to dose 
λz 
The terminal phase rate constant, estimated by linear regression through the 
terminal phase of the log concentration-time profile 


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t½ 
The terminal phase half-life, calculated as: 
z
λ
)
2
ln(
t½ =
 
AUC0-∞ 
The area under the concentration versus time curve from time 0 to infinity (first 
dose only), calculated as AUC0-4h + Clast/λz 
AUC%extrap 
Percentage of AUC0-∞ extrapolated, represented as (1 - AUC0-t/AUC0-∞)*100 (Day l 
only) 
CL/F 
Oral clearance calculated as: 
Dose/AUC0-∞ (Day 1 only) 
6.22. 
Pharmacodynamic Assessments 
The relationship between Cmax, AUC and other PK parameters with efficacy assessments will be 
explored as appropriate. 
6.23. 
Adverse Events, Serious Adverse Events, Pregnancies and Reporting 
6.23.1. 
Definition of Adverse Event, Adverse Drug Reaction and Unexpected Adverse 
Drug Reaction 
Adverse Event (AE):  Any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug-related.   
• All AEs, regardless of relationship to study drug, should be collected beginning from 
the time the subject signs the study consent until the early termination/final visit or 30 
days after the last dose of study drug, whichever is longer. (Any SAE judged by the 
investigator to be related to the study treatment should be reported to the Sponsor 
regardless of the length of time that has passed since study completion.) AEs in study 
subjects include any change in the subject’s condition.  This includes symptoms, 
physical findings, or clinical syndromes. 
• Wherever possible, a specific disease or syndrome, rather than individual associated 
signs and symptoms should be identified by the Investigator and recorded.  However, 
if an observed or reported sign or symptom is not considered a component of a 
specific disease or syndrome by the Investigator, it should be recorded as a separate 
AE.  Additionally, the condition that led to a medical or surgical procedure (e.g., 
surgery, endoscopy, tooth extraction, or transfusion) should be recorded as an AE, not 
the procedure.  Any medical condition already present at screening should not be 
reported as an AE unless the medical condition or signs or symptoms present at 
baseline worsens in severity or seriousness at any time during the study.  Clinically 
significant examination (e.g. electrocardiogram) findings that are detected during the 
study or are present at screening and worsen during the study should be reported as an 
AE. 
• An abnormal laboratory value may be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, whether prescribed in the protocol or 
not.  It is up to the Investigator to determine whether an abnormal laboratory value 


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constitutes an AE.  If an abnormal laboratory value is caused by a disease process, the 
disease process and not the laboratory abnormality should be listed as the AE (e.g., if 
new onset viral hepatitis is causing elevated alanine aminotransferase (ALT), 
hepatitis and not the elevated ALT should be listed as the AE). 
• Examples of laboratory abnormalities that should be considered AEs include those 
that result in withdrawal of the study treatment, withholding study treatment pending 
some investigational outcome, or additional concomitant treatment.  All laboratory 
abnormalities considered to constitute an AE should be recorded on the appropriate 
AE page of the eCRF.  Laboratory abnormalities do not need to be listed as separate 
AEs if they are considered to be part of a clinical syndrome that is being reported as 
an AE.  It is the responsibility of the Investigator to review all safety laboratory 
findings in all subjects.  Abnormal values should be commented upon as to clinical 
relevance or importance on the eCRF or the laboratory report as appropriate.  Medical 
and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE. 
• Every effort must be made by the Investigator to categorize each AE according to its 
severity and its relationship to study drug. 
• Subjects who develop toxicity on study will be followed until the event resolves, 
stabilizes or returns to baseline. 
Adverse Reaction: All noxious and unintended responses to study drug at any dose should be 
considered to be adverse reactions. “Responses to study drug” means that there is a causal 
relationship between the study drug and the responses. “Suspected adverse reaction” implies a 
lesser degree of certainty about causality than “adverse reaction.” 
Unexpected Adverse Reaction: An unexpected adverse reaction is defined as an adverse 
reaction, the nature or severity of which is not consistent with the applicable product 
information.  For the study drug, the reference safety information is included in the version of the 
Investigator's Brochure currently in force.  The reference safety information will be reviewed 
yearly and the periodicity of the review will be harmonized with the reporting period of the 
Development Safety Update Report. 
6.23.2. 
Assessing Severity of Adverse Events 
The assessment of severity must be provided by the Investigator and based on the Investigator’s 
clinical judgment.  Maximum severity should be assigned to one of the following categories: 
• Mild: An AE that is easily tolerated by the subject, causing minimal discomfort and 
not interfering with everyday activities. 
• Moderate: An AE that is sufficiently discomforting to interfere with normal 
everyday activities. 
• Severe: An AE that prevents normal everyday activities. 
An AE that is assessed as severe should not be confused with a serious AE (SAE).  Refer to 
Section 6.23.4.1 for the definition of an SAE. 


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6.23.3. 
Assessing Relationship to Study Treatment 
The Investigator will categorize each AE as to its potential relationship to study drug: unrelated, 
unlikely related, possibly related, probably related and definitely related. Items to be 
considered when assessing the relationship of an AE to the study treatment are as follows:  
• Temporal relationship of the onset of the event to the initiation of the study treatment 
• The course of the event, considering especially the effect of discontinuation of study 
treatment or reintroduction of study treatment, as applicable 
• Whether the event is known to be associated with the study treatment or with other 
similar treatments 
• The presence of risk factors in the study subject known to increase the occurrence of 
the event 
• The presence of non-study treatment-related factors that are known to be associated 
with the occurrence of the event 
The relationship categories of unrelated and unlikely related will be summarized for reporting 
purposes as Not Related. For Not Related events, the time course between the administration of 
study drug and the occurrence or worsening of the AE rules out a causal relationship with study 
drug and another cause of the AE (concomitant drugs, therapies, complications, etc.) is 
suspected. 
The relationship categories of possibly, probably and definitely related will be summarized for 
reporting purposes as Related. Only AEs thought to be caused by the study drug should be 
classified as “related to study drug.” For Related events, the time course between the 
administration of study drug and the occurrence or worsening of the adverse event is consistent 
with a causal relationship and no other cause (concomitant drugs, therapies, complications, etc.) 
can be identified. The definition implies a reasonable possibility of a causal relationship between 
the event and the study drug. This means that there are facts (evidence) or arguments to suggest a 
causal relationship. 
6.23.4. 
Serious Adverse Events 
6.23.4.1. Definition of Serious Adverse Event 
A serious adverse event (experience; SAE) or reaction is any untoward medical occurrence that: 
• Results in death 
• Is life-threatening (Note:  The term “life-threatening” in the definition of “serious” 
refers to an event in which, in view of either the investigator or sponsor, the subject 
was at immediate risk of death at the time of the event; it does not refer to an event 
that hypothetically might have caused death if it were more severe.) 
• Requires inpatient hospitalization or prolongation of an existing hospitalization 
NOTE: Any hospital admission with at least one overnight stay will be considered an 
inpatient hospitalization. An emergency room visit without hospital admission will not be 
recorded as a serious adverse event (SAE) under this criterion, nor will hospitalization for a 


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procedure scheduled or planned before signing of informed consent. However, unexpected 
complications and/or prolongation of hospitalization that occur during elective surgery 
should be recorded as AEs and assessed for seriousness. 
The following hospitalizations are not considered to be SAEs because there is no “AE” 
(i.e., no untoward medical occurrence) associated with the hospitalization: 
− Hospitalizations for respite/hospice care  
− Hospitalization planned prior to informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration) 
• Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• Is a congenital anomaly/birth defect, or 
• Is determined to be an important medical event (at the discretion of the Investigator) 
Note: Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the other outcomes listed in the SAE definition. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
6.23.4.2. Reporting Serious Adverse Events (SAEs) – Procedure for Investigators 
Initial Reports 
SAEs, regardless of causality assessment, must be collected beginning from the time the subject 
signs the study consent until the early termination/final visit or 30 days after the last dose of 
study drug, whichever is longer. All SAEs must be reported to Medpace Clinical Safety within 
24 hours of the knowledge of the occurrence (this refers to any adverse event that meets any of 
the aforementioned seriousness criteria). Any SAE judged by the investigator to be related to the 
study treatment should be reported to the Sponsor regardless of the length of time that has passed 
since study completion. 
To report the SAE, complete the SAE form electronically in the electronic data capture (EDC) 
system for the study. When the form is completed, Medpace Safety personnel will be notified 
electronically and will retrieve the form. If the event meets seriousness criteria and it is not 
possible to access the EDC system, send an email to Medpace Safety at medpace-
safetynotification@medpace.com or call the Medpace SAE hotline (phone number listed below) 
and fax or email the completed paper SAE form to Medpace (fax number/email address listed 
below) within 24 hours of awareness. When the EDC system becomes available, the SAE 
information must be entered within 24 hours of the system becoming available. 
It is very important that the SAE electronic case report form be filled out as completely as 
possible at the time of the initial report, including if possible the investigator’s assessment of 
causality. The minimum information needed for making a preliminary SAE report is the protocol 
number, the subject ID, an adverse event term and the name of the person reporting the 


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information to the Sponsor. Preliminary SAE reports should be followed as soon as possible by 
detailed descriptions including copies of hospital case reports, autopsy reports and other 
documents requested by the Sponsor (see Follow-up Reports, below).   
The Investigator should notify the IRB/EC of the occurrence of the SAE, in writing, in 
accordance with local requirements.  A copy of this communication must be forwarded to the 
clinical research associate (CRA) and filed in the trial master file (TMF). 
Medpace Clinical Safety Contact Information: 
Medpace SAE hotline – USA: 
Telephone: +1-800-730-5779, ext. 2999 or +1-513-579-9911, ext. 2999 
Facsimile: +1-866-336-5320 or +1-513-579-0444 
e-mail: medpace-safetynotification@medpace.com 
 
Medpace SAE hotline – Europe: 
Telephone: +49 89 89 55 718 44 
Fax: +49 89 89 55 718 104 
e-mail: medpace-safetynotification@medpace.com 
Follow-Up Reports 
All AEs and SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.   
Within 24 hours of receipt of follow-up information, the Investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation (e.g., 
subject discharge summary or autopsy reports) to Medpace Clinical Safety via fax or e-mail. If 
the follow-up information changes the investigator’s assessment of causality, this should also be 
noted on the follow-up SAE form. If it is not possible to access the EDC system, refer to the 
procedures outlined above for initial reporting of SAEs.  
6.23.5. 
Pregnancy Reporting 
Any pregnancy following study drug dosing where the estimated date of conception occurred 
either prior to the study termination visit or within 30 days of last study treatment must be 
reported. The investigator should report the pregnancy to Medpace Clinical Safety within 24 
hours of being notified. Medpace Clinical Safety will then forward the Exposure In Utero form 
to the Investigator for completion. The contact information for reporting pregnancies is the 
same as for reporting SAEs (Section 6.23.4.2). 
A subject becoming pregnant while on study drug will immediately be withdrawn from the study 
and early termination study procedures will be performed. 
The subject should be followed by the Investigator until completion of the pregnancy. During the 
pregnancy, fetal growth parameters should be obtained regularly. If the pregnancy ends for any 
reason before the anticipated date, the Investigator should notify Medpace Clinical Safety.  At 
the completion of the pregnancy, the Investigator will document the outcome of the pregnancy. If 
the fetus has a congenital anomaly, the Investigator should follow the procedures for reporting an 
SAE. If the pregnancy results in a live birth, regular reports should be submitted regarding the 
child’s development from birth to three years of age.  


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6.23.6. 
Regulatory Reporting of Adverse Events 
AEs will be reported to the regulatory authorities in compliance with local and regional law and 
established guidance by the Sponsor or by a third party acting on behalf of the Sponsor.  The 
format of these reports will be dictated by the local and regional requirements. 
6.24. 
Clinical Laboratory Tests 
Blood samples for hematology, chemistry, insulin, HbA1c, lipid panel, coagulation, TSH, viral 
screen, hormones and βhCG and urine samples for pregnancy tests and urinalysis, will be 
obtained as shown in the study schedule in Appendix 1.  Approximately 3 mL of blood will be 
collected for hematology, 7 mL for chemistry, 3 mL for coagulation and 4 mL for the viral 
screen.  Testing will be carried out by the central laboratory and will include the laboratory tests 
listed in Table 6.  Subjects need to fast prior to visits S1, T1 and T7 as fasting insulin, glucose 
and/or a lipid panel are to be collected at those visits.  Subjects may be in a seated or supine 
position during blood collection. 
For subjects who are not surgically sterile, a serum pregnancy test will be performed via the 
central laboratory at Screening (Visit S1) and a urine pregnancy test will be performed at the 
study site at all subsequent study visits. 
Abnormal, clinically significant results may be verified to rule out laboratory error.  Persistent 
relevant abnormal values must be followed up until the cause is determined or until they return to 
the previous values.  Abnormal laboratory findings that are considered clinically significant by 
the Investigator should be recorded as AEs (Section 6.23.1). 
Further details on sample collection and handling are provided in the Laboratory Manual. 
Table 6: 
List of Clinical Laboratory Tests 
Hematology 
hematocrit (Hct), hemoglobin (Hgb), platelet count, red blood cell (RBC) 
count, white blood cell (WBC) count with differential 
Chemistry 
albumin (ALB), alkaline phosphatase (ALK-P), alanine aminotransferase 
(ALT; SGPT), aspartate aminotransferase (AST; SGOT), blood urea nitrogen 
(BUN), calcium (Ca), creatinine, glucose, total bilirubin, total protein, 
electrolytes (magnesium, sodium, potassium, chloride, bicarbonate); direct and 
indirect bilirubin will be performed if total bilirubin is elevated 
Metabolic 
insulin, HbA1c, lipid panel (total cholesterol, triglycerides, HDL, LDL) 
Coagulation 
PT, aPTT 
Viral Screen 
HBsAg, HCV, HIV 
Serum Hormone 
Levels 
SHBG, total testosterone, free testosterone, bioavailable testosterone, LH, 
FSH, estradiol, progesterone, AMH, 17-hydroxyprogesterone (Screening 
only), prolactin (Screening only), DHEA-S (Screening only) 
Urinalysis 
appearance, bilirubin, color, glucose, ketones, leukocyte esterase, nitrite, 
occult blood, pH, protein, specific gravity, urobilinogen; microscopic 
examination will be performed if leukocyte esterase, nitrite, and/or occult 
blood are positive 
Ovulation 
urinary pregnanediol-3-glucuronide 


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Hematology 
hematocrit (Hct), hemoglobin (Hgb), platelet count, red blood cell (RBC) 
count, white blood cell (WBC) count with differential 
Other 
serum and urine pregnancy tests, TSH, urine drug screen 
6.24.1. 
Efficacy Laboratory Tests 
Note: From Visit T1 to Visit F2, study site personnel (including Investigators) will be blinded to 
all efficacy laboratory tests listed below, except for fasting glucose, HbA1c and the fasting lipid 
panel. 
6.24.1.1. Urinary Pregnanediol-3-Glucuronide 
Urine will be self-collected by each subject thrice weekly from Visit L1 to Visit F2 for 
evaluation of ovulation during the study via assessment of pregnanediol-3-glucuronide at the 
central laboratory (Kassam 1996). The pregnanediol-3-glucuronide levels will be used to 
estimate the number of ovulations and the ovulation interval during the study. 
6.24.1.2. Serum Hormone Levels 
SHBG, testosterone (total, bioavailable and free), LH, FSH, estradiol, progesterone and AMH 
will be measured at the central laboratory using validated methods at L2, T1, T3, and all 
subsequent study visits except T3.5, T5.5, and T6.5. At Visit S1 (or W1, if wash-out is required), 
SHBG, testosterone, and FSH will be assessed. Screening levels will be used to assess potential 
subjects for eligibility (e.g., elevated androgen levels). Changes in hormone levels during the 
study will be used to assess the efficacy of MLE4901.   
17-hydroxyprogesterone, prolactin and DHEA-S levels will be measured at the central laboratory 
using validated methods at Visit S1 (or W1, if wash-out is required) only to assess whether 
potential subjects meet the inclusion/exclusion criteria associated with these parameters. 
6.24.1.3. Fasting Glucose, Insulin and HbA1c 
Fasting glucose and HbA1c will be measured at Visit S1 and subjects with results suggestive of 
diabetes mellitus will be excluded based on the parameters defined in exclusion criterion #16. 
Fasting glucose, insulin and HbA1c will be measured at the central laboratory using validated 
methods at Visits T1 and T7 and used for evaluations of insulin sensitivity.  
6.24.1.4. Fasting Lipid Panel 
A fasting lipid panel (total cholesterol, LDL, HDL and triglycerides) will be measured at the 
central laboratory using validated methods at Visits S1, T1 and T7 to evaluate for improvements 
in these metabolic syndrome parameters. 
6.24.2. 
Safety Laboratory Tests 
As shown in Appendix 1, hematology and chemistry will be obtained at Screening and at Weeks 
-4, 0 (baseline), 2, 4, 8, 12, 20, 28 (EoT), and 32 (F1). PT, PTT, and TSH will be obtained at 
Screening, Week -4, and Week 28. Subjects on thyroid hormone replacement who require a 
wash-out of medications that affect hormone levels should also have an additional TSH level 
done at the wash-out (W1) visit. Urinalysis will be obtained at Screening, Week 0, and Week 28. 
A serum pregnancy test will be done at Screening, and a urine pregnancy test will be done at all 
other visits. 


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6.24.2.1. Liver Function Tests 
Liver function tests (LFTs: AST, ALT, alkaline phosphatase, and total bilirubin) will be 
collected at Screening and at Weeks -4, 0 (baseline), 2, 4, 6, 8, 12, 16, 20, 24, 28 (EoT), and 32 
(F1). Direct and indirect bilirubin will be obtained if total bilirubin is elevated.  
Elevated AST or ALT >3x ULN occurring after baseline should be managed according to the 
guidance in Appendix 15. 
6.24.3. 
Sample Collection, Storage and Shipping 
Sample collection, storage and shipment procedures for the clinical laboratory samples will be 
provided in the laboratory manual. 
6.25. 
Blood Sample Collection  
In total, approximately 1¼ cup (300 mL) of blood will be collected from each subject 
randomized into the study. 
6.26. 
Removal of Subjects from the Study 
In accordance with the Declaration of Helsinki and subsequent conferences, subjects have the 
right to withdraw from the study at any time for any reason.  The Investigator and the Sponsor 
also have the right to withdraw subjects from the study.  Subjects may be removed from the 
study for the following reasons: 
1. In the Investigator’s judgment, administration of study drug would be detrimental to the 
subject’s health. 
2. The subject withdraws consent for continued participation or refuses further treatment with 
the investigational product. 
3. The subject is noncompliant with the protocol. 
4. The subject becomes pregnant. 
5. The subject dies.  
6. The subjects experiences an SAE or medically important event that would preclude further 
treatment with study drug. 
7. The subject requires long-term therapy with a prohibited medication. 
8. The subject experiences persistent and/or significant increases in LFTs and is required to be 
withdrawn per the guidance in Appendix 15. 
Subjects should return to the investigational site for an Early Termination (ET) Visit after 
withdrawal/removal from the study.   
• If the subject is to be withdrawn from the study prior to Visit T7, the ET visit will 
consist of the Visit T7 procedures (Section 7.3.9), including the TVU. 
• If the subject is to be withdrawn from the study after Visit T7 but before Visit F2, the 
ET visit will consist of the Visit F2 procedures (Section 7.4.2). 
The reason for and date of withdrawal/removal from the study will be documented in the 
subject’s medical records.  Investigational site personnel must attempt to determine whether the 
reason for withdrawal was an AE and if so, this must be reported in accordance with the 


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procedures provided in Section 6.23.  For all subjects who do not complete the study, regardless 
of the duration of treatment, all relevant information related to the withdrawal/removal will be 
entered into the eCRF. 
Subjects who withdraw or are removed from the study after randomization will not be replaced. 
All randomized subjects will be fully accounted for and documented in the final clinical study 
report (CSR). 


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7. 
STUDY ACTIVITIES 
7.1. 
Screening/Wash-out Period  
7.1.1. 
Screening/Wash-out Period, Visit S1 (Screening) 
The Screening Visit should be conducted within 12 weeks prior to the beginning of the Lead-in 
Period. The date of Screening is considered to be the date that the first study-related screening 
assessment is performed.  The subject needs to be fasting after 10 PM (water and maintenance 
medications allowed) the evening prior to the Screening Visit. Blood samples for the Screening 
Visit need to be collected as close to 8 AM as practicable and between 6-10 AM.  
At Screening, appropriate study site personnel should: 
• Obtain and document informed consent from the subject prior to any study 
procedures being performed. 
• Assign a study-specific subject identification number (subject ID). 
• Obtain and record medical history, demographic data, prior and current medications 
and the subject’s self-reported number of menstrual periods/12 months (off of any 
hormone therapy).  
• Administer the MBSQ and the HRQ. 
• Record vital signs, height and weight. 
• Perform and document a complete physical examination (PE).  
• Perform or confirm a Papanicolaou test (Notes: results from 1 year prior to Screening 
are acceptable. Women under 21 years of age at Screening do not require a Pap.) 
• Record the subject’s modified Ferriman-Gallwey score, ISGA score and Savin score. 
• Obtain a 12-lead ECG.  
• Collect fasting blood samples (as close to 8 AM as practicable and between 6-10 AM) 
for hematology, chemistry, HbA1c, lipid panel, PT, aPTT, TSH, HBsAg, hepatitis C 
antibody, HIV test, SHBG, total testosterone, free testosterone, bioavailable 
testosterone, FSH, 17-hydroxyprogesterone, prolactin, DHEA-S and a serum 
pregnancy test. 
NOTE: Subjects who require wash-out of medications that affect hormone levels should 
NOT have their hormone levels (SHBG, total testosterone, free testosterone, bioavailable 
testosterone, FSH, 17-hydroxyprogesterone, prolactin, DHEA-S) drawn at S1. Instead, they 
should complete the required wash-out and return to the site for these hormone levels at a 
wash-out visit (Visit W1). Subjects who do not require wash-out should not undergo a wash-
out visit.  
• Collect a urine sample for urinalysis and urine drug screen. 
• Review and assess relevant inclusion and exclusion criteria. 


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• Obtain a transvaginal ultrasound (TVU) on subjects who meet all of the inclusion 
criteria and none of the exclusion criteria assessable based on the Screening 
procedures (Note: Subjects do not need to wait for Screening/Wash-out hormone 
results prior to proceeding with the TVU and the Lead-in Period.). The TVU results 
should be reviewed prior to Visit L1 to ensure that there are no exclusionary 
abnormalities. 
Note: For subjects who require a wash-out, the transvaginal ultrasound should occur after 
completion of the wash-out and prior to or at Visit L1. Subjects who require a wash-out 
should have hormones drawn after wash-out. 
In addition, if a subject requires the TVU to show polycystic ovarian morphology (PCOM) in 
order to qualify for the study, please note that more than 4 weeks’ wash-out from some 
medications (such as clomiphene and letrozole) may be needed to re-develop PCOM.  
• If the subject requires wash-out, schedule the subject for a wash-out visit (Visit W1) 
so that blood sample collection for that visit will occur as close to 8 AM as 
practicable and between 6-10 AM. Inform the subject that she does not need to be 
fasting for Visit W1. 
• If the subject does not require wash-out, schedule the subject for Visit L1. Inform the 
subject that she does not need to be fasting at Visit L1. 
7.1.2. 
Screening/Wash-out Period, Visit W1 (Wash-out) 
At Wash-out, appropriate study site personnel should: 
• Record adverse events and update medications. 
• Collect blood samples (as close to 8 AM as practicable and between 6-10 AM) for 
SHBG, total testosterone, free testosterone, bioavailable testosterone, FSH, 17-
hydroxyprogesterone, prolactin, and DHEA-S. Subjects on thyroid hormone 
replacement who require wash-out should also have an additional TSH level done. 
• Collect a urine sample for and perform a urine pregnancy test. 
7.2. 
Lead-in Period 
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria assessable 
during the Screening Period, including TVU findings, should enter the 8-week Lead-in Period. 
Note: Subjects do not need to wait for Screening/Wash-out hormone results prior to proceeding 
with the TVU and the Lead-in Period. All Screening/Wash-out hormone results should be 
reviewed and confirmed to be inclusionary prior to Randomization. During the Lead-in Period, 
subjects are trained on the use of the daily electronic diary and on collection and storage of 
thrice-weekly urine samples for assessment of ovulation. Additionally, at the beginning of the 
Lead-in Period, all subjects will undergo a progestin challenge with MPA 10 mg daily for 5 days.  
7.2.1. 
Lead-in Period, Visit L1 
At Visit L1, appropriate study site personnel should: 
• Record adverse events and update medications. 


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• Administer the MBSQ and the HRQ. 
• Record vital signs and weight. 
• Collect a urine sample for and perform a urine pregnancy test. 
• Review and assess relevant inclusion and exclusion criteria. 
• Instruct the subject on the use of the daily menstrual bleeding electronic diary. 
• Instruct the subject on the collection and storage of thrice-weekly urine samples for 
assessment of ovulation and provide the subject with sufficient collection and storage 
materials to last until the subject’s next study visit. Urine should be collected as first 
void samples on non-consecutive days when possible. 
• Instruct the subject on MPA dosing, provide the subject with 5 tablets of MPA 10 mg 
and have the subject self-administer the first dose of MPA with a nonalcoholic 
beverage (except grapefruit juice) while at the study site. Record the time of MPA 
administration. 
• Schedule the subject for the next study visit (Visit L2) so that blood sample collection 
for that visit will occur as close to 8 AM as practicable and between 6-10 AM. 
•  Inform the subject that she does not need to be fasting at Visit L2. 
7.2.2. 
Lead-in Period, Visit L2 
Prior to Visit L2, appropriate study site personnel should review the subject’s menstrual diary 
entries. If the subject did not experience a menstrual period following the progestin challenge, or 
has experienced more than one menstrual period following the progestin challenge, the subject 
should be screen-failed from the study. In addition, subjects may be lead-in failed if the number 
of menstrual periods that occurred during the Lead-in Period is unclear due to poor diary 
compliance. Subjects who fail during the Lead-in Period should return any provisioned devices 
back to the site; stored urine samples may be defrosted with the urine discarded into the toilet, 
and any urine collection materials and kits may be discarded into household trash or recycled as 
appropriate. A menstrual period is defined as 2 or more consecutive days of bleeding, excluding 
spotting. 
At Visit L2, appropriate study site personnel should: 
 
• Record adverse events and update medications. 
• Administer the MBSQ. 
• Record vital signs and weight. 
• Collect blood samples (as close to 8 AM as practicable and between 6-10 AM) for 
hematology, chemistry, PT, aPTT, TSH, SHBG, total testosterone, free testosterone, 
bioavailable testosterone, LH, FSH, estradiol, progesterone and AMH. 
• Collect a urine sample for and perform a urine pregnancy test. 
• Review the subject’s electronic diary entries and reinforce instruction on the use of 
the diary as needed. 


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• Review the subject’s collection and storage of thrice-weekly urine samples and 
reinforce instruction on the collection and storage of these samples as needed. Urine 
should be collected as first void samples on non-consecutive days when possible. 
Provide the subject with sufficient collection and storage materials to last until the 
subject’s next study visit. 
• Schedule the next study visit (Visit T1) so that blood sample collection for hormones 
for that visit will occur as close to 8 AM as practicable and between 6-10 AM.  
• Instruct the subject that she needs to be fasting after 10 PM (water and maintenance 
medications allowed) the evening prior to Visit T1.  
7.3. 
Treatment Period 
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria should 
enter the 28-week Treatment Period. Please note that subjects who have no menstrual periods 
during the 8-week Lead-in Period and those with two or more menstrual periods during the 8-
week Lead-in Period should be excluded from the study, as should any subjects with significant 
findings on TVU other than findings related to PCOS. A menstrual period is defined as 2 or more 
consecutive days of bleeding, excluding spotting. 
During the Treatment Period, subjects will take their assigned study drug and undergo 
assessments to evaluate pharmacokinetics, efficacy, safety and tolerability of study drug. Blood 
samples for hormones for all of the Treatment Period visits (Note: hormones are not scheduled to 
be collected at Visits T2, T3.5, T5.5, or T6.5) need to be collected as close to 8 AM as 
practicable and between 6-10 AM. The subject needs to be fasting after 10 PM (water and 
maintenance medications allowed) the evening prior to Visits T1 and T7. In the evening prior to 
study visits, subjects should take their evening dose of study drug (and also note the date and 
exact time of the last dose prior to Visits T3, T5 and T7). On the morning of study visits, subjects 
should wait to take their morning dose of study drug until directed by site personnel at the study 
site. 
7.3.1. 
Treatment Period, Study Day 1, Visit T1 
At Visit T1, appropriate study site personnel should: 
• Record adverse events and update medications. 
• Review the subject’s electronic diary entries and reinforce instruction on the use of 
the daily diary as needed. Confirm that the subject has had one and only one 
menstrual period during the Lead-in Period. 
• Record vital signs and weight. 
• Perform a complete PE.  
• Collect a urine sample for urinalysis and perform a urine pregnancy test. 
• Obtain a 12-lead ECG.  
• Review inclusion and exclusion criteria to confirm that the subject is eligible for the 
study. 


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• Randomize the subject. 
• Administer the MBSQ, the HRQ, the PCOSQ, the PCOS Acne Questionnaire, the 
EQ-5D-5L, the PHQ-4 and the WPAI:GH.  
• Record the subject’s modified Ferriman-Gallwey hirsutism score, ISGA score and 
Savin score. 
• Collect fasting blood samples (as close to 8 AM as practicable and between 6-10 AM) 
for hematology, chemistry, insulin, HbA1c, lipid panel, SHBG, total testosterone, free 
testosterone, bioavailable testosterone, LH, FSH, estradiol, progesterone and AMH 
prior to administration of study drug. 
• Collect a plasma PK sample within 30 minutes prior to administration of study drug. 
Record the exact time of each PK sample collection. 
• Review the subject’s collection and storage of thrice-weekly urine samples and 
reinforce instruction on the collection and storage of these samples as needed. Urine 
should be collected as first void samples on non-consecutive days when possible. 
Provide the subject with sufficient collection and storage materials to last until the 
subject’s next study visit. 
• Dispense study drug and instruct the subject on self-administration of study drug 
orally twice per day. 
• Ask the subject to self-administer study drug with a nonalcoholic beverage (except 
grapefruit juice) while at the study site. Record the exact time of study drug 
administration. 
• Collect plasma PK samples at 1, 2, 2.5, 3 and 4 hours after administration of study 
drug. Record the exact time of each PK sample collection. 
• Schedule the next study visit (Treatment Period, Visit T2).  
• Instruct the subject that on the morning of Visit T2, she should not take her morning 
dose of study drug at home, but rather will take it at the study site as directed by site 
personnel. 
• Inform the subject that she does not need to be fasting at Visit T2. 
7.3.2. 
Treatment Period, Visit T2 
At Visit T2, appropriate study site personnel should: 
 
• Record adverse events and update medications. 
• Administer the MBSQ. 
• Record vital signs and weight. 
• Record the subject’s ISGA score. 
• Collect blood samples for hematology and chemistry prior to administration of study 
drug. 


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• Collect a urine sample for and perform a urine pregnancy test. 
• Review the subject’s electronic diary entries and reinforce instruction on the use of 
the daily diary as needed. 
• Review the subject’s collection and storage of thrice-weekly urine samples and 
reinforce instruction on the collection and storage of these samples as needed. Urine 
should be collected as first void samples on non-consecutive days when possible. 
Provide the subject with sufficient collection and storage materials to last until the 
subject’s next study visit. 
• Collect study drug and assess compliance. 
• Reinforce self-administration of study drug orally twice per day. 
• Ask the subject to self-administer study drug with a nonalcoholic beverage (except 
grapefruit juice) while at the study site. 
• Schedule the next study visit (Visit T3) so that blood sample collection will occur as 
close to 8 AM as practicable and between 6-10 AM.  
• Instruct the subject that the evening prior to Visit T3, she should note the date and 
exact time of her evening dose of study drug. 
• Instruct the subject that on the morning of Visit T3, she should not take her morning 
dose of study drug at home but rather will take it at the study site as directed by site 
personnel. 
• Inform the subject that she does not need to be fasting at Visit T3. 
7.3.3. 
Treatment Period, Visit T3 
At Visit T3, appropriate study site personnel should: 
 
• Record adverse events and update medications. 
• Record the date and time of the subject’s last dose of study drug prior to the visit. 
• Administer the MBSQ. 
• Record vital signs and weight. 
• Record the subject’s ISGA score. 
• Collect blood samples (as close to 8 AM as practicable and between 6-10 AM) for 
hematology, chemistry, SHBG, total testosterone, free testosterone, bioavailable 
testosterone, LH, FSH, estradiol, progesterone and AMH prior to administration of 
study drug. 
• Collect a plasma PK sample within 30 minutes prior to administration of study drug. 
Record the exact time of each PK sample collection. 
• Collect a urine sample for and perform a urine pregnancy test. 
• Review the subject’s electronic diary entries and reinforce instruction on the use of 
the daily diary as needed. 


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• Review the subject’s collection and storage of thrice-weekly urine samples and 
reinforce instruction on the collection and storage of these samples as needed. Urine 
should be collected as first void samples on non-consecutive days when possible. 
Provide the subject with sufficient collection and storage materials to last until Visit 
T4. 
• Collect study drug and assess compliance. 
• Dispense study drug and instruct the subject on self-administration of study drug 
orally twice per day. 
• Ask the subject to self-administer study drug with a nonalcoholic beverage (except 
grapefruit juice) while at the study site. 
• Schedule the next two study visits (Visits T3.5 and T4). Blood sample collection at 
Visit T4 should occur as close to 8 AM as practicable and between 6-10 AM.  
• Instruct the subject that on the morning of Visit T3.5, she should go ahead and take 
her morning dose of study drug at home. Instruct the subject that on the morning of 
Visit T4, she should NOT take her morning dose of study drug at home but rather will 
take it at the study site as directed by site personnel. 
• Inform the subject that she does not need to be fasting at Visits T3.5 or T4. 
7.3.4. 
Treatment Period, Visit T3.5 
At Visit T3.5, appropriate study site personnel should: 
• Collect a blood sample for AST, ALT, alkaline phosphatase, and total bilirubin. 
7.3.5. 
Treatment Period, Visit T4 
At Visit T4, appropriate study site personnel should: 
 
• Record adverse events and update medications. 
• Administer the MBSQ. 
• Record vital signs and weight. 
• Record the subject’s ISGA score. 
• Collect blood samples (as close to 8 AM as practicable and between 6-10 AM) for 
hematology, chemistry, SHBG, total testosterone, free testosterone, bioavailable 
testosterone, LH, FSH, estradiol, progesterone and AMH prior to administration of 
study drug. 
• Collect a urine sample for and perform a urine pregnancy test. 
• Review the subject’s electronic diary entries and reinforce instruction on the use of 
the daily diary as needed. 
• Review the subject’s collection and storage of thrice-weekly urine samples and 
reinforce instruction on the collection and storage of these samples as needed. Urine 
should be collected as first void samples on non-consecutive days when possible. 


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Provide the subject with sufficient collection and storage materials to last until the 
subject’s next study visit. 
• Collect study drug and assess compliance. 
• Dispense study drug and instruct the subject on self-administration of study drug 
orally twice per day. 
• Ask the subject to self-administer study drug with a nonalcoholic beverage (except 
grapefruit juice) while at the study site. 
• Schedule the next study visit (Visit T5) so that blood sample collection will occur as 
close to 8 AM as practicable and between 6-10 AM.  
• Instruct the subject that the evening prior to Visit T5, she should note the date and 
exact time of her evening dose of study drug. 
• Instruct the subject that on the morning of Visit T5, she should not take her morning 
dose of study drug at home but rather will take it at the study site as directed by site 
personnel. 
• Inform the subject that she does not need to be fasting at Visit T5. 
7.3.6. 
Treatment Period, Visit T5 
At Visit T5, appropriate study site personnel should: 
 
• Record adverse events and update medications. 
• Record the date and time of the subject’s last dose of study drug prior to the visit. 
• Administer the MBSQ, the HRQ, the PCOSQ, the PCOS Acne Questionnaire, the 
EQ-5D-5L, the PHQ-4 and the WPAI:GH. 
• Record vital signs and weight. 
• Perform a brief PE.  
• Record the subject’s ISGA score. 
• Obtain a 12-lead ECG.  
• Collect blood samples (as close to 8 AM as practicable and between 6-10 AM) for 
hematology, chemistry, SHBG, total testosterone, free testosterone, bioavailable 
testosterone, LH, FSH, estradiol, progesterone and AMH prior to administration of 
study drug. 
• Collect a plasma PK sample within 30 minutes prior to administration of study drug. 
Record the exact time of each PK sample collection. 
• Collect a urine sample for and perform a urine pregnancy test. 
• Review the subject’s electronic diary entries and reinforce instruction on the use of 
the daily diary as needed. 


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• Review the subject’s collection and storage of thrice-weekly urine samples and 
reinforce instruction on the collection and storage of these samples as needed. Urine 
should be collected as first void samples on non-consecutive days when possible. 
Provide the subject with sufficient collection and storage materials to last until Visit 
T6. 
• Collect study drug and assess compliance. 
• Dispense study drug and reinforce self-administration of study drug orally twice per 
day. 
• Ask the subject to self-administer study drug with a nonalcoholic beverage (except 
grapefruit juice) while at the study site (all Treatment Period visits). 
• Schedule the next two study visits (Visits T5.5 and T6). Blood sample collection at 
Visit T6 should occur as close to 8 AM as practicable and between 6-10 AM.  
• Instruct the subject that on the morning of Visit T5.5, she should go ahead and take 
her morning dose of study drug at home. Instruct the subject that on the morning of 
Visit T6, she should NOT take her morning dose of study drug at home but rather will 
take it at the study site as directed by site personnel. 
• Inform the subject that she does not need to be fasting at Visits T5.5 or T6. 
7.3.7. 
Treatment Period, Visit T5.5 
At Visit T5.5, appropriate study site personnel should: 
• Collect a blood sample for AST, ALT, alkaline phosphatase, and total bilirubin. 
7.3.8. 
Treatment Period, Visit T6 
At Visit T6, appropriate study site personnel should: 
 
• Record adverse events and update medications. 
• Administer the MBSQ and the HRQ. 
• Record vital signs and weight. 
• Record the subject’s ISGA score. 
• Collect blood samples (as close to 8 AM as practicable and between 6-10 AM) for 
hematology, chemistry, SHBG, total testosterone, free testosterone, bioavailable 
testosterone, LH, FSH, estradiol, progesterone and AMH prior to administration of 
study drug. 
• Collect a urine sample for and perform a urine pregnancy test. 
• Review the subject’s electronic diary entries and reinforce instruction on the use of 
the daily diary as needed. 
• Review the subject’s collection and storage of thrice-weekly urine samples and 
reinforce instruction on the collection and storage of these samples as needed. Urine 
should be collected as first void samples on non-consecutive days when possible. 


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Provide the subject with sufficient collection and storage materials to last until Visit 
T7. 
• Collect study drug and assess compliance. 
• Dispense study drug and reinforce self-administration of study drug orally twice per 
day. 
• Ask the subject to self-administer study drug with a nonalcoholic beverage (except 
grapefruit juice) while at the study site. 
• Schedule the next two study visits (Visits T6.5 and T7). Blood sample collection at 
Visit T7 should occur as close to 8 AM as practicable and between 6-10 AM. 
• Schedule a TVU to be performed within 2 weeks prior to Visit T7. 
• Instruct the subject that on the morning of Visit T6.5, she should go ahead and take 
her morning dose of study drug at home. Inform the subject that she does not need to 
be fasting at Visit T6.5. 
• Instruct the subject that the evening prior to Visit T7, she should note the date and 
exact time of her evening dose of study drug. 
• Instruct the subject that on the morning of Visit T7, she should NOT take her morning 
dose of study drug. 
• Instruct the subject that she needs to be fasting after 10 PM (water and maintenance 
medications allowed) the evening prior to Visit T7. 
7.3.9. 
Treatment Period, Visit T6.5 
At Visit T6.5, appropriate study site personnel should: 
• Collect a blood sample for AST, ALT, alkaline phosphatase and total bilirubin. 
7.3.10. 
Treatment Period, Visit T7 
At Visit T7, appropriate study site personnel should: 
 
• Record adverse events and update medications. 
• Record the date and time of the subject’s last dose of study drug prior to the visit. 
• Administer the MBSQ, the HRQ, the PCOSQ, the PCOS Acne Questionnaire, the 
EQ-5D-5L, the PHQ-4, the WPAI:GH and the PGIC. 
• Record vital signs and weight. 
• Perform a complete PE.  
• Record the subject’s modified Ferriman-Gallwey score, ISGA score and Savin score. 
• Obtain a 12-lead ECG.  
• Collect fasting blood samples (as close to 8 AM as practicable and between 6-10 AM) 
for hematology, chemistry, insulin, HbA1c, lipid panel, PT, aPTT, TSH, SHBG, total 


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testosterone, free testosterone, bioavailable testosterone, LH, FSH, estradiol, 
progesterone and AMH. 
• Collect a plasma PK sample. Record the exact time of each PK sample collection. 
• Collect a urine sample for urinalysis and perform a urine pregnancy test. 
• Perform a TVU (this may be performed within 2 weeks prior to Visit T7). 
• Review the subject’s electronic diary entries and reinforce instruction on the use of 
the daily diary as needed. 
• Review the subject’s collection and storage of thrice-weekly urine samples and 
reinforce instruction on the collection and storage of these samples as needed. Urine 
should be collected as first void samples on non-consecutive days when possible. 
Provide the subject with sufficient collection and storage materials to last until the 
subject’s next study visit. 
• Collect study drug and assess compliance. 
• Schedule the next study visit (Visit F1) so that blood sample collection will occur as 
close to 8 AM as practicable and between 6-10 AM.  
• Inform the subject that she does not need to be fasting at Visit F1. 
7.4. 
Follow-up Period 
During the 8-week Follow-up Period, the durability of study drug effects after discontinuation of 
study drug will be assessed. Blood samples for all of the Follow-up Period visits need to be 
collected as close to 8 AM as practicable and between 6-10 AM. The subject does not need to be 
fasting at any of the visits during the Follow-up Period. 
7.4.1. 
Follow-up Period, Visit F1 
At Visit F1, appropriate study site personnel should: 
• Record adverse events and update medications. 
• Administer the MBSQ. 
• Record vital signs and weight. 
• Record the subject’s ISGA score. 
• Collect blood samples (as close to 8 AM as practicable and between 6-10 AM) for 
hematology, chemistry, SHBG, total testosterone, free testosterone, bioavailable 
testosterone, LH, FSH, estradiol, progesterone and AMH. 
• Collect a urine sample for and perform a urine pregnancy test. 
• Review the subject’s electronic diary entries and reinforce instruction on the use of 
the daily diary as needed. 
• Review the subject’s collection and storage of thrice-weekly urine samples and 
reinforce instruction on the collection and storage of these samples as needed. Urine 


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should be collected as first void samples on non-consecutive days when possible. 
Provide the subject with sufficient collection and storage materials to last until the 
subject’s next study visit. 
• Schedule the next study visit (Visit F2) so that blood sample collection will occur as 
close to 8 AM as practicable and between 6-10 AM. 
• Inform the subject that she does not need to be fasting at Visit F2. 
7.4.2. 
Follow-up Period, Visit F2 
At Visit F2, appropriate study site personnel should: 
 
• Record adverse events and update medications. 
• Administer the MBSQ, the HRQ, the PCOSQ, the PCOS Acne Questionnaire, the 
EQ-5D-5L, the PHQ-4, and the WPAI:GH. 
• Record vital signs and weight. 
• Perform a brief PE.  
• Record the subject’s ISGA score. 
• Collect blood samples (as close to 8 AM as practicable and between 6-10 AM) for 
SHBG, total testosterone, free testosterone, bioavailable testosterone, LH, FSH, 
estradiol, progesterone and AMH. 
• Collect a urine sample for and perform a urine pregnancy test. 
• Review the subject’s electronic diary entries. 
• At the completion of Visit F2, discharge the subject from the study. 
7.5. 
Early Termination Visit 
The Early Termination (ET) Visit will occur if a randomized subject is not able to complete the 
study procedures as detailed in the protocol for any reason. 
• If the subject is to be withdrawn from the study prior to Visit T7, the ET visit will 
consist of the Visit T7 procedures (Section 7.3.9), including the TVU. 
• If the subject is to be withdrawn from the study after Visit T7 but before Visit F2, the 
ET visit will consist of the Visit F2 procedures (Section 7.4.2). 
• At the completion of the ET visit, discharge the subject from the study. 
 


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8. 
QUALITY CONTROL AND ASSURANCE 
Before any subjects can be consented at an investigational site and prior to the conduct of any 
protocol-specific procedures, formal training of investigational site personnel will be conducted.  
The Investigator and all relevant investigational site staff are to be trained on all aspects of the 
study for which they are responsible.  Site personnel may be trained at a formal initiation visit, at 
an Investigator’s Meeting, or by another means as necessary.  Monitoring and auditing 
procedures will be conducted in compliance with the International Conference on Harmonisation 
(ICH) Guidelines for Good Clinical Practice (GCP).  Onsite verification of the eCRFs for 
completeness and clarity, crosschecking with source documents and clarification of 
administrative matters will be performed on a regular basis.  Monitoring visits will occur at 
regular intervals as noted in the monitoring plan.  Through frequent communications with the 
investigational site, the CRA will ensure that the investigation is conducted according to protocol 
design and all applicable regulatory requirements.  Additional details on the monitoring of this 
study are provided in Section 10.5.  During the course of the study, investigational sites, the 
study database and all associated study documentation may be subject to quality assurance audits 
by the Sponsor, or their appointed representatives, on a planned or as-needed basis.  In addition, 
representatives of associated regulatory bodies may conduct inspections at their discretion.  The 
Investigator is responsible for ensuring direct access to all protocol-specific materials for the 
purpose of these activities. 


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9. 
PLANNED STATISTICAL METHODS 
A Statistical Analysis Plan that includes a more technical and detailed description of the planned 
statistical analyses will be prepared prior to study unblinding. 
9.1. 
General Considerations 
9.1.1. 
Sample Size 
Assuming a study dropout rate of approximately 10-20%, a total of 110 subjects will be 
randomized in the study so that each dose group will have 50 subjects at a 1:1 allocation.  
Sample size considerations were based on a multiple comparison Dunnett intersection test and a 
1-sided alpha of 0.025.  The standard deviation of change in days between start of menstruation 
was assumed to be 15 days.  If the mean change in days between onset of menstruation was 
assumed to be 0 for the placebo group and 10 days for at least one active dose group, the study 
has a power of approximately 80-90% as demonstrated in simulations. 
9.1.2. 
Randomization and Stratification 
Patients who are confirmed as having met all study eligibility requirements will be randomized 
in a 1:1 ratio into the placebo and the MLE4901 40 mg BID dose groups.  There are two 
stratification factors;  
1) Baseline self-reported menstrual period frequency: a) <4/year and b) 4-6/year. 
 
2) BMI: a) 22 to <35 kg/m2 (mid-normal to obesity class I) and b) 35-45 kg/m2 (obesity classes 
II/ III). 
This is a double blind study in which subjects will be randomized by a web-based system by 
stratum using central randomization and a variable block design. 
9.2. 
Analysis Populations 
Efficacy – The primary efficacy analyses will include all randomized subjects (Intent-to-Treat; 
ITT). For efficacy analyses, subjects will be included in the treatment group to which they were 
randomized. Additional efficacy analyses will be performed on all subjects who complete at least 
16 weeks of treatment (Evaluable Population). 
Safety – The Safety Population will include all treated subjects. Safety analyses will be based on 
the Safety Population. For the safety analyses, subjects randomized to the placebo group who 
receive MLE4901 will be included in the treatment group of the study drug that they received. 
Pharmacokinetic – The PK Population will include all subjects with measurable drug 
concentrations. PK analyses will be based on the PK population. 
9.3. 
Demographics and Baseline Characteristics 
Demographic and clinical characteristics of subjects randomized into this study will be 
summarized.  For categorical variables, frequencies and percentages will be provided.  Means 
with standard deviations or medians/percentiles will summarize non-categorical variables. 


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9.4. 
Efficacy 
9.4.1. 
Efficacy Endpoints 
9.4.1.1. 
Primary Efficacy Endpoint  
• The change in the duration of menstrual cycles from Baseline to End-of-Treatment (EoT). 
9.4.1.2. 
Key Secondary Efficacy Endpoint 
• The number of menstrual periods during the Treatment Period 
9.4.1.3. 
Additional Efficacy Endpoints 
• The duration of menstrual cycles over the Treatment Period 
• The change from Baseline in the duration of each menstrual cycle over the Treatment Period 
• The change in the ovulation interval from Baseline to EoT 
• The number of ovulations during the Treatment Period 
• The duration of ovulation intervals over the Treatment Period 
• The change from Baseline in the ovulation interval for each ovulation over the Treatment 
Period 
• The time from the start of the last menstrual period prior to randomization to the first 
menstrual period after randomization 
• The time to the first normal menstrual cycle duration 
• The number of consecutive menstrual cycles of 21-35 days’ duration over the Treatment 
Period 
• The time from the last ovulation prior to randomization (or first dose of MPA, if no ovulation 
during Lead-in) to the first ovulation after randomization 
• The time to the first normal ovulation interval 
• The number of consecutive ovulation intervals of 21-35 days’ duration over the Treatment 
Period 
• The proportion of subjects with at least 4 self-reported menstrual periods over the Treatment 
Period  
• The proportion of subjects having menstrual cycles of 21-35 days’ duration for a continuous 
6-month period during the Treatment Period 
• The proportion of subjects having menstrual bleeding of 2-7 days’ duration for a continuous 
6-month period during the Treatment Period 
• The proportion of subjects with normal menstrual cycles for a continuous 6-month period 
during the Treatment Period 
• The change from Baseline in the severity of the subjects’ self-identified Most Bothersome 
Symptom of PCOS 
• The change from Baseline in the severity of each symptom of PCOS (oligo-/amenorrhea, 
hirsutism, acne and alopecia)  
• The change from Baseline in testosterone (total, free and bioavailable), LH, FSH, LH/FSH, 
estradiol, progesterone and AMH 
• The change from Baseline in the modified Ferriman-Gallwey score for hirsutism 
• The change from Baseline in the Investigator’s Static Global Assessment of acne score  
• The change from Baseline in the Savin score for androgenic alopecia 


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• The change from Baseline in fasting glucose, insulin, total cholesterol, LDL, HDL and 
triglycerides 
• The change from Baseline in systolic blood pressure, diastolic blood pressure and body mass 
index 
• The duration of menstrual cycles over the Follow-up Period 
• The duration of ovulation intervals over the Follow-up Period 
• The change from Baseline in the frequency of removal of unwanted hair from the upper lip 
and chin  
• The change from Baseline in the domain scores on the PCOSQ and the PCOS Acne 
Questionnaire 
• The change from Baseline in the score on the EQ-5D-5L health state survey 
• The change from Baseline in the domain scores on the Work Productivity and Activity 
Impairment: General Health Questionnaire (WPAI:GH) 
• The change from Baseline in the mean total score, anxiety subscale score and depression 
subscale score on the PHQ-4 
9.4.2. 
Efficacy Analysis Methodology 
9.4.2.1. 
Primary Efficacy Endpoint  
The Baseline menstrual cycle duration will be measured as the time from the start of the first 
menstrual period after the progestin challenge to the start of the next consecutive menstrual 
period.  The EoT menstrual cycle duration will be the duration between the last two menstrual 
period start dates during the Treatment Period. 
The change in the duration of menstrual cycles from Baseline to EoT will be analyzed with an 
ANOVA model including treatment and stratification factors following the Dunnett intersection 
test procedure to control for multiple comparison testing.  Should the primary endpoint 
distribution depart from an approximate normal distribution, an appropriate non-parametric test 
will be utilized such as the Wilcoxon rank-sum test. 
9.4.2.2. 
Key Secondary Efficacy Endpoint 
The number of menstrual periods during the Treatment Period will be analyzed with an ANOVA 
model including treatment and stratification factors following the Dunnett intersection test 
procedure to control for multiple comparison testing.  Should this key secondary endpoint 
distribution depart from an approximate normal distribution, an appropriate non-parametric test 
will be utilized such as the Wilcoxon rank-sum test.   
9.4.2.3. 
Additional Efficacy Endpoints 
No further adjustments for multiple group comparisons, multiple additional endpoints or multiple 
subgroups of interest are planned. 
The ovulation interval duration will be analyzed in a similar manner as the menstrual cycle 
duration, with the exception that the analysis of this endpoint will utilize an ANOVA, instead of 
an ANCOVA model.  Other continuous endpoints will utilize similar ANCOVA or ANOVA 
model methodology, as appropriate. Responder analyses and other categorical analyses will be 
based on the Cochran-Mantel-Haenszel (CMH) test or Fisher’s exact test, as appropriate.  Time-


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to-event endpoints will be summarized using Kaplan-Meier estimates and compared using the 
log-rank test. 
9.4.2.4. 
Exploratory Endpoints 
Additional efficacy endpoints will be pre-specified in the Statistical Analysis Plan, including 
sensitivity analyses associated with drug compliance and missing data issues. 
9.5. 
Safety 
9.5.1. 
Safety Endpoints  
Safety endpoints will include the incidence of treatment-emergent adverse events and serious 
adverse events, as well as changes from baseline in clinical laboratory tests, vital signs, physical 
examinations and ECG parameters. 
9.5.2. 
Safety Analyses  
Adverse events counts (overall, as well as by severity, causality and seriousness) will be 
tabulated by Medical Dictionary for Regulatory Activities (MedDRA) system organ class and 
preferred term. Descriptive statistics and shift tables will be used to summarize continuous 
laboratory, blood pressure and ECG parameters. Counts and shift tables will be used for 
categorical lab parameters. 
9.6. 
Pharmacokinetics 
9.6.1. 
Pharmacokinetic Endpoints 
• The Cmax, Tmax, AUC, t1/2 and other PK parameters of MLE4901 and its major metabolite (as 
appropriate and as the data allow) 
• The relationship between Cmax and AUC vs. the change in the duration of menstrual cycles 
from Baseline to EoT; other PK/PD relationships may be explored as appropriate and as data 
allow 
9.6.2. 
Pharmacokinetic Analyses  
Individual PK parameters will be derived using the WinNonlin software and table summaries 
will be provided using descriptive summary statistics. 
9.7. 
Interim Analysis 
No interim analysis is planned for this study. 
 


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10. 
ADMINISTRATIVE CONSIDERATIONS 
10.1. 
Institutional Review Board (IRB)/Ethics Committee (EC)  
Prior to initiation of the study at each investigational site, the protocol, the informed consent 
form(s), the subject information sheet(s), details of the subject recruitment procedures and any 
other relevant study documentation will be submitted to the responsible local and/or national 
IRB/EC.  A letter from the IRB/EC indicating approval of the Investigator and study site must be 
submitted to the study Sponsor.  All reviews and approval by the IRB/EC will be in accordance 
with Title 21 of the Code of Federal Regulations (CFR), Part 56. Initial IRB approval and all 
materials approved by the IRB for this study including the subject consent form and recruitment 
materials must be maintained by the Investigator and made available for inspection. 
The Investigator will promptly report any new information that may adversely affect the safety 
of subjects or the conduct of the study to the IRB/EC.  Similarly, the Investigator will submit 
written summaries of the study status to the IRB/EC annually, or more frequently if requested.  
Upon completion of the study, the Investigator will provide the IRB/EC with a brief report of the 
outcome of the study, if required. 
10.2. 
Ethical Conduct of the Study 
The guidelines of the World Medical Association Declaration of Helsinki in its revised edition 
(48th General Assembly, Somerset West, Republic of South Africa, October 1996), the 
guidelines of ICH GCP (CPMP/ICH/135/95), as well as the demands of national drug and data 
protection laws and other applicable regulatory requirements, will be strictly followed.  
10.3. 
Subject Information and Consent 
The Investigator is responsible for ensuring that subjects do not undergo any study-related 
examination or activity before giving informed consent.  The subject must give written consent 
after the receipt of detailed information regarding the study.  The verbal explanation will cover 
all the elements specified in the written information provided to the subject.  If the written 
informed consent is provided by the legal guardian because the subject is unable to do so, a 
written or verbal assent from the subject must also be obtained. 
The Investigator will inform the subject of the aims, methods, anticipated benefits and potential 
hazards of the study, including any discomfort it may entail.  The subject must be given every 
opportunity to clarify any points he/she does not understand and must be provided with more 
information if requested.  At the end of the interview, the subject may be given time to reflect 
and can request more time if needed.  The subject and/or legal guardian will be required to sign 
and date the informed consent form.  After completion, informed consent forms will be kept and 
archived by the PI in the PI study file. 
It should be emphasized to the subject that he or she is at liberty to either discontinue study drug 
and/or withdraw consent to participate at any time, without penalty or loss of benefits to which 
he or she is otherwise entitled.  Subjects who refuse to give or withdraw written informed 
consent may not be included or continued in this study, but this will not affect their subsequent 
care. 


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Please refer to Title 21 of the CFR, Part 50 – Protection of Human Subjects for specific details 
on this regulation. 
10.4. 
Subject Confidentiality 
Personal and sensitive data will be treated as confidential.  The results of the study will be made 
available for review by authorized representatives of the Sponsor and/or submitted to the 
IRB/EC and regulatory authorities.   
Prior to any screening procedures being performed, the subject’s consent is required for the data 
to be used for these purposes and to gain direct access to their medical records for data 
verification purposes.  The subject must be assured that their identity will be protected.  To 
facilitate this, a unique identification number will be assigned and it will be used when reporting 
study-related data. 
Additionally, in the US, the Health Insurance Portability and Accountability Act of 1996 
(“HIPAA”) requires that all subjects grant permission to use their personal health information.  
Therefore, in addition to the protocol-specific ICF, each subject located in the United States (US) 
will be asked to provide authorization to use his/her personal health information by signing a 
separate HIPAA Authorization Form.   
10.5. 
Study Monitoring 
It is understood that the Sponsor or its designee (e.g., the CRA) will contact and visit the 
Investigator regularly for monitoring purposes.  The CRA will be allowed, on request, to inspect 
the various records of the study (i.e., eCRFs, source documents and any other pertinent data), 
provided that subject confidentiality is maintained in accordance with local requirements.  It will 
be the CRA’s responsibility to inspect the eCRFs at regular intervals throughout the study, to 
verify adherence to the protocol and to ensure the completeness, consistency and accuracy of the 
data entered.  The CRA must have access to all subject records needed to verify the entries on the 
eCRF.  The Investigator agrees to cooperate with the CRA to ensure that problems detected 
during these monitoring visits are resolved. 
Before an investigational site can consent a subject into the study, a representative of Millendo 
Therapeutics, Inc. will evaluate the investigational study site to assess the site including but not 
limited to: 
• Determine the adequacy of the facilities including the site’s ability to carry out the 
protocol 
• Discuss with the Investigator(s) and other personnel their responsibilities with regard 
to protocol adherence and the responsibilities of Millendo Therapeutics, Inc. or its 
representatives.  This will also be documented in a Clinical Study Agreement 
between Millendo Therapeutics, Inc. and the Investigator. 
During the study, a monitor from Millendo Therapeutics, Inc. or representative will have regular 
contacts with the investigational site, for the following but not limited to: 
• Provide information and support to the Investigator(s) 
• Confirm that facilities remain acceptable 


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• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms and that investigational product 
accountability checks are being performed 
• Perform source data verification.  This includes a comparison of the data in the case 
report forms with the subject’s medical records at the hospital or practice and other 
records relevant to the study.  This will require direct access to all original records for 
each subject (e.g. clinic charts). 
• Record and report any protocol deviations not previously sent to Millendo 
Therapeutics, Inc. 
• Confirm AEs and SAEs have been properly documented on CRFs and confirm any 
SAEs have been forwarded to Millendo Therapeutics, Inc. and those SAEs that met 
criteria for reporting have been forwarded to the IRB. 
The monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice. 
10.6. 
Audits and Inspections 
Authorized representatives of Millendo Therapeutics, Inc., a regulatory authority, an Ethics 
Committee or an Institutional Review Board may visit the site to perform audits or inspections, 
including source data verification.  Millendo Therapeutics, Inc. may perform Clinical Quality 
Assurance (CQA) audit randomly at a sample of clinical sites, or for cause as warranted. The 
purpose of a Millendo Therapeutics, Inc. CQA audit or inspection is to systematically and 
independently examine all study-related activities and documents to determine whether these 
activities were conducted and data were recorded, analyzed and accurately reported according to 
the protocol, Good Clinical Practice guidelines of the International Conference on 
Harmonization and any applicable regulatory requirements.  These audits will be independent of 
routine monitoring by the CRA and initiated with prior written notification provided to the site. 
The Investigator should contact Millendo Therapeutics, Inc. immediately if contacted by a 
regulatory agency about an inspection. 
10.7. 
Case Report Forms and Study Records 
This study will utilize an electronic data capture system for the management of clinical data.  
The data will be collected in electronic form (i.e., via an eCRF) to allow for data entry at the site 
from source documentation directly into the electronic database.  Access to the electronic system 
will be restricted and users will only be able to access the system via authorized individual 
accounts.  All changes to data in the database will be tracked and time stamped automatically, 
including updates to data entries and resolution of data queries generated by the CRA or data 
reviewer.  
Training will be provided to all system users based on their individual access and use 
requirements initially and ongoing throughout the course of the study as needed.  Documentation 
of training will be kept in the site regulatory file and in Sponsor’s TMF. 
A comprehensive Data Management Plan will be written outlining the standard operating 
procedures, internal/external security safeguards, system and change controls and training 


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procedures and will be filed in the Sponsor’s TMF.  A cumulative record will also be kept of the 
user and access privileges for all authorized users across the study.  
The system and procedures for electronic database set-up, entry, review, access, security and 
auditing are designed in specific compliance with 21 CFR 11 and the Food and Drug 
Administration's (FDA’s) Part 11 Guidance for Industry supplement “Computerized Systems 
Used in Clinical Investigations” dated May 2007.  Any additional electronic systems that may be 
used by vendors (e.g., PK) or clinical sites (e.g., electronic medical records used as source 
documents) should comply with these same regulatory standards.  
As a final step in the data management process, a 100% quality control review will be performed 
on the key efficacy and safety parameters.  In addition, a random subject sample (approximately 
10%) will be selected to perform a database audit.  The purpose of this audit is to detect 
systematic and random errors. 
All unused study materials are to be returned or destroyed as instructed by Millendo 
Therapeutics, Inc. after the study has been completed. 
10.8. 
Data Safety Monitoring Board 
A Data Safety Monitoring Board (DSMB) is planned for this study. The DSMB will be provided 
with a comprehensive safety package that includes AEs, SAEs and laboratory tests. Section 6.23 
specifies the procedures for reporting AEs and SAEs.  SAEs will be reviewed individually, 
cumulatively and in the context of what is already known about the safety profile of MLE4901 to 
assess whether the reported SAEs are a signal of a change in the benefit/risk profile.  All SAEs 
are to be reported by the Investigator to the IRB in a timely manner. Further details regarding the 
responsibilities of the DSMB can be found in the DSMB Charter.   
10.9. 
Protocol Deviations 
Protocol deviations from inclusion/exclusion criteria, concomitant medication restrictions and 
from any other protocol requirements that could, at least hypothetically, result in significant risk 
to the subject and/or affect the outcome of the study will be collected.  Additionally, 
nonadherence to the study procedures or schedule as defined by the protocol such as a missed 
procedure or an out-of-window study visit will be documented as protocol deviations.    
10.10. 
Access to Source Documentation 
The Investigator must permit the authorized Sponsor, agents of the Sponsor and regulatory 
agency employees to enter and inspect any site where the drug or records pertaining to the drug 
are held and to inspect and copy all records relating to an investigation including subject records.  
To ensure the accuracy of data submitted, it is mandatory that representatives of Millendo 
Therapeutics, Inc. and of the regulatory agencies have direct access to source documents (e.g., 
subject medical records, charts, laboratory reports) for the purpose of quality assurance audits 
either by Millendo Therapeutics, Inc. or their appointed representatives.  Subject confidentiality 
will be protected at all times. 


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10.11. 
Data Generation and Analysis 
Data processing and management will be performed by Millendo Therapeutics, Inc. or its 
designee.  Data will be promptly entered into the study database by the site and reviewed and 
issues resolved prior to database closure. 
Personal and sensitive personal data will be treated as confidential.  The results of the study will 
be made available for review by authorized representatives of the Millendo Therapeutics, Inc. 
and/or submitted to the IRB/EC and regulatory authorities. 
10.12. 
Retention of Records 
Copies of all study documents should be retained by the PI for at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least two years have elapsed since 
the formal discontinuation of clinical development of the investigational product, in accordance 
with 21 CFR 312.62.  These documents should be retained for a longer period, however, if 
required by regulatory requirements or by agreement with the Sponsor.  The Investigator must 
inform the Sponsor and obtain agreement prior to study documents being moved or destroyed. It 
is the responsibility of Millendo Therapeutics, Inc. to inform the Investigator/institution as to 
when these documents no longer need to be retained.  The final database will be archived by the 
Millendo Therapeutics, Inc. according to regulatory requirements. 
10.13. 
Financial Disclosure 
Investigators and Subinvestigators are required to provide full disclosure of any financial 
relationship to the Sponsor or its designee(s) prior to participation in any study-related activities.  
Additionally, Investigators and Subinvestigators are required to promptly provide updated 
information to the Sponsor or its designee(s) regarding any relevant changes in financial interests 
that occur during the course of the study and for 1 year after completion of the study.  For 
additional guidance, refer to 21 CFR 312.53(c) (4), 312.64(d), 812.43(c) (5), 812.110(d). 
10.14. 
Premature Termination of the Study 
If the study is prematurely terminated or suspended, the Sponsor will promptly inform the 
Investigators/institutions and the regulatory authority(s) of the termination or suspension and the 
reason(s) for the termination or suspension. The IRB/EC will also be promptly informed and 
provided with the reason(s) for the termination or suspension by Millendo Therapeutics, Inc. or 
by the Investigator/institution, as specified by the applicable regulatory requirement(s).  
10.15. 
Clinical Study Report 
A CSR will be written for this study with a structure and content that will conform to the ICH 
guidance, “Structure and Content of Clinical Study Reports, ICH Topic E3, July 1996.” 
10.16. 
Subject Insurance and Indemnity 
The Sponsor will provide insurance in accordance with local guidelines and requirements as a 
minimum for the subjects’ participating in this study.  The terms of insurance will be kept in the 
Sponsor’s regulatory files. 


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10.17. 
Amendments to the Protocol 
Modifications of the signed protocol are only possible by approved protocol amendments and 
with the agreement of all responsible persons.  The procedure for approval of a protocol 
amendment is identical to that for approval of the protocol.  The IRB/EC must be informed of all 
protocol amendments and should be asked for its opinion as to whether a full re-evaluation of the 
ethical aspects of the study is necessary by the committee.  This should be fully documented. 
The Investigator must not implement any deviation from or change to the protocol without 
discussion and agreement by the Sponsor in writing and prior review and documented 
approval/favorable opinion of the amendment from the relevant IRB or EC, except where it is 
necessary to eliminate an immediate hazard to study subjects or where the change(s) involves 
only logistical or administrative aspects of the study (e.g., change in monitor or change of 
telephone number). 
Protocol amendments will be submitted to the appropriate authority(s) as required by the applicable 
regulatory requirement(s).  


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11. 
LIST OF REFERENCES 
Azziz R, Ehrmann D, Legro RS, Whitcomb R, Hanley R, Fereshetian AG, O’Keefe M, Ghazzi 
MN. Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: a 
multicenter, double blind, placebo-controlled trial. J Clin Endocrinol Metab 86:1626-1632 
(2001). 
Barnard L, Ferriday D, Guenther N, Strauss B, Balen AH, Dye L. Quality of life and 
psychological well being in polycystic ovary syndrome. Hum Reprod 22(8):2279-86 (2007). 
Bazarganipour F, Taghavi SA, Montazeri A, Ahmadi F, Chaman R, Khosravi A. The impact of 
polycystic ovary syndrome on the health-related quality of life: a systematic review and meta-
analysis. Iran J Reprod Med 13(2):61-70 (2015). 
Clarke IJ, Cummins JT. The temporal relationship between gonadotropin releasing hormone 
(GnRH) and luteinizing hormone secretion in ovariectomized ewes. Endocrinology 111, 1737-
1739 (1982). 
Corenthal L, Von Hagen S, Larkins D, Ibrahim J, Santoro N. Benefits of continuous 
physiological pulsatile gonadotropin-releasing hormone therapy in women with polycystic 
ovarian syndrome. Fertil Steril 61:1027-33 (1994).  
Cronin L, Guyatt G, Griffith L, Wong E, Azziz R, Futterweit W, Cook D, Dunaif A. 
Development of a health-related quality-of-life questionnaire (PCOSQ) for women with 
polycystic ovary syndrome (PCOS). J Clin Endocrinol Metab 83(6):1976-87 (1998). 
EQ-5D-5L™ Questionnaire: http://www.euroqol.org/eq-5d-products/eq-5d-5l.html. EuroQoL 
Research Foundation. 
Ferriman D, Gallwey JD. Clinical assessment of body hair growth in women. Journal of Clinical 
Endocrinology 21:1440-1447 (1961). 
Guyatt G, Weaver B, Cronin L, Dooley JA, Azziz R. Health-related quality of life in women 
with polycystic ovary syndrome, a self-administered questionnaire, was validated. J Clin 
Epidemiol 57:1279-1287 (2004). 
Hall JE, Taylor AE, Hayes FJ, Crowley WF Jr. Insights into hypothalamic-pituitary dysfunction 
in polycystic ovary syndrome. J Endocrinol Invest 21(9):602-11 (1998). 
Hatch R, Rosenfield RS, Kim MH, Tredway D. Hirsutism: implications, etiology and 
management. Am J Obstet Gynecol 140:815 (1981).  
Jones GL, Benes K, Clark TL, Denham R, Holder MG, Haynes TJ, Mulgrew NC, Shepherd KE, 
Wilkinson VH, Singh M et al. The polycystic ovary syndrome health-related quality of life 
questionnaire (PCOSQ): a validation. Hum Reprod 19:371-377 (2004). 
Kassam A, Overstreet JW, Snow-Harter C, DeSouza MJ, Gold EB, Lasley BL. Identification of 
anovulation and transient luteal function using a urinary pregnanediol-3-glucuronide ratio 
algorithm. Environ Health Perspect 104:408-413 (1996). 
Knobil E, Neill JD editors. Knobil and Neill's Physiology of Reproduction. 3rd ed. St. Louis 
(MO): Elsevier Academic Press (2006). 


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Kroenke K, Spitzer RL, Williams JBW, Löwe B. An ultra-brief screening scale for anxiety and 
depression: the PHQ-4. Psychosomatics 50:613-621 (2009). 
Lehman MN, Coolen LM, Goodman RL. Minireview: Kisspeptin/neurokinin B/dynorphin 
(KNDy) cells of the arcuate nucleus: a central node in the control of gonadotropin-releasing 
hormone secretion. Endocrinology 151(8):3479-3489 (2010).  
Levine JE, Ramirez VD. Luteinizing hormone-releasing hormone release during the rat estrous 
cycle and after ovariectomy as estimated with push-pull cannulae. Endocrinol 111, 1439-1448 
(1982). 
Löwe B1, Wahl I, Rose M, Spitzer C, Glaesmer H, Wingenfeld K, Schneider A, Brähler E. A 4-
item measure of depression and anxiety: validation and standardization of the Patient Health 
Questionnaire-4 (PHQ-4) in the general population. J Affect Disord 122(1-2):86-95 (2010). 
Maeda K, Ohkura S, Uenoyama Y, Wakabayashi Y, Oka Y, Tsukamura H, et al. Neurobiological 
mechanisms underlying GnRH pulse generation by the hypothalamus. Brain Res 1364:103-15 
(2010). 
March WA, Moore VM, Willson KJ, Phillips DI, Norman RJ, Davies MJ. The prevalence of 
polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. 
Hum Reprod 25(2):544-51 (2010). 
O’Brien SC, Lewis JB, Cunliffe WJ. The Leeds revised acne grading system. J Dermatol Treat 
9:215-220 (1998). 
Pasch L, He SY, Huddleston H, Cedars MI, Beshay A, Zane LT, et al. Clinician vs self-ratings of 
hirsutism in patients with polycystic ovarian syndrome: associations with quality of life and 
depression. JAMA Dermatol 2016 Mar 4. doi: 10.1001/jamadermatol.2016.0358. [Epub ahead of 
print]. 
Rautaharju PM, Zhou SH, Wong S, et al. Sex differences in the evolution of the 
electrocardiographic QT interval with age. Can J Cardiol 8:690-5 (1992). 
Savin RC. Kalamazoo, MI: The Upjohn Company. Evaluating androgenetic alopecia in male and 
female patients (1994). 
Tazorac® Medical Review 2012, 
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202428Orig1s000MedR.pdf. 
US Food and Drug Administration Guidance for Industry: Acne Vulgaris: Developing Drugs for 
Treatment. September 2005. 
Waldstreicher J, Santoro NF, Hall JE. et al. Hyperfunction of the hypothalamic-pituitary axis in 
women with polycystic ovarian disease: indirect evidence for partial gonadotroph 
desensitization. J Clin Endocrinol Metab 66:165–172 (1988). 
Work Productivity and Activity Impairment: General Health Questionnaire (WPAI:GH): 
http://www.reillyassociates.net/WPAI_GH.html 


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12. 
APPENDICES 
 


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Appendix 1. 
STUDY SCHEDULE 
Table 7: 
Study Schedule 
Screening/ 
Wash-out 
Lead-in 
Treatment 
Follow-up 
 Week:† 
-20 to -8 
-8 
-4 
0 
2 
4 
6 
8 
12 
16 
20 
24 
28 
32 
36 
Visit:† 
S1 
(W1c) 
L1 
L2 
T
1 
T
2 
T3 
T3.5 
T4 
T5 
T5.5 
T6 
T6.5 
T7/ 
EoT 
F1 
F2/ 
EoS 
Informed Consent  
X 
 
 
 
 
 
Inclusion/ Exclusion 
Criteria 
X 
 
X 
X 
 
 
 
 
Medical History & 
Demographics 
X 
 
 
 
 
 
Number of Menstrual 
Periods/12 Months 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MBSQ 
X 
 
X 
X 
X X 
X 
 
X 
X 
 
X 
 
X 
X 
X 
HRQ 
X 
 
X 
X 
 
 
X 
 
X 
 
X 
X 
PCOSQ and PCOS 
Acne Questionnaire 
 
X 
 
 
X 
 
 
X 
X 
EQ-5D-5L 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
PHQ-4 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
WPAI:GH 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
PGIC 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Vital Signs, Height 
and Weighta 
X 
 
X 
X 
X X 
X 
 
X 
X 
 
X 
 
X 
X 
X 
Physical 
Examinationb 
X 
 
X 
 
 
X 
 
 
X 
X 
Pap Testb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Screening/ 
Wash-out 
Lead-in 
Treatment 
Follow-up 
 Week:† 
-20 to -8 
-8 
-4 
0 
2 
4 
6 
8 
12 
16 
20 
24 
28 
32 
36 
Visit:† 
S1 
(W1c) 
L1 
L2 
T
1 
T
2 
T3 
T3.5 
T4 
T5 
T5.5 
T6 
T6.5 
T7/ 
EoT 
F1 
F2/ 
EoS 
Modified Ferriman-
Gallwey Score 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
ISGA Score 
X 
 
X X 
X 
 
X 
X 
 
X 
 
X 
X 
X 
Savin Score 
X 
 
X 
 
 
 
 
X 
12-lead ECG 
X 
 
X 
 
 
X 
 
 
X 
Hematology & 
Chemistry 
X 
 
X 
X X 
X 
AST, 
ALT, 
ALK-P, 
T. Bili 
X 
X 
AST, 
ALT, 
ALK-P, 
T. Bili 
X 
AST, 
ALT, 
ALK-P, 
T. Bili 
X 
X 
Insulin, HbA1c, 
Lipid Panel 
Xc 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
PT, aPTT, TSH 
X 
(TSHc) 
X 
 
 
 
 
X 
Viral Screen 
(HBsAg, HCV, HIV) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Hormone 
Levels (SHBG, Total 
T, Free T, 
Bioavailable T, LH, 
FSH, E2, P, AMH, 
17-OHP, Prolactin, 
DHEA-S)c 
Xc 
Xc 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
Serum Pregnancy 
Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test 
X 
X 
X 
X X 
X 
 
X 
X 
 
X 
 
X 
X 
X 
Urinalysis 
X 
 
X 
 
 
 
 
X 


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Screening/ 
Wash-out 
Lead-in 
Treatment 
Follow-up 
 Week:† 
-20 to -8 
-8 
-4 
0 
2 
4 
6 
8 
12 
16 
20 
24 
28 
32 
36 
Visit:† 
S1 
(W1c) 
L1 
L2 
T
1 
T
2 
T3 
T3.5 
T4 
T5 
T5.5 
T6 
T6.5 
T7/ 
EoT 
F1 
F2/ 
EoS 
Urine Drug Screend 
X 
 
 
 
 
 
TVUe 
X 
 
 
 
 
 
X 
Menstrual Bleeding 
Electronic Diary 
Instruction/ Review 
 
X 
X 
X X 
X 
 
X 
X 
 
X 
 
X 
X 
X 
Thrice-Weekly Urine 
Sample Collection 
 
 
Subjects to self-collect first void urine samples three times per week on non-consecutive days when possible at home 
and store samples as directed for assessment of pregnanediol-3-glucuronide for ovulation determination.  
Begin MPA x 5 Days 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
Dispense Study Drug 
 
X  
X 
 
X 
X 
 
X 
 
Collect Study 
Drug/Assess 
Compliance 
 
X 
X 
 
X 
X 
 
X 
 
X 
Time of Last Study 
Drug Dose 
 
 
X 
 
X 
 
 
X 
Plasma PKf 
 
X 
 
X 
 
X 
 
 
X 
Medications 
X 
X 
X 
X 
X X 
X 
 
X 
X 
 
X 
 
X 
X 
X 
Adverse Events 
X 
X 
X 
X X 
X 
 
X 
X 
 
X 
 
X 
X 
X 
17-OHP: 17-hydroxyprogesterone; ALK-P: alkaline phosphatase; AMH: anti-Müllerian hormone; aPTT: activated partial thromboplastin time; DHEA-S: 
dehydroepiandrosterone sulfate; E2: estradiol; ECG: electrocardiogram; EoS: End-of-Study; EoT: End-of-Treatment; EQ-5D-5L: EuroQoL-5 Dimensions-5 
Levels Survey; FSH: follicle-stimulating hormone; HbA1c: hemoglobin A1c; HBsAg: hepatitis B surface antigen; HCV: hepatitis C virus; HIV: human 
immunodeficiency virus; HRQ: Hair Removal Questionnaire; ISGA: Investigator’s Static Global Assessment (of acne); LH: luteinizing hormone; MBSQ: PCOS 
Most Bothersome Symptom Questionnaire; MPA: medroxyprogesterone acetate; PCOSQ: PCOS Questionnaire; P: progesterone; Pap: Papanicolaou; PCOS: 
polycystic ovary syndrome; PE: physical examination; PGIC: Patient’s Global Impression of Change; PHQ-4: Patient’s Health Questionnaire-4; PK: 
pharmacokinetic(s) (samples); PT: prothrombin time; SHBG: sex hormone-binding globulin; T: testosterone; TBili: total bilirubin; TSH: thyroid-stimulating 
hormone; TVU: transvaginal ultrasound; WPAI:GH: Work Productivity and Activity Impairment Questionnaire: General Health 


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† Day 1 of the study is defined as the day the subject first receives study drug in the clinic. Study visits have a window of ± 3 days. Subjects should be fasting 
prior to Visits S1, T1, and T7. The subject should take her evening dose of study drug the evening prior to study visits during the Treatment Period (and also 
note the date and exact time of the last dose prior to Visits T3, T5 and T7). On the morning of Visits T1, T2, T3, T4, T5, and T6, subjects should wait to take 
their morning dose of study drug until directed by site personnel at the study site. On the morning of Visit T7, subjects should not take their morning dose of 
study drug. On the morning of Visits T3.5, 5.5, and 6.5, subjects should go ahead and take the study drug at home prior to the study visit. 
a  Height at Screening only. 
 
b  A complete physical examination (PE) will be performed at Visits S1, T1 and T7. A brief PE will be performed at Visits T5 and F2. At all other visits, targeted 
PEs may be performed if needed based on adverse events and positives from review of systems. A Papanicolaou (Pap) test is done as part of the physical 
examination during Screening only; documented results from a Pap test from within the year prior to Screening may be used instead. Women under 21 years of 
age at Screening do not require a Pap. 
c  Insulin, LH, E2, P, and AMH levels will not be done at Screening or Wash-out. Hormone levels should be drawn in the morning, as close to 8 AM as 
practicable and between 6-10 AM. 17-OHP, prolactin and DHEA-S will be done at Screening (or Wash-out, if wash-out is required) only. Subjects who require 
a wash-out of medications that affect hormone levels should NOT have their hormone levels (SHBG, total testosterone, free testosterone, bioavailable 
testosterone, FSH, 17-hydroxyprogesterone, prolactin, and DHEA-S) drawn at S1. Instead, they should complete the required wash-out and return to the site 
for hormone levels at the wash-out visit (Visit W1). Subjects on thyroid hormone replacement who require wash-out should also have an additional TSH level 
done at Visit W1. Subjects who do not require wash-out should not undergo a wash-out visit. 
d  Urine drug screen for cocaine, amphetamines and opioids.  
e  A TVU should be performed and results reviewed prior to randomization in subjects who meet all other inclusion and exclusion criteria. Subject who require 
wash-out of medications should have hormone levels drawn after wash-out. Subjects do not need to wait for Screening/Wash-out hormone results prior to 
proceeding with the TVU and the Lead-in Period. All Screening/Wash-out hormone results should be reviewed and confirmed to be inclusionary prior to 
Randomization. 
f  At Visit T1, plasma for PK assessments will be collected within 30 minutes before the first dose and at 1, 2, 2.5, 3 and 4 hours postdose. At Visits T3 and T5, a 
trough level will be collected within 30 minutes predose. At Visit T7/EoT, a trough level will be collected. 


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APPENDIX 2. PCOS MOST BOTHERSOME SYMPTOM 
QUESTIONNAIRE 
The following are examples of the questions that would be asked if the questionnaire were 
in paper format. The questions may be modified slightly for other formats (e.g., tablet). 
 
Visits: Screening, Lead-in and Randomization 
A. Most Bothersome Symptom 
Please select the symptom of PCOS that is most bothersome to you. If your most bothersome 
symptom is not listed, please select “Other” and write your most bothersome symptom in the 
space provided. 
1 – Infrequent or absent menstrual periods  
2 – Unwanted facial and/or body hair 
3 - Acne 
4 – Hair thinning or hair loss (on your head) 
 
5 - Other:_________________________ 
 
B. Bothersomeness of PCOS symptoms 
During the past two weeks, how much did each of the following symptoms bother you? 
 
 
 
Not 
at all 
Slightly 
Moderately 
Quite a 
bit 
Extremely 
1. Infrequent or absent menstrual periods 
□ 
□ 
□ 
□ 
□ 
2. Unwanted facial and/or body hair 
□ 
□ 
□ 
□ 
□ 
3. Acne 
□ 
□ 
□ 
□ 
□ 
4. Hair thinning or hair loss (on your head) 
 
□ 
□ 
□ 
□ 
□ 
 
If your most bothersome PCOS symptom from Question A is not listed above, please write 
it in the space provided. 
 
During the past two weeks, how much did this symptom bother you? 
 
 
 
Not 
at all 
Slightly 
Moderately 
Quite a 
bit 
Extremely 
5. <fill in> 
 
□ 
□ 
□ 
□ 
□ 
 
 
 


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Visits: Screening, Lead-in and Randomization, continued 
C. Severity of PCOS symptoms 
 
During the past two weeks, how would you rate your: 
 
 
 
None 
Mild 
Moderate 
Severe 
Very 
severe 
1. Unwanted facial and/or body hair 
□ 
□ 
□ 
□ 
□ 
2. Acne 
□ 
□ 
□ 
□ 
□ 
3. Hair thinning or hair loss (on your head) 
 
□ 
□ 
□ 
□ 
□ 
 
If your most bothersome PCOS symptom from Question A is not listed above, please write 
it in the space provided. 
 
During the past two weeks, how would you rate your: 
 
 
 
None 
Mild 
Moderate 
Severe 
Very 
severe 
4. <fill in> 
 
□ 
□ 
□ 
□ 
□ 
 
 
 


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Visits: All Post-Randomization Visits 
A. Severity of PCOS symptoms 
During the past two weeks, how would you rate your: 
 
 
 
None 
Mild 
Moderate 
Severe 
Very 
severe 
1. Unwanted facial and/or body hair 
□ 
□ 
□ 
□ 
□ 
2. Acne 
□ 
□ 
□ 
□ 
□ 
3. Hair thinning or hair loss (on your head) 
 
□ 
□ 
□ 
□ 
□ 
 
If your most bothersome PCOS symptom from the randomization visit is not listed above, 
please write it in the space provided. 
 
During the past two weeks, how would you rate your: 
 
 
 
None 
Mild 
Moderate 
Severe 
Very 
severe 
4. <fill in> 
 
□ 
□ 
□ 
□ 
□ 
 


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APPENDIX 3. HAIR REMOVAL QUESTIONNAIRE 
 
Over the past two months, approximately how often did you remove unwanted hair from your: 
 
Every 
day 
2-3x/ week 
Once 
per 
week 
2-3x/ 
month 
Once 
per 
month 
Less often 
than once 
per month 
Never 
1. Upper lip: 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
2. Chin: 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
 
 
 


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APPENDIX 4. POLYCYSTIC OVARY SYNDROME QUESTIONNAIRE 
AND PCOS ACNE QUESTIONNAIRE 
 
POLYCYSTIC OVARY SYNDROME QUESTIONNAIRE (PCOSQ) 
To what extent have you felt that growth of visible hair on your chin has been a problem for you during the last two weeks: 
 
A Severe 
Problem 
A Major 
Problem 
A Moderate 
Problem 
Some 
Problem 
A Little 
Problem 
Hardly any 
Problem 
No 
Problem 
1. Growth of visible hair on chin? 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
During the past two weeks, how much of the time have you felt: 
 
All of 
the Time 
Most of 
the Time 
A Good Bit 
of the Time 
Some of 
the time 
A Little of 
the Time 
Hardly any 
of the Time 
None of 
the Time 
2. Depressed as a result of having PCOS? 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
3. Concerned about being overweight? 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
4. Easily tired? 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
5. Concerned with infertility problems? 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
6. Moody as a result of having PCOS 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
In relation to your last menstruation, how much were the following issues a problem for you: 
 
A Severe 
Problem 
A Major 
Problem 
A Moderate 
Problem 
Some 
Problem 
A Little 
Problem 
Hardly any 
Problem 
No 
Problem 
7. Headaches? 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
8. Irregular menstrual periods? 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
To what extent has growth of visible hair on your upper lip been a problem for you during the last two weeks: 
 
A Severe 
Problem 
A Major 
Problem 
A Moderate 
Problem 
Some 
Problem 
A Little 
Problem 
Hardly any 
Problem 
No 
Problem 
9. Growth of visible hair on upper lip? 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
During the past two weeks, how much of the time have you: 
 
All of 
the Time 
Most of 
the Time 
A Good Bit 
of the Time 
Some of 
the time 
A Little of 
the Time 
Hardly any 
of the Time 
None of 
the Time 
10. Had trouble dealing with your weight? 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
11. Had low self-esteem as a result of your having 
PCOS? 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
12. Felt frustration in trying to lose weight? 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
13. Felt afraid of not being able to have children? 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
14. Felt frightened of getting cancer? 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
Over the last two weeks, to what extent have the following issues been a problem for you: 
 
A Severe 
Problem 
A Major 
Problem 
A Moderate 
Problem 
Some 
Problem 
A Little 
Problem 
Hardly any 
Problem 
No 
Problem 
15. Growth of visible hair on your face? 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
16. Embarrassment about excessive body hair? 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
During the past two weeks how much of the time have you been: 
 
All of 
the Time 
Most of 
the Time 
A Good Bit 
of the Time 
Some of 
the time 
A Little of 
the Time 
Hardly any 
of the Time 
None of 
the Time 
17. Worried about having PCOS? 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
18. Self-conscious as a result of having PCOS? 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
 
 


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In relation to your last menstruation, how much were the following issues a problem for you: 
 
A Severe 
Problem 
A Major 
Problem 
A Moderate 
Problem 
Some 
Problem 
A Little 
Problem 
Hardly any 
Problem 
No 
Problem 
19. Abdominal bloating? 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
20. Late menstrual period? 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
21. Menstrual cramps? 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
How much of the time during the last two weeks did you: 
 
All of 
the Time 
Most of 
the Time 
A Good Bit 
of the Time 
Some of 
the time 
A Little of 
the Time 
Hardly any 
of the Time 
None of 
the Time 
22. Feel like you are not sexy because of being 
overweight? 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
23. Feel a lack of control over the situation with 
PCOS? 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
24. Have difficulties staying at your ideal weight? 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
25. Feel sad because of infertility problems? 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
To what extent has growth of visible body hair been a problem for you during the last two weeks: 
 
A Severe 
Problem 
A Major 
Problem 
A Moderate 
Problem 
Some 
Problem 
A Little 
Problem 
Hardly any 
Problem 
No 
Problem 
26. Growth of visible body hair? 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
(Cronin 1998, Jones 2004, Guyatt 2004) 
 
 
PCOS ACNE QUESTIONNAIRE 
To what extent was acne a problem for you during the last two weeks: 
 
A Severe 
Problem 
A Major 
Problem 
A Moderate 
Problem 
Some 
Problem 
A Little 
Problem 
Hardly any 
Problem 
No 
Problem 
1. Acne during the last two weeks? 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
How much of the time during the last two weeks did you: 
 
All of 
the Time 
Most of 
the Time 
A Good Bit 
of the Time 
Some of 
the time 
A Little of 
the Time 
Hardly any 
of the Time 
None of 
the Time 
2. Feel unattractive because of acne? 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
3. Feel depressed as a result of acne? 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
In relation to your last menstruation, how much was acne a problem for you: 
 
A Severe 
Problem 
A Major 
Problem 
A Moderate 
Problem 
Some 
Problem 
A Little 
Problem 
Hardly any 
Problem 
No 
Problem 
4. Acne in relation to your last menstruation? 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
(Barnard 2007) 


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APPENDIX 5. EQ-5D-5L, TABLET VERSION 
English version for the USA 
Please tap the ONE box that best describes your health TODAY. 
 
MOBILITY 
 
I have no problems walking 
□ 
I have slight problems walking  
□ 
I have moderate problems walking  
□ 
I have severe problems walking 
□ 
I am unable to walk 
□ 
SELF-CARE 
 
I have no problems washing or dressing myself 
□ 
I have slight problems washing or dressing myself 
□ 
I have moderate problems washing or dressing myself 
□ 
I have severe problems washing or dressing myself 
□ 
I am unable to wash or dress myself 
□ 
USUAL ACTIVITIES (e.g. work, study, housework, family or leisure activities) 
I have no problems doing my usual activities 
□ 
I have slight problems doing my usual activities 
□ 
I have moderate problems doing my usual activities 
□ 
I have severe problems doing my usual activities 
□ 
I am unable to do my usual activities 
□ 
PAIN/DISCOMFORT 
 
I have no pain or discomfort 
□ 
I have slight pain or discomfort 
□ 
I have moderate pain or discomfort 
□ 
I have severe pain or discomfort 
□ 
I have extreme pain or discomfort 
□ 
ANXIETY/DEPRESSION 
 
I am not anxious or depressed 
□ 
I am slightly anxious or depressed 
□ 
I am moderately anxious or depressed 
□ 
I am severely anxious or depressed 
□ 
I am extremely anxious or depressed 
□ 
 
 


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EQ-5D-5L Visual Analog Scale for the US 
 
• We would like to know how good or bad your health is TODAY.  
• This scale is numbered from 0 to 100.  
100 means the best health you can imagine.  
0 means the worst health you can imagine.  
• Please tap on the scale to indicate how your health is TODAY. 
• Now, please write the number you marked on the scale in the box below.  
 
 
 
 
 
 
YOUR HEALTH TODAY  
 
 
 
http://www.euroqol.org/eq-5d-products/eq-5d-5l.html 


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APPENDIX 6. PATIENT’S HEALTH QUESTIONNAIRE-4 
 
 Over the last 2 weeks, how often have you  
 been bothered by the following problems? 
 (Use “✔” to indicate your answer) 
Not  
at all 
Several 
days 
More than 
half the 
days 
Nearly 
every day 
       1.  Feeling nervous, anxious or on edge 
0 
1 
2 
3 
       2.  Not being able to stop or control worrying 
0 
1 
2 
3 
       3.  Little interest or pleasure in doing things 
0 
1 
2 
3 
       4.  Feeling down, depressed, or hopeless 
0 
1 
2 
3 
 
 
(For office coding: Total Score T______ = ______  + _______ + _______ ) 
 
 
 
Scoring 
 
PHQ-4 total score ranges from 0 to 12, with categories of psychological distress being: 
• None  
0-2 
• Mild 
 
3-5 
• Moderate 6-8 
• Severe  
9-12  
 
Anxiety subscale = sum of items 1 and 2  
(score range, 0 to 6) 
Depression subscale = sum of items 3 and 4 (score range, 0 to 6) 
On each subscale, a score of 3 or greater is considered positive for screening purposes. 
(Kroenke 2009) 
 
 


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APPENDIX 7. WORK PRODUCTIVITY AND ACTIVITY IMPAIRMENT 
QUESTIONNAIRE: GENERAL HEALTH V2.0 
The following questions ask about the effect of your health problems on your ability to work and perform regular activities. By 
health problems we mean any physical or emotional problem or symptom. Please fill in the blanks or circle a number, as 
indicated. 
1. 
Are you currently employed (working for pay)?  
____  NO 
____  YES 
 
If NO, check “NO” and skip to question 6. 
The next questions are about the past seven days, not including today. 
2. 
During the past seven days, how many hours did you miss from work because of your health problems? Include hours you 
missed on sick days, times you went in late, left early, etc., because of your health problems. Do not include time you 
missed to participate in this study. 
_____HOURS 
3. 
During the past seven days, how many hours did you miss from work because of any other reason, such as vacation, 
holidays, time off to participate in this study? 
_____HOURS 
4. 
During the past seven days, how many hours did you actually work? 
_____HOURS (If “0”, skip to question 6.) 
 
5. 
During the past seven days, how much did your health problems affect your productivity while you were working?  
 
Think about days you were limited in the amount or kind of work you could do, days you accomplished less than you 
would like, or days you could not do your work as carefully as usual. If health problems affected your work only a little, 
choose a low number. Choose a high number if health problems affected your work a great deal.  
 
Consider only how much health problems affected  
productivity while you were working. 
Health problems had 
no effect on my work 
 
 
 
 
 
 
 
 
 
 
 
Health problems 
completely prevented 
me from working 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
CIRCLE A NUMBER 
 
6. 
During the past seven days, how much did your health problems affect your ability to do your regular daily activities, 
other than work at a job?  
 
By regular activities, we mean the usual activities you do, such as work around the house, shopping, childcare, 
exercising, studying, etc. Think about times you were limited in the amount or kind of activities you could do and times 
you accomplished less than you would like. If health problems affected your activities only a little, choose a low number. 
Choose a high number if health problems affected your activities a great deal.  
 
Consider only how much health problems affected your ability  
to do your regular daily activities, other than work at a job. 
Health problems had no 
effect on my daily 
activities 
 
 
 
 
 
 
 
 
 
 
 
Health problems 
completely prevented 
me from doing my daily 
activities 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
CIRCLE A NUMBER 
 
http://www.reillyassociates.net/WPAI_GH.html 


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APPENDIX 8. PATIENT’S GLOBAL IMPRESSION OF CHANGE 
 
Compared to when I first started study drug: 
 
Much 
better 
Moderately 
better 
A little 
better 
No 
different 
A little 
worse 
Moderately 
worse 
Much 
worse 
1. My acne is now: 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
2. The unwanted hair on my face and body is now: 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
3. My PCOS is now: 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
4. The regularity of my periods is now: 
□ 
□ 
□ 
□ 
□ 
□ 
□ 


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APPENDIX 9. DAILY MENSTRUAL DIARY 
1. What type of vaginal bleeding did you have during the past 24 hours? If you experienced both 
spotting and bleeding, please select ‘bleeding.’  
  None 
  Spotting 
  Bleeding 
 
2. During the past 24 hours, how heavy was your vaginal bleeding? (Only ask if Q1 is answered 
with ‘bleeding.’) 
  Light 
  Moderate 
  Heavy  
 


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APPENDIX 10. MODIFIED FERRIMAN-GALLWEY HIRSUTISM SCALE 
 
 
Each of the nine androgen-sensitive body areas in the diagram above is assigned a score from 0 
(no excess hair) to 4 and these are summed to provide a hirsutism score (Ferriman 1961; Hatch 
1981). 
 


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APPENDIX 11. INVESTIGATOR’S STATIC GLOBAL ASSESSMENT OF 
ACNE 
0 
= 
Clear skin with no inflammatory or noninflammatory lesions 
1 
= 
Almost clear:  rare non-inflammatory lesions with no more than rare papules 
2 
= 
Mild severity: greater than Grade 1, some noninflammatory lesions with no 
more than a few inflammatory lesions (papules/pustules only; no nodular 
lesions) 
3 
= 
Moderate severity: greater than Grade 2, up to many non-inflammatory lesions 
and           may have some inflammatory lesions, but no more than one small 
nodular lesion 
4 
= 
Severe: greater than Grade 3, up to many noninflammatory and inflammatory 
lesions, but no more than a few nodular lesions 
5 
= 
Very severe: many noninflammatory and inflammatory lesions and more than a 
few nodular lesions. May have cystic lesions 
 
Adapted from US Food and Drug Administration Guidance for Industry: Acne Vulgaris: 
Developing Drugs for Treatment. September 2005, Table 1, page 9. Tazorac® Medical Review 
2012, http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202428Orig1s000MedR.pdf. 
Table 8, p 20. 
 
For photographic equivalents for the above ISGA scores, see the Leeds Revised Acne Grading 
System in Appendix 12 . 
ISGA Score 
Leeds Photographic Equivalents  
(Appendix 12) 
1 
Grade 1.0 
2 
Grade 2.0-3.0 
3 
Grades 4.0-6.0 
4 
Grade 7.0-9.0 
5 
Grades 10.0-12.0 
 


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APPENDIX 12. LEEDS REVISED ACNE GRADING SYSTEM 
(O’Brien 1998) 


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APPENDIX 13. SAVIN SCALE FOR ANDROGENIC ALOPECIA 
 
 
The Savin scale measures overall thinning of the crown scalp and consists of 8 crown density 
images reflecting a range from no hair loss to severe hair loss (Stages I-1, I-2, I-3, I-4, II-1, II-2, 
III, advanced). The ninth image in the scale demonstrates frontal anterior recession. (Savin 1994) 


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APPENDIX 14. PROCEDURES FOR EMERGENCY UNBLINDING 
Study drug for this study will be managed using an online interactive web response system 
(IWRS). Each user will have a unique username and passcode to access the IWRS.  
 
Each site will additionally be provided with a 6-digit emergency unblinding code. Site users will 
be carefully trained to store the unblinding code in a secure but accessible location. Each code 
will be valid for one emergency unblinding action. A new code will be generated and sent to the 
site once an unblinding action has been carried out, or if the original code is lost. If a site 
performs an unblinding, all applicable audit-trail data is captured (username, participant number, 
unblinding date, etc.). 
 
In order to unblind the treatment assignment for a subject, a site user would: 
• Log in to the IWRS 
• Provide the subject ID and birth date of the subject for whom unblinding is requested 
• Provide the 6-digit emergency unblinding code 
 
The IWRS would then provide the treatment group to which the subject was assigned.  
 


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APPENDIX 15. ALGORITHM FOR THE MANAGEMENT OF SUBJECTS 
WITH TRANSAMINASE (AST OR ALT) ELEVATIONS 
>3X ULN 
• This appendix provides an algorithm for the management of subjects with transaminase (AST 
or ALT) elevations >3x ULN with or without bilirubin elevations in the MLE4901-101 
study. 
• Please discuss management of all cases of transaminase elevations >3x ULN with the 
Medical Monitor. Changes to this algorithm are permitted with agreement of the Medical 
Monitor. 
• Other patterns of liver chemistry abnormalities (e.g., bilirubin elevations or alkaline 
phosphatase increased out of proportion to transaminases) may require evaluation and 
management specific to those patterns, please discuss with the Medical Monitor. 
Transaminase (AST or ALT) elevation >3x to ≤8x ULN, total bilirubin <2x ULN 
• Within 24 hours of awareness of initial transaminase elevation, call the subject and: 
o Continue study drug  
o Stop acetaminophen (Tylenol®)/any products containing acetaminophen (pain 
medications, over-the-counter cold medications, etc.), alcohol, herbal and dietary 
supplements, and any other potentially hepatotoxic agents 
o Review current health status for clinical symptoms potentially related to hepatotoxicity 
(e.g., flu-like symptoms, jaundice, fatigue, nausea or vomiting, etc.) 
• If clinical symptoms are reported such as jaundice, flu-like symptoms, general 
fatigue, nausea or vomiting, etc., or if in the investigator’s judgment the subject 
requires emergent evaluation, immediately refer the subject to her local emergency 
department (ED).  
o Review risk factors for hepatitis and exposure to hepatotoxins 
 Obtain a liver-directed medical history (travel, occupational exposures, intercurrent 
illness, risk factors for intentional drug overdose, risk factors for acute viral hepatitis, 
risk factors for hepatic ischemia, family history of liver disease, etc.) 
 Review prescription medications, over the counter medications, herbal and dietary 
supplements, recreational drugs, and foods (e.g., inadvertent ingestion of amanita 
mushrooms) 
 Assess alcohol intake 
o If the subject is completely asymptomatic, and her history does not suggest that emergent 
evaluation is required, schedule a safety visit to occur within 3-4 days.  
 
• Within 3-4 days of awareness of the initial transaminase elevation, have the subject 
return to the site for further assessment and: 
o Conduct a hepatic-focused safety visit 
o Confirm initial assessment of risk factors especially acetaminophen, alcohol, herbal and 
dietary supplements, and concomitant medications  


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o Perform a liver-directed physical examination (e.g., right-sided heart failure, 
hepatomegaly, splenomegaly, vesicular skin lesions (HSV), Kayser-Fleisher rings, 
hypertension, mental status, jaundice, ascites)  
o Laboratory assessments: 
 Obtain AST, ALT, alkaline phosphatase, total bilirubin, LDH, GGT, CBC, PT, INR, 
serum chemistries, phosphate, serum iron, TIBC, anti-HAV IgM, HBsAg, anti-HBc 
IgM, and anti-HCV antibodies 
 Obtain an MLE4901 PK sample 
 If the subject has traveled to Russia, Pakistan, Mexico, or India, also obtain anti-HEV 
antibodies   
 Perform a urine pregnancy test 
 Obtain a urine toxicology screen 
 Obtain an acetaminophen level locally if there is suspicion for acetaminophen toxicity 
o Consider obtaining a RUQ ultrasound, if clinically indicated 
o A study visit that is already scheduled to occur and falls within the 3-4 day period 
following awareness of the initial transaminase elevation may be used to complete 
unscheduled safety visit requirements  
 
• Follow-up evaluation: 
o Continue to monitor the subject and evaluate liver function tests until elevated values 
normalize or return to baseline status. Table 8 provides follow-up monitoring details. 
o Further unscheduled safety visits may be required depending upon the individual 
subject’s clinical course. Please discuss monitoring plans with the Medical Monitor. 
 
Transaminase (AST or ALT) elevation >8x to ≤20x ULN, total bilirubin <2x ULN 
• Within 24 hours of awareness of initial transaminase elevation, call the subject and: 
o Immediately discontinue study drug (permanently) 
o Stop acetaminophen (Tylenol®)/any products containing acetaminophen (pain 
medications, over-the-counter cold medications, etc.), alcohol, herbal and dietary 
supplements, and any other potentially hepatotoxic agents 
o Review current health status for clinical symptoms potentially related to hepatotoxicity 
(e.g., flu-like symptoms, jaundice, fatigue, nausea or vomiting, etc.) 
 If clinical symptoms are reported such as jaundice, flu-like symptoms, general 
fatigue, nausea or vomiting, etc., or if in the investigator’s judgment the subject 
requires emergent evaluation, immediately refer the subject to her local emergency 
department (ED).  
o Review risk factors for hepatitis and exposure to hepatotoxins 
 Obtain a liver-directed medical history (travel, occupational exposures, intercurrent 
illness, risk factors for intentional drug overdose, risk factors for acute viral hepatitis, 
risk factors for hepatic ischemia, family history of liver disease, etc.) 


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 Review prescription medications, over the counter medications, herbal and dietary 
supplements, recreational drugs, and foods (e.g., inadvertent ingestion of amanita 
mushrooms) 
 Assess alcohol intake 
o If the subject is completely asymptomatic, and her history does not suggest that emergent 
evaluation is required, schedule a safety visit as soon as possible (must occur within 24-
48 hours) 
 
• As soon as possible within 48 hours after awareness of the initial transaminase 
elevation, have the subject return to the site for further assessment and: 
o Conduct an unscheduled safety visit/Early Termination visit. The subject does not have to 
be fasting. 
o Confirm that study drug has been stopped 
o Confirm initial assessment of risk factors especially acetaminophen, alcohol, herbal and 
dietary supplements, and concomitant medications  
o Perform a liver-directed physical examination (e.g., right-sided heart failure, 
hepatomegaly, splenomegaly, vesicular skin lesions (HSV), Kayser-Fleisher rings, 
hypertension, mental status, jaundice, ascites), as part of the Early Termination 
procedures  
o Laboratory assessments: 
 Obtain Early Termination visit labs including AST, ALT, alkaline phosphatase, total 
bilirubin, CBC, PT, INR, serum chemistries, and an MLE4901 PK sample; and 
perform a urine pregnancy test (these are already included in the Visit T7 labs) 
 Obtain LDH, GGT, phosphate, serum iron, TIBC, anti-HAV IgM, HBsAg, anti-HBc 
IgM, and anti-HCV antibodies 
 If the subject has traveled to Russia, Pakistan, Mexico, or India, also obtain anti-HEV 
antibodies   
 Obtain a urine toxicology screen 
 Obtain an acetaminophen level locally if there is suspicion for acetaminophen toxicity 
 Consider obtaining a RUQ ultrasound, if clinically indicated 
o Consider referral to appropriate medical specialist (e.g., hepatologist) if deemed 
necessary 
• Follow-up evaluation: 
o Continue to monitor the subject and evaluate liver function tests until elevated values 
normalize or return to baseline status. Table 8 provides follow-up monitoring details. 


Product: MLE4901 
Global Amendment 2 – 08 March 2017 
 Protocol MLE4901-101 
Millendo Therapeutics, Inc. 
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108 
o Further unscheduled safety visits may be required depending upon the individual 
subject’s clinical course. Please discuss monitoring plans with the Medical Monitor. 
 
Transaminase (AST or ALT) elevation >20x ULN or meets Hy’s Law criteria: AST or ALT 
>3x ULN AND total bilirubin ≥2x ULN:   
• As soon as possible after awareness of the initial transaminase elevation, call the subject 
and: 
o Immediately discontinue study drug (permanently) 
o Stop acetaminophen (Tylenol®)/any products containing acetaminophen (pain 
medications, over-the-counter cold medications, etc.), alcohol, herbal and dietary 
supplements, and any other potentially hepatotoxic agents 
o Review current health status for clinical symptoms potentially related to hepatotoxicity 
(e.g., flu-like symptoms, jaundice, fatigue, nausea or vomiting, etc.) 
 If clinical symptoms are reported such as jaundice, flu-like symptoms, general 
fatigue, nausea or vomiting, etc., or if in the investigator’s judgment the subject 
requires emergent evaluation, immediately refer the subject to her local emergency 
department (ED).  
 If the subject is completely asymptomatic, and her history does not suggest that 
emergent evaluation is required, schedule a safety visit as soon as possible. This 
unscheduled safety visit should take place within 24 hours. If a visit cannot be 
scheduled within 24 hours, then the subject should be referred to her local emergency 
department for evaluation and management. 
o Review risk factors for hepatitis and exposure to hepatotoxins: 
 Obtain a liver-directed medical history (travel, occupational hazards, intercurrent 
illness, risk factors for intentional drug overdose, risk factors for acute viral hepatitis, 
risk factors for hepatic ischemia, family history of liver disease, etc.) 
 Review prescription medications, over the counter medications, herbal and dietary 
supplements, recreational drugs, and foods (e.g., inadvertent ingestion of amanita 
mushrooms) 
 Assess alcohol intake 
• As soon as possible within 24 hours after awareness of the initial transaminase 
elevation, have the subject undergo further assessment (at the study site, by a 
hepatology consultant or in the emergency department):  
In the interests of time, the below suggested evaluations, along with any other evaluation that 
the treating physician (ED physician, specialty medical consultant, or PI) considers to be 
necessary, should be performed STAT locally; also send duplicate chemistry (including LFT) 
samples and a PK sample to Covance if possible. 


Product: MLE4901 
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109 
o Have the subject return to the site for an unscheduled safety visit/Early Termination visit. 
The subject does not have to be fasting. Alternatively, the subject may be referred for 
immediate evaluation and management by a hepatology expert or in the local emergency 
department. 
o Confirm that study drug has been stopped 
o Consider a hepatology consultation (if not previously obtained) 
o Confirm initial assessment of risk factors especially acetaminophen, alcohol, herbal and 
dietary supplements and concomitant medications  
o Perform a liver-directed physical examination (e.g., right-sided heart failure, 
hepatomegaly, splenomegaly, vesicular skin lesions (HSV), Kayser-Fleisher rings, 
hypertension, mental status, jaundice, ascites)  
o Obtain AST, ALT, alkaline phophatase, total bilirubin, direct bilirubin, LDH, GGT, 
CBC, PT, INR, serum chemistries, magnesium, phosphate, serum iron, TIBC, anti-HAV 
IgM, HBsAg, anti-HBc IgM, anti-HCV antibodies, hepatitis C RNA, anti-HDV 
antibodies, TSH, acetaminophen level, toxicology screen, and a pregnancy test 
o If subject has traveled to Russia, Pakistan, Mexico, or India, also test for anti-HEV 
antibodies 
o Obtain a plasma sample for PK if possible (this should be stored frozen) 
o Consider obtaining a RUQ ultrasound with Doppler if clinically indicated 
• Follow-up evaluation 
o Continue to monitor the subject and evaluate liver function tests until elevated values 
normalize or return to baseline status. Table 8 provides follow-up monitoring details. 
o Further unscheduled safety visits may be required depending upon the individual 
subject’s clinical course. Please discuss monitoring plans with the Medical Monitor. 
  
 
 


Product: MLE4901 
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 Protocol MLE4901-101 
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110 
 
Table 8: 
Evaluation of Follow-up AST and ALT Values 
If follow-up AST and/or ALT is:  
Action  
>20x ULN or Hy’s Law (AST or ALT >3x 
ULN AND total bilirubin ≥2x ULN) 
• Stop study drug immediately, if not 
previously done 
• Refer the subject for appropriate 
medical specialty consultation, if not 
previously done 
• Obtain AST, ALT, alkaline phosphatase, 
and total bilirubin at least every 3 days 
until AST and ALT are ≤8x ULN 
>8x ULN to ≤20x ULN  
  
 
 
• Stop study drug immediately, if not 
previously done 
• Consider referral to appropriate medical 
specialist (e.g., hepatologist), if not 
previously done  
• Have the subject return to the site for an 
Early Termination visit, if not 
previously done 
• Obtain AST, ALT, alkaline phosphatase, 
and total bilirubin approximately every 
3 days until AST and ALT are ≤8x ULN 
Increasing and >3x to ≤8x ULN 
• Obtain AST, ALT, alkaline phosphatase, 
and total bilirubin approximately every 
3 days until AST and ALT are ≤3x ULN 
Decreasing and >3x to ≤8x ULN 
• Obtain AST, ALT, alkaline phosphatase, 
and total bilirubin approximately every 
7 days until AST and ALT are ≤3x ULN  
 ≤3x ULN  
• Obtain AST, ALT, alkaline phosphatase, 
and total bilirubin approximately every 
14 days until AST and ALT are ≤ 
baseline or stable 
Persistent elevation >5x ULN for 14 or 
more days 
• Stop study drug, if not previously done 
 
 


Product: MLE4901 
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 Protocol MLE4901-101 
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111 
 
Summary Flowchart for the Management of Subjects with Transaminase (AST or ALT) 
Elevations  
 
 
 
AST or ALT >3x to ≤8x 
ULN, total bilirubin <2x 
AST or ALT >8x to ≤20x 
ULN, total bilirubin <2x 
AST or ALT >20x ULN; or 
AST or ALT >3x ULN AND 
total bilirubin ≥2x ULN 
• 
Call subject within 24 hours 
• 
Continue study drug 
• 
Discuss con meds, risk factors, and 
current health status 
If asymptomatic, 
schedule Safety 
visit within 3-4 
days  
If clinical symptoms 
present (e.g., 
jaundice, flu-like 
symptoms, etc.) refer 
subject to local 
emergency 
department  
Repeat LFT monitoring: 
• 
AST or ALT >20x ULN or Hy’s Law (AST or ALT >3x ULN AND total bilirubin 
≥2x ULN), check at least every 3 days 
• 
AST or ALT >8x to ≤20x ULN, check approximately every 3 days 
• 
AST or ALT increasing and >3x to ≤8x ULN, check approximately every 3 days 
• 
AST or ALT decreasing and >3x to ≤8x ULN, check approximately every 7 days 
• 
AST or ALT ≤3x ULN, check approximately every 14 days until ≤ baseline or stable 
• 
AST or ALT >5x ULN for more than 2 weeks  permanently discontinue study 
drug if not previously done 
• 
Call subject as soon as possible 
• 
STOP study drug immediately 
• 
Discuss con meds, risk factors, and 
current health status 
If asymptomatic, 
schedule Safety 
visit/Early 
Termination visit 
as soon as 
possible (within 
1-2 days) 
If clinical symptoms 
present (e.g., 
jaundice, flu-like 
symptoms, etc.) refer 
subject to local 
emergency 
department 
immediately  

SAP_001.pdf: 
 
 
 
 
DATA  ANALYSIS  PLAN 
 
Protocol Title: 
A Double-blind, Randomized, Parallel-group, 
Placebo-controlled Study of MLE4901 for the 
Treatment of Polycystic Ovary Syndrome (PCOS) 
Protocol Number: 
MLE4901-101 
Date of Original Protocol: 
19 May 2016 
Global Amendment 1: 
16 Feb 2017 
Global Amendment 2: 
08 Mar 2017 
 
 
Product: 
MLE4901 
Phase of Study: 
2b 
 
 
Sponsor: 
Millendo Therapeutics, Inc. 
 
 
Data Analysis Plan 
V1.0 / June 29, 2017 
 
 
 
 
 




Millendo Therapeutics, Inc. 
Protocols MLE4901-101 
Data Analysis Plan 
 
Page 3 of 34 
 
 
 
 
REVISION HISTORY 
Version 
Date 
Description of Changes 
1.0 
June 29, 2017 
Original version 


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Protocols MLE4901-101 
Data Analysis Plan 
 
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TABLE OF CONTENTS 
1 
Introduction ............................................................................................................................. 5 
1.1 
Subject Disposition .......................................................................................................... 5 
1.2 
Demographic and Baseline Characteristics ...................................................................... 5 
1.3 
Prior and Concomitant Medications ................................................................................. 5 
1.4 
Adverse Events ................................................................................................................. 5 
1.5 
Clinical Safety Laboratory Evaluations ........................................................................... 6 
1.6 
Vital Signs ........................................................................................................................ 7 
1.7 
12-Lead Electrocardiogram .............................................................................................. 7 
1.8 
Transvaginal Ultrasound Endometrial Thickness ............................................................ 7 
2 
Tables ...................................................................................................................................... 8 
3 
Listings .................................................................................................................................. 31 


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Protocols MLE4901-101 
Data Analysis Plan 
 
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1 
Introduction 
This purpose of this document is to provide specifications for the tables and listings to be 
provided for Millendo Therapeutics Protocol MLE4901-101. Information regarding the study 
objectives and procedures can be found in the Protocol. 
On June 6, 2017, Millendo Therapeutics elected to terminate the MLE4901-101 study due to the 
occurrence of several elevated transaminase levels >3xULN. A total of 55 subjects were 
randomized into the study prior to the termination of randomization. The available data from 
subjects who participated in the study will be used for safety summaries. Due to the limited data 
available, efficacy will not be summarized. Safety data includes adverse events (AEs), vital 
signs, 12-lead electrocardiograms (ECGs), transvaginal ultrasounds (TVUs), and clinical safety 
laboratory assessments. Safety data will be summarized and no formal statistical analysis of the 
safety data will be conducted. All safety summaries will be based on randomized subjects unless 
otherwise specified. Safety summaries will be based on observed values only. All available data 
will be listed. 
1.1 
Subject Disposition 
Counts of subjects who screened, entered the lead-in period, and randomized, as well as counts 
and percentages of subjects who completed the study and who withdrew early from the study, 
with the reason for early withdrawal, will be presented by treatment and in total. 
1.2 
Demographic and Baseline Characteristics 
Descriptive summaries of demographic and baseline characteristics will be presented by 
treatment and for total MLE4901 for all randomized subjects. Baseline measurements refer to 
data collected at Treatment Visit 1.  If a value at Treatment Visit 1 is not available, the last 
measurement on or prior to randomization will be used as baseline. 
Demographic and baseline characteristics include, but are not limited to: age at informed 
consent, sex, race, ethnicity, self-reported menstrual period stratification group (<4 per year, 4-6 
per year), height at screening, baseline body weight, baseline body mass index (BMI), and BMI 
stratification group (22 to <35 kg/m2, 35 to 45 kg/m2).  Continuous variables (age, height, 
weight, BMI) will be summarized by subject count, mean, standard deviation, median, minimum, 
and maximum. Categorical variables (race, sex, ethnicity, stratification groups) will be 
summarized by the number and percentage of subjects in the corresponding categories.  
1.3 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded with the World Health Organization Drug 
Dictionary and listed.  All concomitant medications taken on or after randomization will be 
summarized for all randomized subjects by treatment and for total MLE4901.  
1.4 
Adverse Events 
AEs will be coded and classified by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA).  All AEs reported during the clinical study will 
be recorded on the electronic case report form (eCRF). All AEs, regardless of relationship to 
study drug or procedure, should be collected beginning from the time the subject signs the study 


Millendo Therapeutics, Inc. 
Protocols MLE4901-101 
Data Analysis Plan 
 
Page 6 of 34 
 
consent until the early termination/final visit or 30 days after the last dose of study drug, 
whichever is longer. AEs in study subjects include any change in the subject’s condition. This 
includes symptoms, physical findings, or clinical syndromes. 
AEs beginning on or after randomization will be summarized for all randomized subjects. An 
overview with counts of events and subjects will be provided treatment and for total MLE4901  
for the incidence of AEs in the following categories:  
 Any AE  
 Maximum severity of AE  
 Any study drug related AE  
 Any serious AE (SAE)  
 AE leading to discontinuation from study  
The incidence of AEs will be summarized by treatment and in total by system organ class and 
preferred term. The same summaries will be done for study drug related AEs.   
There were no deaths during the study. Listings will be provided for any SAEs, and for any AEs 
leading to discontinuation from study. In addition, AEs beginning in the lead-in phase will be 
listed for all subjects who entered the lead-in phase. 
1.5 
Clinical Safety Laboratory Evaluations 
Safety laboratory data (chemistry, hematology, metabolic, coagulation, and urinalysis) will be 
summarized by treatment and for total MLE4901 by each scheduled visit for all randomized 
subjects. Change from baseline will be summarized. Baseline measurements for each dose level 
refer to data collected at Treatment Visit 1. If a value at Treatment Visit 1 is not available, the 
last measurement on or prior to randomization will be used as baseline.  
The number and frequency of randomized subjects with laboratory abnormalities on or after 
randomization will be summarized by treatment and for total MLE4901. Laboratory 
abnormalities include: 
 ALT >3xULN 
 AST >3xULN 
 Total Bilirubin >2xULN 
 (ALT or AST ≥3xULN) and Total Bilirubin >2xULN 
 Creatinine >2xULN 
 BUN >2xULN 
 Glucose <50 mg/dL 


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Data Analysis Plan 
 
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 Glucose >200 mg/dL 
 WBC <3 x10^3/uL 
 Hemoglobin <10 g/dL 
 Platelets <100 x10^3/uL 
Shift tables from baseline to the worst post-baseline value will be presented for ALT and AST 
(>1xULN to 3xULN, >3 to 5xULN, >5 to 10xULN, >10 to 15xULN, >15 to 20xULN, 
>20xULN) and alkaline phosphatase and total bilirubin (>1xULN to 1.5xULN, >1.5xULN to 
2xULN, >2xULN). 
1.6 
Vital Signs 
Vital signs (systolic blood pressure, diastolic blood pressure, heart rate, respiratory rate, 
temperature, body weight, and BMI) will be summarized by treatment and for total MLE4901 by 
each scheduled visit for all randomized subjects. Change from baseline will be summarized. 
Baseline measurements for each dose level refer to data collected at Treatment Visit 1. If a value 
at Treatment Visit 1 is not available, the last measurement on or prior to randomization will be 
used as baseline.  
1.7 
12-Lead Electrocardiogram 
ECG interpretations (normal, abnormal not clinically significant, abnormal clinically significant, 
not evaluable) will be tabulated by treatment and for total MLE4901 for all randomized subjects 
by scheduled visit. In addition, the worst result on or after randomization will be tabulated for the 
following categories: 
Highest QTcF 
 >450 msec 
 >480 msec 
 >500 msec 
Highest QTcF Change from Baseline 
 >30 msec 
 >60 msec 
1.8 
Transvaginal Ultrasound Endometrial Thickness 
Endometrial thickness assessed by TVU will be summarized by treatment and for total 
MLE4901 by each scheduled visit for all randomized subjects. Change from baseline will be 
summarized. Baseline measurements for each dose level refer to data collected at Screening. If a 
value at Screening is not available, the last measurement on or prior to randomization will be 
used as baseline. 


Millendo Therapeutics, Inc. 
Protocols MLE4901-101 
Data Analysis Plan 
 
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2 
Tables 
Table 14.1.1.1 ............................................................................................................................... 10 
Subject Disposition 
All Subjects 
Table 14.1.2.1 ............................................................................................................................... 11 
Summary of Demographic and Baseline Characteristics 
All Randomized Subjects 
Table 14.1.3.1 ............................................................................................................................... 13 
Summary of Concomitant Medications 
All Randomized Subjects 
Table 14.3.1.1 ............................................................................................................................... 14 
Overview of Adverse Events Beginning On or After Randomization 
All Randomized Subjects 
Table 14.3.1.2 ............................................................................................................................... 15 
Summary of Adverse Events Beginning On or After Randomization by System Organ Class 
and Preferred Term 
All Randomized Subjects 
Table 14.3.1.3 ............................................................................................................................... 16 
Summary of Study Drug Related Adverse Events Beginning On or After Randomization by 
System Organ Class and Preferred Term 
All Randomized Subjects 
Table 14.3.2.1 ............................................................................................................................... 17 
Listing of All Serious Adverse Events 
All Randomized Subjects 
Table 14.3.2.2 ............................................................................................................................... 18 
Listing of All Adverse Events Leading to Discontinuation of Study Drug 
All Randomized Subjects 
Table 14.3.2.3 ............................................................................................................................... 19 
Listing of Adverse Events Beginning in the Lead-in Phase 
All Subjects Who Entered Lead-in Period 
Table 14.3.3.1 ............................................................................................................................... 20 
Summary of Abnormal Safety Laboratory Parameters 
All Randomized Subjects 
Table 14.3.3.2 ............................................................................................................................... 21 
Shift Table of ALT, AST, Alkaline Phosphatase, and Total Bilirubin 
All Randomized Subjects 
Table 14.3.3.3 ............................................................................................................................... 25 
Summary of Safety Laboratory Parameters by Visit: Chemistry 
All Randomized Subjects 
Table 14.3.3.4 ............................................................................................................................... 25 
Summary of Safety Laboratory Parameters by Visit: Hematology 
All Randomized Subjects 
Table 14.3.3.5 ............................................................................................................................... 25 
Summary of Safety Laboratory Parameters by Visit: Metabolic 
All Randomized Subjects 


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Data Analysis Plan 
 
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Table 14.3.3.6 ............................................................................................................................... 25 
Summary of Safety Laboratory Parameters by Visit: Coagulation 
All Randomized Subjects 
Table 14.3.3.7 ............................................................................................................................... 26 
Summary of Safety Laboratory by Visit: Urinalysis 
All Randomized Subjects 
Table 14.3.4.1 ............................................................................................................................... 27 
Summary of Vital Signs by Visit 
All Randomized Subjects 
Table 14.3.4.2 ............................................................................................................................... 29 
Summary of Abnormal 12-Lead ECG 
All Randomized Subjects 
Table 14.3.4.3 ............................................................................................................................... 30 
Summary of Transvaginal Ultrasound Endometrial Thickness 
All Randomized Subjects 


 
 
Millendo Therapeutics, Inc. 
Protocol MLE4901-101                                                                                                       Page 1 of # 
Table 14.1.1.1 
Subject Disposition 
All Subjects 
______________________________________________________________________________________________________________________________________ 
 
                                                         MLE4901         MLE4901         MLE4901            Total                     
                                       Placebo BID      40 mg BID       60 mg BID       80 mg BID          MLE4901           Total  
Category                                 n   (%)         n   (%)         n   (%)         n   (%)           n   (%)           n   (%) 
______________________________________________________________________________________________________________________________________ 
 
Screened                                                                                                                    ##         
 
Entered Lead-in Period                                                                                                      ##         
 
Randomized                              ##              ##              ##              ##                ##                ##         
 
Completed                               ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#)        ## (###.#) 
 
Early termination                       ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#)        ## (###.#) 
 
Primary reason for early termination: 
   XXXXXXXXXXXXXXXXXXXXXXXXXXXXXX       ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#)        ## (###.#) 
   XXXXXXXXXXXXXXXXXXXXXXXXXXXXXX       ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#)        ## (###.#) 
   XXXXXXXXXXXXXXXXXXXXXXXXXXXXXX       ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#)        ## (###.#) 
   XXXXXXXXXXXXXXXXXXXXXXXXXXXXXX       ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#)        ## (###.#) 
   XXXXXXXXXXXXXXXXXXXXXXXXXXXXXX       ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#)        ## (###.#) 
   XXXXXXXXXXXXXXXXXXXXXXXXXXXXXX       ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#)        ## (###.#) 
______________________________________________________________________________________________________________________________________ 
 
Note: Percentages are calculated with the number of randomized subjects as the denominator. 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                           Database last modified: DDMMYYYY HH:MM 
 
<< Programming Note: Only reasons for withdrawal with total>0 will be displayed. Reasons will be sorted by descending total, then 
alphabetically. >> 


 
 
Millendo Therapeutics, Inc. 
Protocol MLE4901-101                                                                                                       Page 1 of 2 
Table 14.1.2.1 
Summary of Demographic and Baseline Characteristics 
All Randomized Subjects 
______________________________________________________________________________________________________________________________________ 
 
                                                                          MLE4901         MLE4901         MLE4901            Total  
Characteristic                                         Placebo BID       40 mg BID       60 mg BID       80 mg BID          MLE4901  
  Category/Statistic                                      (N=##)          (N=##)          (N=##)          (N=##)            (N=###) 
______________________________________________________________________________________________________________________________________ 
 
Age at Informed Consent 
  n                                                        ##              ##              ##              ##                ##    
  Mean                                                     ##.#            ##.#            ##.#            ##.#              ##.#  
  Standard Deviation                                       ##.##           ##.##           ##.##           ##.##             ##.## 
  Median                                                   ##.#            ##.#            ##.#            ##.#              ##.#  
  Minimum                                                  ##              ##              ##              ##                ##    
  Maximum                                                  ##              ##              ##              ##                ##    
 
Ethnicity, n (%) 
  Hispanic or Latino                                     ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
  Not Hispanic or Latino                                 ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
 
Race, n (%) 
  White                                                  ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
  Black or African American                              ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
  Asian                                                  ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
  American Indian or Alaskan Native                      ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
  Native Hawaiian or Other Pacific Islander              ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
  Multiple                                               ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
 
Self-Reported Menstrual Period Stratification Group, n (%) 
  <4 per year                                            ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
  4-6 per year                                           ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
______________________________________________________________________________________________________________________________________ 
 
Note: Baseline is defined as the measurement at treatment visit 1. If missing, the last value on or prior to randomization will be  
      used as baseline. 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                           Database last modified: DDMMYYYY HH:MM 


 
 
Millendo Therapeutics, Inc. 
Protocol MLE4901-101                                                                                                       Page 2 of 2 
Table 14.1.2.1 
Summary of Demographic and Baseline Characteristics 
All Randomized Subjects 
______________________________________________________________________________________________________________________________________ 
 
                                                                          MLE4901         MLE4901         MLE4901            Total  
Characteristic                                         Placebo BID       40 mg BID       60 mg BID       80 mg BID          MLE4901  
  Category/Statistic                                      (N=##)          (N=##)          (N=##)          (N=##)            (N=###) 
______________________________________________________________________________________________________________________________________ 
 
Height at Screening (cm) 
  n                                                         ##              ##              ##              ##                ##    
  Mean                                                      ##.##           ##.##           ##.##           ##.##             ##.## 
  Standard Deviation                                        ##.###          ##.###          ##.###          ##.###            ##.### 
  Median                                                    ##.##           ##.##           ##.##           ##.##             ##.## 
  Minimum                                                   ##.#            ##.#            ##.#            ##.#              ##.# 
  Maximum                                                   ##.#            ##.#            ##.#            ##.#              ##.# 
 
Baseline Weight (kg) 
  n                                                         ##              ##              ##              ##                ##    
  Mean                                                      ##.##           ##.##           ##.##           ##.##             ##.## 
  Standard Deviation                                        ##.###          ##.###          ##.###          ##.###            ##.### 
  Median                                                    ##.##           ##.##           ##.##           ##.##             ##.## 
  Minimum                                                   ##.#            ##.#            ##.#            ##.#              ##.# 
  Maximum                                                   ##.#            ##.#            ##.#            ##.#              ##.# 
 
Baseline BMI (kg/m2) 
  n                                                         ##              ##              ##              ##                ##    
  Mean                                                      ##.##           ##.##           ##.##           ##.##             ##.## 
  Standard Deviation                                        ##.###          ##.###          ##.###          ##.###            ##.### 
  Median                                                    ##.##           ##.##           ##.##           ##.##             ##.## 
  Minimum                                                   ##.#            ##.#            ##.#            ##.#              ##.# 
  Maximum                                                   ##.#            ##.#            ##.#            ##.#              ##.# 
 
BMI Stratification Group, n (%) 
  22 to <35 kg/m2                                          ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
  35 to 45 kg/m2                                           ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
______________________________________________________________________________________________________________________________________ 
 
Note: Baseline is defined as the measurement at treatment visit 1. If missing, the last value on or prior to randomization will be  
      used as baseline. 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                           Database last modified: DDMMYYYY HH:MM 


 
 
Millendo Therapeutics, Inc. 
Protocol MLE4901-101                                                                                                       Page 1 of # 
Table 14.1.3.1 
Summary of Concomitant Medications 
All Randomized Subjects 
______________________________________________________________________________________________________________________________________ 
 
Anatomical Main Group 
 Therapeutic Subgroup                                                     MLE4901         MLE4901         MLE4901            Total  
  Pharmacological Subgroup                              Placebo BID      40 mg BID       60 mg BID       80 mg BID          MLE4901 
   Chemical Subgroup                                      (N=##)          (N=##)          (N=##)          (N=##)            (N=###) 
    Chemical Substance                                    n   (%)         n   (%)         n   (%)         n   (%)           n   (%) 
______________________________________________________________________________________________________________________________________ 
 
Subjects with any concomitant medications                ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX                         ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
 XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX                         ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
  XXXXXXXXXXXXXXXXXXXXXXXXXXXXXX                         ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
   XXXXXXXXXXXXXXXXXXXXXXXXXXXXX                         ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
    XXXXXXXXXXXXXXXXXXXXXXXXXXXX                         ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX                         ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
 XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX                         ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
  XXXXXXXXXXXXXXXXXXXXXXXXXXXXXX                         ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
   XXXXXXXXXXXXXXXXXXXXXXXXXXXXX                         ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
    XXXXXXXXXXXXXXXXXXXXXXXXXXXX                         ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
______________________________________________________________________________________________________________________________________ 
 
Note: Concomitant medications are those that are taken on or after randomization.  
      %=100*n/N, where n=number of subjects in treatment group in the specified category and N=number of subjects in treatment group.  
      At each level of summation (overall, anatomical main group, pharmacological subgroup, etc.), subjects reporting more than one  
      concomitant medication are counted only once. A subject may contribute to more than one chemical substance. Medications are  
      coded using the WHODrug dictionary March 2016E B2 version. 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                           Database last modified: DDMMYYYY HH:MM 
 
<<Programming Note: Terms are sorted by ATC code though the code itself should not be presented (e.g., A11CA (Vitamin A, plain) 
should come before A11CB (Vitamin A and D in combination)). >> 


 
 
Millendo Therapeutics, Inc. 
Protocol MLE4901-101                                                                                                       Page 1 of 1 
Table 14.3.1.1 
Overview of Adverse Events Beginning On or After Randomization 
All Randomized Subjects 
______________________________________________________________________________________________________________________________________ 
 
                                                                    MLE4901          MLE4901          MLE4901             Total  
                                                  Placebo BID      40 mg BID        60 mg BID        80 mg BID            MLE4901 
                                                    (N=##)           (N=##)           (N=##)           (N=##)             (N=##) 
Category                                          n   (%)  [#]     n   (%)  [#]     n   (%)  [#]     n   (%)  [#]       n   (%)  [#] 
______________________________________________________________________________________________________________________________________ 
 
Subjects with any adverse event (AE)             ## (###.#) ##    ## (###.#) ##    ## (###.#) ##    ## (###.#) ##      ## (###.#) ## 
 
Maximum severity of AE                
   Mild                                          ## (###.#) N/A   ## (###.#) N/A   ## (###.#) N/A   ## (###.#) N/A     ## (###.#) N/A 
   Moderate                                      ## (###.#) N/A   ## (###.#) N/A   ## (###.#) N/A   ## (###.#) N/A     ## (###.#) N/A 
   Severe                                        ## (###.#) N/A   ## (###.#) N/A   ## (###.#) N/A   ## (###.#) N/A     ## (###.#) N/A 
 
Subjects with any AE related to study treatment  ## (###.#) ##    ## (###.#) ##    ## (###.#) ##    ## (###.#) ##      ## (###.#) ## 
 
Subjects with any serious AE                     ## (###.#) ##    ## (###.#) ##    ## (###.#) ##    ## (###.#) ##      ## (###.#) ## 
 
Subjects with any AE leading to  
discontinuation of study treatment               ## (###.#) ##    ## (###.#) ##    ## (###.#) ##    ## (###.#) ##      ## (###.#) ## 
______________________________________________________________________________________________________________________________________ 
 
Note: %=100*n/N, where n is the number of subjects in the specified category and N=number of subjects randomized in the treatment  
      group. [#] = number of adverse events in the specified category. Only AEs that begin on or after randomization are included. AEs  
      related to study drug are defined as those that are probably related, possibly related, or definitely related.  
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                           Database last modified: DDMMYYYY HH:MM 


 
 
Millendo Therapeutics, Inc. 
Data Safety Monitoring Board Report #1                                                                                    Page 1 of # 
Table 14.3.1.2 
Summary of Adverse Events Beginning On or After Randomization by System Organ Class and Preferred Term 
All Randomized Subjects 
______________________________________________________________________________________________________________________________________ 
 
                                                                    MLE4901          MLE4901          MLE4901             Total  
                                                  Placebo BID      40 mg BID        60 mg BID        80 mg BID            MLE4901 
                                                    (N=##)           (N=##)           (N=##)           (N=##)             (N=##) 
Category                                          n   (%)  [#]     n   (%)  [#]     n   (%)  [#]     n   (%)  [#]       n   (%)  [#] 
______________________________________________________________________________________________________________________________________ 
 
Subjects with any adverse event (AE)             ## (###.#) ##    ## (###.#) ##    ## (###.#) ##    ## (###.#) ##      ## (###.#) ## 
 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX           ## (###.#) ##    ## (###.#) ##    ## (###.#) ##    ## (###.#) ##      ## (###.#) ## 
   XXXXXXXXXXXXXXXXXXXXXXXXXXXXX                 ## (###.#) ##    ## (###.#) ##    ## (###.#) ##    ## (###.#) ##      ## (###.#) ## 
   XXXXXXXXXXXXXXXXXXXXXXXXXXXXX                 ## (###.#) ##    ## (###.#) ##    ## (###.#) ##    ## (###.#) ##      ## (###.#) ## 
   XXXXXXXXXXXXXXXXXXXXXXXXXXXXX                 ## (###.#) ##    ## (###.#) ##    ## (###.#) ##    ## (###.#) ##      ## (###.#) ## 
   XXXXXXXXXXXXXXXXXXXXXXXXXXXXX                 ## (###.#) ##    ## (###.#) ##    ## (###.#) ##    ## (###.#) ##      ## (###.#) ## 
 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX           ## (###.#) ##    ## (###.#) ##    ## (###.#) ##    ## (###.#) ##      ## (###.#) ## 
   XXXXXXXXXXXXXXXXXXXXXXXXXXXXX                 ## (###.#) ##    ## (###.#) ##    ## (###.#) ##    ## (###.#) ##      ## (###.#) ## 
   XXXXXXXXXXXXXXXXXXXXXXXXXXXXX                 ## (###.#) ##    ## (###.#) ##    ## (###.#) ##    ## (###.#) ##      ## (###.#) ## 
______________________________________________________________________________________________________________________________________ 
 
Note: %=100*n/N, where n is the number of subjects in the specified category and N=number of subjects randomized in the treatment  
      group. [#] = number of adverse events in the specified category. Only AEs that begin on or after randomization are included. At  
      each level of summation (overall, system organ class, preferred term), subjects reporting more than one AE are counted only  
      once. A subject may contribute to more than one preferred term. AEs are coded using MedDRA dictionary version 19.0. 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                           Database last modified: DDMMYYYY HH:MM 
 
<< Programming Note: Table will be sorted by descending frequency in the total column for system organ class and preferred term 
within system organ class. >> 


 
 
<< Programming Note: The following tables will have the same layout as Table 14.3.1.2: >> 
Table 14.3.1.3 
Summary of Study Drug Related Adverse Events Beginning On or After Randomization by System Organ Class and Preferred Term 
All Randomized Subjects 
 
 
<< Programming Note: Replace 
  
Subjects with any adverse event (AE) 
 
 
With 
  
Subjects with any adverse event (AE) related to study Drug 
 
<< Programming Note: Include the additional footnote: >>  
 
AEs related to study drug are defined as those that are probably related, possibly related, or definitely related.


 
 
Millendo Therapeutics, Inc. 
Data Safety Monitoring Board Report #1                                                                                    Page 1 of # 
Table 14.3.2.1 
Listing of All Serious Adverse Events  
All Randomized Subjects  
______________________________________________________________________________________________________________________________________ 
 
                    Adverse Event Verbatim Term/                                       Relationship to                Other 
Treatment   SAE     Preferred Term/                      Start Date/Time/Day           Study Drug/                    Actions Taken/ 
   Subject  Specify System Organ Class                   Stop Date/Time/Day  Severity  Action Taken with Study Drug   Outcome 
______________________________________________________________________________________________________________________________________  
 
Placebo BID 
   ###-###  #, #    XXXXXXXXXXXXXXXXXXXXXXXXXXX/         DDMMMYYYY/##        XXXXXXXX  XXXXXXXXXXXXXXXXXXXXX/          NONE/ 
                    XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/   DDMMMYYYY/##                  XXXXXXXXXXXXXXXXXXXXX           XXXXXXXXXXXXXX 
                    XXXXXXXXXXXXXXXXXXXXXXXXXXX                                                         
 
            #, #, # XXXXXXXXXXXXXXXXXXXXXXXXXXX/         DDMMMYYYY/##        XXXXXXXX  XXXXXXXXXXXXXXXXXXXXX/          #, #/ 
                    XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/   DDMMMYYYY/##                  XXXXXXXXXXXXXXXXXXXXX           XXXXXXXXXXXXXX 
                    XXXXXXXXXXXXXXXXXXXXXXXXXXX                                                         
 
   ###-###  #, #    XXXXXXXXXXXXXXXXXXXXXXXXXXX/         DDMMMYYYY/##        XXXXXXXX  XXXXXXXXXXXXXXXXXXXXX/          #, #, #/ 
                    XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/   DDMMMYYYY/##                  XXXXXXXXXXXXXXXXXXXXX           XXXXXXXXXXXXXX 
                    XXXXXXXXXXXXXXXXXXXXXXXXXXX                                                         
MLE4901 40 mg BID 
 
MLE4901 60 mg BID 
 
MLE4901 80 mg BID 
______________________________________________________________________________________________________________________________________ 
 
Note: Only AEs that begin on or after randomization are included. AEs are coded using MedDRA dictionary version 19.0. 
      SAE Specify: 1 = congenital anomaly or birth defect, 2 = persistent or significant incapacity or substantial disruption of the  
      ability to conduct normal life functions, 3 = death, 4 = hospitalization/prolongation of hospitalization, 5 = life threatening,  
      6 = other medical important event. 
      Day = start date/stop date – first dose of study drug + 1.  
      Other actions taken: 1 = Concomitant medication added, 2 = Concomitant procedure, 3 = Other 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                           Database last modified: DDMMYYYY HH:MM 


 
 
Millendo Therapeutics, Inc. 
Data Safety Monitoring Board Report #1                                                                                    Page 1 of # 
Table 14.3.2.2 
Listing of All Adverse Events Leading to Discontinuation of Study Drug 
All Randomized Subjects  
______________________________________________________________________________________________________________________________________ 
 
                   Adverse Event Verbatim Term/                                       Relationship to                Other 
Treatment  SAE?    Preferred Term/                      Start Date/Time/Day           Study Drug/                    Actions Taken/ 
   Subject Specify System Organ Class                   Stop Date/Time/Day  Severity  Action Taken with Study Drug   Outcome 
______________________________________________________________________________________________________________________________________  
 
Placebo BID 
   ###-### XXX     XXXXXXXXXXXXXXXXXXXXXXXXXXX/         DDMMMYYYY/##        XXXXXXXX  XXXXXXXXXXXXXXXXXXXXX/          NONE/ 
           #, #    XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/   DDMMMYYYY/##                  XXXXXXXXXXXXXXXXXXXXX           XXXXXXXXXXXXXX 
                   XXXXXXXXXXXXXXXXXXXXXXXXXXX                                                         
 
           XXX     XXXXXXXXXXXXXXXXXXXXXXXXXXX/         DDMMMYYYY/##        XXXXXXXX  XXXXXXXXXXXXXXXXXXXXX/          #, #/ 
           #, #, # XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/   DDMMMYYYY/##                  XXXXXXXXXXXXXXXXXXXXX           XXXXXXXXXXXXXX 
                   XXXXXXXXXXXXXXXXXXXXXXXXXXX                                                         
 
   ###-### XXX     XXXXXXXXXXXXXXXXXXXXXXXXXXX/         DDMMMYYYY/##        XXXXXXXX  XXXXXXXXXXXXXXXXXXXXX/          #, #, #/ 
           #, #    XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/   DDMMMYYYY/##                  XXXXXXXXXXXXXXXXXXXXX           XXXXXXXXXXXXXX 
                   XXXXXXXXXXXXXXXXXXXXXXXXXXX                                                         
MLE4901 40 mg BID 
 
MLE4901 60 mg BID 
 
MLE4901 80 mg BID 
______________________________________________________________________________________________________________________________________ 
 
Note: Only AEs that begin on or after randomization are included. AEs are coded using MedDRA dictionary version 19.0. 
      SAE Specify: 1 = congenital anomaly or birth defect, 2 = persistent or significant incapacity or substantial disruption of the  
      ability to conduct normal life functions, 3 = death, 4 = hospitalization/prolongation of hospitalization, 5 = life threatening,  
      6 = other medical important event. 
      Day = start date/stop date – first dose of study drug + 1.  
      Other actions taken: 1 = Concomitant medication added, 2 = Concomitant procedure, 3 = Other 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                           Database last modified: DDMMYYYY HH:MM 


 
 
Millendo Therapeutics, Inc. 
Data Safety Monitoring Board Report #1                                                                                    Page 1 of # 
Table 14.3.2.3 
Listing of Adverse Events Beginning in the Lead-in Phase 
All Subjects Who Entered Lead-in Period 
______________________________________________________________________________________________________________________________________ 
 
                   Adverse Event Verbatim Term/                                                                      Other 
Treatment  SAE?    Preferred Term/                      Start Date/Time/Day               Relationship to MPA/       Actions Taken/ 
   Subject Specify System Organ Class                   Stop Date/Time/Day    Severity    Action Taken with MPA      Outcome 
______________________________________________________________________________________________________________________________________  
 
Placebo BID 
   ###-### XXX     XXXXXXXXXXXXXXXXXXXXXXXXXXX/         DDMMMYYYY/##          XXXXXXXX  XXXXXXXXXXXXXXXXXXXXX/       NONE/ 
           #, #    XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/   DDMMMYYYY/##                    XXXXXXXXXXXXXXXXXXXXX        XXXXXXXXXXXXXXXX 
                   XXXXXXXXXXXXXXXXXXXXXXXXXXX                                                         
 
           XXX     XXXXXXXXXXXXXXXXXXXXXXXXXXX/         DDMMMYYYY/##          XXXXXXXX  XXXXXXXXXXXXXXXXXXXXX/       #, #/ 
           #, #, # XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/   DDMMMYYYY/##                    XXXXXXXXXXXXXXXXXXXX         XXXXXXXXXXXXXXXXX 
                   XXXXXXXXXXXXXXXXXXXXXXXXXXX                                                         
 
   ###-### XXX     XXXXXXXXXXXXXXXXXXXXXXXXXXX/         DDMMMYYYY/##          XXXXXXXX  XXXXXXXXXXXXXXXXXXXXX/       #, #, #/ 
           #, #    XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/   DDMMMYYYY/##                    XXXXXXXXXXXXXXXXXXXXX        XXXXXXXXXXXXXXXX 
                   XXXXXXXXXXXXXXXXXXXXXXXXXXX                                                         
 
MLE4901 40 mg BID 
 
MLE4901 60 mg BID 
 
MLE4901 80 mg BID 
______________________________________________________________________________________________________________________________________ 
 
Note: Only AEs that begin on or after first dose of medroxyprogesterone acetate (MPA) and prior to randomization are included.  
      AEs are coded using MedDRA dictionary version 19.0. 
      SAE Specify: 1 = congenital anomaly or birth defect, 2 = persistent or significant incapacity or substantial disruption of the  
      ability to conduct normal life functions, 3 = death, 4 = hospitalization/prolongation of hospitalization, 5 = life threatening,  
      6 = other medical important event. 
      Day = start date/stop date – first dose date of MPA + 1.  
      Other actions taken: 1 = Concomitant medication added, 2 = Concomitant procedure, 3 = Other 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                           Database last modified: DDMMYYYY HH:MM 


 
 
Millendo Therapeutics, Inc. 
Protocol MLE4901-101                                                                                                       Page 1 of # 
Table 14.3.3.1 
Summary of Abnormal Safety Laboratory Parameters 
All Randomized Subjects 
______________________________________________________________________________________________________________________________________ 
 
                                                            MLE4901            MLE4901            MLE4901               Total 
                                        Placebo BID        40 mg BID          60 mg BID          80 mg BID             MLE4901 
                                          (N=##)             (N=##)             (N=##)             (N=##)              (N=###) 
Category                                 n/N’ (%)           n/N’ (%)           n/N’ (%)           n/N’ (%)             n/N’ (%) 
______________________________________________________________________________________________________________________________________ 
 
ALT >3xULN                              ##/## (###.#)      ##/## (###.#)      ##/## (###.#)      ##/## (###.#)        ##/## (###.#) 
 
AST >3xULN                              ##/## (###.#)      ##/## (###.#)      ##/## (###.#)      ##/## (###.#)        ##/## (###.#) 
 
Total Bilirubin (T.Bili) >2xULN         ##/## (###.#)      ##/## (###.#)      ##/## (###.#)      ##/## (###.#)        ##/## (###.#) 
 
(ALT or AST >=3xULN) and T.Bili >2xULN  ##/## (###.#)      ##/## (###.#)      ##/## (###.#)      ##/## (###.#)        ##/## (###.#) 
 
Creatinine >2xULN                       ##/## (###.#)      ##/## (###.#)      ##/## (###.#)      ##/## (###.#)        ##/## (###.#) 
 
BUN >2xULN                              ##/## (###.#)      ##/## (###.#)      ##/## (###.#)      ##/## (###.#)        ##/## (###.#) 
 
Glucose <50 mg/dL                       ##/## (###.#)      ##/## (###.#)      ##/## (###.#)      ##/## (###.#)        ##/## (###.#) 
 
Glucose >200 mg/dL                      ##/## (###.#)      ##/## (###.#)      ##/## (###.#)      ##/## (###.#)        ##/## (###.#) 
 
WBC <3 x10^3/uL                         ##/## (###.#)      ##/## (###.#)      ##/## (###.#)      ##/## (###.#)        ##/## (###.#) 
 
Hemoglobin <10 g/dL                     ##/## (###.#)      ##/## (###.#)      ##/## (###.#)      ##/## (###.#)        ##/## (###.#) 
 
Platelets <100 x10^3/uL                 ##/## (###.#)      ##/## (###.#)      ##/## (###.#)      ##/## (###.#)        ##/## (###.#) 
______________________________________________________________________________________________________________________________________ 
 
Note: %=100*n/N’, where n=number of subjects with a value in the category on or after randomization and N’=number of subjects with a 
      result on or after randomization for the specified parameter. 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                           Database last modified: DDMMYYYY HH:MM 
 


 
 
Millendo Therapeutics, Inc. 
Protocol MLE4901-101                                                                                                       Page 1 of 8 
Table 14.3.3.2 
Shift Table of ALT, AST, Alkaline Phosphatase, and Total Bilirubin 
All Randomized Subjects 
______________________________________________________________________________________________________________________________________  
 
                                                                   Worst Post-Baseline Value 
                           --------------------------------------------------------------------------------------------------------- 
                            Normal       >1 to       >3 to      >5 to       >10 to      >15 to 
Parameter/                  or Low       3xULN       5xULN      10xULN      15xULN      20xULN      >20xULN     Missing     Total 
Treatment   Baseline        n   (%)     n   (%)     n   (%)     n   (%)     n   (%)     n   (%)     n   (%)     n   (%)     n   (%)  
______________________________________________________________________________________________________________________________________  
 
ALT         
 
Placebo     Normal or Low  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
BID         >1 – 3xULN     ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
(N=#)       >3 – 5xULN     ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
            >5 – 10xULN    ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
            >10 – 15xULN   ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
            >15 – 20xULN   ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
            >20xULN        ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
            Missing        ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
            Total          ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## (100.0)   
 
MLE4901     Normal or Low  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
40 mg BID   >1 – 3xULN     ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
(N=#)       >3 – 5xULN     ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
            >5 – 10xULN    ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
            >10 – 15xULN   ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
            >15 – 20xULN   ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
            >20xULN        ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
            Missing        ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
            Total          ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## (100.0)   
 
MLE4901     Normal or Low  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
60 mg BID   >1 – 3xULN     ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
(N=#)       >3 – 5xULN     ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
            >5 – 10xULN    ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
            >10 – 15xULN   ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
            >15 – 20xULN   ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
            >20xULN        ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
            Missing        ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
            Total          ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## (100.0)   
_____________________________________________________________________________________________________________________________________   
 
Note: Baseline is defined as the measurement at treatment visit 1. If missing, the last value on or prior to randomization will be  
      used as baseline. 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                           Database last modified: DDMMYYYY HH:MM 


 
 
Millendo Therapeutics, Inc. 
Protocol MLE4901-101                                                                                                       Page 2 of 8 
Table 14.3.3.2 
Shift Table of ALT, AST, Alkaline Phosphatase, and Total Bilirubin 
All Randomized Subjects 
______________________________________________________________________________________________________________________________________  
 
                                                           Worst Post-Baseline Value 
                           --------------------------------------------------------------------------------------------------------- 
                            Normal       >1 to       >3 to      >5 to       >10 to      >15 to 
Parameter/                  or Low       3xULN       5xULN      10xULN      15xULN      20xULN      >20xULN     Missing     Total 
Treatment   Baseline        n   (%)     n   (%)     n   (%)     n   (%)     n   (%)     n   (%)     n   (%)     n   (%)     n   (%)  
______________________________________________________________________________________________________________________________________  
 
ALT         
 
MLE4901     Normal or Low  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
80 mg BID   >1 – 3xULN     ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
(N=#)       >3 – 5xULN     ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
            >5 – 10xULN    ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
            >10 – 15xULN   ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
            >15 – 20xULN   ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
            >20xULN        ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
            Missing        ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
            Total          ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## (100.0)   
 
Total       Normal or Low  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
MLE4901     >1 – 3xULN     ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
(N=#)       >3 – 5xULN     ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
            >5 – 10xULN    ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
            >10 – 15xULN   ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
            >15 – 20xULN   ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
            >20xULN        ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
            Missing        ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)   
            Total          ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## ( ##.#)  ## (100.0)   
_____________________________________________________________________________________________________________________________________   
 
Note: Baseline is defined as the measurement at treatment visit 1. If missing, the last value on or prior to randomization will be  
      used as baseline. 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                           Database last modified: DDMMYYYY HH:MM 
 
 
<< Programming Note: Repeat these two pages for AST. >> 


 
 
Millendo Therapeutics, Inc. 
Protocol MLE4901-101                                                                                                       Page 5 of 8 
Table 14.3.3.2 
Shift Table of ALT, AST, Alkaline Phosphatase, and Total Bilirubin 
All Randomized Subjects 
______________________________________________________________________________________________________________________________________  
 
                                                             Worst Post-Baseline Value 
                                   ------------------------------------------------------------------------------   
                                   Normal         >1 to        >1.5 to                       
Parameter/                         or Low        1.5xULN       2xULN         >2xULN        Missing       Total       
Treatment       Baseline           n   (%)       n   (%)       n   (%)       n   (%)       n   (%)       n   (%)    
______________________________________________________________________________________________________________________________________  
 
ALP         
 
Placebo         Normal or Low     ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)   
BID             >1 - 1.5xULN      ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)   
(N=#)           >1.5 – 2xULN      ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)   
                >2xULN            ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)   
                Missing           ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)   
                Total             ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## (100.0)   
 
MLE4901         Normal or Low     ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)   
40 mg BID       >1 - 1.5xULN      ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)   
(N=#)           >1.5 – 2xULN      ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)   
                >2xULN            ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)   
                Missing           ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)   
                Total             ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## (100.0)   
 
MLE4901         Normal or Low     ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)   
60 mg BID       >1 - 1.5xULN      ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)   
(N=#)           >1.5 – 2xULN      ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)   
                >2xULN            ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)   
                Missing           ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)   
                Total             ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## (100.0)   
_____________________________________________________________________________________________________________________________________   
 
Note: Baseline is defined as the measurement at treatment visit 1. If missing, the last value on or prior to randomization will be  
      used as baseline. 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                           Database last modified: DDMMYYYY HH:MM 
 
  


 
 
Millendo Therapeutics, Inc. 
Protocol MLE4901-101                                                                                                       Page 6 of 8 
Table 14.3.3.2 
Shift Table of ALT, AST, Alkaline Phosphatase, and Total Bilirubin 
All Randomized Subjects 
______________________________________________________________________________________________________________________________________  
 
                                                             Worst Post-Baseline Value 
                                   ------------------------------------------------------------------------------   
                                   Normal         >1 to        >1.5 to                       
Parameter/                         or Low        1.5xULN       2xULN         >2xULN        Missing       Total       
Treatment       Baseline           n   (%)       n   (%)       n   (%)       n   (%)       n   (%)       n   (%)    
______________________________________________________________________________________________________________________________________  
 
ALP         
 
MLE4901         Normal or Low     ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)   
80 mg BID       >1 - 1.5xULN      ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)   
(N=#)           >1.5 – 2xULN      ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)   
                >2xULN            ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)   
                Missing           ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)   
                Total             ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## (100.0)   
 
Total           Normal or Low     ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)   
MLE4901         >1 - 1.5xULN      ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)   
(N=#)           >1.5 – 2xULN      ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)   
                >2xULN            ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)   
                Missing           ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)   
                Total             ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## ( ##.#)    ## (100.0)   
_____________________________________________________________________________________________________________________________________   
 
Note: Baseline is defined as the measurement at treatment visit 1. If missing, the last value on or prior to randomization will be  
      used as baseline. 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                           Database last modified: DDMMYYYY HH:MM 
 
<< Programming Note: Repeat these two pages for ALP and Total Bilirubin. In other words, Pages 1-2 = ALT, Pages 3-4 = AST, 
Pages 5-6 = ALP, and Pages 7-8 = Total Bilirubin.>> 
     
 


 
 
<< Programming Note: The following tables will have the same layout as Table 14.3.4.1: >> 
Table 14.3.3.3 
Summary of Safety Laboratory Parameters by Visit: Chemistry 
All Randomized Subjects 
 
Table 14.3.3.4 
Summary of Safety Laboratory Parameters by Visit: Hematology 
All Randomized Subjects 
 
Table 14.3.3.5 
Summary of Safety Laboratory Parameters by Visit: Metabolic 
All Randomized Subjects 
 
Table 14.3.3.6 
Summary of Safety Laboratory Parameters by Visit: Coagulation 
All Randomized Subjects 
 


 
 
Millendo Therapeutics, Inc. 
Protocol MLE4901-101                                                                                                       Page 1 of # 
Table 14.3.3.7 
Summary of Safety Laboratory by Visit: Urinalysis 
All Randomized Subjects 
______________________________________________________________________________________________________________________________________ 
 
Parameter (Unit)                                                          MLE4901         MLE4901         MLE4901            Total       
   Visit                                                Placebo BID      40 mg BID       60 mg BID       80 mg BID          MLE4901 
      Result/Statistic                                    (N=##)          (N=##)          (N=##)          (N=##)            (N=###) 
______________________________________________________________________________________________________________________________________ 
 
XXXXXXXXXX (XXXXX), n (%) 
   Screening                                               N’=##           N’=##           N’=##           N’=##             N’=## 
      XXXXXXXXXX                                         ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
      XXXXXXXXXX                                         ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
      XXXXXXXXXX                                         ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
      XXXXXXXXXX                                         ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
 
   Treatment Visit 1                                       N’=##           N’=##           N’=##           N’=##             N’=## 
      XXXXXXXXXX                                         ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
      XXXXXXXXXX                                         ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
 
   Treatment Visit 7/EoT                                   N’=##           N’=##           N’=##           N’=##             N’=## 
      XXXXXXXXXX                                         ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
      XXXXXXXXXX                                         ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
      XXXXXXXXXX                                         ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
      XXXXXXXXXX                                         ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
 
XXXXXXXXXX (XXXXX) 
   Screening 
      n                                                    ##              ##              ##              ##                ##    
      Mean                                                 ##.##           ##.##           ##.##           ##.##             ##.## 
      Standard Deviation                                   ##.###          ##.###          ##.###          ##.###            ##.### 
      Median                                               ##.##           ##.##           ##.##           ##.##             ##.## 
      Minimum                                              ##.#            ##.#            ##.#            ##.#              ##.# 
      Maximum                                              ##.#            ##.#            ##.#            ##.#              ##.# 
______________________________________________________________________________________________________________________________________ 
 
Note: %=n/N’, where N’ is the number of subjects with a result at the specified visit. EoT = End of Treatment 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                           Database last modified: DDMMYYYY HH:MM 
 
<< Programming Note: pH and Specific Gravity will be summarized as continuous parameters (mean, SD, etc.). All others will be 
summarized categorically with counts and percentages. >>  


 
 
Millendo Therapeutics, Inc. 
Protocol MLE4901-101                                                                                                       Page 1 of # 
Table 14.3.4.1 
Summary of Vital Signs by Visit 
All Randomized Subjects 
______________________________________________________________________________________________________________________________________ 
 
Parameter (Unit)                                                          MLE4901         MLE4901         MLE4901            Total  
   Visit                                                Placebo BID      40 mg BID       60 mg BID       80 mg BID          MLE4901 
      Statistic                                           (N=##)          (N=##)          (N=##)          (N=##)            (N=###) 
______________________________________________________________________________________________________________________________________ 
 
XXXXXXXXXX (XXXXX)           
   Screening 
      n                                                    ##              ##              ##              ##                ##    
      Mean                                                 ##.##           ##.##           ##.##           ##.##             ##.## 
      Standard Deviation                                   ##.###          ##.###          ##.###          ##.###            ##.### 
      Median                                               ##.##           ##.##           ##.##           ##.##             ##.## 
      Minimum                                              ##.#            ##.#            ##.#            ##.#              ##.# 
      Maximum                                              ##.#            ##.#            ##.#            ##.#              ##.# 
 
   Lead-in Visit 1 
      n                                                    ##              ##              ##              ##                ##    
      Mean                                                 ##.##           ##.##           ##.##           ##.##             ##.## 
      Standard Deviation                                   ##.###          ##.###          ##.###          ##.###            ##.### 
      Median                                               ##.##           ##.##           ##.##           ##.##             ##.## 
      Minimum                                              ##.#            ##.#            ##.#            ##.#              ##.# 
      Maximum                                              ##.#            ##.#            ##.#            ##.#              ##.# 
 
   Lead-in Visit 2 
      n                                                    ##              ##              ##              ##                ##    
      Mean                                                 ##.##           ##.##           ##.##           ##.##             ##.## 
      Standard Deviation                                   ##.###          ##.###          ##.###          ##.###            ##.### 
      Median                                               ##.##           ##.##           ##.##           ##.##             ##.## 
      Minimum                                              ##.#            ##.#            ##.#            ##.#              ##.# 
      Maximum                                              ##.#            ##.#            ##.#            ##.#              ##.# 
 
   Baseline 
      n                                                    ##              ##              ##              ##                ##    
      Mean                                                 ##.##           ##.##           ##.##           ##.##             ##.## 
      Standard Deviation                                   ##.###          ##.###          ##.###          ##.###            ##.### 
      Median                                               ##.##           ##.##           ##.##           ##.##             ##.## 
      Minimum                                              ##.#            ##.#            ##.#            ##.#              ##.# 
      Maximum                                              ##.#            ##.#            ##.#            ##.#              ##.# 
______________________________________________________________________________________________________________________________________ 
 
Note: Baseline is defined as the measurement at treatment visit 1. If missing, the last value on or prior to randomization will be  
      used as baseline. n'=number of subjects with a measurement at both baseline and the specified visit. 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                           Database last modified: DDMMYYYY HH:MM 


 
 
Millendo Therapeutics, Inc. 
Protocol MLE4901-101                                                                                                       Page 2 of # 
Table 14.3.4.1 
Summary of Vital Signs by Visit 
All Randomized Subjects 
______________________________________________________________________________________________________________________________________ 
 
Parameter (Unit)                                                          MLE4901         MLE4901         MLE4901            Total  
   Visit                                                Placebo BID      40 mg BID       60 mg BID       80 mg BID          MLE4901 
      Statistic                                           (N=##)          (N=##)          (N=##)          (N=##)            (N=###) 
______________________________________________________________________________________________________________________________________ 
 
XXXXXXXXXX (XXXXX)           
   Treatment Visit 2 
      n                                                    ##              ##              ##              ##                ##    
      Mean                                                 ##.##           ##.##           ##.##           ##.##             ##.## 
      Standard Deviation                                   ##.###          ##.###          ##.###          ##.###            ##.### 
      Median                                               ##.##           ##.##           ##.##           ##.##             ##.## 
      Minimum                                              ##.#            ##.#            ##.#            ##.#              ##.# 
      Maximum                                              ##.#            ##.#            ##.#            ##.#              ##.# 
 
   Change from Baseline to Treatment Visit 2 
      n'                                                   ##              ##              ##              ##                ##    
      Mean                                                 ##.##           ##.##           ##.##           ##.##             ##.## 
      Standard Deviation                                   ##.###          ##.###          ##.###          ##.###            ##.### 
      Median                                               ##.##           ##.##           ##.##           ##.##             ##.## 
      Minimum                                              ##.#            ##.#            ##.#            ##.#              ##.# 
      Maximum                                              ##.#            ##.#            ##.#            ##.#              ##.# 
 
   Treatment Visit 3 
      n                                                    ##              ##              ##              ##                ##    
      Mean                                                 ##.##           ##.##           ##.##           ##.##             ##.## 
      Standard Deviation                                   ##.###          ##.###          ##.###          ##.###            ##.### 
      Median                                               ##.##           ##.##           ##.##           ##.##             ##.## 
      Minimum                                              ##.#            ##.#            ##.#            ##.#              ##.# 
      Maximum                                              ##.#            ##.#            ##.#            ##.#              ##.# 
 
   Change from Baseline to Treatment Visit 3 
      n'                                                   ##              ##              ##              ##                ##    
      Mean                                                 ##.##           ##.##           ##.##           ##.##             ##.## 
      Standard Deviation                                   ##.###          ##.###          ##.###          ##.###            ##.### 
      Median                                               ##.##           ##.##           ##.##           ##.##             ##.## 
      Minimum                                              ##.#            ##.#            ##.#            ##.#              ##.# 
      Maximum                                              ##.#            ##.#            ##.#            ##.#              ##.# 
______________________________________________________________________________________________________________________________________ 
 
Note: Baseline is defined as the measurement at treatment visit 1. If missing, the last value on or prior to randomization will be  
      used as baseline. n'=number of subjects with a measurement at both baseline and the specified visit. 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                           Database last modified: DDMMYYYY HH:MM
<< Programming Note: Include all scheduled visits through Follow Up Visit 2/EoS. Include all vital signs in the following order: 
systolic BP, diastolic BP, heart rate, respiratory rate, temperature, weight, and BMI. >> 


 
 
Millendo Therapeutics, Inc. 
Protocol MLE4901-101                                                                                                       Page 1 of # 
Table 14.3.4.2 
Summary of Abnormal 12-Lead ECG  
All Randomized Subjects 
______________________________________________________________________________________________________________________________________ 
 
                                                                          MLE4901         MLE4901         MLE4901            Total 
                                                        Placebo BID      40 mg BID       60 mg BID       80 mg BID          MLE4901 
                                                          (N=##)          (N=##)          (N=##)          (N=##)            (N=###) 
Parameter/Category                                        n   (%)         n   (%)         n   (%)         n   (%)           n   (%) 
______________________________________________________________________________________________________________________________________ 
 
Highest QTcF                                               N’=##           N’=##           N’=##           N’=##             N’=## 
     >450 msec                                           ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
     >480 msec                                           ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
     >500 msec                                           ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
 
Highest QTcF Change from Baseline                          N’=##           N’=##           N’=##           N’=##             N’=## 
     >30 msec                                            ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
     >60 msec                                            ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
 
Overall Interpretation, Screening                          N’=##           N’=##           N’=##           N’=##             N’=## 
   Normal                                                ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
   Abnormal Not Clinically Significant                   ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
   Abnormal Clinically Significant                       ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
   Not Evaluable                                         ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
 
Overall Interpretation, Treatment Visit 1                  N’=##           N’=##           N’=##           N’=##             N’=## 
   Normal                                                ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
   Abnormal Not Clinically Significant                   ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
   Abnormal Clinically Significant                       ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
   Not Evaluable                                         ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
 
Overall Interpretation, Treatment Visit 5                  N’=##           N’=##           N’=##           N’=##             N’=## 
   Normal                                                ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
   Abnormal Not Clinically Significant                   ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
   Abnormal Clinically Significant                       ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
   Not Evaluable                                         ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
 
Overall Interpretation, Treatment Visit 7/EoT              N’=##           N’=##           N’=##           N’=##             N’=## 
   Normal                                                ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
   Abnormal Not Clinically Significant                   ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
   Abnormal Clinically Significant                       ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
   Not Evaluable                                         ## (###.#)      ## (###.#)      ## (###.#)      ## (###.#)        ## (###.#) 
______________________________________________________________________________________________________________________________________ 
 
Note: %=100*n/N’, where n=number of subjects with a value in the category on or after randomization and N’=number of subjects with a 
      result on or after randomization for the specified parameter. EoT = End of Treatment 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                           Database last modified: DDMMYYYY HH:MM 


 
 
Millendo Therapeutics, Inc. 
Protocol MLE4901-101                                                                                                       Page 1 of 1 
Table 14.3.4.3 
Summary of Transvaginal Ultrasound Endometrial Thickness 
All Randomized Subjects 
______________________________________________________________________________________________________________________________________ 
 
Parameter (Unit)                                                          MLE4901         MLE4901         MLE4901            Total  
   Visit                                                Placebo BID      40 mg BID       60 mg BID       80 mg BID          MLE4901 
      Statistic                                           (N=##)          (N=##)          (N=##)          (N=##)            (N=###) 
______________________________________________________________________________________________________________________________________ 
 
XXXXXXXXXX (XXXXX)           
   Baseline 
      n                                                    ##              ##              ##              ##                ##    
      Mean                                                 ##.##           ##.##           ##.##           ##.##             ##.## 
      Standard Deviation                                   ##.###          ##.###          ##.###          ##.###            ##.### 
      Median                                               ##.##           ##.##           ##.##           ##.##             ##.## 
      Minimum                                              ##.#            ##.#            ##.#            ##.#              ##.# 
      Maximum                                              ##.#            ##.#            ##.#            ##.#              ##.# 
 
   Treatment Visit 7/EoT 
      n                                                    ##              ##              ##              ##                ##    
      Mean                                                 ##.##           ##.##           ##.##           ##.##             ##.## 
      Standard Deviation                                   ##.###          ##.###          ##.###          ##.###            ##.### 
      Median                                               ##.##           ##.##           ##.##           ##.##             ##.## 
      Minimum                                              ##.#            ##.#            ##.#            ##.#              ##.# 
      Maximum                                              ##.#            ##.#            ##.#            ##.#              ##.# 
 
   Change from Baseline to Treatment Visit 7/EoT 
      n'                                                   ##              ##              ##              ##                ##    
      Mean                                                 ##.##           ##.##           ##.##           ##.##             ##.## 
      Standard Deviation                                   ##.###          ##.###          ##.###          ##.###            ##.### 
      Median                                               ##.##           ##.##           ##.##           ##.##             ##.## 
      Minimum                                              ##.#            ##.#            ##.#            ##.#              ##.# 
      Maximum                                              ##.#            ##.#            ##.#            ##.#              ##.# 
______________________________________________________________________________________________________________________________________ 
 
Note: Baseline is defined as the measurement at Screening. If missing, the last value on or prior to randomization will be used as  
      baseline. n'=number of subjects with a measurement at both baseline and the specified visit. EoT = End of Treatment 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                           Database last modified: DDMMYYYY HH:MM 
 


 
 
3 Listings 
Listing 16.2.1.1 ............................................................................................................................. 34 
Subject Disposition 
All Subjects 
Listing 16.2.1.2 ............................................................................................................................. 34 
Inclusion/Exclusion Criteria Not Met 
All Subjects 
Listing 16.2.2.1 ............................................................................................................................. 34 
Protocol Deviations 
All Subjects 
Listing 16.2.3.1 ............................................................................................................................. 34 
Informed Consent and Randomization 
All Subjects 
Listing 16.2.4.1 ............................................................................................................................. 34 
Demographics 
All Subjects 
Listing 16.2.4.2 ............................................................................................................................. 34 
Reproductive System Medical History 
All Subjects 
Listing 16.2.4.3 ............................................................................................................................. 34 
Substance Use Medical History 
All Subjects 
Listing 16.2.4.4 ............................................................................................................................. 34 
Other Medical History 
All Subjects 
Listing 16.2.4.5 ............................................................................................................................. 34 
Transvaginal Ultrasound: Overall Results 
All Subjects 
Listing 16.2.4.6 ............................................................................................................................. 34 
Transvaginal Ultrasound: Right and Left Ovary Results 
All Subjects 
Listing 16.2.4.7 ............................................................................................................................. 34 
Prior and Concomitant Medications 
All Subjects 
Listing 16.2.4.8 ............................................................................................................................. 34 
Concomitant Procedures 
All Subjects 
Listing 16.2.4.9 ............................................................................................................................. 34 
Prior PCOS-Specific Therapies 
All Subjects 
Listing 16.2.5.1 ............................................................................................................................. 34 
Medroxyprogesterone Acetate Administration 
All Subjects Who Entered Lead-in Period 


 
 
Listing 16.2.5.2 ............................................................................................................................. 34 
Study Drug Administration 
All Randomized Subjects 
Listing 16.2.5.3 ............................................................................................................................. 34 
Medroxyprogesterone Acetate Accountability 
All Subjects Who Entered Lead-in Period 
Listing 16.2.5.4 ............................................................................................................................. 34 
Study Drug Accountability 
All Randomized Subjects 
Listing 16.2.6.1 ............................................................................................................................. 34 
Pharmacokinetic Samples 
All Subjects 
Listing 16.2.6.2 ............................................................................................................................. 34 
Laboratory Values: Hormones 
All Subjects 
Listing 16.2.6.3 ............................................................................................................................. 34 
Investigator’s Static Global Assessment of Acne Score 
All Subjects 
Listing 16.2.6.4 ............................................................................................................................. 34 
Modified Ferriman-Gallwey Score for Hirsutism 
All Subjects 
Listing 16.2.6.5 ............................................................................................................................. 34 
Savin Scale for Alopecia 
All Subjects 
Listing 16.2.7.1 ............................................................................................................................. 34 
Adverse Events 
All Subjects 
Listing 16.2.7.2 ............................................................................................................................. 34 
Additional Serious Adverse Event Details 
All Subjects 
Listing 16.2.7.3 ............................................................................................................................. 34 
Hepatic Events 
All Subjects 
Listing 16.2.8.1 ............................................................................................................................. 34 
Safety Laboratory Values: Chemistry 
All Subjects 
Listing 16.2.8.2 ............................................................................................................................. 34 
Safety Laboratory Values: Hematology 
All Subjects 
Listing 16.2.8.3 ............................................................................................................................. 34 
Safety Laboratory Values: Metabolic 
All Subjects 
Listing 16.2.8.4 ............................................................................................................................. 34 
Safety Laboratory Values: Coagulation 
All Subjects 


 
 
Listing 16.2.8.5 ............................................................................................................................. 34 
Safety Laboratory Values: Urinalysis 
All Subjects 
Listing 16.2.8.6 ............................................................................................................................. 34 
Safety Laboratory Values: Other 
All Subjects 
Listing 16.2.9.1 ............................................................................................................................. 34 
Vital Signs Including Height, Weight, and BMI 
All Subjects 
Listing 16.2.9.2 ............................................................................................................................. 34 
12-Lead ECG 
All Subjects 
Listing 16.2.9.3 ............................................................................................................................. 34 
Physical Examination 
All Subjects 
Listing 16.2.9.4 ............................................................................................................................. 34 
Papanicolaou (PAP) Test 
All Subjects 
Listing 16.2.9.5 ............................................................................................................................. 34 
Pregnancy Test 
All Subjects 


 
 
 
Listing 16.2.1.1 
Subject Disposition 
All Subjects 
Listing 16.2.1.2 
Inclusion/Exclusion Criteria Not Met 
All Subjects 
Listing 16.2.2.1 
Protocol Deviations 
All Subjects 
Listing 16.2.3.1 
Informed Consent and Randomization 
All Subjects 
Listing 16.2.4.1 
Demographics 
All Subjects 
Listing 16.2.4.2 
Reproductive System Medical History 
All Subjects 
Listing 16.2.4.3 
Substance Use Medical History 
All Subjects 
Listing 16.2.4.4 
Other Medical History 
All Subjects 
Listing 16.2.4.5 
Transvaginal Ultrasound: Overall Results 
All Subjects 
Listing 16.2.4.6 
Transvaginal Ultrasound: Right and Left Ovary Results 
All Subjects 
Listing 16.2.4.7 
Prior and Concomitant Medications 
All Subjects 
Listing 16.2.4.8 
Concomitant Procedures 
All Subjects 
Listing 16.2.4.9 
Prior PCOS-Specific Therapies 
All Subjects 
Listing 16.2.5.1 
Medroxyprogesterone Acetate Administration 
All Subjects Who Entered the Lead-in Period 
Listing 16.2.5.2 
Study Drug Administration 
All Randomized Subjects 
Listing 16.2.5.3 
Medroxyprogesterone Acetate Accountability 
All Subjects Who Entered the Lead-in Period 
Listing 16.2.5.4 
Study Drug Accountability 
All Randomized Subjects 
Listing 16.2.6.1 
Pharmacokinetic Samples 
All Subjects 
Listing 16.2.6.2 
Laboratory Values: Hormones 
All Subjects 
Listing 16.2.6.3 
Investigator’s Static Global Assessment of Acne Score 
All Subjects 
Listing 16.2.6.4 
Modified Ferriman-Gallwey Score for Hirsutism 
All Subjects 
Listing 16.2.6.5 
Savin Scale for Alopecia 
All Subjects 
Listing 16.2.7.1 
Adverse Events 
All Subjects 
Listing 16.2.7.2 
Additional Serious Adverse Event Details 
All Subjects 
Listing 16.2.7.3 
Hepatic Events 
All Subjects 
Listing 16.2.8.1 
Safety Laboratory Values: Chemistry 
All Subjects 
Listing 16.2.8.2 
Safety Laboratory Values: Hematology 
All Subjects 
Listing 16.2.8.3 
Safety Laboratory Values: Metabolic 
All Subjects 
Listing 16.2.8.4 
Safety Laboratory Values: Coagulation 
All Subjects 
Listing 16.2.8.5 
Safety Laboratory Values: Urinalysis 
All Subjects 
Listing 16.2.8.6 
Safety Laboratory Values: Other 
All Subjects 
Listing 16.2.9.1 
Vital Signs Including Height, Weight, and BMI 
All Subjects 
Listing 16.2.9.2 
12-Lead ECG 
All Subjects 
Listing 16.2.9.3 
Physical Examination 
All Subjects 
Listing 16.2.9.4 
Papanicolaou (PAP) Test 
All Subjects 
Listing 16.2.9.5 
Pregnancy Test 
All Subjects