Clinical trial NCT03053271
Conditions: Cushing Syndrome
Keywords: Endogenous Cushing's Syndrome ATR-101 CS
Sponsor: Millendo Therapeutics US, Inc.
Start date: 2017-04-13; Completion date: 2019-08-12
Enrollment: 4 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 2 multicenter, randomized, double-blind, placebo controlled study of ATR-101 to evaluate the efficacy and safety of orally-administered ATR-101 in adults with endogenous Cushing's syndrome. Following wash-out (if needed), all eligible subjects will enter an open-label intra-subject dose-escalation period of 8 weeks' duration, followed either by a double-blind randomized withdrawal period of 4 weeks' duration (if the subject meets randomization criteria) or by an additional open label dosing period of 4 weeks' duration (if the subject does not meet randomization criteria).It is anticipated that the overall duration of the study per subject will range from approximately 16-22 weeks.

Detailed description:

Arms: arm 1: During the 4-week randomized withdrawal period, eligible subjects will receive ATR-101 at the same dose level being used at the completion of the open-label dose-escalation period. arm 2: During the 4-week randomized withdrawal period, eligible subjects will receive a placebo that matches the same ATR-101 dose level being used at the completion of the open-label dose-escalation period.
Interventions: intervention 1: ATR-101 intervention 2: Placebo
Intervention descriptions: intervention 1: During the 4-week randomized withdrawal period, subjects will be dosed for 4 weeks at the same dose level being used at the completion of the open-label dose-escalation period. intervention 2: During the 4-week randomized withdrawal period, subjects will be dosed for 4 weeks with placebo that matches the same ATR-101 dose level being used at the completion of the open-label dose-escalation period.

Protocol documents:
Prot_000.pdf: 
 
 
PRODUCT NAME: ATR-101 
STUDY NUMBER: ATR-101-301 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of ATR-101 
for the Treatment of Cushing’s Syndrome 
 
 
Study Phase: 2 
Product Name: ATR-101 
IND Number: 129885 
EudraCT Number: 2016-002240-17 
NCT Number: NCT03053271 
 
Indication: Endogenous Cushing’s Syndrome 
 
Sponsor: Millendo Therapeutics, Inc. 
 
Sponsor Medical Contact: Vivian H. Lin, M.D.  
 
Original Protocol: 24 May 2016 
Global Protocol Amendment 1: 30 August 2016 
Country-Specific Protocol Amendment 1/UK: 06 April 2017 
Global Protocol Amendment 2: 14 March 2018 
 
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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INVESTIGATOR’S AGREEMENT 
 
Study Title: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of ATR-101 for 
the Treatment of Cushing’s Syndrome 
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 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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SPONSOR SIGNATURE 
 
Study Title: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of ATR-101 for 
the Treatment of Cushing’s Syndrome 
SPONSOR SIGNATURE 
I have read and approve the protocol and appendices. My signature, in conjunction with the 
signature of the Investigator, confirms the agreement of both parties that the clinical trial will be 
conducted in accordance with the protocol and all applicable laws and regulations, including, but 
not limited to, the International Council on Harmonisation (ICH) Guidelines for GCP, the US 
Code of Federal Regulations (CFR) and the ethical principles that have their origins in the 
Declaration of Helsinki, as well as all applicable privacy laws.  
 
Name: 
Pharis Mohideen, MD 
Please print 
 
Title: 
 
 
Chief Medical Officer 
Signature: 
 
_______________________ 
Date: 
 
_______________________ 
Address: 
301 N. Main St. 
 
 
Suite 100 
 
 
Ann Arbor, MI 48104 
 
 


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SYNOPSIS 
Name of Sponsor/Company: 
Millendo Therapeutics, Inc. 
Name of Investigational Product: 
ATR-101 
 
Title of Study:  
A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of ATR-101 for the Treatment of Cushing’s 
Syndrome 
Study Center(s): Approximately 14 sites in the United States and the United Kingdom 
Studied Period:  
Estimated date first subject enrolled: October 2016 
Estimated date last subject completed: December 2021 
Phase of Development:  
2 
Objectives:  
Primary:  
• 
To evaluate the efficacy and safety of orally-administered ATR-101 in adults with endogenous Cushing’s 
syndrome 
Secondary:   
• 
To evaluate the changes in adrenal steroids and adrenal steroid intermediates 
• 
To evaluate the change in adrenocorticotropic hormone (ACTH) 
• 
To evaluate the change in metabolic syndrome-related parameters, including fasting glucose, insulin, lipid 
panel, blood pressure and body mass index (BMI) 
• 
To assess the safety and tolerability of ATR-101 
• 
To determine the pharmacokinetics (PK) of ATR-101 and its major metabolites 
• 
To evaluate the PK/pharmacodynamic (PD) relationships of ATR-101 
Methodology:  
This Phase 2 multicenter study consists of two parts: an open-label intra-subject dose-escalation period of 8 
weeks’ duration, followed either by a double-blind randomized withdrawal period of 4 weeks’ duration (if the 
subject meets randomization criteria) or by an additional open label dosing period of 4 weeks’ duration (if the 
subject does not meet randomization criteria). A study schematic is shown in Figures 1, 2, and 3 below. A 
detailed schedule of study assessments is presented in Appendix 1. 
Figure 1: 
Study Schematic, Screening and Open-Label Dose-Escalation Periods 
 


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Figure 2: 
Study Schematic, Double-Blind Randomized Withdrawal Period 
 
 
Figure 3: 
Study Schematic, Additional Open-Label Dosing Period 
 
During a screening period of up to 8 weeks’ duration, subjects will undergo a wash-out of medications used to 
treat Cushing’s syndrome (if needed) and will then perform two 24-hour (hr) urine collections for baseline 
urinary free cortisol (UFC) assessment within 28 days prior to enrollment into the open-label dose-escalation 
period. At enrollment, all eligible subjects will be assigned to one of two 24-hr UFC strata. Strata will be 
assigned according to baseline 24-hr UFC values, calculated as the mean of all 24-hr UFC levels obtained 
within the 28 days prior to enrollment:  
• 
Stratum I: 24-hr UFC 1.3 to < 4 × upper limit of normal (ULN) 
• 
Stratum II: 24-hr UFC 4 to 10 × ULN 
Enrollment into a particular stratum may be limited to ensure the inclusion of subjects in both strata. 
Open-Label Dose-Escalation Period: The open-label dose-escalation period will be 8 weeks in duration and 
will allow each subject to receive three dose levels of ATR-101 (i.e., 250 mg twice daily (BID), 500 mg BID, 


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and 1000 mg BID). The 250 mg and 500 mg BID dose levels will each be used for 2 weeks, and the 1000 mg 
BID dose level will be used for 4 weeks.  
• 
Study Days 1-14: At Visit T1, all subjects will be assigned to take the same starting dose of ATR-101, 250 
mg BID, at the beginning of the open-label dose-escalation period. Twenty-four-hour UFCs will be 
assessed on Days 13 and 14 (collections start on Days 13 and 14, respectively, and finish on Days 14 and 
15, respectively).  
• 
Study Days 15-28: At Visit T2, all subjects will be assigned to take the next higher dose of ATR-101, 500 
mg BID. Twenty-four-hour UFCs will be assessed on Days 27 and 28 (collections start on Days 27 and 28, 
respectively, and finish on Days 28 and 29, respectively).  
• 
Study Days 29-56: At Visit T3, all subjects will be assigned to take the next higher dose of ATR-101, 1000 
mg BID. Twenty-four-hour UFCs will be assessed on Days 41, 42, 50, 51, and 56 (collections start on Days 
41, 42, 50, 51, and 56, respectively, and finish on Days 42, 43, 51, 52, and 57, respectively). 
At any time, the ATR-101 dose may be down-titrated as needed for safety reasons at the discretion of the 
Investigator. There will be no wash-out period between the open-label dose-escalation period and either the 
double-blind randomized withdrawal period or the additional open-label dosing period. 
Double-blind Randomized Withdrawal Period: The double-blind randomized withdrawal period will be up to 
4 weeks in duration. A subject is eligible to enter the double-blind randomized withdrawal period if the mean of 
the Day 50 and Day 51 (“mean Day 50/51”) 24-hr UFCs meets at least one of the following randomization 
criteria: 
• 
24-hr UFC ≤ ULN 
• 
24-hr UFC ≤ 50% relative to the baseline value  
Eligible subjects will be randomized in a 1:1 ratio to receive either ATR-101 at the same dose level on which 
they achieved the mean Day 50/51 24-hr UFC ≤ ULN (or ≤ 50% of their baseline value) or matching placebo. 
Subjects will continue in the double-blind randomized withdrawal period for 4 weeks or until their mean Day 
64/65 24-hr UFC is > 1.3 x ULN and has also increased by > 50% relative to their mean Day 50/51 24-hr UFC, 
whichever comes first. Subjects who are not eligible to be randomized will enter the Additional Open-Label 
Dosing Period instead of the Double Blind Randomized Withdrawal Period (see below).  
• 
Study Days 57-70: Twenty-four-hour UFCs will be collected on Days 64 and 65 (collections start on Days 
64 and 65, respectively, and finish on Days 65 and 66, respectively). At the time of Visit R2 (Day 71), if 
the mean Day 64/65 24-hr UFC result is available and is > 1.3 x ULN, and has also increased by > 50% 
relative to the mean Day 50/51 24-hr UFC, the subject will complete the End-of-Treatment (EoT) visit 
(Visit R3) instead of Visit R2 and may then be started on another agent at the discretion of his or her 
physician. Otherwise, the subject will continue in the double-blind, randomized withdrawal period. 
• 
Study Days 71-85: Twenty-four-hour UFCs will be collected on Days 79 and 84 (collections start on Days 
79 and 84, respectively, and finish on Days 80 and 85, respectively). The EoT visit (Visit R3) will be 
completed on Day 85. Note: if the mean Day 64/65 24-hr UFC was not available at the time of Visit R2, 
but subsequently is found to meet criteria for study completion, the EoT visit should be performed as soon 
as practicable, rather than on Day 85. Additionally, if the Day 79 or Day 84 24-hr UFC is > ULN, after 
completion of the EoT visit (Visit R3) the subject may begin treatment with another agent at the discretion 
of his or her physician. 
Additional Open-Label Dosing Period: The additional open-label dosing period will be 4 weeks in duration. 
A subject is eligible to enter the additional open-label dosing period if they do not meet any of the 
randomization criteria described in the above section.  
Eligible subjects will be assigned to take ATR-101 1000 mg BID (or a lower dose if needed for safety, at the 
discretion of the Investigator). Subjects will continue in the additional open-label dosing period for 4 weeks.  
• 
Study Days 57-70: Twenty-four-hour UFCs will be collected on Days 69 and 70 (collections start on Days 
69 and 70, and finish on Days 70 and 71, respectively). 


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• 
Study Days 71-85: Twenty-four-hour UFCs will be collected on Days 79 and 84 (collections start on Days 
79 and 84, respectively, and finish on Days 80 and 85, respectively). The EoT visit (Visit A3) will be 
completed on Day 85. Note: if the Day 79 or Day 84 24-hr UFC is > ULN, after completion of the EoT 
visit (Visit A3) the subject may begin treatment with another agent at the discretion of his or her physician. 
Follow-up Period: During the follow-up period, subjects will continue to be monitored for safety. Subjects 
whose most recent 24-hr UFC is ≤ ULN will have a follow-up visit (Visit F1) at the study site 2 weeks after 
their ET/EoT visit. Subjects whose most recent 24-hr UFC is > ULN will have a follow-up telephone visit 
instead of a study site visit. 
• 
Study Days 86-98: If the Day 79 24-hr UFC is ≤ ULN, a follow-up visit (Visit F1) at the study site will be 
scheduled for Day 98, 2 weeks after the EoT visit. This visit will consist largely of safety assessments. 
Subjects whose Day 84 24-hr UFC is also ≤ ULN will begin a 24-hr urine collection on Day 92 and finish 
on Day 93. If the Day 79, Day 84 or Day 92 24-hr UFC is > ULN, a telephone visit will be conducted on 
Day 98 instead of a study site visit (in case of discrepant results, the latest result should be used). If the Day 
92 24-hr UFC result is unknown at the time the Day 98 visit is due, the subject will proceed with having the 
Day 98 visit at the study site. 
• 
Subjects whose Day 92 24-hr UFC is ≤ ULN should continue to be followed up and have morning serum 
ACTH and 24-hr UFC assessed every 2-4 weeks until their 24-hr UFC is > ULN or until the Investigator 
and the Medical Monitor agree that the subject is stable. 
Throughout the course of the study, safety evaluations will include assessment of AEs, concomitant 
medications, clinical laboratory tests, vital signs, physical examinations (PEs) and 12-lead electrocardiograms 
(ECGs). 
It is anticipated that the overall duration of the study per subject will range from approximately 16-22 weeks, 
depending upon the duration (if any) required for wash-out and the duration of follow-up. 
Number of Subjects (planned): Approximately 16 adults with endogenous Cushing’s syndrome 
Diagnosis and Criteria for Inclusion:  
Inclusion Criteria: 
Each subject must meet all of the following criteria to be enrolled in this study:  
1. Provision of signed and dated informed consent prior to any study-specific procedures 
2. Men and women 18-80 years of age (inclusive) at screening 
3. Subjects must have a confirmed diagnosis of endogenous Cushing’s syndrome as evidenced by 
baseline UFC 1.3 to 10 × ULN (mean of all 24-hr UFC levels obtained during the screening period within 
28 days of enrollment into the open-label dose-escalation period) AND documentation at any time of ONE 
of the following three criteria: 
• 
For subjects with a diagnosis of pituitary Cushing’s syndrome, either:  
− 
Magnetic resonance imaging (MRI) confirmation of pituitary adenoma (greater than or equal to 
0.6 cm), OR  
− 
For subjects with a pituitary microadenoma less than 0.6 cm, bilateral inferior petrosal sinus 
sampling (BIPSS) showing an ACTH gradient > 2 before or > 3 after corticotropin-releasing 
hormone (CRH) or desmopressin (DDAVP) stimulation, OR  
− 
For subjects who have had prior pituitary surgery: histopathology confirming an ACTH-staining 
adenoma 
• 
For subjects with a diagnosis of adrenal Cushing’s syndrome: MRI or computed tomography (CT) of 
the adrenal glands showing an adrenal tumor 
• 
For subjects with a diagnosis of ectopic ACTH as the cause of their Cushing’s syndrome: ACTH-
dependent Cushing’s syndrome and either: 
− 
MRI showing no pituitary adenoma, OR  
− 
MRI showing only a small pituitary adenoma (< 0.6 cm) AND a negative BIPSS, OR  
− 
For subjects who have had prior pituitary surgery: histopathology that is negative for an ACTH-
staining adenoma 


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4. Subjects with a history of prior pituitary surgery must be at least 3 months post-surgery at the time of the 
screening visit 
5. Body mass index (BMI) between 18 and 60 kg/m2, inclusive, at screening 
6. Female subjects must be postmenopausal > 2 years OR must have been 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 include oral contraceptives, contraceptive implants, Depo-Provera®, contraceptive patch, 
vaginal ring, male condom, female condom, spermicide, diaphragm with spermicide, cervical cap with 
spermicide, contraceptive sponge, or an intrauterine device (IUD); IUDs must have been in place for at 
least 28 days prior to first dose of study drug. 
Exclusion Criteria: 
Subjects who meet any of the following criteria will be excluded from participation in the study: 
1. Pseudo-Cushing’s syndrome, cyclic Cushing’s syndrome or current iatrogenic Cushing’s syndrome 
2. Subjects who are considered candidates for surgical treatment of Cushing’s syndrome, unless it is clearly 
documented that the subject has refused such surgery or that surgery cannot be scheduled for at least the 
anticipated duration of the study  
3. Normal late night salivary cortisol value during screening, unless the subject’s history clearly demonstrates 
that he or she does not have pseudo-Cushing’s or cyclic Cushing’s. If the subject has a normal late night 
salivary cortisol, and the PI feels the subject does not have pseudo-Cushing’s or cyclic Cushing’s, the 
subject may be enrolled with approval of the medical monitor 
4. Normal 24-hr UFC during screening (this would be suggestive of cyclic Cushing’s)  
5. Radiotherapy of the pituitary within 6 months prior to or during screening 
6. For subjects with pituitary Cushing’s syndrome, any compression of the optic chiasm or the presence of a 
tumor within 2 mm of the optic chiasm on the most recent pituitary MRI prior to or during screening 
7. Use of or medical requirement for any of the following medications within the timeframes specified below 
prior to collection of the first 24-hr UFC during Screening and throughout study participation (see Section 
5.11 for additional prohibited and restricted medications): 
• 
Inhibitors of steroidogenesis (ketoconazole, metyrapone): 1 week 
• 
Pituitary-directed agents: Dopamine agonists (bromocriptine, cabergoline) and PPARγ agonists 
(rosiglitazone or pioglitazone): 4 weeks 
• 
Octreotide LAR, Lanreotide SR and Lanreotide autogel: 14 weeks 
• 
Octreotide (immediate release formulation): 1 week 
• 
Pasireotide: 4 weeks 
• 
Mitotane: 26 weeks 
• 
Mifepristone: 3 weeks 
8. Uncontrolled diabetes mellitus, as evidenced by HbA1c > 9.0% at screening 
9. Uncontrolled hypertension, defined as systolic blood pressure > 160 mmHg or diastolic blood pressure > 90 
mmHg during screening. Note: if appropriate, subjects may have blood pressure medications adjusted and 
blood pressure reassessed at an unscheduled visit prior to Visit T1. 
10. Any history of gastric or small intestinal surgery or any current disease that causes malabsorption. Note: 
irritable bowel syndrome is acceptable for inclusion 
11. Alcohol or substance abuse (cocaine, amphetamines and/or opioids) within the year prior to screening 
12. Abnormal laboratory values as per the guidelines listed below or any other clinically significant, 
unexplained laboratory abnormality according to the Investigator: 
• 
Serum ALT or AST > 3 × ULN 
• 
Serum total bilirubin > 1.5 × ULN 
• 
Serum creatinine > 1.5 × ULN 
• 
Glomerular filtration rate < 60 mL/min/1.73 m2 
13. Pregnant, breast-feeding, having conceived within the 6 months prior to screening, or having an intent to 
become pregnant during the study period 
14. QTc > 470 msec on electrocardiogram at screening (subjects with a single QTc > 470 msec may have 2 
additional ECGs taken during screening and the QTcs averaged; if the average QTc is > 470 msec then the 
subject is excluded) 
15. Known history of Gilbert’s syndrome 


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16. HIV, hepatitis B, or hepatitis C positivity at screening 
17. Any malignancy within the previous 5 years, other than curatively treated basal or squamous cell skin 
cancer or cervical carcinoma in situ  
18. Previous exposure to any amount of ATR-101 
19. Participation in any study of an investigational drug within 30 days prior to screening 
20. Significant psychiatric disease, recent severe physical stress, malnutrition, chronic excessive exercise, or 
any other medical or psychiatric condition 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:  
ATR-101 250-mg and 500-mg tablets for oral administration, one tablet twice per day for the 250 mg and 500 
mg BID doses, respectively; and two 500-mg tablets twice per day for the 1000 mg BID dose 
Duration of Treatment:  
8 weeks in the open-label dose-escalation period and up to 4 weeks in the double-blind randomized withdrawal 
period or the additional open-label period 
Reference Therapy, Dosage and Mode of Administration:  
Placebo matching tablets for the ATR-101 500-mg tablets during the double-blind randomized withdrawal 
period 
Study Endpoints: 
Primary Efficacy Endpoint:  
• 
The proportion of subjects with either a normal 24-hr UFC or a reduction in 24-hr UFC of ≥ 50% relative to 
their baseline value at the end of the double-blind randomized withdrawal period 
Secondary Efficacy Endpoints: The secondary efficacy endpoints will include the following. Unless otherwise 
specified in the Statistical Analysis Plan, the endpoints will be evaluated for each post-baseline visit, at the end 
of the open-label dose-escalation period and at the end of the double-blind randomized withdrawal period, for the 
ITT population as a whole and for each baseline UFC stratum.  
• 
The proportion of subjects with a normal 24-hr UFC at the end of the double-blind randomized withdrawal 
period 
• 
The proportion of subjects with a reduction in 24-hr UFC of ≥ 50% relative to their baseline value at the 
end of the double-blind randomized withdrawal period 
• 
The proportion of subjects with a normal 24-hr UFC at the end of the open-label dose-escalation period and 
at the end of the additional open-label dosing period 
• 
The proportion of subjects with a reduction in 24-hr UFC of ≥ 50% relative to their baseline value at the 
end of the open-label dose-escalation period and at the end of the additional open-label dosing period 
• 
The change and percentage change in the 24-hr UFC from randomization at the end of the double-blind 
randomized withdrawal period 
• 
The change and percentage change in the 24-hr UFC from baseline at the end of the open-label dose-
escalation period and at the end of the additional open-label dosing period 
• 
The proportion of subjects with a normal late night salivary cortisol at the end of the double-blind 
randomized withdrawal period 
• 
The proportion of subjects with a normal late night salivary cortisol at the end of the open-label dose-
escalation period and at the end of the additional open-label dosing period 
• 
The change and percentage change in the late night salivary cortisol from randomization at the end of the 
double-blind randomized withdrawal period 
• 
The change and percentage change in the late night salivary cortisol from baseline at the end of the open-
label dose-escalation period and at the end of the additional open-label dosing period 
• 
The change and percentage change from baseline in blood hormone levels, including 11-DOC, 17-OHP, A, 
A4, ACTH, cortisol, DHEA, DHEAS, free T, P, renin, SHBG and total T 


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• 
The change from baseline in fasting glucose, insulin, lipid panel, systolic blood pressure, diastolic blood 
pressure and BMI 
Pharmacokinetic Endpoints: 
• 
The Cmax, Tmax, AUC, t1/2 and other PK parameters of ATR-101 and its major metabolites (as appropriate 
and as the data allow) 
• 
The relationship between Cmax and AUC vs. the percentage change in 24-hr UFC; other PK/PD 
relationships may be explored as appropriate and as data allow 
Safety Endpoints: Safety endpoints will include the incidence of treatment-emergent adverse events and 
serious adverse events, as well as changes from baseline in PEs, safety laboratory tests and ECG parameters. 
Statistical Methods: 
A Statistical Analysis Plan that includes a more technical and detailed description of the planned statistical 
analyses will be prepared prior to unblinding of the double-blind randomized withdrawal period of the study.  
Analysis Populations:  
Efficacy – The primary efficacy analysis population will be the Intent-to-Treat (ITT) population, based on all 
subjects who are randomized into the double-blind randomized withdrawal period and take at least one dose of 
double-blind study drug. The modified ITT (mITT) population, based on all subjects who complete at least 2 
weeks in the double-blind randomized withdrawal period of the study, will be used for additional analyses. For 
efficacy analyses, subjects will be included in the treatment group to which they were randomized. 
Safety – The safety population will include all treated subjects. Safety analyses will be based on the safety 
population. For the safety analyses for the double-blind randomized withdrawal period, subjects randomized to 
the placebo group who receive ATR-101 will be included in the treatment group of the active 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: 
A sample size of 16 enrolled patients is sufficient per clinical considerations. No formal sample size calculation 
was performed. 
Analysis Methodology: 
Primary endpoint – The primary efficacy endpoint, the proportion of subjects with either a normal 24-hr UFC or 
a reduction in UFC of ≥ 50% relative to their baseline value at the end of the double-blind randomized 
withdrawal period, will be evaluated using the Cochran-Mantel-Haenszel (CMH) test, controlling for baseline 
24-hr UFC stratum. 
Secondary endpoints – No further adjustments for multiple group comparisons, multiple additional endpoints or 
multiple subgroups of interest are planned. 
Responder analyses and other categorical analyses will be based on the CMH test or Fisher’s exact test, as 
appropriate and if the data allow. Continuous endpoints will be evaluated using ANCOVA or ANOVA model 
methodology, as appropriate and if the data allow. 
Exploratory endpoints – Additional efficacy endpoints may 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, blood pressure and ECG 
parameters. Counts and shift tables will be used for categorical lab parameters. 
Pharmacokinetic endpoints – PK assessments will be performed at each dose level to determine ATR-101 
exposures and to profile PK/PD relationships. PK assessments will include Cmax, AUC0-4 and trough levels. 
Individual subject PK data will be analyzed along with pooling of subjects’ data at each dose level. 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 .........................................................................................................................16 
LIST OF FIGURES .......................................................................................................................16 
LIST OF ABBREVIATIONS ........................................................................................................17 
1. 
INTRODUCTION ......................................................................................................20 
1.1. 
Background .................................................................................................................20 
1.2. 
Rationale for the Use of ATR-101 in Cushing’s Syndrome .......................................20 
1.2.1. 
Preclinical Studies ......................................................................................................21 
1.2.2. 
Clinical Studies ...........................................................................................................22 
1.3. 
Research Hypothesis ...................................................................................................22 
1.4. 
Rationale for Conducting This Study .........................................................................22 
2. 
STUDY OBJECTIVES ..............................................................................................23 
2.1. 
Primary Objective .......................................................................................................23 
2.2. 
Secondary Objectives .................................................................................................23 
3. 
INVESTIGATIONAL PLAN .....................................................................................24 
3.1. 
Overall Study Design ..................................................................................................24 
3.1.1. 
Screening Period .........................................................................................................25 
3.1.2. 
Open-Label Dose-Escalation Period ...........................................................................25 
3.1.3. 
Double-blind Randomized Withdrawal Period ..........................................................26 
3.1.4. 
Additional Open-Label Dosing Period .......................................................................27 
3.1.5. 
Follow-up Period ........................................................................................................27 
3.2. 
Rationale for Study Design .........................................................................................27 
3.3. 
Study Duration ............................................................................................................28 
3.4. 
Number of Subjects ....................................................................................................28 
3.5. 
Treatment Assignment ................................................................................................28 
3.6. 
Special Safety Topics .................................................................................................29 
3.7. 
Lowering the Dose for Safety Purposes .....................................................................29 
3.8. 
Criteria for Study Termination ...................................................................................29 
4. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................31 
4.1. 
Inclusion Criteria ........................................................................................................31 


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4.2. 
Exclusion Criteria .......................................................................................................31 
4.3. 
Subject Withdrawal Criteria .......................................................................................33 
5. 
TREATMENT OF SUBJECTS ..................................................................................34 
5.1. 
Assignment of Subject Identification Numbers ..........................................................34 
5.2. 
Description of Study Drug ..........................................................................................34 
5.3. 
Study Drug Packaging and Labeling ..........................................................................35 
5.4. 
Study Drug Storage and Accountability .....................................................................35 
5.5. 
Study Drug Administration.........................................................................................35 
5.6. 
Dose Escalation ..........................................................................................................36 
5.7. 
Study Drug Compliance .............................................................................................36 
5.8. 
Randomization and Blinding ......................................................................................36 
5.9. 
Additional Open-Label Dosing ...................................................................................37 
5.10. 
Study Drug Handling and Disposal ............................................................................37 
5.11. 
Concomitant Medications ...........................................................................................37 
5.12. 
Prohibited and Restricted Medications .......................................................................37 
5.13. 
Prohibited Procedures .................................................................................................38 
6. 
STUDY PROCEDURES ............................................................................................39 
6.1. 
Allowable Variation in Time of Procedures ...............................................................39 
6.2. 
Informed Consent .......................................................................................................39 
6.3. 
Eligibility ....................................................................................................................39 
6.4. 
Medical History ..........................................................................................................40 
6.5. 
Prior and/or Concomitant Medication Assessments ...................................................40 
6.6. 
Vital Signs, Height, Weight and Body Mass Index ....................................................40 
6.7. 
Physical Examination .................................................................................................40 
6.8. 
Electrocardiography and Determination of QTc ........................................................40 
6.9. 
Adverse Events, Serious Adverse Events and Reporting ...........................................41 
6.9.1. 
Definition of Adverse Event, Adverse Drug Reaction and Unexpected 
Adverse Drug Reaction ...............................................................................................41 
6.9.2. 
Assessing Severity of Adverse Events .......................................................................42 
6.9.3. 
Assessing Relationship to Study Treatment ...............................................................42 
6.9.4. 
Serious Adverse Events ..............................................................................................43 
6.9.4.1. 
Definition of Serious Adverse Event ..........................................................................43 
6.9.4.2. 
Reporting SAEs – Procedure for Investigators ...........................................................44 


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6.9.5. 
Pregnancy Reporting ..................................................................................................45 
6.9.6. 
Regulatory Reporting of Adverse Events ...................................................................45 
6.10. 
Laboratory Tests .........................................................................................................46 
6.10.1. 
Efficacy Assessments .................................................................................................47 
6.10.1.1. 
24-Hour Urinary Free Cortisol ...................................................................................47 
6.10.1.2. 
Salivary Cortisol .........................................................................................................47 
6.10.1.3. 
Blood Hormone Levels ...............................................................................................48 
6.10.1.4. 
Glucose, Insulin and HbA1c .......................................................................................48 
6.10.1.5. 
Lipid Panel ..................................................................................................................48 
6.10.2. 
Pharmacokinetic Assessments ....................................................................................48 
6.10.3. 
Pharmacodynamic Assessments .................................................................................50 
6.10.4. 
Blood Sample Collection, Storage and Shipping .......................................................50 
7. 
STUDY ACTIVITIES ................................................................................................51 
7.1. 
Screening Visit, Visit S1.............................................................................................51 
7.2. 
Open-label Dose-escalation Period .............................................................................52 
7.2.1. 
Visit T1 (Day 1) ..........................................................................................................52 
7.2.2. 
Between Visits T1 and T2, Between Visits T2 and T3 and Between Visits T3 
and R1/A1 ...................................................................................................................53 
7.2.3. 
Visit T2 (Day 15) ........................................................................................................54 
7.2.4. 
Visit T3 (Day 29) ........................................................................................................55 
7.2.5. 
Telephone Visit Between Visits T3 and R1/A1 (Day 43) ..........................................56 
7.3. 
Double-blind Randomized Withdrawal Period ..........................................................57 
7.3.1. 
Visit R1 (Day 57) ........................................................................................................57 
7.3.2. 
Between Visits R1 and R2 and Between Visits R2 and R3/ET ..................................58 
7.3.3. 
Visit R2 (Day 71) ........................................................................................................59 
7.3.4. 
Visit R3 (Day 85; End-of-Treatment)/Early Termination ..........................................60 
7.4. 
Additional Open-Label Dosing Period .......................................................................61 
7.4.1. 
Visit A1 (Day 57) .......................................................................................................61 
7.4.2. 
Between Visits A1 and A2 and Between Visits A2 and A3/ET .................................62 
7.4.3. 
Visit A2 (Day 71) .......................................................................................................63 
7.4.4. 
Visit A3 (Day 85; End-of-Treatment)/Early Termination ..........................................64 
7.5. 
Follow-up Period ........................................................................................................65 
7.5.1. 
Between Visits R3/A3/ET and F1 ..............................................................................65 


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7.5.2. 
Follow-up, Visit F1 (End-of-Study (EoS); End of Trial) ...........................................65 
8. 
QUALITY CONTROL AND ASSURANCE ............................................................67 
9. 
STATISTICS ..............................................................................................................68 
9.1. 
General Considerations ...............................................................................................68 
9.2. 
Sample Size ................................................................................................................68 
9.3. 
Analysis Populations ..................................................................................................68 
9.4. 
Demographics and Baseline Characteristics ...............................................................68 
9.5. 
Treatment ....................................................................................................................68 
9.6. 
Efficacy .......................................................................................................................68 
9.6.1. 
Efficacy Endpoints ......................................................................................................68 
9.6.1.1. 
Primary Efficacy Endpoint .........................................................................................68 
9.6.1.2. 
Secondary Efficacy Endpoints ....................................................................................68 
9.6.2. 
Efficacy Analysis Methodology .................................................................................69 
9.6.2.1. 
Primary Efficacy Endpoint .........................................................................................69 
9.6.2.2. 
Secondary Efficacy Endpoints ....................................................................................69 
9.6.2.3. 
Exploratory Endpoints ................................................................................................70 
9.7. 
Safety ..........................................................................................................................70 
9.7.1. 
Safety Endpoints .........................................................................................................70 
9.7.2. 
Safety Analyses ..........................................................................................................70 
9.8. 
Pharmacokinetics and Pharmacodynamics .................................................................70 
9.8.1. 
Pharmacokinetic and Pharmacodynamic Endpoints ...................................................70 
9.8.2. 
Pharmacokinetic and Pharmacodynamic Analyses ....................................................70 
9.9. 
Interim Analysis ..........................................................................................................70 
10. 
ADMINISTRATIVE CONSIDERATIONS ..............................................................71 
10.1. 
Institutional Review Board (IRB)/Ethics Committee (EC) ........................................71 
10.2. 
Ethical Conduct of the Study ......................................................................................71 
10.3. 
Subject Information and Consent ...............................................................................71 
10.4. 
Subject Confidentiality ...............................................................................................72 
10.5. 
Study Monitoring ........................................................................................................72 
10.6. 
Audits and Inspections ................................................................................................73 
10.7. 
Case Report Forms and Study Records ......................................................................73 
10.8. 
Data Safety Monitoring Board ....................................................................................74 
10.9. 
Protocol Deviations ....................................................................................................74 


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10.10. 
Access to Source Documentation ...............................................................................74 
10.11. 
Data Generation and Analysis ....................................................................................74 
10.12. 
Retention of Records ..................................................................................................75 
10.13. 
Financial Disclosure ...................................................................................................75 
10.14. 
Premature Termination of the Study ...........................................................................75 
10.15. 
Clinical Study Report .................................................................................................75 
10.16. 
Subject Insurance and Indemnity ................................................................................75 
10.17. 
Amendments to the Protocol ......................................................................................75 
11. 
LIST OF REFERENCES ............................................................................................77 
12. 
APPENDICES ............................................................................................................78 
APPENDIX 1. STUDY SCHEDULE .........................................................................................79 
APPENDIX 2. DRUGS THAT PROLONG THE QT/QTC INTERVAL ..................................84 
APPENDIX 3. DRUGS KNOWN TO INTERACT WITH CYP3A4 ........................................87 
APPENDIX 4. DRUGS THAT MAY INTERACT WITH P-GLYCOPROTEIN .....................89 
APPENDIX 5. PROCEDURES FOR EMERGENCY UNBLINDING .....................................90 
APPENDIX 6. ENDOCRINE SOCIETY CLINICAL PRACTICE GUIDELINE ON 
THE DIAGNOSIS AND TREATMENT OF ADRENAL INSUFFICIENCY 
(INCLUDING HYPOALDOSTERONISM) ..............................................................91 
 


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LIST OF TABLES 
Table 1: 
Abbreviations ..............................................................................................................17 
Table 2: 
Investigational Product ...............................................................................................34 
Table 3: 
List of Clinical Laboratory Tests ................................................................................46 
Table 4: 
Pharmacokinetic Sampling Time Points .....................................................................49 
Table 5: 
Pharmacokinetic Parameters .......................................................................................50 
Table 6: 
Study Schedule, Screening and Open-Label Dose-Escalation Periods ......................79 
Table 7: 
Study Schedule, Double-Blind Randomized Withdrawal Period and Follow-
Up Period ....................................................................................................................80 
Table 8: 
Study Schedule, Additional Open-Label Dosing Period and Follow-Up 
Period ..........................................................................................................................81 
 
LIST OF FIGURES 
Figure 1: 
Study Schematic, Screening and Open-Label Dose-Escalation Periods ....................24 
Figure 2: 
Study Schematic, Double-Blind Randomized Withdrawal Period .............................24 
Figure 3: 
Study Schematic, Additional Open-Label Dosing Period ..........................................25 
 
  


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LIST OF ABBREVIATIONS 
Table 1: 
Abbreviations  
Abbreviation 
Explanation 
11-DOC 
11-deoxycorticosterone 
17-OHP 
17-hydroxyprogesterone 
A 
aldosterone 
A4 
androstenedione 
ACAT1 
acyl-CoA:cholesterol acyltransferase 1 
ACC 
adrenocortical carcinoma 
ACTH 
adrenocorticotropic hormone 
AE 
adverse event 
ALB 
albumin 
ALK-P 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
aPTT 
activated partial thromboplastin time 
ATC 
Anatomical Therapeutic Chemical 
AUC 
area under the concentration-time curve 
AUC0-4 
area under the concentration-time curve from time zero to 4 hrs post-
dose 
AUC0-4/D 
dose-normalized AUC0-4 
AUC0-24 
area under the concentration-time curve from time zero to 24 hrs 
post-dose 
AUC0-∞ 
area under the concentration-time curve from time zero to infinity 
AUC0-t 
area under the concentration-time curve up to the last quantifiable 
concentration time point (t) 
AUC%extrap 
the percentage of AUC0-∞ extrapolated 
BID 
twice daily 
BIPSS 
bilateral inferior petrosal sinus sampling 
BMI 
body mass index 
BUN 
blood urea nitrogen 
Ca 
calcium 
CE 
cholesteryl ester 
CFR 
Code of Federal Regulations 
CL 
clearance 
CL/F 
oral clearance calculated as dose/AUC0-∞ 
Clast 
last quantifiable concentration 
Cmax 
maximum observed concentration 
Cmax/D 
dose-normalized Cmax 
CMH 
Cochran-Mantel-Haenszel 
CQA 
clinical quality assurance 
CRA 
clinical research associate 


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Abbreviation 
Explanation 
CRH 
corticotrophin-releasing hormone 
CSR 
clinical study report 
CT 
computed tomography 
CYP 
cytochrome P450 
DDAVP 
desmopressin 
demog 
demographics 
DHEA 
dehydroepiandrosterone 
DHEA-S 
dehydroepiandrosterone sulfate 
DSMB 
Data Safety Monitoring Board 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EoS 
end-of-study 
EoT 
end-of-treatment 
ET 
early termination 
excl 
exclusion 
EudraCT 
European Clinical Trials Database 
DHEA-S 
dehydroepiandrosterone sulfate 
FC 
free cholesterol 
GC 
glucocorticoid 
GCP 
Good Clinical Practice(s) 
GFR 
Glomerular filtration rate 
GLP 
Good Laboratory Practices 
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 
Hgb 
hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
ID 
identification number 
IMP 
investigational medicinal product 
incl 
inclusion 
IND 
Investigational new drug 
INR 
international normalized ratio 
IRB 
institutional review board 
ITT 
intent-to-treat 
IUD 
intrauterine device 


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Abbreviation 
Explanation 
IVRS/IWRS 
interactive voice/web response system 
λz 
terminal phase rate constant 
LDL 
low density lipoprotein 
MC 
mineralocorticoid 
MDR1 
multidrug resistance protein 1 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
P 
progesterone 
P-gp 
permeability glycoprotein 
PD 
pharmacodynamic 
PE 
physical examination 
PK 
pharmacokinetic(s) 
PO 
per os (by mouth) 
PPARγ 
peroxisome proliferator-activated receptor gamma 
PT 
prothrombin time 
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 
RECIST 
response evaluation criteria in solid tumors 
SAE 
serious adverse event 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvate transaminase 
SHBG 
sex hormone binding globulin 
T 
testosterone 
t1/2 
terminal phase half-life 
TBD 
to be determined 
TdP 
torsades des pointes 
Tmax 
time of maximum concentration 
TMF 
trial master file 
UFC 
urinary free cortisol 
ULN 
upper limit of normal 
US/USA 
United States/United States of America 
WBC 
white blood cell 
WHO 
World Health Organization 
 


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1. 
INTRODUCTION 
1.1. 
Background 
Cushing’s syndrome is a condition that results from the chronic effects of excessive 
glucocorticoids. Exogenous Cushing’s syndrome, the most common form, is due to treatment 
with glucocorticoid medications. Endogenous Cushing’s syndrome is rare, with an incidence of 
2-3 cases per million per year, and is usually divided into adrenocorticotropic hormone (ACTH)-
dependent causes and ACTH-independent causes.1  Cushing’s disease, the most common cause 
(~70-80%) of endogenous Cushing’s syndrome, is due to an ACTH-secreting pituitary tumor.2  
Cushing’s disease is further classified as being due to micro- or macroadenomas based on the 
size of the pituitary tumor.2  Other causes of endogenous Cushing’s syndrome include primary 
adrenal gland tumors and ectopic (non-pituitary) ACTH-secreting tumors.1  
Cushing’s syndrome of any cause results in the clinical manifestations of weight gain, 
hypertension, diabetes, decreased short-term memory, depression, hirsutism, recurrent infection, 
weak bones and other adverse effects.3,4,5   If left untreated, Cushing’s syndrome can be life-
threatening. Mortality rates for untreated, uncontrolled Cushing’s syndrome are high with 
cardiovascular causes being most common.3,4  
Treatment of endogenous Cushing’s syndrome depends upon the etiology. For Cushing’s 
disease, surgical intervention via transsphenoidal resection of the pituitary tumor serves as first 
line therapy. The success rate depends largely upon the size of the tumor (micro- vs. macro-
adenoma) and the expertise of the surgeon. Overall, ~65-90% of Cushing’s disease patients with 
microadenomas are cured with transsphenoidal surgery.6  Success rates fall significantly for 
subsequent surgeries and recurrence rates are as high as 20%.6  External beam radiation also 
serves a role in the management of Cushing’s disease, usually in the setting of failed 
transsphenoidal surgery. Success rates with radiation therapy are highly variable and results can 
take years.7  For Cushing’s syndrome due to non-pituitary causes, including ectopic ACTH-
secreting tumors and adrenocortical tumors or bilateral adrenal hyperplasia, surgical intervention 
serves as the primary treatment modality. Medical therapies for Cushing’s disease are generally 
used immediately prior to transsphenoidal surgery or following surgery if there is disease 
recurrence. Medical therapies can be broadly categorized as steroidogenesis inhibitors 
(ketoconazole, metyrapone), cortisol receptor blockers (mifepristone) or centrally-acting agents 
(somatostatin analogues, dopamine agonists).7  In the United States (US), only mifepristone and 
pasireotide (a somatostatin analogue) are labeled for the treatment of Cushing’s syndrome and 
Cushing’s disease, respectively. Consequently, there is a need for additional therapies for 
Cushing’s syndrome. 
1.2. 
Rationale for the Use of ATR-101 in Cushing’s Syndrome 
ATR-101, an acyl-CoA:cholesterol acyltransferase 1 (ACAT1) inhibitor, may provide an 
extremely valuable tool for the clinician managing Cushing’s syndrome. ACAT1 is a membrane-
bound enzyme that catalyzes the esterification of free cholesterol (FC) to cholesteryl ester (CE). 
ACAT1 is highly expressed in the adrenal glands compared with other tissues8 and ATR-101 is 
found at higher levels in the adrenal glands compared to other sites in the body.9  Both of these 
factors are likely to contribute to the selectivity of ATR-101’s effects. In the adrenal glands, CE 
serves as a substrate reservoir for steroid biosynthesis. At low doses/exposures, ATR-101 results 


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in reduction of the CE reservoir and leads to reduced synthesis of adrenal steroids. Higher 
doses/exposures of ATR-101 cause further disruption of the normal FC/CE ratio, which leads to 
endoplasmic reticulum stress and activation of the unfolded protein response. If left unresolved, 
this cascade results in apoptosis. The results present a clear molecular understanding of the dose-
dependent, novel mechanism of action of ATR-101. Dose-dependent inhibition of adrenal 
steroidogenesis across the entire steroidogenic pathway may result in dose-dependent decreases 
in all steroids including cortisol and may provide an opportunity to normalize these cortisol 
levels in Cushing’s syndrome patients. Use of ATR-101 in the treatment of Cushing’s syndrome 
is supported by extensive mechanism-of-action studies, robust non-clinical proof-of concept data 
and exposure of approximately 50 patients with adrenocortical carcinoma (ACC) in a Phase 1 
study.  
1.2.1. 
Preclinical Studies 
ATR-101 has been studied extensively in vitro and in vivo. Two proof-of-concept dog studies 
have been conducted, which validate the mechanism-of-action studies.9  In the first study, normal 
beagle dogs (N=3) were administered ATR-101 at 3 mg/kg/day for 7 days, followed by 30 
mg/kg/day for 7 days. At the conclusion of the study, adrenal CE levels were markedly 
decreased and there were dose-and time-dependent decreases in the levels of all adrenal steroids 
and steroid intermediates tested. The second study was conducted in dogs with naturally-
occurring Cushing’s syndrome. Ten dogs with confirmed Cushing’s syndrome (three of adrenal 
and seven of pituitary etiology) were treated as follows: four dogs received 2 weeks of treatment 
(3 mg/kg/day x 1 week, followed by 30 mg/kg/day x 1 week); six dogs received 4 weeks of 
treatment (3 mg/kg/day x 1 week, followed by 30 mg/kg/day x 3 weeks). Nine out of 10 dogs 
experienced reductions in ACTH-stimulated cortisol concentrations. The mean reduction in post-
ACTH stimulated cortisol concentration was 51.5% at the time of study completion. Plasma 
baseline cortisol concentrations at initial and final evaluations were not significantly different, 
although baseline cortisol concentrations did decrease in 4 of 10 dogs. ATR-101 was well 
tolerated in both dog studies with no meaningful safety issues identified. These studies, along 
with the in vitro mechanism-of-action studies, support the use of ATR-101 in endocrine diseases 
of adrenal dysfunction. 
Additional evidence of the adrenal-specific effects of ATR-101 comes from 4-week and 13-week 
dog toxicity studies. In the 13-week dog study, nine of 12 animals (four males, five females) at 
30 mg/kg BID and three of eight animals (one male, two females) at 10 mg/kg BID exhibited 
clinical signs consistent with adrenal insufficiency (subsequently resulting in a change from 30 
to 20 mg/kg BID and from 10 to 7.5 mg/kg BID). The earliest presentation occurred on Day 17. 
Replacement glucocorticoid (GC) and mineralocorticoid (MC) therapy with subcutaneous 
prednisone and fludrocortisone resulted in marked clinical improvements. Similar but less robust 
effects (e.g., no changes in basal cortisol) were observed in the 4-week study and replacement 
GC/MC therapy was not required. ATR-101-related gross pathologic changes consisted of 
bilaterally small adrenal glands in both sexes at ≥ 3 mg/kg BID, which correlated with atrophy of 
the adrenal cortex microscopically. Both 4-week and 13-week studies suggested that the effects 
of ATR-101, even at the higher doses, are partially reversible. The post-treatment observation 
period following the 13-week study was 4 weeks, with mean effects demonstrating signs of 
recovery in both male (2/2) and female (1/2) dogs. The decreases in adrenal function (decreases 
in basal and ACTH-stimulated cortisol measurements), decreased adrenal weights and histologic 
changes, were all anticipated effects based upon published studies.10,11  


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1.2.2. 
Clinical Studies  
Two clinical studies (ATR-101-001 and ATR-101-101) have been initiated with ATR-101. Study 
ATR-101-001 is a Phase 1, first-in-human, maximum tolerated dose (MTD) study to determine 
the safety of ATR-101 in subjects with ACC, a rare but highly malignant and aggressive cancer. 
ATR-101 doses for this indication are markedly higher than those proposed for the treatment of 
Cushing’s syndrome and are targeted for apoptotic effects. Mean area under the curve (AUC0-24) 
values as high as ~45,000 ng⋅hr/mL have been observed with acceptable toxicity and the MTD 
has yet to be defined. Antitumor activity in this study is being evaluated by objective measures 
of tumor size (RECIST criteria) and assessment of adrenal cortical steroid production. As of 
March 1, 2016, 54 ACC subjects have been exposed to ATR-101 at doses ranging from 1.6 to 
102.4 mg/kg/day. The most commonly observed reactions have been mild or moderate nausea, 
vomiting and diarrhea at the higher doses of ATR-101. There has been one serious adverse event 
(SAE) of vomiting and diarrhea that was considered to be related to ATR-101 by the 
Investigator. One subject with baseline liver dysfunction had a reversible non-serious grade 3 
increase of alanine aminotransferase (ALT). Hypersensitivity rashes have been observed as has 
self-limiting dysuria. 
Study ATR-101-101, a randomized, 3-way crossover food effect study, was performed in 
14 healthy human volunteers. Subjects took a 500-mg tablet of ATR-101 under three different 
administration conditions: in the fasted state with water, in the fasted state with cola (an acidic 
beverage), or after a standard high-fat meal. ATR-101 exposure was approximately 1.9-fold 
higher when taken after a meal than when taken in the fasted state with water. Administration 
with cola resulted in exposure to ATR-101 that was approximately 1.2 times the exposure when 
taken fasted with water. ATR-101 was very well tolerated in the food effect study with no SAEs 
and few adverse events (AEs), none of which changed the safety profile of ATR-101. 
Additional information may be found in the current version of the Investigator’s Brochure.9  
In summary, ATR-101 presents an intriguing spectrum of dose-dependent therapeutic options 
ranging from inhibition of adrenal steroidogenesis at lower doses to apoptotic effects at higher 
doses. There have been no previous studies of ATR-101 in subjects with Cushing’s syndrome. 
The use of ATR-101 for the treatment of Cushing’s syndrome presents a novel therapeutic 
approach. 
1.3. 
Research Hypothesis 
The study will evaluate the hypothesis that treatment of adult subjects with endogenous 
Cushing’s syndrome with ATR-101 will result in decreases in cortisol production and that 
subsequent randomized withdrawal from ATR-101 or continued treatment will demonstrate a 
return towards baseline levels or maintenance of effect, respectively. 
1.4. 
Rationale for Conducting This Study 
This Phase 2 study of ATR-101 will be used to establish the proof-of-concept for the use of 
ATR-101 in adult subjects with endogenous Cushing’s syndrome.  


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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
• To evaluate the efficacy and safety of orally-administered ATR-101 in adults with 
endogenous Cushing’s syndrome 
2.2. 
Secondary Objectives 
• To evaluate the changes in adrenal steroids and adrenal steroid intermediates 
• To evaluate the change in ACTH 
• To evaluate the change in metabolic syndrome-related parameters, including fasting glucose, 
insulin, lipid panel, blood pressure and body mass index (BMI) 
• To assess the safety and tolerability of ATR-101 
• To determine the pharmacokinetics (PK) of ATR-101 and its major metabolites 
• To evaluate the PK/pharmacodynamic (PD) relationships of ATR-101 


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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This Phase 2 multicenter study consists of two parts: an open-label intra-subject dose-escalation 
period of 8 weeks’ duration, followed either by a double-blind randomized withdrawal period of 
4 weeks’ duration (if the subject meets randomization criteria) or by an additional open label 
dosing period of 4 weeks’ duration (if the subject does not meet randomization criteria). A study 
schematic is shown in Figures 1, 2, and 3 below. 
Figure 1: 
Study Schematic, Screening and Open-Label Dose-Escalation Periods 
 
 
Figure 2: 
Study Schematic, Double-Blind Randomized Withdrawal Period 
 
 


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Figure 3: 
Study Schematic, Additional Open-Label Dosing Period 
 
3.1.1. 
Screening Period 
During a screening period of up to 8 weeks’ duration, subjects will undergo a wash-out of 
medications used to treat Cushing’s syndrome (if needed) and will then perform two 24-hour (hr) 
urine collections for baseline urinary free cortisol (UFC) assessment within 28 days prior to 
enrollment into the open-label dose-escalation period. At enrollment, all eligible subjects will be 
assigned to one of two 24-hr UFC strata. Strata will be assigned according to baseline 24-hr UFC 
values, calculated as the mean of all 24-hr UFC levels obtained within the 28 days prior to 
enrollment:  
• Stratum I: 24-hr UFC 1.3 to < 4 × upper limit of normal (ULN) 
• Stratum II: 24-hr UFC 4 to 10 × ULN 
Enrollment into a particular stratum may be limited to ensure the inclusion of subjects in both 
strata.  
3.1.2. 
Open-Label Dose-Escalation Period 
The open-label dose-escalation period will be 8 weeks in duration and will allow each subject to 
receive three dose levels of ATR-101 (i.e., 250 mg BID, 500 mg BID, and 1000 mg BID). The 
250 mg and 500 mg BID dose levels will each be used for 2 weeks, and the 1000 mg BID dose 
level will be used for 4 weeks. 
• Study Days 1-14: At Visit T1, all subjects will be assigned to take the same starting dose of 
ATR-101, 250 mg BID, at the beginning of the open-label dose-escalation period. Twenty-
four-hour UFCs will be assessed on Days 13 and 14 (collections start on Days 13 and 14, 
respectively, and finish on Days 14 and 15, respectively).  
• Study Days 15-28: At Visit T2, all subjects will be assigned to take the next higher dose of 
ATR-101, 500 mg BID. Twenty-four-hour UFCs will be assessed on Days 27 and 28 


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(collections start on Days 27 and 28, respectively, and finish on Days 28 and 29, 
respectively).  
• Study Days 29-56: At Visit T3, all subjects will be assigned to take the next higher dose of 
ATR-101, 1000 mg BID. Twenty-four-hour UFCs will be assessed on Days 41, 42, 50, 51, 
and 56 (collections start on Days 41, 42, 50, 51, and 56, respectively, and finish on Days 42, 
43, 51, 52, and 57, respectively). 
At any time, the ATR-101 dose may be down-titrated as needed for safety reasons at the 
discretion of the Investigator. There will be no wash-out period between the open-label dose-
escalation period and either the double-blind randomized withdrawal period or the additional 
open-label dosing period. 
3.1.3. 
Double-blind Randomized Withdrawal Period 
The double-blind randomized withdrawal period will be up to 4 weeks in duration. A subject is 
eligible to enter the double-blind randomized withdrawal period if the mean of the Day 50 and 
Day 51 (“mean Day 50/51”) 24-hr UFCs meets at least one of the following randomization 
criteria: 
• 24-hr UFC ≤ ULN 
• 24-hr UFC ≤ 50% relative to the baseline value  
Eligible subjects will be randomized in a 1:1 ratio to receive either ATR-101 at the same dose 
level being used at the completion of the open-label dose-escalation period (expected to be 1000 
mg BID) or matching placebo. Subjects will continue in the double-blind randomized withdrawal 
period for 4 weeks or until their mean Day 64/65 24-hr UFC is > 1.3 x ULN and has also 
increased by > 50% relative to their mean Day 50/51 24-hr UFC, whichever comes first. Subjects 
who are not eligible to be randomized will enter the Additional Open-Label Dosing Period 
instead of the Double Blind Randomized Withdrawal Period (see below).  
• Study Days 57-70: Twenty-four-hour UFCs will be collected on Days 64 and 65 (collections 
start on Days 64 and 65, respectively, and finish on Days 65 and 66, respectively). At the 
time of Visit R2 (Day 71), if the mean Day 64/65 24-hr UFC result is available and is > 1.3 x 
ULN, and has also increased by > 50% relative to the mean Day 50/51 24-hr UFC, the 
subject will complete the End-of-Treatment (EoT) visit (Visit R3) instead of Visit R2 and 
may then be started on another agent at the discretion of his or her physician. Otherwise, the 
subject will continue in the double-blind, randomized withdrawal period. 
• Study Days 71-85: Twenty-four-hour UFCs will be collected on Days 79 and 84 (collections 
start on Days 79 and 84, respectively, and finish on Days 80 and 85, respectively). The EoT 
visit (Visit R3) will be completed on Day 85. Note: if the mean Day 64/65 24-hr UFC was 
not available at the time of Visit R2, but subsequently is found to meet criteria for study 
completion, the EoT visit should be performed as soon as practicable, rather than on Day 85. 
Additionally, if the Day 79 or Day 84 24-hr UFC is > ULN, after completion of the EoT visit 
(Visit R3) the subject may begin treatment with another agent at the discretion of his or her 
physician. 


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3.1.4. 
Additional Open-Label Dosing Period 
The additional open-label dosing period will be 4 weeks in duration. A subject is eligible to enter 
the additional open-label dosing period if they do not meet any of the randomization criteria 
described in the above section.  
Eligible subjects will be assigned to take ATR-101 1000 mg BID (or a lower dose if needed for 
safety, at the discretion of the Investigator). Subjects will continue in the additional open-label 
dosing period for 4 weeks.  
• Study Days 57-70: Twenty-four-hour UFCs will be collected on Days 69 and 70 (collections 
start on Days 69 and 70, and finish on Days 70 and 71, respectively). 
• Study Days 71-85: Twenty-four-hour UFCs will be collected on Days 79 and 84 (collections 
start on Days 79 and 84, respectively, and finish on Days 80 and 85, respectively). The EoT 
visit (Visit A3) will be completed on Day 85. Note: if the Day 79 or Day 84 24-hr UFC is > 
ULN, after completion of the EoT visit (Visit A3) the subject may begin treatment with 
another agent at the discretion of his or her physician. 
3.1.5. 
Follow-up Period 
During the follow-up period, subjects will continue to be monitored for safety. Subjects whose 
most recent 24-hr UFC is ≤ ULN will have a follow-up visit (Visit F1/End-of-Study, EoS; this is 
the same as the end of trial) at the study site 2 weeks after their ET/EoT visit. Subjects whose 
most recent 24-hr UFC is > ULN will have a follow-up telephone visit instead of a study site 
visit.  
• Study Days 86-98: If the Day 79 24-hr UFC is ≤ ULN, a follow-up visit (Visit F1) at the 
study site will be scheduled for Day 98, 2 weeks after the EoT visit. This visit will consist 
largely of safety assessments. Subjects whose Day 84 24-hr UFC is also ≤ ULN will begin a 
24-hr urine collection on Day 92 and finish on Day 93. If the Day 79, Day 84 or Day 92 24-
hr UFC is > ULN, a telephone visit will be conducted on Day 98 instead of a study site visit 
(in case of discrepant results, the latest result should be used). If the Day 92 24-hr UFC result 
is unknown at the time the Day 98 visit is due, the subject will proceed with having the Day 
98 visit at the study site. 
• Subjects whose Day 92 24-hr UFC is ≤ ULN should continue to be followed up and have 
morning serum ACTH and 24-hr UFC assessed every 2-4 weeks until their 24-hr UFC is > 
ULN or until the Investigator and the Medical Monitor agree that the subject is stable. 
Throughout the course of the study, safety evaluations will include assessment of AEs, 
concomitant medications, clinical laboratory tests, vital signs, physical examinations (PEs) and 
12-lead electrocardiograms (ECGs). 
A detailed schedule of study assessments is presented in Appendix 1. 
3.2. 
Rationale for Study Design  
This Phase 2 study will assess the ability of ATR-101 at various dose levels to suppress cortisol 
production in subjects with endogenous Cushing’s syndrome. For subjects who meet 
randomization criteria, this study consists of an open-label dose-escalation period followed by a 
relatively brief (up to 4 weeks) placebo-controlled double-blind randomized withdrawal period 


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(where subjects are randomized in a 1:1 ratio either to continue to receive ATR-101 or matching 
placebo). This study design permits a placebo comparison with ATR-101 while minimizing the 
time during which subjects may experience elevated cortisol levels. Subjects who do not meet 
randomization criteria at the end of the open-label dose-escalation period will continue into an 
additional 4-week open-label dosing period, which permits assessment of efficacy following a 
longer duration of dosing with ATR-101. 
The double-blinded withdrawal period of the study is randomized in order to minimize any bias 
in determining which subject receives ATR-101 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 control rate for 
the assessment of efficacy. Stratification by baseline cortisol level allows for a balance of 
subjects with higher and lower levels in the treatment groups.  
Based on toxicity investigations in preclinical species, previous clinical observations in PK and 
PD responses, expected bioavailability and safety demonstrated in a previous ATR-101 study in 
subjects with ACC, the doses of 250 mg BID, 500 mg BID and 1000 mg BID have been selected 
to evaluate the clinical effects of ATR-101 in subjects with Cushing’s syndrome. 
3.3. 
Study Duration 
It is anticipated that the overall duration of the study per subject will range from approximately 
16-22 weeks, depending upon the duration (if any) required for wash-out and the duration of 
follow-up.  
3.4. 
Number of Subjects 
Approximately 16 subjects are planned to be enrolled in this study. At enrollment, all eligible 
subjects will be assigned to one of two 24-hr UFC strata. Strata will be assigned according to 
baseline 24-hr UFC level: 1.3 to < 4 × ULN (Stratum I) and 4 to 10 × ULN (Stratum II). 
Enrollment into a particular stratum may be limited to ensure the inclusion of subjects in both 
strata. The subject population will consist of adults with endogenous Cushing’s syndrome with 
24-hr UFC 1.3 to 10 × ULN.  
The study will be conducted at approximately 14 sites in North America and the United 
Kingdom. 
3.5. 
Treatment Assignment 
There are a total of 3 dose levels for ATR-101 during the open-label dose-escalation period:  
• 250 mg BID 
• 500 mg BID  
• 1000 mg BID 


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All enrolled subjects will be assigned to take the same starting dose of ATR-101, 250 mg BID. 
Dose escalation to the next higher dose of ATR-101, 500 mg BID, will occur at Visit T2. Further 
dose escalation to the next higher dose of ATR-101, 1000 mg BID, will occur at Visit T3. 
A subject may enter the double-blind randomized withdrawal period if the mean Day 50/51 24-hr 
UFC is ≤ ULN or ≤ 50% relative to the baseline value. Such subjects will be randomized 1:1 to 
receive either ATR-101 at the same dose level on which they achieved the mean Day 50/51 24-hr 
UFC ≤ ULN (or ≤ 50% of their baseline value) (expected to be 1000 mg BID) or matching 
placebo in a double-blinded manner. 
Subjects who do not meet any of the randomization criteria will enter the additional open-label 
dosing period and receive ATR-101 1000 mg BID.   
3.6. 
Special Safety Topics 
Preclinical studies at exposure levels much higher than those anticipated for this study have 
identified adrenal suppression with apoptotic histologic changes. The predicted exposures in this 
study are much lower; however, occurrence of such changes is a possibility. The investigative 
staff should be familiar with the warnings and precautions for ATR-101 as presented in the 
Investigator’s Brochure.9   
Adrenal suppression may present as adrenal insufficiency or as hypoaldosteronism. Subjects 
presenting with unexplained symptoms suggestive of adrenal insufficiency, such as fatigue, 
nausea, low blood pressure, characteristic electrolyte abnormalities (hyponatremia and 
hyperkalemia), etc., should be promptly evaluated for adrenal insufficiency and given 
replacement corticosteroids and/or mineralocorticoids as clinically indicated.   
Subjects who develop unexplained persistent hyperkalemia and/or hyperchloremic metabolic 
acidosis should be evaluated for hypoaldosteronism. Subjects with confirmed hypoaldosteronism 
should receive mineralocorticoid replacement (e.g., fludrocortisone at a starting dose of 50-100 
µg/day) and should not be on any salt restrictions. Guidelines for the diagnosis and treatment of 
adrenal insufficiency and hypoaldosteronism may be found in Appendix 6.12 
3.7. 
Lowering the Dose for Safety Purposes 
Study drug doses may be decreased in the open-label period if a subject develops adrenal 
insufficiency or hypoaldosteronism, or if required for another safety-related reason in the opinion 
of the Investigator. Any adjustments to the study drug dose should be discussed with the Medical 
Monitor. If subjects cannot tolerate the lowest dose of study drug (i.e., 250 mg BID), they should 
be discontinued from the study and undergo an ET visit. 
3.8. 
Criteria for Study Termination 
Specific stopping criteria will not be defined due to the relatively small sample size. However, 
the frequency of study visits and safety laboratory tests will enable the early detection of any 
suspected adverse drug reactions. Due to the mechanism of action of ATR-101, Investigators 
should be alert to the potential for relative and absolute adrenal insufficiency. In addition, a 
single occurrence of the following safety events will trigger an expedited safety meeting, 
consisting of at least the Medical Monitor and the Sponsor Chief Medical Officer, to review the 
case.  


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• Hepatic toxicity such as marked elevations in transaminases (> 5x ULN) or simultaneous 
elevations in hepatic transaminases > 3x ULN and bilirubin > 2x ULN (i.e., Hy’s Law) 
• Severe renal impairment (e.g., creatinine clearance < 30 mL/min or glomerular filtration rate 
< 30 mL/min/1.73 m2) 
• Severe cardiovascular dysfunction such as new arrhythmia, valvular dysfunction, or NYHA 
Class III or IV heart failure  
If it is determined 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. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1. 
Inclusion Criteria 
Each subject must meet all of the following criteria to be enrolled in this study:  
1. Provision of signed and dated informed consent prior to any study-specific procedures 
2. Men and women 18-80 years of age (inclusive) at screening 
3. Subjects must have a confirmed diagnosis of endogenous Cushing’s syndrome as evidenced 
by baseline UFC 1.3 to 10 × ULN (mean of all 24-hr UFC levels obtained during the 
screening period within 28 days of enrollment into the open-label dose-escalation period) 
AND documentation at any time of ONE of the following three criteria: 
• For subjects with a diagnosis of pituitary Cushing’s syndrome, either:  
− Magnetic resonance imaging (MRI) confirmation of pituitary adenoma (greater than 
or equal to 0.6 cm), OR  
− For subjects with a pituitary microadenoma less than 0.6 cm, bilateral inferior 
petrosal sinus sampling (BIPSS) showing an ACTH gradient > 2 before or > 3 after 
corticotropin-releasing hormone (CRH) or desmopressin (DDAVP) stimulation, OR  
− For subjects who have had prior pituitary surgery: histopathology confirming an 
ACTH-staining adenoma 
• For subjects with a diagnosis of adrenal Cushing’s syndrome: MRI or computed 
tomography (CT) of the adrenal glands showing an adrenal tumor 
• For subjects with a diagnosis of ectopic ACTH as the cause of their Cushing’s syndrome: 
ACTH-dependent Cushing’s syndrome and either: 
− MRI showing no pituitary adenoma, OR  
− MRI showing only a small pituitary adenoma (< 0.6 cm) AND a negative BIPSS, OR  
− For subjects who have had prior pituitary surgery: histopathology that is negative for 
an ACTH-staining adenoma 
4. Subjects with a history of prior pituitary surgery must be at least 3 months post-surgery at the 
time of the screening visit 
5. Body mass index (BMI) between 18 and 60 kg/m2, inclusive, at screening 
6. Female subjects must be postmenopausal > 2 years OR must have been 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 include oral 
contraceptives, contraceptive implants, Depo-Provera®, contraceptive patch, vaginal ring, 
male condom,  female condom, spermicide, diaphragm with spermicide, cedrvical cap with 
spermicide, contraceptive sponge, or an intrauterine device (IUD); IUDs must have been in 
place for at least 28 days prior to first dose of study drug. 
4.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from participation in the study: 
1. Pseudo-Cushing’s syndrome, cyclic Cushing’s syndrome or current iatrogenic Cushing’s 
syndrome 


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2. Subjects who are considered candidates for surgical treatment of Cushing’s syndrome, unless 
it is clearly documented that the subject has refused such surgery or that surgery cannot be 
scheduled for at least the anticipated duration of the study 
3. Normal late night salivary cortisol value during screening unless the subject’s history clearly 
demonstrates that he or she does not have pseudo-Cushing’s or cyclic Cushing’s. If the 
subject has a normal late night salivary cortisol, and the PI feels the subject does not have 
pseudo-Cushing’s or cyclic Cushing’s, the subject may be enrolled with approval of the 
medical monitor  
4. Normal 24-hr UFC during screening (this would be suggestive of cyclic Cushing’s) 
5. Radiotherapy of the pituitary within 6 months prior to or during screening 
6. For subjects with pituitary Cushing’s syndrome, any compression of the optic chiasm or the 
presence of a tumor within 2 mm of the optic chiasm on the most recent pituitary MRI prior 
to or during screening 
7. Use of or medical requirement for any of the following medications within the timeframes 
specified below prior to collection of the first 24-hr UFC during Screening and throughout 
study participation (see Section 5.11 for additional prohibited and restricted medications): 
• Inhibitors of steroidogenesis (ketoconazole, metyrapone): 1 week 
• Pituitary-directed agents: Dopamine agonists (bromocriptine, cabergoline) and PPARγ 
agonists (rosiglitazone or pioglitazone): 4 weeks 
• Octreotide LAR, Lanreotide SR and Lanreotide autogel: 14 weeks 
• Octreotide (immediate release formulation): 1 week 
• Pasireotide: 4 weeks 
• Mitotane: 26 weeks 
• Mifepristone: 3 weeks 
8. Uncontrolled diabetes mellitus, as evidenced by HbA1c > 9.0% at screening 
9. Uncontrolled hypertension, defined as systolic blood pressure > 160 mmHg or diastolic 
blood pressure > 90 mmHg during screening. Note: if appropriate, subjects may have blood 
pressure medications adjusted and blood pressure reassessed at an unscheduled visit prior to 
Visit T1. 
10. Any history of gastric or small intestinal surgery or any current disease that causes 
malabsorption. Note: irritable bowel syndrome is acceptable for inclusion 
11. Alcohol or substance abuse (cocaine, amphetamines and/or opioids) within the year prior to 
screening 
12. Abnormal laboratory values as per the guidelines listed below or any other clinically 
significant, unexplained laboratory abnormality according to the Investigator: 
• Serum ALT or AST > 3 × ULN 
• Serum total bilirubin > 1.5 × ULN 
• Serum creatinine > 1.5 × ULN 
• Glomerular filtration rate < 60 mL/min/1.73 m2 
13. Pregnant, breast-feeding, having conceived within the 6 months prior to screening, or having 
an intent to become pregnant during the study period 
14. QTc > 470 msec on electrocardiogram at screening (subjects with a single QTc > 470 msec 
may have 2 additional ECGs taken during screening and the QTcs averaged; if the average 
QTc is > 470 msec then the subject is excluded) 
15. Known history of Gilbert’s syndrome 
16. HIV, hepatitis B, or hepatitis C positivity at screening 


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17. Any malignancy within the previous 5 years, other than curatively treated basal or squamous 
cell skin cancer or cervical carcinoma in situ 
18. Previous exposure to any amount of ATR-101 
19. Participation in any study of an investigational drug within 30 days prior to screening 
20. Significant psychiatric disease, recent severe physical stress, malnutrition, chronic excessive 
exercise, or any other medical or psychiatric condition 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 
4.3. 
Subject Withdrawal Criteria 
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, it is in the best interest of the subject to discontinue study 
participation. 
2. The subject experiences an adverse event that would preclude further treatment with the 
study drug.  
3. The subject withdraws consent for continued participation or refuses further treatment with 
the investigational product. 
4. The subject is noncompliant with the protocol. 
5. The subject becomes pregnant. 
6. The subject cannot tolerate the lowest dose of study drug. 
Subjects should return to the study site for an ET visit (which consists of the same procedures as 
at Visit R3) after withdrawal/removal from the clinical study. The reason for and date of 
withdrawal/removal from the study must 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 procedures provided in Section 6.9. 
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 electronic case 
report form (eCRF). 
Subjects who withdraw or are removed from the clinical study after enrollment into the open-
label dose-escalation period will not be replaced. All enrolled subjects will be fully accounted for 
and documented in the final clinical study reports (CSRs). 
 


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5. 
TREATMENT OF SUBJECTS 
5.1. 
Assignment of Subject Identification Numbers 
Once the subject has signed the informed consent form (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. Once the subject ID has been assigned, the site will 
contact the interactive voice/web response system (IVRS/IWRS) to register the subject ID. 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 ATR-101 Drug Product consists of a white, round, immediate release tablet of strengths 
250 mg or 500 mg of ATR-101 for oral administration. The 250-mg and 500-mg tablets are 
similar in appearance to each other. A placebo tablet (ATR-101 Drug Product Placebo) has been 
developed to match the appearance of the active 250-mg and 500-mg tablets in size, shape, color 
and weight. The tablet formulations are described in Table 2. 
Table 2: 
Investigational Product 
 
Investigational Product 
Product Name: 
ATR-101 
Placebo 
Dosage Form: 
tablet 
tablet 
Unit Dose 
250 mg or 500 mg or  
2 x 500 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 
similar to ATR-101 500-mg 
tablets 
Inactive Ingredients 
Mannitol, microcrystalline 
cellulose, croscarmellose 
sodium, pregelatinized starch, 
hypromellose, magnesium 
stearate and Opadry II white 
Microcrystalline cellulose, 
lactose monohydrate, 
croscarmellose sodium, 
magnesium stearate and  
Opadry II white 
Manufacturer 
Corealis Pharma, Inc. 
Corealis Pharma, Inc. 
 
A certificate of analysis for each lot of ATR-101 Drug Product Tablets and ATR-101 Drug 
Product Placebo Tablets will be provided to the Sponsor prior to shipment. For more information 
regarding the manufacturer and fill/finish, refer to the Investigator’s Brochure.9   


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5.3. 
Study Drug Packaging and Labeling 
The formulation and bulk packaging of ATR-101 Drug Product and Drug Product Placebo 
tablets will be conducted according to standard procedures. Study drug will be packaged and 
labeled by the Sponsor’s designated contract packager and labelled according to regulatory 
requirements. Study drug will be provided to sites as blinded clinical supplies. Additional details 
will be provided in the Pharmacy Manual. 
5.4. 
Study Drug Storage and Accountability 
Study drug must be kept in a secured location and stored at controlled room temperature at the 
study site within its original container. A daily temperature log for monitoring of proper storage 
conditions must be maintained by the site.  
Access to drug must be restricted to designated study personnel only. Under no circumstances 
should the Investigator or 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 the Sponsor. The Investigator must maintain records of the delivery of the 
study drug to the study site, the inventory at the site, use for each subject and return of the study 
drug to a delegate 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 the Sponsor. This log must be kept current and should 
contain the following information: 
• Identification (subject ID number and initials) of subject to whom the study drug was 
dispensed 
• The dates and kit numbers for 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 ATR-101 will be provided in the Pharmacy 
Manual. 
5.5. 
Study Drug Administration 
Study drug doses should be taken approximately 12 hrs apart (twice per day dosing). The time of 
day that the dose is taken should be as consistent as possible (e.g., every morning at 
8 AM (08:00) and every evening at 8 PM (20:00)).  
Study drug should be taken immediately after consumption of food. No specific food contents 
are required and subjects should maintain usual eating practices. If a full meal is not possible or 
not aligned with a subject’s usual eating practices, a light snack should be consumed prior to 
taking study drug.  
On the morning of study visits, subjects should not take their study drug (if applicable) until 
directed by study site personnel. At each study visit from T1 to R2/A2, a trough PK level will be 
collected within 30 minutes prior to dosing and subjects will eat a breakfast prior to dose 
administration. See the Pharmacy Manual for more details. 


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5.6. 
Dose Escalation 
During the 8-week open-label dose-escalation period, all subjects will initially be assigned to 
take ATR-101 250 mg BID. At Visits T2 and T3, dose escalation to the next higher dose level 
(500 mg and 1000 mg BID, respectively) will occur. 
5.7. 
Study Drug Compliance 
The investigational product is to be dispensed by qualified personnel at the study site and only to 
subjects enrolled in 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.  
5.8. 
Randomization and Blinding 
After the open-label dose-escalation period, subjects whose mean Day 50/51 24-hr UFC level is 
≤ ULN or ≤ 50% relative to their baseline value will undergo a placebo-controlled, double-blind 
randomized withdrawal from ATR-101 in which they will be randomized either to continue 
ATR-101 or placebo. Randomization will be stratified by baseline 24-hr UFC level (calculated as 
the mean of all 24-hr UFC levels obtained within the 28 days prior to enrollment into the open-
label dose-escalation period).  
Subjects will continue on the dose of ATR-101 on which they achieved the mean Day 50/51 24-
hr UFC ≤ ULN (or ≤ 50% of their baseline value) or a matching placebo. The matching placebo 
tablets for the ATR-101 500-mg tablets will maintain double-blind status. Subjects will be 
administered ATR-101 and/or placebo tablets BID as described in Section 5.5. 
The following personnel will be unblinded as to the exact content of investigational treatments 
(i.e., the randomization code) during the double-blind randomized withdrawal period: 
• Personnel analyzing the PK samples 
The randomization list will be kept in a secure location until after database lock at the end of the 
study. However, the study drug assignment will be available if unblinding is required for an 
SAE. The procedures for emergency unblinding are provided in Appendix 5. 
Subjects will be assigned to one of two 24-hr UFC strata. Strata will be assigned by the 
IVRS/IWRS system according to the baseline 24-hr UFC value, calculated as the mean of all 
24-hr UFC levels obtained within the 28 days prior to enrollment into the open-label dose-
escalation period:  
• Stratum I: 1.3 to < 4 × ULN 
• Stratum II: 4 to 10 × ULN 
Enrollment into a particular stratum may be limited to ensure the inclusion of subjects in both 
strata.  


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5.9. 
Additional Open-Label Dosing 
Subjects who do not meet any of the randomization criteria, i.e., those whose mean Day 50/51 
24-hr UFC is not sufficiently low, will enter an additional open-label dosing period rather than 
the randomized withdrawal period and be assigned to take ATR-101 1000 mg BID (or a lower 
dose if needed for safety, at the discretion of the Investigator). 
5.10. 
Study Drug Handling and Disposal 
At the time of study close-out, the Sponsor will direct the site regarding the disposition of any 
unused study drug whether it is to be destroyed or be returned to the Sponsor’s designated 
location. The Sponsor or Designee will ensure that a final report of drug accountability is 
prepared and maintained by the investigative site. Additional details on the inventory of study 
drug will be provided in the 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 (i.e., from screening (Visit S1) until the end of the study/end of trial (Visit F1)), 
any medication given other than the study drug (including blood transfusions and parenteral 
fluids) is to be considered a concomitant medication and must be documented on the eCRF. See 
Section 6.5 for additional details regarding documentation of prior and concomitant medications. 
5.12. 
Prohibited and Restricted Medications 
The following medications are prohibited from within the timeframes specified below prior to 
Day -14 through the end of the study and should be washed out for at least the timeframes 
indicated prior to the collection of blood and salivary hormone levels and 24-hr UFCs during the 
screening period: 
• Inhibitors of steroidogenesis (ketoconazole, metyrapone): 1 week 
• Pituitary-directed agents: Dopamine agonists (bromocriptine, cabergoline) and PPARγ 
agonists (rosiglitazone or pioglitazone): 4 weeks 
• Octreotide LAR, Lanreotide SR and Lanreotide autogel: 14 weeks 
• Octreotide (immediate release formulation): 1 week 
• Pasireotide: 4 weeks 
• Mitotane: 26 weeks 
• Mifepristone: 3 weeks 
• Fenofibrate: 5 days 
• Carbenoxolone: 4 days 


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The use of the following medications is restricted as follows: 
• Anti-lipid medications should remain at the same dose and frequency of use as at screening 
during the study 
• Changes in antidiabetic medications should be limited to those that are medically necessary 
Drugs and foods (such as black licorice) that inhibit 11-HSD2 can increase UFC levels and are 
prohibited during the study.  
ATR-101 is most soluble in acidic conditions.  Proton pump inhibitors are prohibited and 
calcium preparations and antacids should not be used from 2 hrs before to 2 hrs after ATR-101 
administration. 
Medications that are known to prolong the QT/QTc interval at therapeutic exposures 
(Appendix 2, List A) and those that only cause prolonged QT intervals in unusual circumstances 
(e.g., overdosage; Appendix 2, Lists B and C) should be used with caution. 
ATR-101 is metabolized by CYP enzymes and is a moderate inhibitor of CYP3A4. As a 
consequence, ATR-101 may interfere with the metabolism of other medicines that are 
metabolized by CYP3A4.  In addition, the metabolism of ATR-101 may be affected by other 
medicines or foods such as grapefruit products that inhibit CYP3A4; thus, grapefruit products 
should be avoided. Drugs known to be metabolized by CYP3A4 are shown in Appendix 3 and 
should be used with caution if they are known to interact with weak or moderate CYP3A4 
inhibitors. 
Preclinical data indicate that ATR-101 may compete with certain drugs for P-glycoprotein (P-gp) 
in the intestinal lumen.  Consequently, the drugs listed in Appendix 4 should be used with 
caution, as they may have an impact on the level of ATR-101 or vice versa.  Note that some of 
these drugs may also appear in Appendices 2 or 3, and may be contraindicated by those 
properties.  
5.13. 
Prohibited Procedures 
The following procedures are prohibited during the study: 
• Elective pituitary or adrenal surgery 
• Bariatric surgery or other elective gastrointestinal surgeries that may affect absorption 
 


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6. 
STUDY PROCEDURES 
Subjects need to be fasting after 10 PM (22:00; water and maintenance medications allowed) the 
evening prior to Visits S1, R1/A1, and R3/A3/ET to allow for collection of the fasting lipid 
panel, glucose and insulin (if the subject is not fasting, proceed with the visit but mark the 
sample collection as being non-fasting). All blood hormone collections should be performed 
between 6-10 AM (06:00-10:00), as close to 8 AM (08:00) as practicable. All early morning 
saliva collections should be performed 30-45 minutes after awakening for the day. All late night 
saliva collections should be performed between 10 PM-12 AM (22:00-00:00). 
If applicable (i.e., Visits T2 to R3/A3/ET), subjects should take their evening dose of study drug 
the evening prior to study visits (and also note the approximate time of the dose). On the 
morning of Visits T1 to R2/A2, subjects should wait to take their morning dose of study drug 
until directed by site personnel at the study site. 
6.1. 
Allowable Variation in Time of Procedures 
The indicated study days for assessments 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 from Visit T1 to Visit R3/A3 are to be completed within  
+ 2 days of the planned date. All other assessments may be completed within ± 7 days of the 
planned date. If a positive window is used, the timing of subsequent assessments may be re-
anchored. The Medical Monitor or designee should be contacted to discuss any assessments that 
will occur outside of these windows.  
6.2. 
Informed Consent 
Prior to any study specific screening evaluations and clinical trial participation, written informed 
consent will be obtained from each subject to be involved in the clinical trial by using the 
Institutional Review Board or Ethics Committee (IRB/EC)-approved 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 study inclusion/exclusion criteria will be done at/after the screening visit (Visit S1), 
before enrolling the subject into the open-label dose-escalation period at Visit T1 and before 
either randomizing the subject or enrolling the subject into the additional open-label dosing 
period at Visit R1/A1. Please note that prior to enrolling the subject into the open-label dose-
escalation period, regarding the laboratory values, only the Visit T1 pregnancy test (if applicable 
and if performed at the site), and the Visit S1 hematology, chemistry, PT, PTT, INR, HbA1c, 
lipid panel, serology, pregnancy test (if applicable), urinalysis, urine drug screen, 24-hr UFC, 
and salivary cortisol levels need to be reviewed. The screening blood hormone levels are for 
baselining purposes and the results do not need to be available prior to enrolling the subject.  


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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 that should be recorded include any treatments taken from 
screening (Visit S1) until the end of the study/end of trial (Visit F1), as well as any radiotherapy 
for Cushing’s syndrome performed at any time prior to screening and any treatments for 
Cushing’s syndrome taken within the year prior to screening. Any treatments given during the 
study other than ATR-101, including blood transfusions, parenteral fluids and herbal 
preparations, are considered to be concomitant therapies and must be recorded on the eCRF. 
6.6. 
Vital Signs, Height, Weight and Body Mass Index 
Vital signs (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 PE will be obtained at Visits S1, T1, R1/A1, and R3/A3/ET. A brief PE will be 
performed at Visits T2, T3, R2/A2, and F1 (if the subject has their follow-up visit at the study 
site), with particular attention to assessing the subjects for adrenal insufficiency. At all other 
visits, targeted PEs may be performed if needed based on adverse events and positives from 
review of systems. 
The following systems will be examined for a complete PE: HEENT, respiratory, cardiovascular, 
gastrointestinal/hepatobiliary (specifically the presence of hepatomegaly or splenomegaly will be 
assessed), musculoskeletal, neurological and dermatologic. On a brief PE, the following systems 
will be examined: respiratory, cardiovascular, gastrointestinal/hepatobiliary and any areas 
pertinent to any adverse events and positives from review of systems.  
6.8. 
Electrocardiography and Determination of QTc 
All subjects will have 12-lead ECGs performed at Visits S1, R1/A1, and R3/A3/ET prior to 
study drug dosing (if applicable). The ECG test tracings will be interpreted by usual clinic 


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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.13   
6.9. 
Adverse Events, Serious Adverse Events and Reporting 
6.9.1. 
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 last study visit or 30 days after the last dose 
of study drug, whichever is later. (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 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 ALT, hepatitis and not the elevated ALT should be listed as the AE). 


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• 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. 
6.9.2. 
Assessing Severity of Adverse Events 
The assessment of severity must be provided by the Investigator and based on the Investigator’s 
clinical judgement. 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 6.9.4.1  for the definition of an SAE. 
6.9.3. 
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 


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• 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. 
6.9.4. 
Serious Adverse Events 
6.9.4.1. 
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 
an SAE under this criterion, nor will hospitalization for a 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: 


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− 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. 
6.9.4.2. 
Reporting 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 last study 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 hrs 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 hrs of awareness. When the EDC system becomes available, the SAE 
information must be entered within 24 hrs 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 
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).  


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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 hrs 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.  
The Investigator should notify the IRB/EC of the occurrence of the SAE, in writing, in 
accordance with local requirements.  
6.9.5. 
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 hrs 
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 6.9.4.2). 
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. 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.  
6.9.6. 
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. 


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6.10. 
Laboratory Tests 
Blood, urine and saliva samples for assessments of efficacy, safety and PK will be obtained as 
shown in the study schedule in Appendix 1. Please see the Laboratory Manual for blood 
collection volumes. Testing of clinical laboratory samples will be carried out by the central 
clinical laboratory and will include the tests listed in Table 3. Testing of PK samples will be 
carried out by the central PK laboratory. Samples may also be assessed for other parameters 
relevant to steroid metabolism. Subjects need to fast from 10 PM (22:00; water and maintenance 
medications allowed) the evening prior to Visits S1, R1 and R3/ET. Subjects need to be in a 
seated position for at least 15 minutes prior to collection of blood hormone levels so that renin 
and aldosterone levels are stable. For other blood tests, subjects may be seated or supine.  
For all female subjects of childbearing potential, 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 (preferred; however, if required by the institution/IRB/EC, a serum or urine sample 
may be submitted to a laboratory for pregnancy testing instead) 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 baseline value. Abnormal laboratory findings that are considered clinically significant by the 
Investigator should be recorded as AEs as appropriate (Section 6.9). 
Table 3: 
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 (including calculated glomerular filtration 
rate), glucose, total bilirubin, total protein, electrolytes (magnesium, sodium, 
potassium, chloride, bicarbonate) 
Coagulation 
PT, aPTT, INR 
Metabolic 
insulin, HbA1c, lipid panel (total cholesterol, LDL, HDL, triglycerides) 
Hormones 
11-DOC, 17-OHP, A, A4, ACTH, cortisol, DHEA, DHEAS, free T, P, renin, 
SHBG, total T 
Urinalysis 
appearance, bilirubin, color, glucose, ketones, microscopic examination of 
sediment, nitrite, occult blood, pH, protein, specific gravity, urobilinogen 
Other 
HBsAg, HCV, HIV, serum and urine pregnancy tests, urine drug screen, 
UFC (including total volume and total creatinine), salivary cortisol 
11-DOC, 11-deoxycorticosterone; 17-OHP, 17-hydroxyprogesterone; A, aldosterone; A4, androstenedione; 
ACTH, adrenocorticotropic hormone; aPTT, activated partial thromboplastic time; DHEA, 
dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate; HbA1c, hemoglobin A1c; HBsAg, 
hepatitis B surface antigen; HCV, hepatitis C virus; HDL-C, high-density lipoprotein cholesterol; HIV, human 
immunodeficiency virus; INR, international normalized ratio; LDL-C, low-density lipoprotein cholesterol; P, 
progesterone; PT, prothrombin time; SHBG, sex hormone binding globulin; T, testosterone; UFC, urinary free 
cortisol 


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6.10.1. 
Efficacy Assessments 
6.10.1.1. 24-Hour Urinary Free Cortisol 
24-hr urine collections for assessment of UFC will be performed using the standard procedure 
(see Laboratory Manual). If a urine collection is suspected to be incomplete, a repeat 24-hr UFC 
may be performed with approval of the Medical Monitor. 
Two collections will be done during the screening period, within 28 days prior to enrollment into 
the open-label dose-escalation period (Visit T1), and results reviewed for eligibility prior to 
enrollment. Subjects who require wash-out of medications should perform these collections 
AFTER wash-out. 
During the Open-Label Dose-Escalation Period of the study, subjects will begin a 24-hr urine 
collection on Days 13, 14, 27, 28, 41, 42, 50, 51, and 56. In addition, subjects in the Double-
Blind Randomized Withdrawal Period of the study will begin a 24-hr urine collection on Days 
64, 65, 79, and 84; and subjects in the Additional Open-Label Dosing Period of the study will 
begin a 24-hr urine collection on Days 69, 70, 79, and 84. The collections that occur within 2 
days before study visits should be brought to the corresponding study visit (along with any other 
samples that had not been previously submitted). For all other collections, when completed, a 
visiting nurse may assist with processing and shipping these 24-hr collections to the central 
laboratory, or the subject may submit them to the study site, per subject preference.  
The mean of the Day 50 and the Day 51 (“mean Day 50/51”) 24-hr UFC results will be used by 
the Investigator to determine whether the subject meets criteria for randomization. For subjects 
in the Double-Blind Randomized Withdrawal Period of the study, the mean of the Day 64 and 
the Day 65 (“mean Day 64/65”) 24-hr UFC results, if available at the time of Visit R2, will be 
used by the Investigator to determine whether the subject should undergo Visit R3 rather than 
Visit R2. The Day 79 result and the Day 84 result will be used to make the initial determinations 
of whether the subject’s follow-up visit should be conducted at the study site or via telephone.  
In addition, subjects whose Day 84 24-hr UFC is ≤ ULN will collect an additional 24-hr urine 
sample for UFC on Day 92. This result, if available at the time the Day 98 visit is due, will also 
be used to determine whether the subject’s follow-up visit should be conducted at the study site 
or via telephone.  
Subjects whose Day 92 24-hr UFC is ≤ ULN should continue to be followed up and have 
morning serum ACTH and 24-hr UFC assessed every 2-4 weeks until their 24-hr UFC is > ULN 
or until the Investigator and the Medical Monitor agree that the subject is stable. 
Further details on sample collection and handling are provided in the Laboratory Manual. 
6.10.1.2. Salivary Cortisol 
Two early morning (30-45 minutes after awakening for the day) and two late night (10 PM – 
12 AM; 22:00-00:00) saliva collections for salivary cortisol should be performed during the 
screening period within 28 days of enrollment into the open-label dose-escalation period and 
results reviewed for eligibility prior to enrollment. The two early morning collections should be 
done on different days from each other, as should the two late night collections. Subjects who 
require wash-out of medications should perform these collections AFTER wash-out.  


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During the Open-Label Dose-Escalation Period of the study, subjects will perform an early 
morning saliva collection and a late night saliva collection at home on Days 13, 14, 27, 28, 41, 
42, 50, 51, and 56. In addition, subjects in the Double-Blind Randomized Withdrawal Period of 
the study will perform an early morning saliva collection and a late night saliva collection at 
home on Days 64, 65, 79, and 84; and subjects in the Additional Open-Label Dosing Period of 
the study will perform an early morning saliva collection and a late night saliva collection at 
home on Days 69, 70, 79, and 84. The collections that occur within 2 days before study visits 
should be brought to the corresponding study visit. For all other collections, when completed, a 
visiting nurse may assist with processing and shipping these collections to the central laboratory, 
or the subject may submit them to the study site, per subject preference. All saliva samples will 
be submitted to the central laboratory for processing. 
Further details on sample collection and handling are provided in the Laboratory Manual. 
6.10.1.3. Blood Hormone Levels 
Levels of 11-DOC, 17-OHP, A, A4, ACTH, cortisol, DHEA, DHEAS, free T, P, renin, SHBG 
and total T will be measured at the central laboratory using validated methods at all study visits. 
Changes in hormone levels during the study will be used to assess the efficacy of ATR-101.  
Further details on sample collection and handling are provided in the Laboratory Manual. 
6.10.1.4. Glucose, Insulin and HbA1c 
Subjects need to be fasting after 10 PM (22:00; water and maintenance medications allowed) the 
evening prior to Visits S1, R1/A1, and R3/A3/ET to allow for determination of fasting glucose 
and fasting insulin levels. Fasting glucose, insulin and HbA1c will be measured at the central 
laboratory using validated methods for these visits and used for calculations of insulin 
sensitivity. Further details on sample collection and handling are provided in the Laboratory 
Manual. 
6.10.1.5. Lipid Panel 
Subjects need to be fasting after 10 PM (22:00; water and maintenance medications allowed) the 
evening prior to Visits S1, R1/A1, and R3/A3/ET to allow for collection of the fasting lipid 
panel. Fasting lipids (total cholesterol, LDL, HDL and triglycerides) will be measured at the 
central laboratory using validated methods for these study visits. Further details on sample 
collection and handling are provided in the Laboratory Manual.  
6.10.2. 
Pharmacokinetic Assessments 
Approximately 4 mL of blood will be drawn at each sampling time point: 


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Table 4: 
Pharmacokinetic Sampling Time Points 
Visit 
Sampling Time Points (Morning Dose Only) 
T1, T2, T3 
0 (within 30 min predose), 1 (± 5 min), 2 (± 10 min),  
3 (± 10 min) and 4 hr (± 10 min) 
R1, R2 
0 hr (trough, within 30 min predose) 
R3/ET 
0 hr 
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 hr post-dose 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 ATR-101 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 ATR-101 and its major metabolites as data permit and as 
appropriate: 


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Table 5: 
Pharmacokinetic Parameters 
Clast 
The last quantifiable drug concentration determined directly from individual 
concentration-time data 
Cmax 
The maximum drug concentration 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 concentration-time curve from time zero to the time of 
the last quantified concentration, calculated using the linear-up/log-down 
trapezoidal rule 
AUC0-4 
The area under the concentration-time curve from time zero to 4 h after 
dosing, calculated using the linear-up/log-down trapezoidal rule 
AUC0-4/D 
Dose-normalized AUC0-4, calculated as the ratio of AUC0-4 to dose 
λz 
The terminal phase rate constant, estimated by linear regression through the 
terminal phase of the log concentration-time profile 
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 AUC0-4 + Clast/λz 
AUC%extrap 
Percentage of AUC0-∞ extrapolated, represented as  
(1 - AUC0-t/AUC0-∞)*100 
CL/F 
Oral clearance calculated as: 
Dose/AUC0-∞ (Day 1 only) 
6.10.3. 
Pharmacodynamic Assessments 
The relationship between Cmax, AUC and other PK parameters with efficacy assessments 
(Section 6.10.1) will be explored as appropriate. 
6.10.4. 
Blood Sample Collection, Storage and Shipping  
Sample collection, storage and shipment procedures for clinical laboratory samples are provided 
in the Laboratory Manual. 
 


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7. 
STUDY ACTIVITIES 
During the study, blood samples for hormones should be collected between 6-10 AM (06:00-
10:00), as close to 8 AM (08:00) as practicable. Early morning saliva samples should be 
collected 30-45 minutes after awakening for the day. Late night saliva samples should be 
collected between 10 PM and 12 AM (22:00-00:00). Within this protocol, references to the study 
day of a 24-hr UFC collection mean that the collection was to have begun on that study day (e.g., 
a “Day 14” 24-hr UFC is one that was to have begun on Day 14 and completed on Day 15). All 
sample collections and study visits and procedures from Visit T1 to Visit R3/A3/ET have a 
window of + 2 days. All other sample collections, study visits, and procedures have a window of 
± 7 days. 
Study visit designations (S1, T1, etc.) are shown in the detailed schedule of study assessments 
presented in Appendix 1. 
7.1. 
Screening Visit, Visit S1 
The screening visit should be conducted within 56 days (8 weeks) prior to enrollment into the 
open-label dose-escalation period. The date of screening is considered to be the date that the first 
study-related screening assessment is performed. 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 number. 
• Contact the IVRS/IWRS to register the subject in the study  
• Obtain and record medical history, demographic data and prior and current medications. 
• Record vital signs, height and weight. 
• Perform a complete PE.  
• Obtain a 12-lead ECG.  
• Collect fasting blood samples for hematology, chemistry, PT, aPTT, INR, insulin, HbA1c, 
lipid panel, HBsAg, HCV, HIV, hormones (11-DOC, 17-OHP, A, A4, ACTH, cortisol, 
DHEA, DHEAS, free T, P, renin, SHBG and total T) and serum pregnancy test.  
− Note: Subjects who require wash-out of medications that affect cortisol levels should 
NOT have their hormone levels drawn at S1. Instead, they should complete the required 
wash-out and return to the site for hormone levels later during the screening period.  
− All blood hormone collections should be performed between 6-10 AM (06:00-10:00), as 
close to 8 AM (08:00) as practicable. 
− Subjects need to be in a seated position for at least 15 minutes prior to collection of blood 
hormone levels so that renin and aldosterone levels are stable.  
− If the subject is not fasting, proceed with the visit but mark the sample collection as being 
non-fasting. 


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• Collect a urine sample for urinalysis and urine drug screen. 
• Review all assessable inclusion and exclusion criteria. 
• Provide instructions to the subject regarding 24-hr urine samples and early morning (30-45 
minutes after awakening for the day) and late night (10 PM-12 AM; 22:00-00:00) saliva 
samples to be collected at home prior to the next visit.  
− During the screening period, subjects must perform two 24-hr urine collections, two early 
morning saliva collections and two late night saliva collections within 28 days prior to 
enrollment into the open-label dose-escalation period (Visit T1). The two early morning 
collections should be done on different days from each other, as should the two late night 
collections. These samples need to be submitted to the central laboratory for processing 
in time for results to be reviewed for eligibility prior to enrollment. 
− Per subject preference, these samples may be brought to the study site, or a visiting nurse 
may assist with processing the samples and shipping them to the central laboratory.  
− Subjects who require wash-out of medications should perform these collections AFTER 
wash-out.  
• Schedule the next study visit (Visit T1) so that the blood hormone sample collections for that 
visit will occur as close to 8 AM (08:00) as practicable and between 6-10 AM (06:00-10:00). 
7.2. 
Open-label Dose-escalation Period 
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria should be 
enrolled and enter the 8-week open-label dose-escalation period. During the open-label dose-
escalation period, subjects will take their assigned study drug and undergo assessments to 
evaluate efficacy, safety, tolerability and PK of study drug. At Visit T1, all subjects will initially 
be assigned to take ATR-101 250 mg BID. After 2 weeks, at Visit T2, all subjects will be 
assigned to take the next higher dose of ATR-101, 500 mg BID. After 2 additional weeks, at 
Visit T3, all subjects will be assigned to take the next higher dose of ATR-101, 1000 mg BID. At 
any time, the ATR-101 dose may be down-titrated as needed for safety reasons at the discretion 
of the Investigator. 
7.2.1. 
Visit T1 (Day 1) 
At Visit T1, appropriate study site personnel should: 
• Record adverse events and update medications. 
• Record vital signs and weight. 
• Perform a complete PE.  
• Collect a urine sample for urinalysis and, if the subject is a woman of childbearing potential, 
perform a urine pregnancy test (preferred; or submit a serum or urine sample to a laboratory 
for pregnancy testing if required by your institution/IRB/EC). 
• Review all inclusion and exclusion criteria to confirm that the subject is eligible for the 
study, including all 24-hr UFC and late night salivary cortisol levels collected within the past 
28 days. 


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• Review the mean of all 24-hr UFC levels obtained within the past 28 days to determine the 
subject’s 24-hr UFC stratum (1.3 to < 4 × ULN (Stratum I) or 4 to 10 × ULN (Stratum II)). 
• Please note that prior to enrolling the subject, regarding the laboratory values, only the Visit 
T1 pregnancy test (if applicable and if performed at the site), and the Visit S1 hematology, 
chemistry, PT, PTT, INR, HbA1c, lipid panel, serology, pregnancy test (if applicable), 
urinalysis, urine drug screen, 24-hr UFC, and salivary cortisol levels, need to be reviewed. 
The screening blood hormone levels are for baselining purposes and the results do not need 
to be available prior to the enrolling the subject. 
• Contact the IVRS/IWRS to confirm enrollment of the subject into the open-label dose-
escalation period and obtain study drug assignment.  
• Collect blood samples for hematology, chemistry, hormones (11-DOC, 17-OHP, A, A4, 
ACTH, cortisol, DHEA, DHEAS, free T, P, renin, SHBG and total T) and PK within 
30 minutes prior to administration of study drug. 
− All blood hormone collections should be performed between 6-10 AM (06:00-10:00), as 
close to 8 AM (08:00) as practicable. 
− Subjects need to be in a seated position for at least 15 minutes prior to collection of blood 
hormone levels so that renin and aldosterone levels are stable. 
• Dispense open-label study drug (ATR-101 250-mg tablets) and instruct the subject on self-
administration of study drug orally with food BID. 
• Have the subject eat breakfast. 
• 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 1, 2, 3 and 4 hrs after administration of study drug. Record the 
exact time of each PK sample collection. 
• Provide instructions to the subject regarding 24-hr urine samples and saliva samples to be 
collected at home prior to the next visit (Section 7.2.2). 
• Schedule the next study visit (Visit T2) so that the blood hormone sample collections for that 
visit will occur as close to 8 AM (08:00) as practicable and between 6-10 AM (06:00-10:00).  
• Remind the subjects that they will need to record the approximate time of their evening study 
drug dose prior to their next visit.  
• Remind the subjects that on the morning of their next visit, they should wait to take their 
morning dose of study drug until directed by site personnel at the study site, and they will 
need to bring the 24-hr urine and saliva samples collected on or prior to Day 14 to the study 
site. 
7.2.2. 
Between Visits T1 and T2, Between Visits T2 and T3 and Between Visits T3 and 
R1/A1 
On Days 13, 14, 27, 28, 41, 42, 50, 51, and 56 during the open-label dose-escalation period, 
subjects should: 
 


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• Collect an early morning saliva sample. 
• Collect a late night saliva sample. 
• Begin a 24-hr urine collection. 
In addition, at the indicated study days during the open-label dose-escalation period, subjects 
should: 
• Days 14, 28 and 56 (the day prior to Visits T2, T3 and R1/A1, respectively): Record the 
approximate time of the evening study drug dose.  
• Days 15, 29, and 57 (the day of Visits T2, T3, and R1/A1, respectively): Take any collected 
saliva samples and 24-hr urine samples (i.e., the Day 13/14, 27/28, and 56 saliva samples and 
24-hr urine samples, respectively; and any other saliva samples and urine samples that were 
not previously submitted) to the study site. 
• Days 43 and 52: Take the 24-hr urine collection and any collected saliva samples to the study 
site, or a visiting nurse will assist with processing the samples and shipping them to the 
central laboratory, per subject preference. 
• Day 56 (the evening prior to Visit R1): Fast after 10 PM (22:00; water and maintenance 
medications allowed). 
7.2.3. 
Visit T2 (Day 15) 
At Visit T2, appropriate study site personnel should: 
 
• Receive the Day 13 and Day 14 saliva collections and 24-hr urine collections from the 
subject and submit these to the central laboratory for analysis. 
• Record adverse events and update medications. 
• Record vital signs and weight. 
• Perform a brief PE, with particular attention to assessing the subject for possible adrenal 
insufficiency.  
• Collect blood samples for hematology, chemistry, hormones (11-DOC, 17-OHP, A, A4, 
ACTH, cortisol, DHEA, DHEAS, free T, P, renin, SHBG and total T) and PK within 30 
minutes prior to administration of study drug. 
− All blood hormone collections should be performed between 6-10 AM (06:00-10:00), as 
close to 8 AM (08:00) as practicable. 
− Subjects need to be in a seated position for at least 15 minutes prior to collection of blood 
hormone levels so that renin and aldosterone levels are stable. 
• If the subject is a woman of childbearing potential, collect a urine sample and perform a 
urine pregnancy test (preferred; or submit a serum or urine sample to a laboratory for 
pregnancy testing if required by your institution/IRB/EC). 
• Record the date and time of the subject’s last previous study drug dose (expected to have 
occurred the evening prior to the visit). 


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• Collect study drug and assess compliance. 
• Contact IVRS/IWRS to obtain study drug assignment. 
• Dispense open-label study drug (ATR-101 500-mg tablets) and instruct the subject on self-
administration of study drug orally with food BID. 
• Have the subject eat breakfast. 
• 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 1, 2, 3 and 4 hrs after administration of study drug. Record the 
exact time of each PK sample collection. 
• Provide instructions to the subject regarding 24-hr urine samples and saliva samples to be 
collected at home prior to the next visit (Section 7.2.2). 
• Schedule the next study visit (Visit T3) so that the blood hormone sample collections for that 
visit will occur as close to 8 AM (08:00) as practicable and between 6-10 AM (06:00-10:00).  
• Remind the subjects that they will need to record the approximate time of their evening study 
drug dose prior to their next visit. 
• Remind the subjects that on the morning of their next visit, they should wait to take their 
morning dose of study drug until directed by site personnel at the study site, and that they 
will need to bring the 24-hr urine and saliva samples collected on or prior to Day 28 to the 
study site. 
7.2.4. 
Visit T3 (Day 29) 
At Visit T3, appropriate study site personnel should: 
 
• Receive the Day 27 and Day 28 saliva collections and 24-hr urine collections (and any other 
collections that were not previously submitted) from the subject and submit these to the 
central laboratory for analysis. 
• Record adverse events and update medications. 
• Record vital signs and weight. 
• Perform a brief PE, with particular attention to assessing the subject for possible adrenal 
insufficiency.  
• Collect blood samples for hematology, chemistry, hormones (11-DOC, 17-OHP, A, A4, 
ACTH, cortisol, DHEA, DHEAS, free T, P, renin, SHBG and total T) and PK within 30 
minutes prior to administration of study drug. 
− All blood hormone collections should be performed between 6-10 AM (06:00-10:00), as 
close to 8 AM (08:00) as practicable. 
− Subjects need to be in a seated position for at least 15 minutes prior to collection of blood 
hormone levels so that renin and aldosterone levels are stable. 


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• If the subject is a woman of childbearing potential, collect a urine sample and perform a 
urine pregnancy test (preferred; or submit a serum or urine sample to a laboratory for 
pregnancy testing if required by your institution/IRB/EC). 
• Record the date and time of the subject’s last previous study drug dose (expected to have 
occurred the evening prior to the visit). 
• Collect study drug and assess compliance. 
• Contact IVRS/IWRS to obtain study drug assignment. 
• Dispense open-label study drug and instruct the subject on self-administration of study drug 
orally with food BID. 
• Have the subject eat breakfast. 
• 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 1, 2, 3 and 4 hrs after administration of study drug. Record the 
exact time of each PK sample collection. 
• Provide instructions to the subject regarding 24-hr urine samples and saliva samples to be 
collected at home prior to the next visit (Section 7.2.2). 
• Schedule the next study visit (Visit R1/A1) so that the blood hormone sample collections for 
that visit will occur as close to 8 AM (08:00) as practicable and between 6-10 AM (06:00-
10:00).  
• Remind the subjects that the evening prior to their next visit, they need to be fasting after 10 
PM (22:00; water and maintenance medications allowed) and they will need to record the 
approximate time of their evening study drug dose.  
• Remind the subjects that on the morning of their next visit, they should wait to take their 
morning dose of study drug until directed by site personnel at the study site, and that they 
will need to bring the 24-hr urine and saliva samples collected on or prior to Day 56 to the 
study site (if not previously submitted). 
7.2.5. 
Telephone Visit Between Visits T3 and R1/A1 (Day 43) 
At the Day 43 telephone visit, appropriate study site personnel should:  
• Contact the subject by telephone. 
• Record adverse events, with particular attention to assessing the subject for possible adrenal 
insufficiency, and update medications. 
• Remind the subjects that on the morning of their next visit, they should wait to take their 
morning dose of study drug until directed by site personnel at the study site, and that they 
will need to bring the 24-hr urine and saliva samples collected on or prior to Day 56 to the 
study site (if not previously submitted). 


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7.3. 
Double-blind Randomized Withdrawal Period 
Subjects whose mean Day 50/51 24-hr UFC level is ≤ ULN or ≤ 50% of their baseline value are 
eligible to enter the 4-week double-blind randomized withdrawal period. (Subjects who do not 
meet either of these randomization criteria will instead enter an additional 4-week open-label 
dosing period, described in Section 7.4.) Subjects entering the randomized withdrawal period 
will be randomized in a 1:1 ratio either to continue to receive ATR-101 at the dose at which they 
achieved mean Day 50/51 24-hr UFC ≤ ULN or ≤ 50% of their baseline value (expected to be 
1000 mg BID), or matching placebo. Randomization will be stratified by baseline 24-hr UFC 
level (calculated as the mean of all 24-hr UFC levels obtained within the 28 days prior to 
enrollment into the open-label dose-escalation period). Subjects’ 24-hr UFC levels will be 
followed during this period to determine the efficacy of ATR-101 in maintaining lowered levels 
compared to placebo. 
During the double-blind randomized withdrawal period, the Investigator should assess the mean 
Day 64/65 24-hr UFC result as soon as possible to determine whether the subject meets criteria 
for study completion. Subjects are considered to have completed the study during the double-
blind randomized withdrawal period when their mean Day 64/65 24-hr UFC level is > 1.3 x 
ULN and has also increased by > 50% relative to their mean Day 50/51 24-hr UFC level, or if 
they reach Visit R3 without meeting these criteria. When subjects are found to have completed 
the study, they should return to the study site immediately for Visit R3. 
7.3.1. 
Visit R1 (Day 57) 
Prior to Visit R1, the Investigator should review the baseline 24-hr UFC level (calculated as the 
mean of all 24-hr UFC levels obtained within the 28 days prior to enrollment into the open-label 
dose-escalation period) and compare it to the mean Day 50/51 24-hr UFC result to determine 
whether the subject meets criteria to enter the double-blind randomized withdrawal period of the 
study (the subject is eligible if the mean Day 50/51 24-hr UFC is ≤ ULN or ≤ 50% of the 
baseline value). If the subject does not meet criteria to enter the double-blind randomized 
withdrawal period, the subject should instead enter an additional 4-week open-label dosing 
period, described in Section 7.4.  
At Visit R1, appropriate study site personnel should: 
• Receive the Day 56 saliva collections and 24-hr urine collection (and any other collections 
that were not previously submitted) from the subject and submit these to the central 
laboratory for analysis. 
• Record adverse events and update medications. 
• Record vital signs and weight. 
• Perform a complete PE. 
• Obtain a 12-lead ECG.  
• Collect fasting blood samples for hematology, chemistry, PT, aPTT, INR, insulin, HbA1c, 
lipid panel, hormones (11-DOC, 17-OHP, A, A4, ACTH, cortisol, DHEA, DHEAS, free T, 
P, renin, SHBG and total T) and PK within 30 minutes prior to administration of study drug. 


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− All blood hormone collections should be performed between 6-10 AM (06:00-10:00), as 
close to 8 AM (08:00) as practicable. 
− Subjects need to be in a seated position for at least 15 minutes prior to collection of blood 
hormone levels so that renin and aldosterone levels are stable. 
− If the subject is not fasting, proceed with the visit but mark the sample collection as being 
non-fasting. 
• Collect a urine sample for urinalysis and, if the subject is a woman of childbearing potential, 
perform a urine pregnancy test (preferred; or submit a serum or urine sample to a laboratory 
for pregnancy testing if required by your institution/IRB/EC). 
• Record the date and time of the subject’s last previous study drug dose (expected to have 
occurred the evening prior to the visit). 
• Collect study drug and assess compliance. 
• Confirm that the subject meets criteria for randomization into the double-blind randomized 
withdrawal period of the study. If not, enroll the subject into the additional open-label dosing 
period of the study, described in Section 7.4. 
• Contact IVRS/IWRS to randomize the subject into the double-blind randomized withdrawal 
period and obtain study drug assignment. 
• Dispense blinded study drug and instruct the subject on self-administration of study drug 
orally with food BID. 
• Have the subject eat breakfast. 
• 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. 
• Provide instructions to the subject regarding 24-hr urine samples and saliva samples to be 
collected at home prior to the next visit (Section 7.3.2). 
• Schedule the next study visit (Visit R2) so that the blood hormone sample collections for that 
visit will occur as close to 8 AM (08:00) as practicable and between 6-10 AM (06:00-10:00).  
• Remind the subjects that they will need to record the approximate time of their evening study 
drug dose prior to their next visit.  
• Remind the subjects that on the morning of their next visit, they should wait to take their 
morning dose of study drug until directed by site personnel at the study site. 
7.3.2. 
Between Visits R1 and R2 and Between Visits R2 and R3/ET 
On Days 64, 65, 79, and 84 during the double-blind randomized withdrawal period, subjects 
should: 
 
• Collect an early morning saliva sample. 
• Collect a late night saliva sample. 
• Begin a 24-hr urine collection. 


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In addition, at the indicated study days during the double-blind randomized withdrawal period, 
subjects should: 
• Days 66 and 80: Take the 24-hr urine collections and any collected saliva samples to the 
study site, or a visiting nurse will assist with processing the samples and shipping them to the 
central laboratory, per subject preference. 
• Days 70 and 84 (the day prior to Visits R2 and R3/ET, respectively): Record the approximate 
time of the evening study drug dose. 
• Day 85 (the day of Visit R3/ET): Take the Day 84 24-hr urine collection and any collected 
saliva samples (i.e., the Day 84 samples, and any other samples that were not previously 
submitted) to the study site. 
• Day 84 (the evening prior to Visit R3/ET): Fast after 10 PM (22:00; water and maintenance 
medications allowed). 
7.3.3. 
Visit R2 (Day 71) 
At the time of Visit R2, if the Day 64 and Day 65 24-hr UFC results are available, the 
Investigator should assess the mean to determine whether the subject meets criteria for study 
completion. Subjects are considered to have met criteria for completing the study when their 
mean Day 64/65 24-hr UFC level is > 1.3 x ULN and has also increased by > 50% relative to 
their Day 50/51 24-hr UFC level, or if they reach Visit R3 without meeting these criteria. If 
subjects are found to have met criteria for completing the study, their next study visit should be 
Visit R3, rather than Visit R2.  
At Visit R2, appropriate study site personnel should: 
• Record adverse events and update medications. 
• Record vital signs and weight. 
• Perform a brief PE, with particular attention to assessing the subject for adrenal 
insufficiency. 
• Collect blood samples for hematology, chemistry, hormones (11-DOC, 17-OHP, A, A4, 
ACTH, cortisol, DHEA, DHEAS, free T, P, renin, SHBG and total T) and PK within 30 
minutes prior to administration of study drug. 
− All blood hormone collections should be performed between 6-10 AM (06:00-10:00), as 
close to 8 AM (08:00) as practicable. 
− Subjects need to be in a seated position for at least 15 minutes prior to collection of blood 
hormone levels so that renin and aldosterone levels are stable. 
• If the subject is a woman of childbearing potential, collect a urine sample and perform a 
urine pregnancy test (preferred; or submit a serum or urine sample to a laboratory for 
pregnancy testing if required by your institution/IRB/EC). 
• Record the date and time of the subject’s last previous study drug dose (expected to have 
occurred the evening prior to the visit). 
• Collect study drug and assess compliance. 


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• Contact IVRS/IWRS to obtain study drug assignment.  
• Dispense blinded study drug and instruct the subject on self-administration of study drug 
orally with food BID. 
• Have the subject eat breakfast. 
• 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. 
• Provide instructions regarding 24-hr urine samples and saliva samples to be collected at 
home prior to the next visit (Section 7.3.2). 
• Schedule the next study visit (Visit R3) so that blood hormone sample collections for that 
visit will occur as close to 8 AM (08:00) as practicable and between 6-10 AM (06:00-10:00).  
• Remind the subjects that the evening prior to their next visit, they need to be fasting after 10 
PM (22:00; water and maintenance medications allowed) and they will need to record the 
approximate time of their evening study drug dose.  
• Remind the subjects that on the morning of their next visit, they should not take any study 
drug, and that they will need to bring the 24-hr urine and saliva samples collected on or prior 
to Day 84 to the study site (if not previously submitted). 
7.3.4. 
Visit R3 (Day 85; End-of-Treatment)/Early Termination 
At Visit R3 (EoT)/ET, appropriate study site personnel should: 
• Receive the Day 84 saliva collections and 24-hr urine collection (and any other collections 
that were not previously submitted) from the subject and submit these to the central 
laboratory for analysis.  
• Record adverse events and update medications. 
• Record vital signs and weight. 
• Perform a complete PE.  
• Obtain a 12-lead ECG.  
• Collect fasting blood samples for hematology, chemistry, PT, aPTT, INR, insulin, HbA1c, 
lipid panel, hormones (11-DOC, 17-OHP, A, A4, ACTH, cortisol, DHEA, DHEAS, free T, 
P, renin, SHBG and total T) and PK. 
− All blood hormone collections should be performed between 6-10 AM (06:00-10:00), as 
close to 8 AM (08:00) as practicable. 
− Subjects need to be in a seated position for at least 15 minutes prior to collection of blood 
hormone levels so that renin and aldosterone levels are stable. 
− If the subject is not fasting, proceed with the visit but mark the sample collection as being 
non-fasting. 


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• Collect a urine sample for urinalysis and, if the subject is a woman of childbearing potential, 
perform a urine pregnancy test (preferred; or submit a serum or urine sample to a laboratory 
for pregnancy testing if required by your institution/IRB/EC). 
• Record the date and time of the subject’s last previous study drug dose (expected to have 
occurred the evening prior to the visit). 
• Collect study drug and assess compliance. 
• If the subject’s most recent available 24-hr UFC result is ≤ ULN, then: 
− A Day 92 24-hr UFC may or may not be needed. Provide instructions regarding a 24-hr 
urine sample to be collected at home starting in 7 days (Day 92 or R3/ET+7) (Section 
7.5.1). If the Day 84 24-hr UFC result is > ULN, inform the subject that they will not 
need to collect this sample. 
− Schedule the next study visit (Visit F1). 
• If the subject’s most recent 24-hr UFC is > ULN, follow up with the subject via telephone in 
13 days to assess for new AEs. Subjects who have ongoing AEs should be followed up as 
appropriate. After completing Visit R3/ET, subjects whose most recent 24-hr UFC is > ULN 
may begin treatment with another agent for Cushing’s syndrome at the discretion of their 
physicians.  
7.4. 
Additional Open-Label Dosing Period 
Subjects whose mean Day 50/51 24-hr UFC level does NOT meet randomization criteria (i.e., it 
is NOT either ≤ ULN or ≤ 50% of their baseline value) are eligible to enter the 4-week additional 
open-label dosing period. (Subjects who DO meet either of these randomization criteria will 
instead enter the 4-week double-blind randomized withdrawal period, described in Section 7.3.) 
Subjects entering the additional open-label dosing period will be assigned to take ATR-101 1000 
mg BID. Subjects’ 24-hr UFC levels will be followed during this period to determine the 
efficacy of a longer duration of dosing with ATR-101 in achieving lowered levels. 
7.4.1. 
Visit A1 (Day 57) 
At Visit A1, appropriate study site personnel should: 
• Receive the Day 56 saliva collections and 24-hr urine collection (and any other collections 
that were not previously submitted) from the subject and submit these to the central 
laboratory for analysis. 
• Record adverse events and update medications. 
• Record vital signs and weight. 
• Perform a complete PE. 
• Obtain a 12-lead ECG.  
• Collect fasting blood samples for hematology, chemistry, PT, aPTT, INR, insulin, HbA1c, 
lipid panel, hormones (11-DOC, 17-OHP, A, A4, ACTH, cortisol, DHEA, DHEAS, free T, 
P, renin, SHBG and total T) and PK within 30 minutes prior to administration of study drug. 


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− All blood hormone collections should be performed between 6-10 AM (06:00-10:00), as 
close to 8 AM (08:00) as practicable. 
− Subjects need to be in a seated position for at least 15 minutes prior to collection of blood 
hormone levels so that renin and aldosterone levels are stable. 
− If the subject is not fasting, proceed with the visit but mark the sample collection as being 
non-fasting. 
• Collect a urine sample for urinalysis and, if the subject is a woman of childbearing potential, 
perform a urine pregnancy test (preferred; or submit a serum or urine sample to a laboratory 
for pregnancy testing if required by your institution/IRB/EC). 
• Record the date and time of the subject’s last previous study drug dose (expected to have 
occurred the evening prior to the visit). 
• Collect study drug and assess compliance. 
• Confirm that the subject does NOT meet criteria for randomization into the double-blind 
randomized withdrawal period of the study. 
• Contact IVRS/IWRS to enroll the subject in the additional open-label dosing period and 
obtain study drug assignment. 
• Dispense open-label study drug and instruct the subject on self-administration of study drug 
orally with food BID. 
• Have the subject eat breakfast. 
• 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. 
• Provide instructions to the subject regarding 24-hr urine samples and saliva samples to be 
collected at home prior to the next visit (Section 7.4.2). 
• Schedule the next study visit (Visit A2) so that the blood hormone sample collections for that 
visit will occur as close to 8 AM (08:00) as practicable and between 6-10 AM (06:00-10:00).  
• Remind the subjects that they will need to record the approximate time of their evening study 
drug dose prior to their next visit.  
• Remind the subjects that on the morning of their next visit, they should wait to take their 
morning dose of study drug until directed by site personnel at the study site, and that they 
will need to bring the 24-hr urine and saliva samples collected on or prior to Day 70 to the 
study site (if not previously submitted). 
7.4.2. 
Between Visits A1 and A2 and Between Visits A2 and A3/ET 
On Days 69, 70, 79, and 84 during the additional open-label dosing period, subjects should: 
• Collect an early morning saliva sample. 
• Collect a late night saliva sample. 
• Begin a 24-hr urine collection. 


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In addition, at the indicated study days during the open-label dose-escalation period, subjects 
should: 
• Day 80: Take the 24-hr urine collection and any collected saliva samples to the study site, or 
a visiting nurse will assist with processing the samples and shipping them to the central 
laboratory, per subject preference. 
• Days 70 and 84 (the day prior to Visits A2 and A3/ET, respectively): Record the approximate 
time of the evening study drug dose. 
• Day 85 (the day of Visit A3/ET): Take the Day 84 24-hr urine collection and any collected 
saliva samples (i.e., the Day 84 samples, and any other samples that were not previously 
submitted) to the study site. 
• Day 84 (the evening prior to Visit A3/ET): Fast after 10 PM (22:00; water and maintenance 
medications allowed). 
7.4.3. 
Visit A2 (Day 71) 
At Visit A2, appropriate study site personnel should: 
• Receive the Day 69 and Day 70 saliva collections and 24-hr urine collections (and any other 
collections that were not previously submitted) from the subject and submit these to the 
central laboratory for analysis. 
• Record adverse events and update medications. 
• Record vital signs and weight. 
• Perform a brief PE, with particular attention to assessing the subject for adrenal 
insufficiency. 
• Collect blood samples for hematology, chemistry, hormones (11-DOC, 17-OHP, A, A4, 
ACTH, cortisol, DHEA, DHEAS, free T, P, renin, SHBG and total T) and PK within 30 
minutes prior to administration of study drug. 
− All blood hormone collections should be performed between 6-10 AM (06:00-10:00), as 
close to 8 AM (08:00) as practicable. 
− Subjects need to be in a seated position for at least 15 minutes prior to collection of blood 
hormone levels so that renin and aldosterone levels are stable. 
• If the subject is a woman of childbearing potential, collect a urine sample and perform a 
urine pregnancy test (preferred; or submit a serum or urine sample to a laboratory for 
pregnancy testing if required by your institution/IRB/EC). 
• Record the date and time of the subject’s last previous study drug dose (expected to have 
occurred the evening prior to the visit). 
• Collect study drug and assess compliance. 
• Contact IVRS/IWRS to obtain study drug assignment.  
• Dispense open-label study drug and instruct the subject on self-administration of study drug 
orally with food BID. 


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• Have the subject eat breakfast. 
• 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. 
• Provide instructions regarding 24-hr urine samples and saliva samples to be collected at 
home prior to the next visit (Section 7.4.2). 
• Schedule the next study visit (Visit A3) so that blood hormone sample collections for that 
visit will occur as close to 8 AM (08:00) as practicable and between 6-10 AM (06:00-10:00).  
• Remind the subjects that the evening prior to their next visit, they need to be fasting after 10 
PM (22:00; water and maintenance medications allowed) and they will need to record the 
approximate time of their evening study drug dose.  
• Remind the subjects that on the morning of their next visit, they should not take any study 
drug, and that they will need to bring the 24-hr urine and saliva samples collected on or prior 
to Day 84 to the study site (if not previously submitted). 
7.4.4. 
Visit A3 (Day 85; End-of-Treatment)/Early Termination 
At Visit A3 (EoT)/ET, appropriate study site personnel should: 
• Receive the Day 84 saliva collections and 24-hr urine collection (and any other collections 
that were not previously submitted) from the subject and submit these to the central 
laboratory for analysis.  
• Record adverse events and update medications. 
• Record vital signs and weight. 
• Perform a complete PE.  
• Obtain a 12-lead ECG.  
• Collect fasting blood samples for hematology, chemistry, PT, aPTT, INR, insulin, HbA1c, 
lipid panel, hormones (11-DOC, 17-OHP, A, A4, ACTH, cortisol, DHEA, DHEAS, free T, 
P, renin, SHBG and total T) and PK. 
− All blood hormone collections should be performed between 6-10 AM (06:00-10:00), as 
close to 8 AM (08:00) as practicable. 
− Subjects need to be in a seated position for at least 15 minutes prior to collection of blood 
hormone levels so that renin and aldosterone levels are stable. 
− If the subject is not fasting, proceed with the visit but mark the sample collection as being 
non-fasting. 
• Collect a urine sample for urinalysis and, if the subject is a woman of childbearing potential, 
perform a urine pregnancy test (preferred; or submit a serum or urine sample to a laboratory 
for pregnancy testing if required by your institution/IRB/EC). 
• Record the date and time of the subject’s last previous study drug dose (expected to have 
occurred the evening prior to the visit). 


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• Collect study drug and assess compliance. 
• If the subject’s most recent available 24-hr UFC result is ≤ ULN, then: 
− A Day 92 24-hr UFC may or may not be needed. Provide instructions regarding a 24-hr 
urine sample to be collected at home starting in 7 days (Day 92 or R3/ET+7) (Section 
7.5.1). If the Day 84 24-hr UFC result is > ULN, inform the subject that they will not 
need to collect this sample.  
− Schedule the next study visit (Visit F1). 
• If the subject’s most recent available 24-hr UFC result is > ULN, follow up with the subject 
via telephone in 13 days to assess for new AEs. Subjects who have ongoing AEs should be 
followed up as appropriate. After completing Visit A3/ET, subjects whose most recent 24-hr 
UFC is > ULN may begin treatment with another agent for Cushing’s syndrome at the 
discretion of their physicians.  
7.5. 
Follow-up Period 
During the follow-up period, the continued safety of the subjects after discontinuation of study 
drug will be assessed. 
7.5.1. 
Between Visits R3/A3/ET and F1 
At the indicated study days, subjects whose Day 84 24-hr UFC result was ≤ ULN should: 
• Day 92 (R3/ET+7): Begin a 24-hr urine collection. 
• Day 93 (R3/ET+8): Take the 24-hr urine collection to the study site, or a visiting nurse will 
assist with processing the sample and shipping it to the central laboratory, per subject 
preference. 
7.5.2. 
Follow-up, Visit F1 (End-of-Study (EoS); End of Trial) 
The target study day for the follow-up (EoS; end-of-trial) visit is 13 days after Visit R3/A3/ET. 
Only subjects whose most recent available 24-hr UFC is ≤ ULN need to have a follow-up visit at 
the study site. All other subjects should be followed up via telephone to assess for new AEs and 
concomitant medications. Subjects who have ongoing AEs should be followed up as appropriate. 
Subjects whose Day 92 24-hr UFC is ≤ ULN should continue to be followed up and have 
morning serum ACTH and 24-hr UFC assessed every 2-4 weeks until their 24-hr UFC is > ULN 
or until the Investigator and the Medical Monitor agree that the subject is stable. 
At Visit F1 (EoS; end of trial), appropriate study site personnel should: 
• Record adverse events and update medications. 
• Record vital signs and weight. 
• Perform a brief PE, with particular attention to assessing the subject for adrenal 
insufficiency. 
• Collect blood samples for hematology, chemistry and hormones (11-DOC, 17-OHP, A, A4, 
ACTH, cortisol, DHEA, DHEAS, free T, P, renin, SHBG and total T). 


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− All blood hormone collections should be performed between 6-10 AM (06:00-10:00), as 
close to 8 AM (08:00) as practicable. 
− Subjects need to be in a seated position for at least 15 minutes prior to collection of blood 
hormone levels so that renin and aldosterone levels are stable. 
• If the subject is a woman of childbearing potential, collect a urine sample and perform a 
urine pregnancy test (preferred; or submit a serum or urine sample to a laboratory for 
pregnancy testing if required by your institution/IRB/EC). 
• If the subject’s most recent available 24-hr UFC result is ≤ ULN, then: 
− Provide instructions regarding a 24-hr urine sample to be collected at home within 2-4 
weeks after the previous sample.  
− Schedule the next study visit (unscheduled follow-up). 
• At the completion of Visit F1 and all follow-ups, once the 24-hr UFC is > ULN, 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 Council 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. 
STATISTICS 
9.1. 
General Considerations  
A Statistical Analysis Plan that includes a more technical and detailed description of the planned 
statistical analyses will be prepared prior to unblinding of the double-blind randomized 
withdrawal period of the study. 
9.2. 
Sample Size 
A sample size of 16 enrolled patients in the open-label dose-escalation period is sufficient per 
clinical considerations. No formal sample size calculation was performed. 
9.3. 
Analysis Populations  
Efficacy – The primary efficacy analysis population will be the Intent-to-Treat (ITT) population, 
based on all subjects who are randomized to the double-blind randomized withdrawal period and 
take at least one dose of double-blind study drug. The modified ITT (mITT) population, based on 
all subjects who complete at least 2 weeks in the double-blind randomized withdrawal period of 
the study, will be used for additional analyses. For efficacy analyses, subjects will be included in 
the treatment group to which they were randomized. 
Safety – The safety population will include all treated subjects. Safety analyses will be based on 
the safety population. For the safety analyses for the double-blind randomized withdrawal 
period, subjects randomized to the placebo group who receive ATR-101 will be included in the 
treatment group of the active 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. 
9.4. 
Demographics and Baseline Characteristics 
Demographic and clinical characteristics of subjects enrolled onto 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. 
9.5. 
Treatment 
A frequency distribution will be generated for the dose levels administered. Any deviations to 
the dose-escalation criteria will also be noted.  
9.6. 
Efficacy 
9.6.1. 
Efficacy Endpoints 
9.6.1.1. 
Primary Efficacy Endpoint  
• The proportion of subjects with either a normal 24-hr UFC or a reduction in 24-hr UFC of  
≥ 50% relative to their baseline value at the end of the double-blind randomized withdrawal 
period 
9.6.1.2. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints will include the following. If the data allow, unless otherwise 
specified in the Statistical Analysis Plan, the endpoints will be evaluated for each post-baseline 


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visit, at the end of the open-label dose-escalation period and at the end of the double-blind 
randomized withdrawal period, for the ITT population as a whole and for each baseline UFC 
stratum.  
• The proportion of subjects with a normal 24-hr UFC at the end of the double-blind 
randomized withdrawal period 
• The proportion of subjects with a reduction in 24-hr UFC of ≥ 50% relative to their baseline 
value at the end of the double-blind randomized withdrawal period 
• The proportion of subjects with a normal 24-hr UFC at the end of the open-label dose-
escalation period and at the end of the additional open-label dosing period 
• The proportion of subjects with a reduction in 24-hr UFC of ≥ 50% relative to their baseline 
value at the end of the open-label dose-escalation period and at the end of the additional 
open-label dosing period 
• The change and percentage change in the 24-hr UFC from randomization at the end of the 
double-blind randomized withdrawal period  
• The change and percentage change in the 24-hr UFC from baseline at the end of the open-
label dose-escalation period and at the end of the additional open-label dosing period 
• The proportion of subjects with a normal late night salivary cortisol at the end of the double-
blind randomized withdrawal period 
• The proportion of subjects with a normal late night salivary cortisol at the end of the open-
label dose-escalation period and at the end of the additional open-label dosing period 
• The change and percentage change in the late night salivary cortisol from randomization at 
the end of the double-blind randomized withdrawal period 
• The change and percentage change in the late night salivary cortisol from baseline at the end 
of the open-label dose-escalation period and at the end of the additional open-label dosing 
period 
• The change and percentage change from baseline in blood hormone levels, including 11-
DOC, 17-OHP, A, A4, ACTH, cortisol, DHEA, DHEAS, free T, P, renin, SHBG and total T 
• The change from baseline in fasting glucose, insulin, lipid panel, systolic blood pressure, 
diastolic blood pressure and BMI 
9.6.2. 
Efficacy Analysis Methodology 
9.6.2.1. 
Primary Efficacy Endpoint  
The primary efficacy endpoint, the proportion of subjects with either a normal 24-hr UFC or a 
reduction in UFC of ≥ 50% relative to their baseline value at the end of the double-blind 
randomized withdrawal period, will be evaluated using the Cochran-Mantel-Haenszel (CMH) 
test, controlling for baseline 24-hr UFC stratum. 
Note: the baseline 24-hr UFC is calculated as the mean of all 24-hr UFC levels obtained within 
the 28 days prior to enrollment into the open-label dose-escalation period. 
9.6.2.2. 
Secondary Efficacy Endpoints 
No further adjustments for multiple group comparisons, multiple additional endpoints or multiple 
subgroups of interest are planned. 


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Responder analyses and other categorical analyses will be based on the CMH test or Fisher’s 
exact test, as appropriate and if the data allow. Continuous endpoints will be evaluated using 
ANCOVA or ANOVA model methodology, as appropriate and if the data allow. 
9.6.2.3. 
Exploratory Endpoints 
Additional efficacy endpoints may be pre-specified in the Statistical Analysis Plan, including 
sensitivity analyses associated with drug compliance and missing data issues. 
9.7. 
Safety 
9.7.1. 
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, PEs and 
ECG parameters. 
9.7.2. 
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. 
9.8. 
Pharmacokinetics and Pharmacodynamics 
9.8.1. 
Pharmacokinetic and Pharmacodynamic Endpoints 
• The Cmax, Tmax, AUC, t1/2 and other PK parameters of ATR-101 and its major metabolites (as 
appropriate and as the data allow) 
• The relationship between Cmax and AUC vs. the percentage change in 24-hr UFC; other 
PK/PD relationships may be explored as appropriate and as data allow 
9.8.2. 
Pharmacokinetic and Pharmacodynamic Analyses 
PK assessments will be performed at each dose level to determine ATR-101 exposures and to 
profile PK/PD relationships. PK assessments will include Cmax, AUC0-4 and trough levels. 
Individual subject PK data will be analyzed along with pooling of subjects’ data at each dose 
level. Individual PK parameters will be derived using the WinNonlin software, and table 
summaries will be provided using descriptive summary statistics. PK/PD analyses will be 
detailed in the Statistical Analysis Plan.  
9.9. 
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 Investigator in the Investigator 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. 
Please refer to Title 21 of the CFR, Part 50 – Protection of Human Subjects for specific details 
on this regulation. 


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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 
• 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 


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• 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, GCP guidelines of the ICH 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 
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 


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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 not planned for this study since all subjects will 
receive treatment with ATR-101 during the intra-subject dose-escalation period and the overall 
small size of the study generally limits the value of pooling data across the study population. All 
Investigators will have the ability to assess benefit:risk for each of their subjects in almost real 
time. The Medical Monitor and Sponsor will have access to safety and efficacy data from across 
the entire study population. The study design limits the duration of ATR-101 treatment and 
assesses safety every 2 weeks.  
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. 
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. 


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10.12. 
Retention of Records 
Copies of all study documents should be retained by the Investigator 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. 
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 


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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 
1. Nieman L, Biller B, Findling J, et al. The Diagnosis of Cushing’s Syndrome: An Endocrine 
Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008;93(5):1526-1540. 
2. Cuevas-Ramos D, Fleseriu M. Treatment of Cushing’s disease: a mechanistic update. 
Journal of Endocrinology 2014;223(2) R19-R39 
3. Arnaldi G, Angeli A, Atkinson AB, et al. Diagnosis and Complications of Cushing’s 
Syndrome: A Consensus Statement. Clin Endocrinol Metab 2003;88(12):5593-5602.  
4. Etxabe J, Vazquez J. Morbidity and mortality in Cushing’s disease: an epidemiological 
approach. Clin Endocrinol 1994;40(4);479-84.  
5. Graham B, Tucker W. Opportunistic infections in endogenous Cushing’s syndrome. Ann 
Intern Med 1984;101(3):334-8. 
6. Biller B, Grossman A, Stewart P, et al. Treatment of Adrenocorticotropin-Dependent 
Cushing’s Syndrome: A Consensus Statement. J Clin Endocrinol Metab 2008;93(7):2454-
2462. 
7. Nieman LK, Biller BMK, Findling JW, et al. Treatment of Cushing’s Syndrome: An 
Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2015;100(8):2807-
2831. 
8. Raturi A, Simmen T. Where the endoplasmic reticulum and the mitochondria tie the knot: the 
mitochondria-associated membrane (MAM). Biochim Biophys Acta 2013;1833:213-24. 
9. ATR-101 Investigator’s Brochure 
10. Dominick MA, McGuire EJ, Reindel JR, et al. Subacute toxicity of a novel inhibitor of 
acyl-CoA:cholesterol acyltransferase in beagle dogs. Fund Appl Toxicol 1993;20:217-24. 
11. Reindel JF, Dominick MA, Bocan TMA, et al. Toxicologic effects of a novel 
acyl-CoA:cholesterol acyltransfease inhibitor in cynomolgus monkeys. Toxicol Pathol 
1994;22:510-18. 
12. Bornstein SR, Allolio B, Wiebke A, et al. Diagnosis and Treatment of Primary Adrenal 
Insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 
2016 ;101 :364-89. 
13.  Rautaharju PM, Zhou SH, Wong S, et al. Sex differences in the evolution of the 
electrocardiographic QT interval with age. Can J Cardiol 1992;8:690-5. 


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12. 
APPENDICES 
 
 


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APPENDIX 1. STUDY SCHEDULE 
Table 6: 
Study Schedule, Screening and Open-Label Dose-Escalation Periods 
 
Screening 
Open-Label Dose-Escalation Period 
Study Day:† -56 to -1 
1 
13 
14 
15 
27 
28 
29 
41 
42 
43 
50 
51 
52 
56 
Visit:† 
S1 
T1 
 
 
T2 
 
 
T3 
 
 
tel 
 
 
 
 
Study Drug Dose:* 
None 
ATR-101  
250 mg BID 
ATR-101  
500 mg BID 
ATR-101  
1000 mg BID 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History & Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs, Height and Weighta 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
Physical Examinationb 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology & Chemistry 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
PT, aPTT, INR, Insulin, HbA1c, Lipidsc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology (HBsAg, HCV, HIV) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Hormone Levelsd 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
Plasma PKe 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
Serum/Urine Pregnancy Testf 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
Urinalysis/Urine Drug Screeng 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Begin 24-Hr Urine Collectionh 
XXh 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
Early Morning Salivary Cortisoli 
XXi 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
Late Night Salivary Cortisoli 
XXi 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
Submit Completed 24-Hr Urine Collections 
and Saliva Collections to Central Labh,i 
XXh,i 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Enrollment into Open-Label Dose- 
Escalation Period 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense Study Drug 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
Collect Study Drug/Assess Compliance 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
Prior and Concomitant Medications 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Adverse Eventsk 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Footnotes are located at the end of Appendix 1. 
 
 


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Table 7: 
Study Schedule, Double-Blind Randomized Withdrawal Period and Follow-Up Period 
 
Double-Blind Randomized Withdrawal Period 
Follow-Up Period 
Study Day:† 
57 
64 
65 
66 
71 
79 
80 
84 
85 
92^ 
93^ 
98^ 
Visit:† 
R1 
 
 
 
R2 
 
 
 
R3 
EoT/ 
ET 
 
 
F1 
EoS 
Study Drug Dose:* 
ATR-101 1000 mg BID or Placebo 
None 
Inclusion/Exclusion 
X§ 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs and Weight 
X 
 
 
 
X 
 
 
 
X 
 
 
X^ 
Physical Examinationb 
X 
 
 
 
X 
 
 
 
X 
 
 
X^ 
12-lead ECG 
X 
 
 
 
 
 
 
 
X 
 
 
 
Hematology & Chemistry 
X 
 
 
 
X 
 
 
 
X 
 
 
X^ 
PT, aPTT, INR, Insulin, HbA1c, Lipidsc 
X 
 
 
 
 
 
 
 
X 
 
 
 
Blood Hormone Levelsd 
X 
 
 
 
X 
 
 
 
X 
 
 
X^ 
Plasma PKe 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Serum/Urine Pregnancy Testf 
X 
 
 
 
X 
 
 
 
X 
 
 
X^ 
Urinalysis 
X 
 
 
 
 
 
 
 
X 
 
 
 
Begin 24-Hr Urine Collectionh 
 
X 
X 
 
 
X 
 
X 
 
X^ 
 
 
Early Morning Salivary Cortisoli 
 
X 
X 
 
 
X 
 
X 
 
 
 
 
Late Night Salivary Cortisoli 
 
X 
X 
 
 
X 
 
X 
 
 
 
 
Submit Completed 24-Hr Urine Collections and/or 
Saliva Collections to Central Labh,i 
X 
 
 
X 
 
 
X 
 
X 
 
X^ 
 
Dispense Study Drug 
X 
 
 
 
X 
 
 
 
 
 
 
 
Collect Study Drug/Assess Compliance 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Enrollment into Double-Blind Randomized 
Withdrawal Period 
X§ 
 
 
 
 
 
 
 
 
 
 
 
Study Completion Assessmentj 
 
 
 
 
X 
 
 
 
 
 
 
 
Prior and Concomitant Medications 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Adverse Eventsk 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Footnotes are located at the end of Appendix 1. 
 
 
 
 


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Table 8: 
Study Schedule, Additional Open-Label Dosing Period and Follow-Up Period 
 
Additional Open-Label Dosing Period 
Follow-Up Period 
Study Day:† 
57 
69 
70 
71 
79 
80 
84 
85 
92^ 
93^ 
98^ 
Visit:† 
A1 
 
 
A2 
 
 
 
A3 
EoT/ 
ET 
 
 
F1 
EoS 
Study Drug Dose:* 
ATR-101 1000 mg BID 
None 
Inclusion/Exclusion 
X§ 
 
 
 
 
 
 
 
 
 
 
Vital Signs and Weight 
X 
 
 
X 
 
 
 
X 
 
 
X^ 
Physical Examinationb 
X 
 
 
X 
 
 
 
X 
 
 
X^ 
12-lead ECG 
X 
 
 
 
 
 
 
X 
 
 
 
Hematology & Chemistry 
X 
 
 
X 
 
 
 
X 
 
 
X^ 
PT, aPTT, INR, Insulin, HbA1c, Lipidsc 
X 
 
 
 
 
 
 
X 
 
 
 
Blood Hormone Levelsd 
X 
 
 
X 
 
 
 
X 
 
 
X^ 
Plasma PKe 
X 
 
 
X 
 
 
 
X 
 
 
 
Serum/Urine Pregnancy Testf 
X 
 
 
X 
 
 
 
X 
 
 
X^ 
Urinalysis 
X 
 
 
 
 
 
 
X 
 
 
 
Begin 24-Hr Urine Collectionh 
 
X 
X 
 
X 
 
X 
 
X^ 
 
 
Early Morning Salivary Cortisoli 
 
X 
X 
 
X 
 
X 
 
 
 
 
Late Night Salivary Cortisoli 
 
X 
X 
 
X 
 
X 
 
 
 
 
Submit Completed 24-Hr Urine Collections and/or 
Saliva Collections to Central Labh,i 
X 
 
 
X 
 
X 
 
X 
 
X^ 
 
Dispense Study Drug 
X 
 
 
X 
 
 
 
 
 
 
 
Collect Study Drug/Assess Compliance 
X 
 
 
X 
 
 
 
X 
 
 
 
Enrollment into Additional Open-Label Dosing 
Period 
X§ 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medications 
X 
 
 
X 
 
 
 
X 
 
 
X 
Adverse Eventsk 
X 
 
 
X 
 
 
 
X 
 
 
X 
Footnotes are located at the end of Appendix 1. 
 
 
 
 
 


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†  Study assessments, procedures and visits from T1-R3/A3/ET have a window of + 2 days. All other study assessments, procedures and visits have a window of ± 7 days. Day 1 of 
the study is defined as the day the subject first receives study drug in the clinic. Subjects who are discontinued from the study should undergo an ET visit, which consists of the 
same procedures as R3/A3. Target study day numbers provided are for subjects who complete the full duration of the study.  
^ Subjects whose Day 84 24-hr UFC is ≤ ULN should collect a repeat 24-hr UFC starting 7 days after R3/A3/ET. If the repeat 24-hr UFC is also ≤ ULN, the subject should return 
for a follow-up visit at the study site 13 days after R3/A3/ET. Only subjects whose most recent 24-hr UFC is ≤ ULN need to have a follow-up visit at the study site. Such 
subjects should continue to be followed up and have morning serum ACTH and 24-hr UFC assessed every 2-4 weeks until their 24-hr UFC is > ULN or until the Investigator 
and the Medical Monitor agree that the subject is stable. All other subjects should be followed-up via a telephone call (instead of having a follow-up visit at the study site). 
* Subjects should take the evening dose of study drug with food the evening prior to study visits during the open-label intra-subject dose-escalation period, the double-blind 
randomized withdrawal period, and the additional open-label dosing period. On the morning of study visits (except S1, R3/A3/ET and F1), subjects should not take their study 
drug until directed by study site personnel. Subjects should document the time of their last study drug dose prior to each visit. 
§ Prior to randomization into the double-blind randomized withdrawal period or enrollment into the additional open-label dosing period, subjects should be evaluated for meeting 
randomization criteria. A subject is eligible to enter the double-blind randomization period if the mean Day 50/51 24-hr UFC is ≤ ULN or is ≤ 50% of the baseline value. 
Subjects whose mean Day 50/51 24-hr UFC does not meet either of these criteria are eligible to enter the additional open-label dosing period. 
 
a  Height at screening only. 
b  A complete physical examination (PE) will be performed at S1, T1, R1/A1 and R3/A3/ET. A brief PE will be performed at T2, T3, R2/A2 and F1, with particular attention to 
assessing the subjects for adrenal insufficiency. At all other visits, targeted PEs may be performed if needed based on adverse events and positives from review of systems. 
c  Subjects should be fasting after 10 PM (22:00; water and maintenance medications allowed) the evening prior to S1, R1/A1 and R3/A3/ET. 
d  Blood hormone levels to be assessed include 11-DOC, 17-OHP, A, A4, ACTH, cortisol, DHEA, DHEAS, free T, P, renin, SHBG and total T. All blood hormone levels should 
be drawn in the morning, as close to 8 AM (08:00) as practicable and between the hours of 6-10 AM (06:00-10:00). During the screening period, subjects who require a wash-
out of medications that affect cortisol levels should NOT have their hormone levels drawn until they have completed the required wash-out. 
e  At each study visit from T1 to R2/A2, a trough PK level will be collected within 30 minutes prior to dosing. At T1, T2, and T3, plasma for PK assessments will then be collected 
1, 2, 3 and 4 hours post-dose. At R3/A3/ET, a trough PK level will be collected (no study drug will be dosed).  
f  Pregnancy tests will be performed on female subjects of childbearing potential only. A serum pregnancy test will be performed at S1; a urine pregnancy test will be performed at 
all other visits unless otherwise required by the institution/IRB/EC. 
g  Urine drug screen at S1 only for cocaine, amphetamines and opioids.  
h  TWO 24-hr urine collections for UFC should be performed during the screening period within 28 days of enrollment into the open-label dose-escalation period and results 
reviewed for eligibility prior to enrollment. Subjects who require wash-out of medications should perform these collections AFTER wash-out. Subjects whose Day 84 24-hr 
UFC is ≤ ULN will perform a 24-hr urine collection on Day 92. A visiting nurse may assist with processing and shipping the Screening and Day 41, 42, 50, 51, 64 (if 
applicable), 65 (if applicable), 79, and 92 (if applicable) urine collections to the central laboratory; or the subject may submit these to the study site for shipping to the central 
laboratory, per subject preference (all other collections should be brought by the subject to the next visit at the study site).  
i  TWO early morning (30-45 minutes after awakening for the day) and TWO late night (10 PM - 12 AM; 22:00-00:00) saliva collections for salivary cortisol should be performed 
during the screening period within 28 days of enrollment into the open-label dose-escalation period and results reviewed for eligibility prior to enrollment. Subjects who require 
wash-out of medications should perform these collections AFTER wash-out. A visiting nurse may assist with processing and shipping the Screening and Day 41, 42, 50, 51, 64 
(if applicable), 65 (if applicable), and 79 saliva collections to the central laboratory; or the subject may submit these to the study site for shipping to the central laboratory, per 
subject preference (all other collections should be brought by the subject to the next visit at the study site).  
j   For subjects in the double-blind randomized withdrawal period, if the mean Day 64/65 24-hr UFC result is available prior to or at the time of R2, study completion assessment 
will be performed: if subjects are found to have met criteria for completing the study (i.e., 24-hr UFC is > 1.3 x ULN and has also increased by > 50% relative to the mean Day 
50/51 24-hr UFC), R3 will be conducted, rather than R2 (i.e., the subject will skip R2). If the mean Day 64/65 24-hr UFC does not meet criteria for completing the study, or the 
result is not available at the time of R2, the subject will proceed with R2. 
k  Adverse events will be collected from the time the subject signs the informed consent form until the last study visit or 30 days after the last dose of study drug, whichever is 
later. 


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11-DOC, 11-deoxycorticosterone; 17-OHP, 17-hydroxyprogesterone; A, aldosterone; A4, androstenedione; ACTH, adrenocorticotropic hormone; aPTT, activated partial 
thromboplastic time; demog, demographics; DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate; ECG, electrocardiogram; ET, Early Termination; excl, 
exclusion; HbA1c, hemoglobin A1c; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HIV, human immunodeficiency virus; incl, inclusion; INR, international 
normalized ratio; P, progesterone; PE, physical examination; PK, pharmacokinetic(s) (samples); PT, prothrombin time; SHBG, sex hormone binding globulin; T, testosterone; tel, 
telephone visit; UFC, urinary free cortisol; ULN, upper limit of normal 
 
 


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APPENDIX 2. DRUGS THAT PROLONG THE QT/QTC INTERVAL 
 
Appendix 2, List A. Drugs that prolong the QT interval 
 
 
Generic Name 
Brand Name 
Class/Clinical Use 
Comments 
Amiodarone 
Pacerone® 
Anti-arrhythmic/abnormal heart rhythm 
Females > Males,TdP risk 
regarded as low 
Arsenic trioxide 
Trisenox® 
Anti-cancer/leukemia 
 
Astemizole 
Hismanal® 
Antihistamine/allergic rhinitis 
No longer available in US 
Azithromycin 
Zithromax® 
Antibiotic/bacterial infection 
 
Bepridil 
Vascor® 
Anti-anginal/heart pain 
Females > Males 
Chloroquine 
Aralen® 
Anti-malarial/malaria infection 
 
Chlorpromazine 
Thorazine® 
Anti-psychotic/anti-emetic/schizophrenia/nausea 
 
Cisapride 
Propulsid® 
GI stimulant/heartburn 
No longer available in US  
Citalopram 
Celexa® 
Anti-depressant/depression 
 
Clarithromycin 
Biaxin® 
Antibiotic/bacterial infection 
 
Disopyramide 
Norpace® 
Anti-arrhythmic/abnormal heart rhythm 
Females > Males 
Dofetilide 
Tikosyn® 
Anti-arrhythmic/abnormal heart rhythm 
Females > Males 
Domperidone 
Motilium® 
Anti-nausea/nausea 
Not available in US  
Droperidol 
Inapsine® 
Sedative; anti-nausea/ anesthesia adjunct, nausea 
 
Erythromycin 
E.E.S.®  
Antibiotic; GI stimulant/bacterial infection; increase GI 
motility 
Females > Males 
Erythromycin 
Erythrocin® 
Antibiotic; GI stimulant/bacterial infection; increase GI 
motility 
Females > Males 
Escitalopram 
Cipralex® 
Antidepressant/major depression/anxiety disorders 
 
Escitalopram 
Lexapro® 
Antidepressant/major depression/anxiety disorders 
 
Flecainide 
Tambocor® 
Anti-arrhythmic/abnormal heart rhythm 
 
Halofantrine 
Halfan® 
Anti-malarial/malaria infection 
Females > Males 
Haloperidol 
Haldol® 
Anti-psychotic/schizophrenia, agitation 
TdP risk with IV 
administration or overdosage 
Ibutilide 
Corvert® 
Anti-arrhythmic/abnormal heart rhythm 
Females > Males 
Levomethadyl 
Orlaam® 
Opiate agonist/pain control, narcotic dependence 
Not available in US  
Mesoridazine 
Serentil® 
Anti-psychotic/schizophrenia 
 
Methadone 
Dolophine® 
Opiate agonist/pain control, narcotic dependence 
Females > Males 
Methadone 
Methadose® 
Opiate agonist/pain control, narcotic dependence 
Females > Males 
Moxifloxacin 
Avelox® 
Antibiotic/bacterial infection 
 
Pentamidine 
NebuPent® 
Anti-infective/pneumocystis pneumonia 
 Females > Males 
Pentamidine 
Pentam® 
Anti-infective/pneumocystis pneumonia 
 Females > Males 
Pimozide 
Orap® 
Anti-psychotic/Tourette's tics 
 Females > Males 
Probucol 
Lorelco® 
Antilipidemic/hypercholesterolemia 
No longer available in US  
Procainamide 
Pronestyl® 
Anti-arrhythmic/abnormal heart rhythm 
 
Procainamide 
Procan® 
Anti-arrhythmic/abnormal heart rhythm 
 
Quinidine 
Quinaglute® 
Anti-arrhythmic/abnormal heart rhythm 
Females > Males 
Quinidine 
Cardioquin® 
Anti-arrhythmic/abnormal heart rhythm 
Females > Males 
Sevoflurane 
Ulane® 
Anesthetic, general/anesthesia 
Label warning for patients with 
congenital long QT or patients 
taking QT-prolonging drugs 
Sevoflurane 
Sojourn® 
Anesthetic, general/anesthesia 
Label warning for patients with 
congenital long QT or patients 
taking QT-prolonging drugs 
Sotalol 
Betapace® 
Anti-arrhythmic/abnormal heart rhythm 
Females > Males 
Sparfloxacin 
Zagam® 
Antibiotic/bacterial infection 
No longer available in US  
Terfenadine 
Seldane® 
Antihistamine/allergic rhinitis 
No longer available in US  
Thioridazine 
Mellaril® 
Anti-psychotic/schizophrenia 
 
Vandetanib 
Caprelsa® 
Anti-cancer/thyroid cancer 
 


Product: ATR-101 
 
ATR-101-301 
Global Protocol Amendment 2 
 
14 March 2018 
Millendo Therapeutics, Inc. 
CONFIDENTIAL 
85 
Appendix 2, List B.  Drugs with conditional risk of QT prolongation 
Generic Name 
Brand Name 
Class/Clinical Use 
Comments 
Amisulpride 
Solian® and others 
Antipsychotic, atypical 
Risk of TdP with overdosage - not available in 
US 
Amitriptyline 
Elavil® 
Tricyclic antidepressant/depression 
Risk of TdP with overdosage 
Ciprofloxacin 
Cipro® 
Antibiotic/bacterial infection 
Drug interaction risk - metabolic inhibitor 
Clomipramine 
Anafranil® 
Tricyclic antidepressant/depression 
 
Desipramine 
Pertofrane® 
Tricyclic antidepressant/depression 
Risk of TdP with overdosage 
Diphenhydramine 
Benadryl® 
Antihistamine/allergic rhinitis, insomnia 
Risk of QT increase/TdP with overdosage 
Diphenhydramine 
Nytol® 
Antihistamine/allergic rhinitis, insomnia 
Risk of QT increase/TdP with overdosage 
Doxepin 
Sinequan® 
Tricyclic antidepressant/depression 
 
Fluconazole 
Diflucan® 
Anti-fungal/fungal infection 
Drug interaction risk metabolic inhibitor. Can 
also increase QT at high doses - 800 mg/day 
Fluoxetine 
Sarafem® 
Antidepressant/depression 
 
Fluoxetine 
Prozac® 
Antidepressant/depression 
 
Galantamine 
Reminyl® 
Cholinesterase inhibitor /dementia, 
Alzheimer's 
 
Imipramine 
Norfranil® 
Tricyclic antidepressant/depression 
Risk of TdP with overdosage 
Itraconazole 
Sporanox® 
Anti-fungal/fungal infection 
Drug interaction risk - metabolic inhibitor 
Ketoconazole 
Nizoral® 
Anti-fungal/fungal infection 
Prolongs QT & drug interaction risk – 
metabolic inhibitor 
Nortriptyline 
 Pamelor® 
Tricyclic antidepressant/depression 
 
Paroxetine 
Paxil® 
Antidepressant/depression 
 
Protriptyline 
Vivactil® 
Tricyclic antidepressant/depression 
 
Ritonavir 
Norvir® 
Protease inhibitor/HIV 
 
Sertraline 
Zoloft® 
Antidepressant/depression 
 
Solifenacin 
VESIcare® 
muscarinic receptor antagonist/treatment 
of overactive bladder 
 
Trazodone 
Desyrel® 
Antidepressant/depression, insomnia 
 
Trimethoprim-
Sulfa 
Septra® or 
Bactrim® 
Antibiotic/bacterial infection 
 
Trimipramine 
Surmontil® 
Tricyclic antidepressant/depression 
 
 
 
 


Product: ATR-101 
 
ATR-101-301 
Global Protocol Amendment 2 
 
14 March 2018 
Millendo Therapeutics, Inc. 
CONFIDENTIAL 
86 
Appendix 2, List C.   Drugs with possible risk of QT prolongation 
Generic Name 
Brand Name 
Class/Clinical Use 
Comments 
Alfuzosin 
Uroxatral® 
Alpha1-blocker/benign prostatic hyperplasia 
 
Amantadine 
Symmetrel® 
Dopaminergic/anti-viral/anti-infective/ 
Parkinson's disease 
 
Artenimol+piperaquine 
Eurartesim® 
Anti-malarial 
Not available in US 
Atazanavir 
Reyataz® 
Protease inhibitor/HIV 
 
Bedaquiline 
Sirturo® 
Anti-infective/Drug resistant tuberculosis 
Black box for QT 
Chloral hydrate 
Noctec® 
Sedative/sedation/insomnia 
 
Clozapine 
Clozaril® 
Anti-psychotic/schizophrenia 
 
Dolasetron 
Anzemet® 
Anti-nausea/nausea, vomiting 
 
Dronedarone 
Multaq® 
Anti-arrhythmic/atrial fibrillation 
 
Eribulin 
Halaven® 
Anti-cancer/metastatic breast neoplasias 
 
Famotidine 
Pepcid® 
H2-receptor antagonist/peptic ulcer/ GERD 
 
Felbamate 
Felbatrol® 
Anti-convulsant/seizure 
 
Fingolimod 
Gilenya® 
Immunosuppressant/multiple sclerosis 
 
Foscarnet 
Foscavir® 
Anti-viral/HIV infection 
 
Fosphenytoin 
Cerebyx® 
Anti-convulsant/seizure 
 
Gatifloxacin 
Tequin® 
Antibiotic/bacterial infection 
Oral/IV forms no longer 
available in US and Canada 
Gemifloxacin 
Factive® 
Antibiotic/bacterial infection 
 
Granisetron 
Kytril® 
Anti-nausea/nausea and vomiting 
 
Iloperidone 
Fanapt® 
Antipsychotic, atypical/schizophrenia 
 
Indapamide 
Lozol® 
Diuretic/stimulate urine & salt loss 
 
Isradipine 
Dynacirc® 
Anti-hypertensive/high blood pressure 
 
Lapatinib 
Tykerb® 
Anti-cancer/breast cancer, metastatic 
 
Lapatinib 
Tyverb® 
Anti-cancer/breast cancer, metastatic 
 
Levofloxacin 
Levaquin® 
Antibiotic/bacterial infection  
 
Lithium 
Lithobid® 
Anti-mania/bipolar disorder 
 
Lithium 
Eskalith® 
Anti-mania/bipolar disorder 
 
Mirtazapine 
Remeron 
Antidepressant  
 
Moexipril/HCTZ 
Uniretic® 
Anti-hypertensive/high blood pressure 
 
Nicardipine 
Cardene® 
Anti-hypertensive/high blood pressure 
 
Nilotinib 
Tasigna® 
Anti-cancer/leukemia 
 
Octreotide 
Sandostatin® 
Endocrine/acromegaly, carcinoid diarrhea 
 
Ofloxacin 
Floxin® 
Antibiotic/bacterial infection 
 
Olanzapine 
Zyprexa® 
Antipsychotic, atypical/schizophrenia, bipolar 
Combo with fluoxetine: 
Symbyax 
Ondansetron 
Zofran® 
Anti-emetic/nausea and vomiting 
 
Oxytocin 
Pitocin® 
Oxytocic/labor stimulation 
 
Paliperidone 
Invega® 
Antipsychotic, atypical/schizophrenia 
  
Perflutren lipid 
microspheres 
Definity® 
Imaging contrast agent/echocardiography 
 
Quetiapine 
Seroquel® 
Anti-psychotic/schizophrenia 
 
Ranolazine 
Ranexa® 
Anti-anginal/chronic angina 
 
Risperidone 
Risperdal® 
Anti-psychotic/schizophrenia 
 
Roxithromycin 
Rulide® 
Antibiotic/bacterial infection 
Not available in US 
Sertindole 
Serdolect® 
Antipsychotic, atypical/anxiety, schizophrenia 
Not available in US 
Sertindole 
Serlect® 
Antipsychotic, atypical/anxiety, schizophrenia 
Not available in US 
Sunitinib 
Sutent® 
Anti-cancer/RCC, GIST 
 
Tacrolimus 
Prograf® 
Immunosuppressant/ Immune suppression 
 
Tamoxifen 
Nolvadex® 
Anti-cancer/breast cancer 
 
Telithromycin 
Ketek® 
Antibiotic/bacterial infection 
 
Tizanidine 
Zanaflex® 
Muscle relaxant  
 
Vardenafil 
Levitra® 
phosphodiesterase inhibitor/ vasodilator 
 
Venlafaxine 
Effexor® 
Antidepressant/depression 
 
Voriconazole 
VFend® 
Anti-fungal/anti-fungal 
 
Ziprasidone 
Geodon® 
Anti-psychotic/schizophrenia 
 
 


Product: ATR-101 
 
ATR-101-301 
Global Protocol Amendment 2 
 
14 March 2018 
Millendo Therapeutics, Inc. 
CONFIDENTIAL 
87 
APPENDIX 3. DRUGS KNOWN TO INTERACT WITH CYP3A4 
SUBSTRATES: 3A4,5,7 
Macrolide Antibiotics: 
clarithromycin 
erythromycin (not 3A5) 
NOT azithromycin 
telithromycin 
Anti-arrhythmics: 
quinidine-OH (not3A5) 
Benzodiazepines: 
alprazolam 
diazepam-3OH 
midazolam 
triazolam 
Immune Modulators: 
cyclosporine 
tacrolimus (FK506) 
HIV Antivirals: 
indinavir 
nelfinavir 
ritonavir 
saquinavir 
Prokinetic: 
cisapride 
Antihistamines: 
astemizole 
chlorpheniramine 
terfenadine 
Calcium Channel Blockers: 
amlodipine 
diltiazem 
felodipine 
lercanidipine 
nifedipine2 
nisoldipine 
nitrendipine 
verapamil 
HMG CoA Reductase 
Inhibitors: 
atorvastatin 
cerivastatin 
lovastatin 
NOT pravastatin 
NOT rosuvastatin 
simvastatin 
Steroid 6beta-OH: 
estradiol 
hydrocortisone 
progesterone 
testosterone 
 
 
 
Miscellaneous: 
alfentanyl 
aprepitant 
aripiprazole 
buspirone 
cafergot 
caffeine 
cilostazol 
cocaine 
codeine 
dapsone 
dexamethasone 
dextromethorphan 
docetaxel 
domperidone 
eplerenone 
fentanyl 
finasteride 
gleevec 
haloperidol 
irinotecan 
LAAM 
lidocaine 
methadone 
nateglinide 
ondansetron 
pimozide 
propranolol 
quetiapine 
quinine 
risperidone 
rivaroxaban 
salmeterol 
sildenafil 
sirolimus 
tamoxifen 
taxol 
terfenadine 
trazodone 
vincristine 
zaleplon 
ziprasidone 
zolpidem 
 
INHIBITORS 3A4,5,7 
HIV Antivirals: 
indinavir 
nelfinavir 
ritonavir 
 
Antibiotics 
clarithromycin 
itraconazole 
ketoconazole 
nefazodone 
saquinavir 
telithromycin 
aprepitant 
erythromycin 
fluconazole 
 
Grapefruit juice 
 
Miscellaneous 
verapamil 
diltiazem 
cimetidine 
amiodarone 
NOT azithromycin 
chloramphenicol 
ciprofloxacin 
delaviridine 
diethyldithiocarbamate 
fluvoxamine 
gestodene 
imatinib 
mibefradil 
mifepristone 
norfloxacin 
norfluoxetine 
star fruit 
voriconazole 
 
 


Product: ATR-101 
 
ATR-101-301 
Global Protocol Amendment 2 
 
14 March 2018 
 
CONFIDENTIAL 
88 
 
 
Appendix 3. Drugs known to interact with CYP3A4, continued. 
 
INDUCERS 3A4,5,7 
HIV Antivirals: 
efavirenz 
nevirapine 
 
 
 
 
 
Miscellaneous 
barbiturates 
carbamazepine 
glucocorticoids 
modafinil 
oxcarbazepine 
phenobarbital 
 
 
phenytoin 
pioglitazone 
rifabutin 
rifampin 
St. John's wort 
troglitazone 
 
Adapted from © Cytochrome P450 Drug Interaction Table 
www.drug-interactions.com 
 
 
 


Product: ATR-101 
 
ATR-101-301 
Global Protocol Amendment 2 
 
14 March 2018 
Millendo Therapeutics, Inc. 
CONFIDENTIAL 
89 
APPENDIX 4. DRUGS THAT MAY INTERACT WITH P-
GLYCOPROTEIN 
Transporter  
MDR1/P-gp  
 
 Ofloxacin  
Inhib  
 Gene 
ABCB1  
 
 Pentazocine  
Inhib  
 Amiodarone  
S/Inhib  
 
 Prazosin  
Induc  
 Amitriptyline  
Inhib  
 
 Prochlorperazine  
Inhib  
 Amprenavir  
Induc  
 
 Progesterone  
Inhib/Induc  
 Astemizole  
Inhib  
 
 Propafenone  
Inhib  
 Atorvastatin  
S/Inhib  
 
 Propranolol  
S/Inhib  
 Boceprevir  
S/Inhib  
 
 Quercetin  
Induc  
 Bromocriptine  
Inhib  
 
 Quinidine  
S/Inhib  
 Carvedilol  
Inhib  
 
 Quinine  
Inhib  
 Chlorpromazine  
Inhib  
 
 Reserpine  
inhib  
 Clarithromycin  
Inhib  
 
 Retinoic acid  
Induc  
 Clotrimazole  
Induc  
 
 Rifampin  
S/Induc  
 Cyclosporine  
S/Inhib  
 
 Ritonavir  
S/inhib  
 Desipramine  
Inhib  
 
 Saquinavir  
S/Inhib  
 Dexverapamil  
Inhib  
 
 Simvastatin  
 S/Inhib 
 Diltiazem  
S/Inhib  
 
 St. John’s Wort  
Induc  
 Dipyridamole  
Inhib  
 
 Tacrolimus  
S/Inhib  
 Disulfiram  
Inhib  
 
 Tamoxifen  
Inhib  
 Doxepin  
Inhib  
 
 Telaprevir  
S/Inhib  
 Erythromycin  
S/Inhib  
 
 Temsirolimus  
S/Inhib  
 Fluphenazine  
Inhib  
 
 Testosterone  
Inhib  
 Glibenclamide  
Inhib  
 
 Trimipramine  
Inhib  
 Haloperidol  
Inhib  
 
 Vaspodar  
Inhib  
 Imipramine  
Inhib  
 
 Verapamil  
S/Inhib  
 Indinavir  
S/Induc  
 
Inhib = Inhibition;  
Induc = Induction;  
S = Substrate;  
MDR = multidrug resistance protein 
 
Source: Pharmacology Weekly 
http://www.pharmacologyweekly.com/content/
pages/medications-drugs-substrates-inhibitors-
inducers-efflux-transporter 
 Itraconazole  
S/Inhib  
 
 Ketoconazole  
Inhib  
 
 Lidocaine  
S/Inhib  
 
 Lovastatin  
S/Inhib  
 
 Maprotiline  
Inhib  
 
 Mefloquine  
Inhib  
 
 Meperidine  
Inhib  
 
 Methadone  
Inhib  
 
 Mibefradil  
Inhib  
 
 Midazolam  
Inhib  
 
 Mifepristone  
Inhib  
 
 Nelfinavir  
S/Induc  
 
 Nicardipine  
S/Inhib  
 
 Nifedipine  
Inhib  
 
 
 


Product: ATR-101 
 
ATR-101-301 
Global Protocol Amendment 2 
 
14 March 2018 
Millendo Therapeutics, Inc. 
CONFIDENTIAL 
90 
APPENDIX 5. 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.  
 


Product: ATR-101 
 
ATR-101-301 
Global Protocol Amendment 2 
 
14 March 2018 
Millendo Therapeutics, Inc. 
CONFIDENTIAL 
91 
APPENDIX 6. 
ENDOCRINE SOCIETY CLINICAL PRACTICE 
GUIDELINE ON THE DIAGNOSIS AND TREATMENT OF 
ADRENAL INSUFFICIENCY (INCLUDING 
HYPOALDOSTERONISM) 
 

SAP_001.pdf: 
 
 
 
 
DATA  ANALYSIS  PLAN 
 
Protocol Title: 
A Phase 2 Randomized, Double-Blind, Placebo-
Controlled Study of ATR-101 for the Treatment of 
Cushing’s Syndrome 
Protocol Number: 
ATR-101-301 
Current Protocol: 
Global Amendment 2 / 14-MAR-2019 
NCT Number: 
NCT03053271 
Product: 
Nevanimibe HCl (ATR-101) 
Phase of Study: 
2 
 
 
Sponsor: 
Millendo Therapeutics US, Inc. 
 
 
Data Analysis Plan 
V1.0 / 18-SEP-2019 
 
 
 
 
 


 
 
 
 
Protocol: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of ATR-101 for 
the Treatment of Cushing’s Syndrome 
Protocol Number: 
ATR-101-301 
Current Protocol: 
Global Amendment 2 / 14-MAR-2019 
DAP: 
V1.0 / 18-SEP-2019 
This Data Analysis Plan has been reviewed and approved by: 
 
 
 
 
 
 
Miriam Zangmeister, MS 
Project Statistician 
Medpace 
 
DD-MMM-YYYY 
 
 
 
 
 
 
Phillippa Miranda, MD 
Medical Director 
Medpace 
 
DD-MMM-YYYY 
 
 
 
 
 
 
Vivian Lin, MD 
Vice President, Clinical Development 
Millendo Therapeutics US, Inc. 
 
DD-MMM-YYYY 


Millendo Therapeutics, Inc. 
Protocol ATR-101-301 
Data Analysis Plan 
 
Page 3 of 54 
 
 
 
 
REVISION HISTORY 
Version 
Date 
Description of Changes 
1.0 
18-SEP-2019 
Original signed version 


Millendo Therapeutics, Inc. 
Protocol ATR-101-301 
Data Analysis Plan 
 
Page 4 of 54 
 
 
 
 
TABLE OF CONTENTS 
1 
Introduction ............................................................................................................................. 5 
1.1 
Subject Disposition .......................................................................................................... 5 
1.2 
Demographic and Baseline Characteristics ...................................................................... 5 
1.3 
24 Hour Urinary Free Cortisol ......................................................................................... 5 
1.4 
Pharmacokinetics ............................................................................................................. 5 
1.4.1 
Handling Missing Data or Concentration Below the Lower Limit of Quantification .. 6 
1.4.2 
Pharmacokinetic Parameters ......................................................................................... 6 
1.4.3 
Pharmacokinetic Summaries ........................................................................................ 7 
1.5 
Adverse Events ................................................................................................................. 7 
1.6 
Clinical Safety Laboratory Evaluations ........................................................................... 8 
2 
Tables ...................................................................................................................................... 9 
3 
Figures ................................................................................................................................... 21 
4 
Listings .................................................................................................................................. 24 


Millendo Therapeutics, Inc. 
Protocols MLE4901-101 
Data Analysis Plan 
 
Page 5 of 54 
 
1 
Introduction 
This purpose of this document is to provide specifications for the tables and listings to be 
provided for Millendo Therapeutics Protocol ATR-101-301. Information regarding the study 
objectives and procedures can be found in the Protocol. 
On August 12, 2019, Millendo Therapeutics elected to discontinue the ATR-101-301 study based 
on an analysis of the feasibility of patient recruitment and a reprioritization of resources. A total 
of 4 subjects entered the open-label dose-escalation period of the study, but no subjects entered 
the double-blind randomized withdrawal period prior to study discontinuation. The available data 
from subjects who participated in the study will be used for safety summaries, but no formal 
statistical analysis of safety data will be conducted. The efficacy parameter of 24-hour urinary 
free cortisol (24-hr UFC) will be summarized but formal statistical analysis will not be 
performed due to the limited data available.  
All available data will be listed. All summaries will be based on observed values only. 
1.1 
Subject Disposition 
Counts of subjects who screened, entered the open-label dose-escalation period (i.e. dosed), and 
entered the double-blind randomized withdrawal period (i.e. 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 in total. 
1.2 
Demographic and Baseline Characteristics 
Descriptive summaries of demographic and baseline characteristics will be presented for all 
dosed subjects. Baseline measurements refer to the last measurement prior to the first dose of 
study drug. 
Demographic and baseline characteristics include, but are not limited to: age at informed 
consent, sex, race, ethnicity, height at screening, baseline body weight, and baseline body mass 
index (BMI).  Continuous variables (age, height, weight, BMI) will be summarized by subject 
count, mean, standard deviation, median, minimum, and maximum. Categorical variables (race, 
sex, ethnicity) will be summarized by the number and percentage of subjects in the 
corresponding categories.  
1.3 
24 Hour Urinary Free Cortisol 
Descriptive summaries of 24-hr UFC will be presented for all dosed subjects by scheduled visit.  
1.4 
Pharmacokinetics 
Plasma PK samples will be collected to determine the concentrations of nevanimibe HCl (ATR-
101; hereafter, “nevanimibe”). Planned sampling time points are listed in the table below. No 
subjects entered the double-blind randomized withdrawal period, therefore PK samples are not 
available for R1 and R2. 
Visit 
Sampling Time Points (Morning Dose Only) 
T1 (Day 1, 250 mg BID),  
0 (within 30 min predose), 1 (± 5 min), 2 (± 10 min), 3 (± 


Millendo Therapeutics, Inc. 
Protocols MLE4901-101 
Data Analysis Plan 
 
Page 6 of 54 
 
Visit 
Sampling Time Points (Morning Dose Only) 
T2 (Day 15, 500 mg) BID, and 
T3 (Day 29, 1000 mg BID) 
10 min) and 4 hr (± 10 min) 
Early Termination 
0 hr 
 
The exact time of each sample collection will be recorded. If the exact time (measured from 
dosing) is outside of the collection window for nominal time points, the corresponding 
concentration will be excluded from concentration versus time descriptive statistical summaries 
and plots, but will still be used in the calculations of PK parameter estimates. 
1.4.1 Handling Missing Data or Concentration Below the Lower Limit of Quantification 
Concentrations below the limit of quantitation (BLQ) before the first measurable concentration 
in a profile will be assigned a value of zero. A single BLQ value between measurable 
concentrations in a profile will be set to missing in the derivation of PK parameters, statistical 
analyses, and the individual subject plots. BLQ values that occur after the last measurable 
concentration will also be set to missing in the derivation of PK parameters and in the individual 
subject plots. 
In cases of missing pre-dose at T1 visit, the missing concentrations will be assumed as zero. In 
cases of missing pre-dose on T2 or T3 visits, the minimum observed concentration during the 
dosing interval may be used as pre-dose concentration values. For other cases, the missing data 
will not be imputed. 
1.4.2 Pharmacokinetic Parameters 
The following PK parameters will be estimated at T1, T2, and T3 visits for nevanimibe as data 
permit and as appropriate. 
PK Parameter 
Definition 
Cmax 
The maximum drug concentration determined directly from individual 
concentration-time data 
Tmax 
The observed time to reach maximum concentration 
AUC0-t 
The area under the concentration-time curve from time zero to the time of the 
last quantified concentration  
AUC0-4 
The area under the concentration-time curve from time zero to 4 h after 
dosing 
λz 
The terminal phase rate constant, estimated by linear regression through the 
terminal phase of the log concentration-time profile 


Millendo Therapeutics, Inc. 
Protocols MLE4901-101 
Data Analysis Plan 
 
Page 7 of 54 
 
PK Parameter 
Definition 
t½ 
The terminal phase half-life, calculated as: t½ = ln(2) ÷ λz 
AUC0-∞ 
The area under the concentration versus time curve from time 0 to infinity 
(first dose only), calculated as AUC0-t + Clast/λz 
AUC%extrap 
Percentage of AUC0-∞ extrapolated, represented as (1 - AUC0-t/AUC0-∞)×100 
 
Plasma PK parameters will be calculated by standard non-compartmental analysis (NCA) for all 
dosed subjects with available data. The actual dosing and sampling time points will be used for 
evaluation of PK data. The linear up/log down method will be used in the computation of AUCs. 
The λz will not be presented for subjects who do not exhibit a terminal elimination phase in their 
concentration-time profiles. In order to estimate terminal elimination rate constant, λz, linear 
regression of concentration in logarithm scale versus time will be performed using at least 3 data 
points. Uniform weighting will be selected to perform the regression analysis to estimate λz. 
Generally, the constant λz will not be assigned if one of the following happens: 
1. Tmax is one of the 3 last data points, 
2. The regression coefficient (R-squared) is less than 0.80, 
3. The estimated elimination rate indicates a positive slope, or 
4. The terminal elimination phase is not linear (as appears in a semi-logarithmic scale) 
based on visual inspection. 
If the λz is not assigned, the values of associated PK parameters will not be calculated. In the 
cases where AUC%extrap exceeds 20%, the λz will be assigned but the λz and the corresponding 
λz-related PK parameters will be flagged and listed with an explanatory footnote. 
1.4.3 Pharmacokinetic Summaries 
Plasma concentrations of nevanimibe will be summarized by nevanimibe dose (250 mg, 500 mg, 
1000 mg) by time point, including plots in linear and semi-log scales. If the exact time (measured 
from dosing) is outside the collection window for the scheduled time point, the corresponding 
concentration is excluded from the summary of that time point. 
Individual concentrations at each nevanimibe dose level will be plotted in linear and semi-log 
scales. 
PK parameters at at each nevanimibe dose level will be summarized. 
1.5 
Adverse Events 
Adverse events (AEs) will be coded and classified by system organ class and preferred term 
using the Medical Dictionary for Regulatory Activities (MedDRA) version 18.0. All AEs, 


Millendo Therapeutics, Inc. 
Protocols MLE4901-101 
Data Analysis Plan 
 
Page 8 of 54 
 
regardless of relationship to study drug, should be collected beginning from the time the subject 
signs the study consent until the last study visit or 30 days after the last dose of study drug, 
whichever is later. (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. 
Treatment-emergent adverse events (TEAEs) will be defined as any adverse event beginning on 
or after the first dose date of study drug. AE subject counts will be provided for all dosed 
subjects in total and by treatment at AE onset (nevanimibe 250 mg, 500 mg, or 1000 mg). 
An overview with counts of events and subjects will be provided for the incidence of AEs in the 
following categories.  
• Any AE  
• Any TEAE 
• Maximum severity of TEAE  
• Any study drug related TEAE  
• Maximum severity of study drug related TEAE 
• Any serious AE (SAE)  
• AE leading to discontinuation from study drug 
The incidence of TEAEs will be summarized by treatment at onset and in total by system organ 
class and preferred term. The same summaries will be done for study drug related TEAEs.   
1.6 
Clinical Safety Laboratory Evaluations 
Shift tables from baseline to the worst post-dose value will be presented for ALT and AST 
(>1xULN to 3xULN, >3xULN to 5xULN, >5xULN) and alkaline phosphatase and total bilirubin 
(>1xULN to 1.5xULN, >1.5xULN to 2xULN, >2xULN). 
 


Millendo Therapeutics, Inc. 
Protocols MLE4901-101 
Data Analysis Plan 
 
Page 9 of 54 
 
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 Dosed Subjects 
Table 14.2.1.1 ............................................................................................................................... 13 
Summary of 24 hour Urinary Free Cortisol 
All Dosed Subjects 
Table 14.2.2.1 ............................................................................................................................... 14 
Summary of Pharmacokinetic Plasma Concentrations 
All Dosed Subjects 
Table 14.2.2.2 ............................................................................................................................... 15 
Pharmacokinetic Plasma Parameter Listing and Summary 
All Dosed Subjects 
Table 14.3.1.1 ............................................................................................................................... 16 
Overview of Adverse Events 
All Dosed Subjects 
Table 14.3.1.2 ............................................................................................................................... 17 
Summary of Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
All Dosed Subjects 
Table 14.3.1.3 ............................................................................................................................... 18 
Summary of Study Drug Related Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term 
All Dosed Subjects 
Table 14.3.3.1 ............................................................................................................................... 19 
Shift Table of ALT, AST, Alkaline Phosphatase, and Total Bilirubin 
All Dosed Subjects 


 
 
Millendo Therapeutics US, Inc. 
Protocol ATR-101-301                                                                                                       Page 1 of # 
Table 14.1.1.1 
Subject Disposition 
All Subjects 
______________________________________________________________________________________________________________________________________ 
 
                                                                     Total  
Category                                                             n   (%) 
______________________________________________________________________________________________________________________________________ 
 
Screened                                                            ##         
 
Entered Open-Label Dose-Escalation Period (i.e. Dosed)               4         
   Nevanimibe 250 mg BID                                             4 (###.#) 
   Nevanimibe 500 mg BID                                             4 (###.#) 
   Nevanimibe 1000 mg BID                                            3 (###.#) 
 
Entered Double-Blind Randomized Withdrawal Period                   ## (###.#) 
 
Completed the Study                                                 ## (###.#) 
 
Early termination                                                   ## (###.#) 
 
Primary reason for early termination: 
   XXXXXXXXXXXXXXXXXXXXXXXXXXXXXX                                   ## (###.#) 
   XXXXXXXXXXXXXXXXXXXXXXXXXXXXXX                                   ## (###.#) 
   XXXXXXXXXXXXXXXXXXXXXXXXXXXXXX                                   ## (###.#) 
   XXXXXXXXXXXXXXXXXXXXXXXXXXXXXX                                   ## (###.#) 
______________________________________________________________________________________________________________________________________ 
 
Percentages are calculated with the number of subjects that entered the open-label dose escalation period as the denominator. 
Note: Subject 103-001 received nevanimibe 250 mg BID, 250 mg BID, and 500 mg BID at T1, T2, and T3 visits, respectively, instead of 
the planned 250 mg BID, 500 mg BID, and 1000 mg BID doses. 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM 
 
<< Programming Note: Only reasons for withdrawal with total>0 will be displayed. Reasons will be sorted by descending total, then 
alphabetically. If reason of “other” occurs in the data, it will always appear last. >> 


 
 
Millendo Therapeutics US, Inc. 
Protocol ATR-101-301                                                                                                       Page 1 of 2 
Table 14.1.2.1 
Summary of Demographic and Baseline Characteristics 
All Dosed Subjects 
______________________________________________________________________________________________________________________________________ 
 
Characteristic                                                  Total 
  Category/Statistic                                            (N=#) 
______________________________________________________________________________________________________________________________________ 
 
Age at Informed Consent 
  n                                                              ##    
  Mean                                                           ##.#  
  Standard Deviation                                             ##.## 
  Median                                                         ##.#  
  Minimum                                                        ##    
  Maximum                                                        ##    
 
Sex, n (%) 
  Female                                                       ## (###.#) 
  Male                                                         ## (###.#) 
 
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                                                     ## (###.#) 
______________________________________________________________________________________________________________________________________ 
 
Baseline is defined as the last measurement prior to the first dose of study drug. 
%=100*n/N where n is the number of subjects in the specified category and N is the number of dosed subjects. 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM 


 
 
Millendo Therapeutics US, Inc. 
Protocol ATR-101-301                                                                                                       Page 2 of 2 
Table 14.1.2.1 
Summary of Demographic and Baseline Characteristics 
All Dosed Subjects 
______________________________________________________________________________________________________________________________________ 
 
Characteristic                                               Total 
  Category/Statistic                                         (N=#) 
______________________________________________________________________________________________________________________________________ 
 
Height at Screening (cm) 
  n                                                          ##    
  Mean                                                       ##.## 
  Standard Deviation                                         ##.### 
  Median                                                     ##.## 
  Minimum                                                    ##.# 
  Maximum                                                    ##.# 
 
Baseline Weight (kg) 
  n                                                          ##    
  Mean                                                       ##.## 
  Standard Deviation                                         ##.### 
  Median                                                     ##.## 
  Minimum                                                    ##.# 
  Maximum                                                    ##.# 
 
Baseline Body Mass index (kg/m2) 
  n                                                          ##    
  Mean                                                       ##.## 
  Standard Deviation                                         ##.### 
  Median                                                     ##.## 
  Minimum                                                    ##.# 
  Maximum                                                    ##.# 
______________________________________________________________________________________________________________________________________ 
 
Baseline is defined as the last measurement prior to the first dose of study drug.  
%=100*n/N where n is the number of subjects in the specified category and N is the number of dosed subjects. 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM 


 
 
Millendo Therapeutics US, Inc. 
Protocol ATR-101-301                                                                                                       Page 1 of 1 
Table 14.2.1.1 
Summary of 24 hour Urinary Free Cortisol 
All Dosed Subjects 
______________________________________________________________________________________________________________________________________ 
 
Parameter (Unit)                                                                              
   Statistic             Screening    T1         T2         T3         ET^                        
______________________________________________________________________________________________________________________________________ 
 
XXXXXXXXXX (XXXXX)           
   n                        4          4          4          4          2          
   Mean                    ##.##      ##.##      ##.##      ##.##      ##.##       
   Standard Deviation      ##.###     ##.###     ##.###     ##.###     ##.###      
   Median                  ##.##      ##.##      ##.##      ##.##      ##.##       
   Minimum                 ##.#       ##.#       ##.#       ##.#       ##.#        
   Maximum                 ##.#       ##.#       ##.#       ##.#       ##.#        
______________________________________________________________________________________________________________________________________ 
 
For Screening values, the screening collections 1 and 2 are averaged for each subject prior to summarization. The 24-hr UFC values 
shown are those collected after each of the indicated visits, and prior to the next visit, as follows: 
T1 = Open Label Dose Escalation Visit 1 
T2 = Open Label Dose Escalation Visit 2 
T3 = Open Label Dose Escalation Visit 3 
^ET = End of Treatment/Early Termination Visit. Subjects 103-001 and 201-003 (both enrolled under Global Protocol Amendment 1) had 24-
hr UFC summarized as occurring at ET. These collections began at Day 51 and Day 48, respectively. For 103-001, this was 8 days after 
last dose. For 201-003, it was the same day as last dose. 
For subject 112-001, who was enrolled under Global Protocol Amendment 2, collections 1 and 2 for each timepoint are averaged prior to 
summarization. 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM 
 
<< Programming Note: Source: LB.LBCAT = “24 HOUR URINE” and LBTEST = “Cortisol Excretion Rate, Free”. >> 
  


 
 
Millendo Therapeutics US, Inc. 
Protocol ATR-101-301                                                                                                       Page 1 of 1 
Table 14.2.2.1 
Summary of Pharmacokinetic Plasma Concentrations 
All Dosed Subjects 
______________________________________________________________________________________________________________________________________ 
 
Analyte (Unit)          Scheduled                 Standard            Standard                                   Geometric   Geometric 
  Dose Level            Time Point  N    Mean     Deviation   CV%     Error     Median   Minimum     Maximum     Mean        CV%  
______________________________________________________________________________________________________________________________________ 
 
Nevanimibe (XXXX) 
  Nevanimibe 250 mg     Pre-dose    ##   #.###    #.####      ##.#    #.####    #.###    #.##        #.##        #.###       ##.# 
                        1 hour      ##   #.###    #.####      ##.#    #.####    #.###    #.##        #.##        #.###       ##.# 
                        2 hours     ##   #.###    #.####      ##.#    #.####    #.###    #.##        #.##        #.###       ##.# 
                        3 hours     ##   #.###    #.####      ##.#    #.####    #.###    #.##        #.##        #.###       ##.# 
                        4 hours     ##   #.###    #.####      ##.#    #.####    #.###    #.##        #.##        #.###       ##.# 
 
  Nevanimibe 500 mg     Pre-dose    ##   #.###    #.####      ##.#    #.####    #.###    #.##        #.##        #.###       ##.# 
                        1 hour      ##   #.###    #.####      ##.#    #.####    #.###    #.##        #.##        #.###       ##.# 
                        2 hours     ##   #.###    #.####      ##.#    #.####    #.###    #.##        #.##        #.###       ##.# 
                        3 hours     ##   #.###    #.####      ##.#    #.####    #.###    #.##        #.##        #.###       ##.# 
                        4 hours     ##   #.###    #.####      ##.#    #.####    #.###    #.##        #.##        #.###       ##.# 
 
  Nevanimibe 1000 mg    Pre-dose    ##   #.###    #.####      ##.#    #.####    #.###    #.##        #.##        #.###       ##.# 
                        1 hour      ##   #.###    #.####      ##.#    #.####    #.###    #.##        #.##        #.###       ##.# 
                        2 hours     ##   #.###    #.####      ##.#    #.####    #.###    #.##        #.##        #.###       ##.# 
                        3 hours     ##   #.###    #.####      ##.#    #.####    #.###    #.##        #.##        #.###       ##.# 
                        4 hours     ##   #.###    #.####      ##.#    #.####    #.###    #.##        #.##        #.###       ##.# 
______________________________________________________________________________________________________________________________________ 
 
Subjects with missing samples, below the limit of quantitation (BLQ) results that are set to missing, or samples collected out of 
window are not included. Geometric CV% = 100*(exp(SD^2)-1)^0.5, where SD is the standard deviation of the log-transformed data.   
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM 
 
 


 
 
Millendo Therapeutics US, Inc. 
Protocol ATR-101-301                                                                                                       Page 1 of X 
Table 14.2.2.2 
Pharmacokinetic Plasma Parameter Listing and Summary 
All Dosed Subjects 
______________________________________________________________________________________________________________________________________ 
 
                                                                                 AUC          AUC         AUC       
             Dose Level           Cmax       Tmax      Lambda Z     T1/2       (0-last)      (0-4)       (0-inf)     AUC%extrap 
Analyte        Subject/Statistic (ng/mL)     (h)        (/h)        (h)        (h*ng/mL)    (h*ng/mL)   (h*ng/mL)      (%) 
______________________________________________________________________________________________________________________________________ 
 
Nevanimibe  Nevanimibe 250 mg 
 
               ###-###             ###       ##.##      #.###       ##.##         ###          ###        ###          ###.#   
               ###-### [1]         ###       ##.##      #.###       ##.##         ###          ###        ###          ###.#   
               ###-###             ###       ##.##      #.###       ##.##         ###          ###        ###          ###.#   
               ###-###             ###       ##.##      #.###       ##.##       
      
               n                   ###       ##         #           ##            ###          ###        ###          ###   
               Mean                ###.#     ##.###     #.####      ##.###        ###.#        ###.#      ###.#        ###.## 
               Standard Deviation  ###.##    ##.####    #.#####     ##.####       ###.##       ###.##     ###.##       ###.### 
               CV%                 ###.#     ##.#       #.#         ##.#          ###.#        ###.#      ###.#        ###.#   
               Standard Error      ###.##    ##.####    #.#####     ##.####       ###.##       ###.##     ###.##       ###.### 
               Median              ###.#     ##.###     #.####      ##.###        ###.#        ###.#      ###.#        ###.##   
               Minimum             ###       ##.##      #.###       ##.##         ###          ###        ###          ###.#   
               Maximum             ###       ##.##      #.###       ##.##         ###          ###        ###          ###.#   
               Geometric Mean      ###.#     N/A        N/A         N/A           ###.#        ###.#      ###.#        N/A     
               Geometric CV%       ###.#     N/A        N/A         N/A           ###.#        ###.#      ###.#        N/A     
______________________________________________________________________________________________________________________________________ 
 
Geometric CV%=100*(exp(SD^2)-1)^0.5, where SD is the standard deviation of the log-transformed data. N/A=Not Applicable. 
[1] AUCextr > 20%, implying greater uncertainty in pharmacokinetic parameters dependent on the definition of the terminal phase and/or 
    this extrapolation. 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM 
 
 
<<Programming Note: Repeat for each dose level. >> 
 


 
 
Millendo Therapeutics US, Inc. 
Protocol ATR-101-301                                                                                                       Page 1 of 1 
Table 14.3.1.1 
Overview of Adverse Events 
All Dosed Subjects 
______________________________________________________________________________________________________________________________________ 
 
                                                                              Nevanimibe Dose at Onset 
                                                                ------------------------------------------------ 
                                                                  250 mg BID       500 mg BID       1000 mg BID           Total      
                                                                    (N=#)            (N=#)            (N=#)               (N=#)      
Category                                                         n   (%)   e      n   (%)   e      n   (%)   e         n   (%)   e   
______________________________________________________________________________________________________________________________________ 
 
Subjects with any adverse event (AE)                                                                                   # (###.#) #   
 
Subjects with any treatment-emergent AE (TEAE)                   # (###.#) #      # (###.#) #      # (###.#) #         # (###.#) #   
 
Maximum severity of TEAE              
   Mild                                                          # (###.#) N/A    # (###.#) N/A    # (###.#) N/A       # (###.#) N/A 
   Moderate                                                      # (###.#) N/A    # (###.#) N/A    # (###.#) N/A       # (###.#) N/A 
   Severe                                                        # (###.#) N/A    # (###.#) N/A    # (###.#) N/A       # (###.#) N/A 
 
Subjects with any study drug related TEAE                        # (###.#) #      # (###.#) #      # (###.#) #         # (###.#) #   
 
Maximum severity of study drug related TEAE 
   Mild                                                          # (###.#) N/A    # (###.#) N/A    # (###.#) N/A       # (###.#) N/A 
   Moderate                                                      # (###.#) N/A    # (###.#) N/A    # (###.#) N/A       # (###.#) N/A 
   Severe                                                        # (###.#) N/A    # (###.#) N/A    # (###.#) N/A       # (###.#) N/A 
 
Subjects with any serious AE (SAE)                               # (###.#) #      # (###.#) #      # (###.#) #         # (###.#) #   
 
Subjects with any AE leading to discontinuation of study drug    # (###.#) #      # (###.#) #      # (###.#) #         # (###.#) #   
______________________________________________________________________________________________________________________________________ 
 
%=100*n/N, where n is the number of subjects in the specified category and N is the number of dosed subjects per column. e = number of 
AEs in the specified category. AEs are summarized by the dose level at the onset of the event. TEAEs are defined as any AE beginning 
on or after the first dose date of study drug. Study drug related AEs include those that are possibly, probably, or definitely 
related. 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM 


 
 
Millendo Therapeutics US, Inc. 
Data Safety Monitoring Board Report #1                                                                                    Page 1 of # 
Table 14.3.1.2 
Summary of Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
All Dosed Subjects 
______________________________________________________________________________________________________________________________________ 
 
                                                                              Nevanimibe Dose at Onset 
                                                                ------------------------------------------------ 
                                                                  250 mg BID       500 mg BID       1000 mg BID           Total      
System Organ Class                                                  (N=#)            (N=#)            (N=#)               (N=#)      
   Preferred Term                                                n   (%)   e      n   (%)   e      n   (%)   e         n   (%)   e   
______________________________________________________________________________________________________________________________________ 
 
Subjects with any TEAE                                           # (###.#) #      # (###.#) #      # (###.#) #         # (###.#) #   
 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX                           # (###.#) #      # (###.#) #      # (###.#) #         # (###.#) #   
   XXXXXXXXXXXXXXXXXXXXXXXXXXXXX                                 # (###.#) #      # (###.#) #      # (###.#) #         # (###.#) #   
   XXXXXXXXXXXXXXXXXXXXXXXXXXXXX                                 # (###.#) #      # (###.#) #      # (###.#) #         # (###.#) #   
   XXXXXXXXXXXXXXXXXXXXXXXXXXXXX                                 # (###.#) #      # (###.#) #      # (###.#) #         # (###.#) #   
   XXXXXXXXXXXXXXXXXXXXXXXXXXXXX                                 # (###.#) #      # (###.#) #      # (###.#) #         # (###.#) #   
 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX                           # (###.#) #      # (###.#) #      # (###.#) #         # (###.#) #   
   XXXXXXXXXXXXXXXXXXXXXXXXXXXXX                                 # (###.#) #      # (###.#) #      # (###.#) #         # (###.#) #   
   XXXXXXXXXXXXXXXXXXXXXXXXXXXXX                                 # (###.#) #      # (###.#) #      # (###.#) #         # (###.#) #   
______________________________________________________________________________________________________________________________________ 
 
%=100*n/N, where n is the number of subjects in the specified category and N is the number of dosed subjects per column. e = number of 
adverse events in the specified category. Treatment-emergent adverse events (TEAEs) are defined as any AE beginning on or after the 
first dose date of study drug. AEs are summarized by the dose level at the onset of the event. 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 18.0. 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM 
 
<< Programming Note: Table will be sorted by descending frequency (n then e) 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 Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
All Dosed Subjects 
 
 
<< Programming Note: Replace 
  
Subjects with any TEAE 
 
 
With 
  
Subjects with any study drug related TEAE 
 
<< Programming Note: Include the additional footnote: >>  
 
Study drug related AEs include those that are possibly, probably, or definitely related.


 
 
Millendo Therapeutics US, Inc. 
Protocol ATR-101-301                                                                                                       Page 1 of 2 
Table 14.3.3.1 
Shift Table of ALT, AST, Alkaline Phosphatase, and Total Bilirubin 
All Dosed Subjects 
______________________________________________________________________________________________________________________________________  
 
                                                 Highest Post-Baseline Value 
                           --------------------------------------------------------------------- 
                            Normal       >1 to       >3 to      
                            or Low       3xULN       5xULN      >5xULN      Missing     Total 
Parameter   Baseline        n   (%)     n   (%)     n   (%)     n   (%)     n   (%)     n   (%)  
______________________________________________________________________________________________________________________________________  
 
ALT         Normal or Low   # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)     
            >1 – 3xULN      # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)     
            >3 – 5xULN      # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)     
            >5xULN          # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)     
            Missing         # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)     
            Total           # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (100.0)  
 
AST         Normal or Low   # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)     
            >1 – 3xULN      # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)     
            >3 – 5xULN      # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)     
            >5xULN          # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)     
            Missing         # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)     
            Total           # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (100.0)  
_____________________________________________________________________________________________________________________________________   
 
ALT = Alanine Aminotransferase. AST = Aspartate Aminotransferase. ULN = upper limit of normal. 
Baseline is defined as the last measurement prior to the first dose of study drug. 
%=100*n/N, where n is the number of subjects in the specified category and N is the number of dosed subjects (N=4). 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM 


 
 
Millendo Therapeutics US, Inc. 
Protocol ATR-101-301                                                                                                       Page 2 of 2 
Table 14.3.3.1 
Shift Table of ALT, AST, Alkaline Phosphatase, and Total Bilirubin 
All Dosed Subjects 
______________________________________________________________________________________________________________________________________  
 
                                                              Highest Post-Baseline Value 
                                        --------------------------------------------------------------------- 
                                         Normal       >1 to       >1.5 to      
                                         or Low       1.5xULN     2xULN      >2xULN      Missing     Total 
Parameter              Baseline          n   (%)     n   (%)     n   (%)     n   (%)     n   (%)     n   (%)  
______________________________________________________________________________________________________________________________________  
 
Alkaline Phosphatase   Normal or Low     # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)     
                       >1 – 1.5xULN      # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)     
                       >1.5 – 2xULN      # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)     
                       >2xULN            # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)     
                       Missing           # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)     
                       Total             # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (100.0)  
 
Bilirubin              Normal or Low     # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)     
                       >1 – 1.5xULN      # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)     
                       >1.5 – 2xULN      # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)     
                       >2xULN            # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)     
                       Missing           # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)     
                       Total             # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (##.#)    # (100.0)  
_____________________________________________________________________________________________________________________________________   
 
ALT = Alanine Aminotransferase. AST = Aspartate Aminotransferase. ULN = upper limit of normal. 
Baseline is defined as the last measurement prior to the first dose of study drug. 
%=100*n/N, where n is the number of subjects in the specified category and N is the number of dosed subjects (N=4). 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM 
 
  
 
 
 


 
 
3 Figures 
Figure 14.2.1.1 .............................................................................................................................. 22 
Mean Nevanimibe Plasma Concentrations 
All Dosed Subjects 
Figure 14.2.1.2 .............................................................................................................................. 23 
Individual ATR-101 Plasma Concentrations 
All Dosed Subjects 


 
 
Millendo Therapeutics US, Inc. 
Protocol ATR-101-301                                                                                                       Page 1 of 1 
Figure 14.2.1.1 
Mean Nevanimibe Plasma Concentrations 
All Dosed Subjects 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM 


 
 
Millendo Therapeutics US, Inc. 
Protocol ATR-101-301                                                                                                       Page 1 of 4 
Figure 14.2.1.2 
Individual ATR-101 Plasma Concentrations 
All Dosed Subjects 
 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM 
 
 
 


 
 
4 Listings 
Listing 16.2.1.1 ............................................................................................................................. 27 
Subject Disposition: Informed Consent and Enrollment 
All Subjects 
Listing 16.2.1.2 ............................................................................................................................. 28 
Inclusion/Exclusion Criteria Not Met 
All Subjects 
Listing 16.2.1.3 ............................................................................................................................. 29 
Subject Disposition: End of Study 
All Dosed Subjects 
Listing 16.2.1.4 ............................................................................................................................. 30 
Follow-Up Telephone Visit 
All Dosed Subjects 
Listing 16.2.2.1 ............................................................................................................................. 31 
Protocol Deviations 
All Subjects 
Listing 16.2.4.1 ............................................................................................................................. 32 
Demographics 
All Subjects 
Listing 16.2.4.2 ............................................................................................................................. 33 
Cushing’s Syndrome Medical History 
All Subjects 
Listing 16.2.4.3 ............................................................................................................................. 34 
Tobacco Use 
All Subjects 
Listing 16.2.4.4 ............................................................................................................................. 35 
General Medical History 
All Subjects 
Listing 16.2.4.5 ............................................................................................................................. 36 
Pituitary Radiotherapy 
All Subjects 
Listing 16.2.4.6 ............................................................................................................................. 37 
Prior and Concomitant Medications 
All Subjects 
Listing 16.2.4.7 ............................................................................................................................. 38 
Concomitant Procedures 
All Subjects 
Listing 16.2.5.1 ............................................................................................................................. 39 
Study Drug Administration 
All Dosed Subjects 
Listing 16.2.5.2 ............................................................................................................................. 40 
Study Drug Accountability 
All Dosed Subjects 
Listing 16.2.5.3 ............................................................................................................................. 41 
Study Drug Exposure and Compliance 
All Dosed Subjects 


 
 
Listing 16.2.6.1 ............................................................................................................................. 42 
24 Hour Urine Laboratory Results 
All Subjects 
Listing 16.2.6.2 ............................................................................................................................. 43 
ARUP Laboratories: Plasma and Serum Samples 
All Subjects 
Listing 16.2.6.3 ............................................................................................................................. 44 
ARUP Laboratories: Urine Samples 
All Subjects 
Listing 16.2.6.4 ............................................................................................................................. 45 
Salivary Cortisol 
All Subjects 
Listing 16.2.6.5 ............................................................................................................................. 46 
Hormones 
All Subjects 
Listing 16.2.6.6 ............................................................................................................................. 47 
Pharmacokinetic Samples 
All Dosed Subjects 
Listing 16.2.7.1 ............................................................................................................................. 48 
Adverse Events 
All Subjects 
Listing 16.2.8.1 ............................................................................................................................. 49 
Safety Laboratory Values: Chemistry 
All Subjects 
Listing 16.2.8.2 ............................................................................................................................. 50 
Safety Laboratory Values: Hematology 
Screened Subjects 
Listing 16.2.8.3 ............................................................................................................................. 50 
Safety Laboratory Values: Lipids 
Screened Subjects 
Listing 16.2.8.4 ............................................................................................................................. 50 
Safety Laboratory Values: Coagulation 
Screened Subjects 
Listing 16.2.8.5 ............................................................................................................................. 50 
Safety Laboratory Values: Urinalysis 
Screened Subjects 
Listing 16.2.8.6 ............................................................................................................................. 50 
Safety Laboratory Values: Serology and Urine Drug Screen 
Screened Subjects 
Listing 16.2.8.7 ............................................................................................................................. 51 
Serum and Urine Pregnancy Test 
All Subjects 
Listing 16.2.9.1 ............................................................................................................................. 52 
Vital Signs 
All Subjects 
Listing 16.2.9.2 ............................................................................................................................. 53 


 
 
12-Lead Electrocardiogram 
All Subjects 
Listing 16.2.9.3 ............................................................................................................................. 54 
Physical Examination 
All Subjects 


 
 
Millendo Therapeutics US, Inc. 
Protocol ATR-101-301                                                                                                       Page 1 of 1 
Listing 16.2.1.1 
Subject Disposition: Informed Consent and Enrollment 
All Subjects 
______________________________________________________________________________________________________________________________________ 
 
                                                                                                         Did Subject Continue to the 
           Date of        Did Subject Enroll                                                             Double-Blind Randomized 
           Informed       In the Open-Label        Date       Date of                                    Withdrawal Period or the 
Subject    Consent        Dose Escalation Period?  Enrolled   Screen Failure  Reason for Screen Failure  Additional Open-Label Dosing? 
______________________________________________________________________________________________________________________________________ 
 
###-###    DDMMMYYYY      YES                      DDMMMYYYY                                             NO 
###-###    DDMMMYYYY      NO                                  DDMMMYYYY       XXXXXXXXXXXXXXXXXXXXXXXX 
###-###    DDMMMYYYY      YES                      DDMMMYYYY                                             NO 
###-###    DDMMMYYYY      YES                      DDMMMYYYY                                             NO 
###-###    DDMMMYYYY      YES                      DDMMMYYYY                                             NO 
###-###    DDMMMYYYY      NO                                  DDMMMYYYY       XXXXXXXXXXXXXXXXXXXXXXXX 
###-###    DDMMMYYYY      NO                                  DDMMMYYYY       XXXXXXXXXXXXXXXXXXXXXXXX 
###-###    DDMMMYYYY      NO                                  DDMMMYYYY       XXXXXXXXXXXXXXXXXXXXXXXX 
###-###    DDMMMYYYY      NO                                  DDMMMYYYY       XXXXXXXXXXXXXXXXXXXXXXXX 
______________________________________________________________________________________________________________________________________ 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM 
<< Programming Note: Refer to records where DS.DSDECOD =  “INFORMED CONSENT OBTAINED”, DS.DSSCAT = 
“ENROLLMENT”, DS.DSSCAT = “SCREEN FAILURE”, and DS.DSCAT = “PROTOCOL MILESTONE”. >>  


 
 
Millendo Therapeutics US, Inc. 
Protocol ATR-101-301                                                                                                       Page 1 of # 
Listing 16.2.1.2 
Inclusion/Exclusion Criteria Not Met 
All Subjects 
______________________________________________________________________________________________________________________________________ 
 
Subject                   Category           Criterion   Description 
______________________________________________________________________________________________________________________________________ 
 
###-### (SF)              XXXXXXXXX             ##       XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
 
###-###                   XXXXXXXXX             ##       XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
 
                          XXXXXXXXX             ##       XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
 
###-###                   XXXXXXXXX             ##       XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
 
###-###                   XXXXXXXXX             ##       XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
 
###-###                   XXXXXXXXX             ##       XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
 
###-### (SF)              XXXXXXXXX             ##       XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
 
###-### (SF)              XXXXXXXXX             ##       XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
 
###-### (SF)              XXXXXXXXX             ##       XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
 
###-### (SF)              XXXXXXXXX             ##       XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
______________________________________________________________________________________________________________________________________ 
 
SF = Screen failure subject 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM 
<< Programming Note: Only use the last 2 digits of IE.IETESTCD for the criterion number.  >>  
 


 
 
Millendo Therapeutics US, Inc. 
Protocol ATR-101-301                                                                                                       Page 1 of 1 
Listing 16.2.1.3 
Subject Disposition: End of Study 
All Dosed Subjects 
______________________________________________________________________________________________________________________________________ 
 
                                                      Date (Day) of 
           Date of       Date (Day) of    Completed   Completion/ 
Subject    First Dose    Last Dose        Study?      Early Termination     Primary Reason for Early Termination 
______________________________________________________________________________________________________________________________________ 
 
###-###    DDMMMYYYY     DDMMMYYYY (##)   XXX         DDMMMYYYY (##)        XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
###-###    DDMMMYYYY     DDMMMYYYY (##)   XXX         DDMMMYYYY (##)        XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
###-###    DDMMMYYYY     DDMMMYYYY (##)   XXX         DDMMMYYYY (##)        XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
###-###    DDMMMYYYY     DDMMMYYYY (##)   XXX         DDMMMYYYY (##)        XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
______________________________________________________________________________________________________________________________________ 
 
Day = Date – first dose date +1. 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM 
 


 
 
Millendo Therapeutics US, Inc. 
Protocol ATR-101-301                                                                                                       Page 1 of 1 
Listing 16.2.1.4 
Follow-Up Telephone Visit 
All Dosed Subjects 
______________________________________________________________________________________________________________________________________ 
 
           Was the Subject                     Any Adverse Events    Started or Stopped 
           Reached for       Date (Day)        Since Last            Any Medications Since 
Subject    Follow-Up?        of Contact        Study Visit?          Last Study Visit? 
______________________________________________________________________________________________________________________________________ 
 
###-###    XXX               DDMMMYYYY (##)    XXX                   XXX 
###-###    XXX               DDMMMYYYY (##)    XXX                   XXX 
###-###    XXX               DDMMMYYYY (##)    XXX                   XXX 
###-###    XXX               DDMMMYYYY (##)    XXX                   XXX 
______________________________________________________________________________________________________________________________________ 
 
Day = Date – first dose date +1. 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM 


 
 
Millendo Therapeutics US, Inc. 
Protocol ATR-101-301                                                                                                       Page 1 of # 
Listing 16.2.2.1 
Protocol Deviations 
All Subjects 
______________________________________________________________________________________________________________________________________ 
 
                Date of       Date of     Pre-                                       CSR                                     
Subject         Verification  Occurrence  Approved?  Category     Description        Reportable?   Action Type              Confirmed? 
______________________________________________________________________________________________________________________________________ 
 
###-###         DDMMMYYYY     DDMMMYYYY   XXX        XXXXXXXXXXX  XXXXXXXXXXXXXXXXX  XXX           XXXXXXXXXXXXXXXXXXXXXX   XXX 
                DDMMMYYYY     DDMMMYYYY   XXX        XXXXXXXXXXX  XXXXXXXXXXXXXXXXX  XXX           XXXXXXXXXXXXXXXXXXXXXX   XXX 
                DDMMMYYYY     DDMMMYYYY   XXX        XXXXXXXXXXX  XXXXXXXXXXXXXXXXX  XXX           XXXXXXXXXXXXXXXXXXXXXX   XXX 
                DDMMMYYYY     DDMMMYYYY   XXX        XXXXXXXXXXX  XXXXXXXXXXXXXXXXX  XXX           XXXXXXXXXXXXXXXXXXXXXX   XXX 
 
###-### (SF)    DDMMMYYYY     DDMMMYYYY   XXX        XXXXXXXXXXX  XXXXXXXXXXXXXXXXX  XXX           XXXXXXXXXXXXXXXXXXXXXX   XXX 
                DDMMMYYYY     DDMMMYYYY   XXX        XXXXXXXXXXX  XXXXXXXXXXXXXXXXX  XXX           XXXXXXXXXXXXXXXXXXXXXX   XXX 
                DDMMMYYYY     DDMMMYYYY   XXX        XXXXXXXXXXX  XXXXXXXXXXXXXXXXX  XXX           XXXXXXXXXXXXXXXXXXXXXX   XXX 
                DDMMMYYYY     DDMMMYYYY   XXX        XXXXXXXXXXX  XXXXXXXXXXXXXXXXX  XXX           XXXXXXXXXXXXXXXXXXXXXX   XXX 
 
###-###         DDMMMYYYY     DDMMMYYYY   XXX        XXXXXXXXXXX  XXXXXXXXXXXXXXXXX  XXX           XXXXXXXXXXXXXXXXXXXXXX   XXX 
                DDMMMYYYY     DDMMMYYYY   XXX        XXXXXXXXXXX  XXXXXXXXXXXXXXXXX  XXX           XXXXXXXXXXXXXXXXXXXXXX   XXX 
                DDMMMYYYY     DDMMMYYYY   XXX        XXXXXXXXXXX  XXXXXXXXXXXXXXXXX  XXX           XXXXXXXXXXXXXXXXXXXXXX   XXX 
                DDMMMYYYY     DDMMMYYYY   XXX        XXXXXXXXXXX  XXXXXXXXXXXXXXXXX  XXX           XXXXXXXXXXXXXXXXXXXXXX   XXX 
 
###-###         DDMMMYYYY     DDMMMYYYY   XXX        XXXXXXXXXXX  XXXXXXXXXXXXXXXXX  XXX           XXXXXXXXXXXXXXXXXXXXXX   XXX 
                DDMMMYYYY     DDMMMYYYY   XXX        XXXXXXXXXXX  XXXXXXXXXXXXXXXXX  XXX           XXXXXXXXXXXXXXXXXXXXXX   XXX 
                DDMMMYYYY     DDMMMYYYY   XXX        XXXXXXXXXXX  XXXXXXXXXXXXXXXXX  XXX           XXXXXXXXXXXXXXXXXXXXXX   XXX 
                DDMMMYYYY     DDMMMYYYY   XXX        XXXXXXXXXXX  XXXXXXXXXXXXXXXXX  XXX           XXXXXXXXXXXXXXXXXXXXXX   XXX 
______________________________________________________________________________________________________________________________________ 
 
SF = Screen failure subject. CSR = Clinical Study Report. 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM 


 
 
Millendo Therapeutics US, Inc. 
Protocol ATR-101-301                                                                                                       Page 1 of # 
Listing 16.2.4.1 
Demographics 
All Subjects 
______________________________________________________________________________________________________________________________________ 
 
              Protocol     Date of     Age                                         
Subject       Version      Birth     (Years)  Sex     Ethnicity         Race              Race, Specify         
______________________________________________________________________________________________________________________________________ 
 
###-## (SF)   XXXXXXXXXX   DDMMMYYYY   ##     XXXX    XXXXXXXXXXXXX     XXXXXXXXXXXX      XXXXXXXXXXXXXXXXXXXXXXXX  
###-##        XXXXXXXXXX   DDMMMYYYY   ##     XXXX    XXXXXXXXXXXXX     XXXXXXXXXXXX      XXXXXXXXXXXXXXXXXXXXXXXX  
###-##        XXXXXXXXXX   DDMMMYYYY   ##     XXXX    XXXXXXXXXXXXX     XXXXXXXXXXXX      XXXXXXXXXXXXXXXXXXXXXXXX 
###-##        XXXXXXXXXX   DDMMMYYYY   ##     XXXX    XXXXXXXXXXXXX     XXXXXXXXXXXX      XXXXXXXXXXXXXXXXXXXXXXXX 
###-## (SF)   XXXXXXXXXX   DDMMMYYYY   ##     XXXX    XXXXXXXXXXXXX     XXXXXXXXXXXX      XXXXXXXXXXXXXXXXXXXXXXXX  
###-## (SF)   XXXXXXXXXX   DDMMMYYYY   ##     XXXX    XXXXXXXXXXXXX     XXXXXXXXXXXX      XXXXXXXXXXXXXXXXXXXXXXXX  
###-## (SF)   XXXXXXXXXX   DDMMMYYYY   ##     XXXX    XXXXXXXXXXXXX     XXXXXXXXXXXX      XXXXXXXXXXXXXXXXXXXXXXXX  
###-##        XXXXXXXXXX   DDMMMYYYY   ##     XXXX    XXXXXXXXXXXXX     XXXXXXXXXXXX      XXXXXXXXXXXXXXXXXXXXXXXX 
###-##        XXXXXXXXXX   DDMMMYYYY   ##     XXXX    XXXXXXXXXXXXX     XXXXXXXXXXXX      XXXXXXXXXXXXXXXXXXXXXXXX 
______________________________________________________________________________________________________________________________________ 
 
SF = Screen failure subject 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM 


 
 
Millendo Therapeutics US, Inc. 
Protocol ATR-101-301                                                                                                       Page 1 of # 
Listing 16.2.4.2 
Cushing’s Syndrome Medical History 
All Subjects 
______________________________________________________________________________________________________________________________________ 
 
             Diagnosis                                                        History of Prior    Previous Pituitary 
Subject      Date       Etiology    How was the etiology confirmed?           Pituitary Surgery?  Radiotherapy? 
______________________________________________________________________________________________________________________________________ 
 
###-### (SF) DDMMMYYYY  XXXXXXXXX   XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX    XXX                 XXX 
                                    XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
 
###-###      DDMMMYYYY  XXXXXXXXX   XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX    XXX                 XXX 
 
###-### (SF) DDMMMYYYY  XXXXXXXXX   XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX    XXX                 XXX 
 
###-###      DDMMMYYYY  XXXXXXXXX   XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX    XXX                 XXX 
                                    XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
 
###-###      DDMMMYYYY  XXXXXXXXX   XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX    XXX                 XXX 
                                    XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
______________________________________________________________________________________________________________________________________ 
 
SF = Screen failure subject 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM 
 
 


 
 
Millendo Therapeutics US, Inc. 
Protocol ATR-101-301                                                                                                       Page 1 of # 
Listing 16.2.4.3 
Tobacco Use 
All Subjects 
______________________________________________________________________________________________________________________________________ 
 
Subject       Cigarette Use         Frequency         Other Tobacco Product use 
______________________________________________________________________________________________________________________________________ 
 
###-### (SF)  NEVER SMOKED                            NEVER USED 
  
###-###       FORMERLY SMOKED       XXXXXXXXXXXXXXX   NEVER USED 
 
###-###       XXXXXXXXXXXXXXX       XXXXXXXXXXXXXXX   XXXXXXXXXX 
 
###-###       XXXXXXXXXXXXXXX       XXXXXXXXXXXXXXX   XXXXXXXXXX 
______________________________________________________________________________________________________________________________________ 
 
SF = Screen failure subject 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM 
<< Programming Note: If other data is reported, e.g. number of cigarettes, other tobacco product information, or start/stop dates, 
then add columns for the additional data.  >>  
 


 
 
Millendo Therapeutics US, Inc. 
Protocol ATR-101-301                                                                                                       Page 1 of # 
Listing 16.2.4.4 
General Medical History 
All Subjects 
______________________________________________________________________________________________________________________________________ 
 
                 System Organ Class/ 
                 Preferred Term/ 
Subject          Event/Diagnosis                     Start Date         Stop Date 
______________________________________________________________________________________________________________________________________ 
 
###-### (SF)     XXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/     DDMMMYYYY          DDMMMYYYY 
                 XXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/ 
                 XXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
 
                 XXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/     DDMMMYYYY          ONGOING 
                 XXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/ 
                 XXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
 
###-###          XXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/     DDMMMYYYY          DDMMMYYYY 
                 XXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/ 
                 XXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
______________________________________________________________________________________________________________________________________ 
 
SF = Screen failure subject. Medical history is coded using MedDRA dictionary version 18.0. 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM 
<< Programming Note: Only include records where MHPRESP=null. Sort by USUBJID, MHSTDTC, MHENDTC, MHTERM.  >>  
 


 
 
Millendo Therapeutics US, Inc. 
Protocol ATR-101-301                                                                                                       Page 1 of # 
Listing 16.2.4.5 
Pituitary Radiotherapy 
All Subjects 
______________________________________________________________________________________________________________________________________ 
 
Subject         Date of First Dose        Date of Last Dose         Comments 
______________________________________________________________________________________________________________________________________ 
 
###-###         DDMMMYYYY                 DDMMMYYYY                 XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
______________________________________________________________________________________________________________________________________ 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM 


 
 
Millendo Therapeutics US, Inc. 
Protocol ATR-101-301                                                                                                       Page 1 of # 
Listing 16.2.4.6 
Prior and Concomitant Medications 
All Subjects 
______________________________________________________________________________________________________________________________________ 
 
             Medication Name/                                                                                       
             Preferred Term/                Start Date/                                                           
Subject      Chemical Substance             End Date     Indication        Dose     Units       Frequency        Route 
______________________________________________________________________________________________________________________________________ 
 
###-###      XXXXXXXXXXXXXXXXXXXXXXXXXXX/   DDMMMYYYY/   XXXXXXXXXXXXXXXX  XXXXXXX  XXXXX       OTHER: XXXXXXX   XXXXXXXXXXX 
             XXXXXXXXXXXXXXXXXXXXXXXXXXX/   DDMMMYYYY       
             XXXXXXXXXXXXXXXXXXXXXXXXXXX       
 
             XXXXXXXXXXXXXXXXXXXXXXXXXXX/   DDMMMYYYY/   XXXXXXXXXXXXXXXX  XXXXXXX  OTHER:      XXXXXXXXXX       XXXXXXXXXXX 
             XXXXXXXXXXXXXXXXXXXXXXXXXXX/   ONGOING                                 XXXXXXXXXX 
             XXXXXXXXXXXXXXXXXXXXXXXXXXX       
 
             XXXXXXXXXXXXXXXXXXXXXXXXXXX/   DDMMMYYYY/   XXXXXXXXXXXXXXXX  XXXXXXX  XXXXX       XXXXXXXXXX       OTHER: XXXXXXXXXX 
             XXXXXXXXXXXXXXXXXXXXXXXXXXX/   ONGOING       
             XXXXXXXXXXXXXXXXXXXXXXXXXXX       
 
###-###      XXXXXXXXXXXXXXXXXXXXXXXXXXX/   DDMMMYYYY/   XXXXXXXXXXXXXXXX  XXXXXXX  XXXXX       XXXXXXXXXX       XXXXXXXXXXX 
             XXXXXXXXXXXXXXXXXXXXXXXXXXX/   DDMMMYYYY       
             XXXXXXXXXXXXXXXXXXXXXXXXXXX       
 
###-###      XXXXXXXXXXXXXXXXXXXXXXXXXXX/   DDMMMYYYY/   XXXXXXXXXXXXXXXX  XXXXXXX  XXXXX       XXXXXXXXXX       XXXXXXXXXXX 
             XXXXXXXXXXXXXXXXXXXXXXXXXXX/   DDMMMYYYY       
             XXXXXXXXXXXXXXXXXXXXXXXXXXX       
______________________________________________________________________________________________________________________________________ 
 
Medications are coded with the WHO Drug March 2016E B2 dictionary version. 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM 
<< Programming Note: Sort by USUBJID, CMSTDTC, CMENDTC, CMTRT.  >>  
 


 
 
Millendo Therapeutics US, Inc. 
Protocol ATR-101-301                                                                                                       Page 1 of # 
Listing 16.2.4.7 
Concomitant Procedures 
All Subjects 
______________________________________________________________________________________________________________________________________ 
 
Subject         Procedure                      Indication        Start Date        Stop Date 
______________________________________________________________________________________________________________________________________ 
 
###-###         XXXXXXXXXXXXXXXXXXXXXXXXXXX    XXXXXXXXXXXXXXXX  DDMMMYYYY         DDMMMYYYY 
 
                XXXXXXXXXXXXXXXXXXXXXXXXXXX    XXXXXXXXXXXXXXXX  DDMMMYYYY         ONGOING   
 
###-###         XXXXXXXXXXXXXXXXXXXXXXXXXXX    XXXXXXXXXXXXXXXX  DDMMMYYYY         DDMMMYYYY 
 
###-###         XXXXXXXXXXXXXXXXXXXXXXXXXXX    XXXXXXXXXXXXXXXX  DDMMMYYYY         DDMMMYYYY 
 
###-###         XXXXXXXXXXXXXXXXXXXXXXXXXXX    XXXXXXXXXXXXXXXX  DDMMMYYYY         DDMMMYYYY 
______________________________________________________________________________________________________________________________________ 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM 
<< Programming Note: Sort by USUBJID, PRSTDTC, PRENDTC, PRTRT.  >>  
 


 
 
Millendo Therapeutics US, Inc. 
Protocol ATR-101-301                                                                                                       Page 1 of 1 
Listing 16.2.5.1 
Study Drug Administration 
All Dosed Subjects 
______________________________________________________________________________________________________________________________________ 
 
                                                                       Did Subject Consume     
                                                     Date/Time of      Food Prior to          Was the Planned Dose 
Subject    Visit            Treatment Name           Administration    Administration?        Administered On Site? 
______________________________________________________________________________________________________________________________________ 
  
###-###    XXXXXXXXXXXX     Nevanimibe 250 mg BID    DDMMMYYYY/HH:MM   XXX                    XXX 
           XXXXXXXXXXXX     Nevanimibe 500 mg BID    DDMMMYYYY/HH:MM   XXX                    XXX 
           XXXXXXXXXXXX     Nevanimibe 1000 mg BID   DDMMMYYYY/HH:MM   XXX                    XXX 
 
###-###    XXXXXXXXXXXX     XXXXXXXXXXXXXX           DDMMMYYYY/HH:MM   XXX                    XXX 
           XXXXXXXXXXXX     XXXXXXXXXXXXXX           DDMMMYYYY/HH:MM   XXX                    XXX 
           XXXXXXXXXXXX     XXXXXXXXXXXXXX           DDMMMYYYY/HH:MM   XXX                    XXX 
 
###-###    XXXXXXXXXXXX     XXXXXXXXXXXXXX           DDMMMYYYY/HH:MM   XXX                    XXX 
           XXXXXXXXXXXX     XXXXXXXXXXXXXX           DDMMMYYYY/HH:MM   XXX                    XXX 
           XXXXXXXXXXXX     XXXXXXXXXXXXXX           DDMMMYYYY/HH:MM   XXX                    XXX 
 
###-###    XXXXXXXXXXXX     XXXXXXXXXXXXXX           DDMMMYYYY/HH:MM   XXX                    XXX 
           XXXXXXXXXXXX     XXXXXXXXXXXXXX           DDMMMYYYY/HH:MM   XXX                    XXX 
           XXXXXXXXXXXX     XXXXXXXXXXXXXX           DDMMMYYYY/HH:MM   XXX                    XXX 
______________________________________________________________________________________________________________________________________ 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM 
 
<< Programming Note: Only include records where ECOCCUR = “Y”.  >>  


 
 
Millendo Therapeutics US, Inc. 
Protocol ATR-101-301                                                                                                       Page 1 of # 
Listing 16.2.5.2 
Study Drug Accountability 
All Dosed Subjects 
______________________________________________________________________________________________________________________________________ 
 
                                                     Dispense                     Return 
                                              -----------------------     ----------------------- 
           Bottle                                          Number of                   Number of     80-120% 
Subject    Number    Treatment                 Date        Tablets         Date        Tablets       Compliant? 
______________________________________________________________________________________________________________________________________ 
 
###-###    #####     Nevanimibe 250 mg BID     DDMMMYYYY   ##              DDMMMYYYY   ##            XXX 
           #####     Nevanimibe 500 mg BID     DDMMMYYYY   ##              DDMMMYYYY   ##            XXX 
           #####     Nevanimibe 1000 mg BID    DDMMMYYYY   ##              DDMMMYYYY   ##            XXX 
           #####     Nevanimibe 1000 mg BID    DDMMMYYYY   ##              DDMMMYYYY   ##            XXX 
 
###-###    #####     XXXXXXXXXXXXXXXXXXX       DDMMMYYYY   ##              DDMMMYYYY   ##            XXX 
           #####     XXXXXXXXXXXXXXXXXXX       DDMMMYYYY   ##              DDMMMYYYY   ##            XXX 
           #####     XXXXXXXXXXXXXXXXXXX       DDMMMYYYY   ##              DDMMMYYYY   ##            XXX 
______________________________________________________________________________________________________________________________________ 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM 
 
<< Programming Note: Sort by Subject, Dispense Date, Return Date. The compliance question is sourced from SUPPDA where 
QNAM = “COMP”. >>  


 
 
Millendo Therapeutics US, Inc. 
Protocol ATR-101-301                                                                                                       Page 1 of 1 
Listing 16.2.5.3 
Study Drug Exposure and Compliance 
All Dosed Subjects 
______________________________________________________________________________________________________________________________________ 
 
                 Nevanimibe 250 mg BID                    Nevanimibe 500 mg BID                    Nevanimibe 1000 mg BID 
          -----------------------------------      -----------------------------------      -----------------------------------            
           Number of   Days of    Compliance        Number of   Days of    Compliance        Number of   Days of    Compliance 
Subject    Tablets     Exposure   (%)               Tablets     Exposure   (%)               Tablets     Exposure   (%)        
______________________________________________________________________________________________________________________________________ 
  
###-###    ##          ##         ###.#             ##          ##         ###.#             ##          ##         ###.# 
 
###-###    ##          ##         ###.#             ##          ##         ###.#              
 
###-###    ##          ##         ###.#             ##          ##         ###.#             ##          ##         ###.# 
 
###-###    ##          ##         ###.#             ##          ##         ###.#             ##          ##         ###.# 
______________________________________________________________________________________________________________________________________ 
 
Number of tablets = number of tablets dispensed – number of tablets returned. 
Days of exposure = last dose date of the specified dose level – first dose date of the specified dose level +1.  
Compliance = 100*number of tablets/(days of exposure*2) for the 250 mg BID and 500 mg BID groups. 
Compliance = 100*number of tablets/(days of exposure*4) for the 1000 mg BID group. 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM 
 
<< Programming Note: For the last dose level (i.e. 500 mg for subject 103-001 and 1000 mg for others), exposure = TRTEDT – 
TR03SDT + 1. For other dose levels, assume that the “last dose date of the specified dose level” is the day before the first dose date 
of the next dose level. For example for 250 mg (except 103-001), exposure = TR02SDT – TR01SDT. >>  
 


 
 
Millendo Therapeutics US, Inc. 
Protocol ATR-101-301                                                                                                       Page 1 of # 
Listing 16.2.6.1 
24 Hour Urine Laboratory Results 
All Subjects 
______________________________________________________________________________________________________________________________________ 
             
                                                            Collection Start    Collection End                       
Subject            Parameter (Unit)          Visit          Date/Time           Date/Time              Result     Normal Range   Flag 
______________________________________________________________________________________________________________________________________ 
  
###-### (SF)       XXXXXXXXXXX (XXXXX)       XXXXXXXXXXXX   DDMMMYYYY/HH:MM     DDMMMYYYY/HH:MM        XXXXX      XX – XX         
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     DDMMMYYYY/HH:MM        XXXXX      XX - XX        HIGH 
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     DDMMMYYYY/HH:MM        XXXXX      XX - XX         
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     DDMMMYYYY/HH:MM        XXXXX      XX - XX         
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     DDMMMYYYY/HH:MM        XXXXX      XX - XX        LOW 
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     DDMMMYYYY/HH:MM        XXXXX      XX - XX         
 
                   XXXXXXXXXXX (XXXXX)       XXXXXXXXXXXX   DDMMMYYYY/HH:MM     DDMMMYYYY/HH:MM        XXXXX      XX – XX         
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     DDMMMYYYY/HH:MM        XXXXX      XX - XX         
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     DDMMMYYYY/HH:MM        XXXXX      XX - XX         
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     DDMMMYYYY/HH:MM        XXXXX      XX - XX         
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     DDMMMYYYY/HH:MM        XXXXX      XX - XX         
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     DDMMMYYYY/HH:MM        XXXXX      XX - XX         
 
###-###            XXXXXXXXXXX (XXXXX)       XXXXXXXXXXXX   DDMMMYYYY/HH:MM     DDMMMYYYY/HH:MM        XXXXX      XX – XX         
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     DDMMMYYYY/HH:MM        XXXXX      XX - XX         
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     DDMMMYYYY/HH:MM        XXXXX      XX - XX         
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     DDMMMYYYY/HH:MM        XXXXX      XX - XX         
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     DDMMMYYYY/HH:MM        XXXXX      XX - XX         
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     DDMMMYYYY/HH:MM        XXXXX      XX - XX         
 
###-###            XXXXXXXXXXX (XXXXX)       XXXXXXXXXXXX   DDMMMYYYY/HH:MM     DDMMMYYYY/HH:MM        XXXXX      XX – XX         
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     DDMMMYYYY/HH:MM        XXXXX      XX - XX         
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     DDMMMYYYY/HH:MM        XXXXX      XX - XX         
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     DDMMMYYYY/HH:MM        XXXXX      XX - XX         
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     DDMMMYYYY/HH:MM        XXXXX      XX - XX         
______________________________________________________________________________________________________________________________________ 
 
SF = Screen failure subject. 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM 
<< Programming Note: Include all results where LBCAT = “24 HOUR URINE”.   
In all lab listings, report results in US conventional units (LBORRES variables). >> 


 
 
Millendo Therapeutics US, Inc. 
Protocol ATR-101-301                                                                                                       Page 1 of # 
Listing 16.2.6.2 
ARUP Laboratories: Plasma and Serum Samples 
All Subjects 
______________________________________________________________________________________________________________________________________ 
             
                                                            Date/Time of                      
Subject            Parameter (Unit)          Visit          Collection          Result     Normal Range   Flag 
______________________________________________________________________________________________________________________________________ 
  
###-### (SF)       XXXXXXXXXXX (XXXXX)       XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX – XX         
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX        HIGH 
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX         
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX         
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX        LOW 
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX         
 
                   XXXXXXXXXXX (XXXXX)       XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX – XX         
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX         
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX         
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX         
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX         
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX         
 
###-###            XXXXXXXXXXX (XXXXX)       XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX – XX         
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX         
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX         
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX         
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX         
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX         
 
###-###            XXXXXXXXXXX (XXXXX)       XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX – XX         
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX         
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX         
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX         
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX         
______________________________________________________________________________________________________________________________________ 
 
SF = Screen failure subject. 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM 
<< Programming Note: Include all results where LBCAT = “ARUP LABORATORIES” and LBSPEC in (“PLASMA”, “SERUM”)>> 


 
 
<< Programming Note: The following will have the same layout as listing 16.2.6.1. Include all results where LBCAT = “ARUP 
LABORATORIES” and LBSPEC = “URINE”. >> 
Listing 16.2.6.3 
ARUP Laboratories: Urine Samples 
All Subjects 
 


 
 
Millendo Therapeutics US, Inc. 
Protocol ATR-101-301                                                                                                       Page 1 of # 
Listing 16.2.6.4 
Salivary Cortisol 
All Subjects 
______________________________________________________________________________________________________________________________________ 
             
                                                                           Date/Time of                      
Subject            Parameter (Unit)          Visit          Time Point     Collection          Result     Normal Range   Flag 
______________________________________________________________________________________________________________________________________ 
  
###-### (SF)       XXXXXXXXXXX (XXXXX)       XXXXXXXXXXXX   XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX – XX         
                                             XXXXXXXXXXXX   XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX        HIGH 
                                             XXXXXXXXXXXX   XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX         
                                             XXXXXXXXXXXX   XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX         
                                             XXXXXXXXXXXX   XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX        LOW 
                                             XXXXXXXXXXXX   XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX         
 
                   XXXXXXXXXXX (XXXXX)       XXXXXXXXXXXX   XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX – XX         
                                             XXXXXXXXXXXX   XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX         
                                             XXXXXXXXXXXX   XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX         
                                             XXXXXXXXXXXX   XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX         
                                             XXXXXXXXXXXX   XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX         
                                             XXXXXXXXXXXX   XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX         
 
###-###            XXXXXXXXXXX (XXXXX)       XXXXXXXXXXXX   XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX – XX         
                                             XXXXXXXXXXXX   XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX         
                                             XXXXXXXXXXXX   XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX         
                                             XXXXXXXXXXXX   XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX         
                                             XXXXXXXXXXXX   XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX         
                                             XXXXXXXXXXXX   XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX         
 
###-###            XXXXXXXXXXX (XXXXX)       XXXXXXXXXXXX   XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX – XX         
                                             XXXXXXXXXXXX   XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX         
                                             XXXXXXXXXXXX   XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX         
                                             XXXXXXXXXXXX   XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX         
                                             XXXXXXXXXXXX   XXXXXXXXXXXX   DDMMMYYYY/HH:MM     XXXXX      XX - XX         
______________________________________________________________________________________________________________________________________ 
 
SF = Screen failure subject. 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM 
<< Programming Note: Include all results where LBSPEC = “SALIVA” (includes LBCAT = “HORMONES” and “ARUP 
LABORATORIES”). >> 
<< Programming Note: I am waiting to see how the salivary cortisol collection CRFs are mapped to see how best to list the data 
(SC1 = questions about shift work, travel, altered wake/sleep and LB_SC1 = smoking question) >> 


 
 
<< Programming Note: The following will have the same layout as listing 16.2.6.2. Include all results where LBCAT 
in(“HORMONES”, “QUEST DIAGNOSTICS”) and LBSPEC NE “SALIVA”.  >> 
Listing 16.2.6.5 
Hormones 
All Subjects 


 
 
Millendo Therapeutics US, Inc. 
Protocol ATR-101-301                                                                                                       Page 1 of # 
Listing 16.2.6.6 
Pharmacokinetic Samples 
All Dosed Subjects 
______________________________________________________________________________________________________________________________________ 
 
                    Last Dose Prior 
Subject             to PK Sampling   Sampling                          Nevanimibe    If Not Collected, 
  Visit             Date/Time        Time Point     Date/Time          (<<unit>>)    Specify Reason 
______________________________________________________________________________________________________________________________________ 
 
###-###     
  XXXXXXXXXXXXXXX   DDMMMYYYY/HH:MM  XXXXXXXXXXX    DDMMMYYYY/HH:MM     #######    
                                     XXXXXXXXXXX    DDMMMYYYY/HH:MM     #######    
                                     XXXXXXXXXXX    DDMMMYYYY/HH:MM     #######    
                                     XXXXXXXXXXX    DDMMMYYYY/HH:MM     #######    
  XXXXXXXXXXXXXXX                                   NOT DONE                          XXXXXXXXXXXXXXXXXXXXXXXXXXX 
  XXXXXXXXXXXXXXX   DDMMMYYYY/HH:MM  XXXXXXXXXXX    DDMMMYYYY/HH:MM     #######    
                                     XXXXXXXXXXX    DDMMMYYYY/HH:MM     #######    
                                     XXXXXXXXXXX    DDMMMYYYY/HH:MM     #######    
                                     XXXXXXXXXXX    DDMMMYYYY/HH:MM     #######    
  XXXXXXXXXXXXXXX                                   NOT DONE                          XXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
______________________________________________________________________________________________________________________________________ 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM 
 
<<Programming Note: Include footnotes for the lower limits of quantitation if provided. Include columns for each metabolite 
provided, delete if not needed. >> 
 


 
 
Millendo Therapeutics US, Inc. 
Protocol ATR-101-301                                                                                                       Page 1 of # 
Listing 16.2.7.1 
Adverse Events 
All Subjects 
______________________________________________________________________________________________________________________________________ 
 
        TEAE?/      Adverse Event/                                         Severity/                             
        Onset Dose/ Preferred Term/              Start Date/Day  Duration  Relationship   Action Taken          Outcome/ 
Subject SAE?        System Organ Class           End Date/Day     (Days)   to Study Drug  with Study Drug       Other Action Taken 
_________________________________________________________________________________________________________________________________ 
 
###-### YES/        XXXXXXXXXXXXXXXXXXXXX/       DDMMMYYYY/##      ##      XXXXXX/        DOSE NOT CHANGED      XXXXXXX/   
        250 mg/     XXXXXXXXXXXXXXXXXXXXX/       DDMMMYYYY/##              XXXXXXXXXXXX                         XXXXXXXXXXXXXX    
        NO          XXXXXXXXXXXXXXXXXXXXX                                                                       
 
        YES/        XXXXXXXXXXXXXXXXXXXXX/       DDMMMYYYY/##      ##      XXXXXX/        DRUG INTERRUPTED      XXXXXXX/   
        1000 mg/    XXXXXXXXXXXXXXXXXXXXX/       DDMMMYYYY/##              XXXXXXXXXXXX   Last Dose: DDMMMYYYY  XXXXXXXXXXXXXX    
        XXX         XXXXXXXXXXXXXXXXXXXXX                                                 Restart: DDMMMYYYY     
 
###-### NO/         XXXXXXXXXXXXXXXXXXXXX/       DDMMMYYYY/##      ##      XXXXXX/        XXXXXXXXXXXXX         XXXXXXX/   
        Pre-dose/   XXXXXXXXXXXXXXXXXXXXX/       DDMMMYYYY/##              XXXXXXXXXXXX                         XXXXXXXXXXXXXX    
        XXX         XXXXXXXXXXXXXXXXXXXXX                                                                        
 
###-### YES/        XXXXXXXXXXXXXXXXXXXXX/       DDMMMYYYY/##      ##      XXXXXX/        XXXXXXXXXXXXX         XXXXXXX/   
        500 mg/     XXXXXXXXXXXXXXXXXXXXX/       DDMMMYYYY/##              XXXXXXXXXXXX                         XXXXXXXXXXXXXX    
        XXX         XXXXXXXXXXXXXXXXXXXXX                                                                        
______________________________________________________________________________________________________________________________________ 
 
TEAEs are defined as any AE beginning on or after the first dose date of study drug. 
Onset dose is the subject’s Nevanimibe dose level on the reported start date of the event. 
For AEs starting prior to first dose of study drug, day = start date/end date – first dose of study drug. 
Otherwise, day = start date/end date – first dose date OF THE ONSET DOSE LEVEL +1.  
Duration = end date – start date + 1. 
AEs are coded using MedDRA dictionary version 18.0. 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM 
 
<<Programming Note: Refer to EC.ECCAT=”EXCEPTION DOSE” for the date of last dose prior to interruption and the date of 
restart. If any additional free text is mapped to SUPPAE (e.g. outcome sequelae or specify other action taken), then list it with the text 
of the parent field. >> 
 


 
 
Millendo Therapeutics US, Inc. 
Protocol ATR-101-301                                                                                                       Page 1 of # 
Listing 16.2.8.1 
Safety Laboratory Values: Chemistry 
All Subjects 
______________________________________________________________________________________________________________________________________ 
             
                                                            Date/Time of                         
Subject            Parameter (Unit)          Visit          Collection             Result     Normal Range   Flag [1] 
______________________________________________________________________________________________________________________________________ 
  
###-### (SF)       XXXXXXXXXXX (XXXXX)       XXXXXXXXXXXX   DDMMMYYYY/HH:MM        XXXXX      XX – XX        XX 
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM        XXXXX      XX - XX        XX 
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM        XXXXX      XX - XX        XX 
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM        XXXXX      XX - XX        XX 
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM        XXXXX      XX - XX        XX 
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM        XXXXX      XX - XX        XX 
 
                   XXXXXXXXXXX (XXXXX)       XXXXXXXXXXXX   DDMMMYYYY/HH:MM        XXXXX      XX – XX        XX 
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM        XXXXX      XX - XX        XX 
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM        XXXXX      XX - XX        XX 
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM        XXXXX      XX - XX        XX 
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM        XXXXX      XX - XX        XX 
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM        XXXXX      XX - XX        XX 
 
###-###            XXXXXXXXXXX (XXXXX)       XXXXXXXXXXXX   DDMMMYYYY/HH:MM        XXXXX      XX – XX        XX 
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM        XXXXX      XX - XX        XX 
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM        XXXXX      XX - XX        XX 
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM        XXXXX      XX - XX        XX 
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM        XXXXX      XX - XX        XX 
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM        XXXXX      XX - XX        XX 
 
###-###            XXXXXXXXXXX (XXXXX)       XXXXXXXXXXXX   DDMMMYYYY/HH:MM        XXXXX      XX – XX        XX 
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM        XXXXX      XX - XX        XX 
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM        XXXXX      XX - XX        XX 
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM        XXXXX      XX - XX        XX 
                                             XXXXXXXXXXXX   DDMMMYYYY/HH:MM        XXXXX      XX - XX        XX 
______________________________________________________________________________________________________________________________________ 
 
SF = Screen failure subject. 
[1] Laboratory Flag: RH=Reference High, RL=Reference Low, NH=Notable High, NL=Notable Low, CH=Critical High, CL=Critical Low 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM 
<< Programming Note: Including all non-missing LBORRES where LBCAT = “CHEMISTRY”. Exclude LBTESTCD = “HCG” since 
that is a pregnancy test which is included in another listing. >> 
 


 
 
Programming Note: The following listings will have the same layout as Listing 16.2.8.1. 
Listing 16.2.8.2 
Safety Laboratory Values: Hematology 
Screened Subjects 
 
Listing 16.2.8.3 
Safety Laboratory Values: Lipids 
Screened Subjects 
 
Listing 16.2.8.4 
Safety Laboratory Values: Coagulation 
Screened Subjects 
 
Listing 16.2.8.5 
Safety Laboratory Values: Urinalysis 
Screened Subjects 
 
Listing 16.2.8.6 
Safety Laboratory Values: Serology and Urine Drug Screen 
Screened Subjects 
 


 
 
Millendo Therapeutics US, Inc. 
Protocol ATR-101-301                                                                                                       Page 1 of # 
Listing 16.2.8.7 
Serum and Urine Pregnancy Test 
All Subjects 
______________________________________________________________________________________________________________________________________ 
 
                                   Date of Last         Collection       Urine Test  Serum Test 
Subject       Visit                Menstrual Period     Date/Time        Result      Result       Reason Not Done 
______________________________________________________________________________________________________________________________________ 
 
###-### (SF)  XXXXXXXXXXXXXX       DDMMMYYYY            DDMMMYYYY/HH:MM  XXXXXXXX    XXXXXXXXXX   XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
              XXXXXXXXXXXXXX       DDMMMYYYY            DDMMMYYYY/HH:MM  XXXXXXXX    XXXXXXXXXX   XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
              XXXXXXXXXXXXXX       DDMMMYYYY            DDMMMYYYY/HH:MM  XXXXXXXX    XXXXXXXXXX   XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
              XXXXXXXXXXXXXX       DDMMMYYYY            DDMMMYYYY/HH:MM  XXXXXXXX    XXXXXXXXXX   XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
              XXXXXXXXXXXXXX       DDMMMYYYY            DDMMMYYYY/HH:MM  XXXXXXXX    XXXXXXXXXX   XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
 
###-###       XXXXXXXXXXXXXX       DDMMMYYYY            DDMMMYYYY/HH:MM  XXXXXXXX    XXXXXXXXXX   XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
              XXXXXXXXXXXXXX       DDMMMYYYY            DDMMMYYYY/HH:MM  XXXXXXXX    XXXXXXXXXX   XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
              XXXXXXXXXXXXXX       DDMMMYYYY            DDMMMYYYY/HH:MM  XXXXXXXX    XXXXXXXXXX   XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
              XXXXXXXXXXXXXX       DDMMMYYYY            DDMMMYYYY/HH:MM  XXXXXXXX    XXXXXXXXXX   XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
              XXXXXXXXXXXXXX       DDMMMYYYY            DDMMMYYYY/HH:MM  XXXXXXXX    XXXXXXXXXX   XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
______________________________________________________________________________________________________________________________________ 
 
SF = Screen failure subject. 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM 
<< Programming Note: Include all records where LB.LBTESTCD = “HCG” and LBNAM = null. >> 


 
 
Millendo Therapeutics US, Inc. 
Protocol ATR-101-301                                                                                                       Page 1 of # 
Listing 16.2.9.1 
Vital Signs 
All Subjects 
______________________________________________________________________________________________________________________________________ 
             
                            Date         SBP    DBP      HR    Temperature    RR        Weight         Height         BMI     
Subject       Visit         Performed   (mmHg) (mmHg)   (bpm)   (Units)      (bpm)     (Units)         (Units)       (kg/m2)  
______________________________________________________________________________________________________________________________________ 
 
###-### (SF)  XXXXXXXXXXXX  DDMMMYYYY    ###    ###      ###     ### (°F)      ###     ###.# (kg)     ###.# (cm)      ##.#    
              XXXXXXXXXXXX  DDMMMYYYY    ###    ###      ###     ### (°F)      ###     ###.# (kg)     ###.# (cm)      ##.#    
              XXXXXXXXXXXX  DDMMMYYYY    ###    ###      ###     ### (°C)      ###     ###.# (lb)     ###.# (in)      ##.#    
 
###-###       XXXXXXXXXXXX  DDMMMYYYY    ###    ###      ###     ### (°F)      ###     ###.# (kg)     ###.# (cm)      ##.#    
              XXXXXXXXXXXX  DDMMMYYYY    ###    ###      ###     ### (°F)      ###     ###.# (kg)     ###.# (cm)      ##.#    
              XXXXXXXXXXXX  DDMMMYYYY    ###    ###      ###     ### (°C)      ###     ###.# (lb)     ###.# (in)      ##.#    
 
###-###       XXXXXXXXXXXX  DDMMMYYYY    ###    ###      ###     ### (°F)      ###     ###.# (kg)     ###.# (cm)      ##.#    
              XXXXXXXXXXXX  DDMMMYYYY    ###    ###      ###     ### (°F)      ###     ###.# (kg)     ###.# (cm)      ##.#    
              XXXXXXXXXXXX  DDMMMYYYY    ###    ###      ###     ### (°C)      ###     ###.# (lb)     ###.# (in)      ##.#    
______________________________________________________________________________________________________________________________________ 
 
SF = Screen failure subject. 
SBP = systolic blood pressure. DBP = diastolic blood pressure. HR = heart rate (bpm = beats per minute).  
RR = respiratory rate (bpm = breaths per minute). BMI = Body Mass Index. 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM 


 
 
Millendo Therapeutics US, Inc. 
Protocol ATR-101-301                                                                                                       Page 1 of # 
Listing 16.2.9.2 
12-Lead Electrocardiogram 
All Subjects 
______________________________________________________________________________________________________________________________________ 
             
Subject                 Date           Heart Rate    ---- Interval (msec) ----- 
  Visit                 Performed     (beats/min)    PR   QRS  QT   QTcF   RR       Overall Interpretation   Describe Abnormality 
______________________________________________________________________________________________________________________________________ 
 
###-### (SF) 
  XXXXXXXXXXXXXXXXXX    DDMMMYYYY        ###         ###  ###  ###  ###    ###      NORMAL                   XXXXXXXXXXXXXXXXXXXXXXXX 
  XXXXXXXXXXXXXXXXXX    DDMMMYYYY        ###         ###  ###  ###  ###    ###      ABNORMAL, NCS            XXXXXXXXXXXXXXXXXXXXXXXX 
  XXXXXXXXXXXXXXXXXX    DDMMMYYYY        ###         ###  ###  ###  ###    ###      ABNORMAL, CS             XXXXXXXXXXXXXXXXXXXXXXXX 
  XXXXXXXXXXXXXXXXXX    DDMMMYYYY        ###         ###  ###  ###  ###    ###      XXXXXXXXXXXXXXXXXX       XXXXXXXXXXXXXXXXXXXXXXXX 
 
###-###  
  XXXXXXXXXXXXXXXXXX    DDMMMYYYY        ###         ###  ###  ###  ###    ###      XXXXXXXXXXXXXXXXXX       XXXXXXXXXXXXXXXXXXXXXXXX 
  XXXXXXXXXXXXXXXXXX    DDMMMYYYY        ###         ###  ###  ###  ###    ###      XXXXXXXXXXXXXXXXXX       XXXXXXXXXXXXXXXXXXXXXXXX 
  XXXXXXXXXXXXXXXXXX    DDMMMYYYY        ###         ###  ###  ###  ###    ###      XXXXXXXXXXXXXXXXXX       XXXXXXXXXXXXXXXXXXXXXXXX 
  XXXXXXXXXXXXXXXXXX    DDMMMYYYY        ###         ###  ###  ###  ###    ###      XXXXXXXXXXXXXXXXXX       XXXXXXXXXXXXXXXXXXXXXXXX 
______________________________________________________________________________________________________________________________________ 
 
SF = Screen failure subject. NCS = not clinically significant. CS = clinically significant. 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM 


 
 
Millendo Therapeutics US, Inc. 
Protocol ATR-101-301                                                                                                       Page 1 of # 
Listing 16.2.9.3 
Physical Examination 
All Subjects 
______________________________________________________________________________________________________________________________________ 
             
Subject       Visit              Date of Exam     Result                         Describe Findings 
______________________________________________________________________________________________________________________________________ 
 
###-### (SF)  XXXXXXXXXXXXXXX    DDMMMYYYY        NORMAL                         XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
              XXXXXXXXXXXXXXX    DDMMMYYYY        ABNORMAL NCS                   XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
              XXXXXXXXXXXXXXX    DDMMMYYYY        NO CHANGE FROM PREVIOUS EXAM   XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
              XXXXXXXXXXXXXXX    DDMMMYYYY        ABNORMAL CS                    XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
              XXXXXXXXXXXXXXX    DDMMMYYYY        XXXXXXXXXXXXXXXXXXXXXXXXXXXX   XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
              XXXXXXXXXXXXXXX    DDMMMYYYY        XXXXXXXXXXXXXXXXXXXXXXXXXXXX   XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
 
###-###       XXXXXXXXXXXXXXX    DDMMMYYYY        XXXXXXXXXXXXXXXXXXXXXXXXXXXX   XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
              XXXXXXXXXXXXXXX    DDMMMYYYY        XXXXXXXXXXXXXXXXXXXXXXXXXXXX   XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
              XXXXXXXXXXXXXXX    DDMMMYYYY        XXXXXXXXXXXXXXXXXXXXXXXXXXXX   XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
              XXXXXXXXXXXXXXX    DDMMMYYYY        XXXXXXXXXXXXXXXXXXXXXXXXXXXX   XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
              XXXXXXXXXXXXXXX    DDMMMYYYY        XXXXXXXXXXXXXXXXXXXXXXXXXXXX   XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
              XXXXXXXXXXXXXXX    DDMMMYYYY        XXXXXXXXXXXXXXXXXXXXXXXXXXXX   XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
              XXXXXXXXXXXXXXX    DDMMMYYYY        XXXXXXXXXXXXXXXXXXXXXXXXXXXX   XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
______________________________________________________________________________________________________________________________________ 
 
SF = Screen failure subject. CS = Clinically significant. NCS = Not clinically significant. 
 
Program Name: XXXXXXXX.sas                  Run Date: DDMMMYYYY HH:MM                 Clinical database last extracted: DDMMYYYY HH:MM