Clinical trial NCT02804178
Conditions: Congenital Adrenal Hyperplasia
Keywords: ATR-101 classic congenital adrenal hyperplasia 21-hydroxylase deficiency CAH
Sponsor: Millendo Therapeutics, Inc.
Start date: 2016-05-18; Completion date: 2017-08-17
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 2 multicenter, single-blind, multiple dose study to evaluate the safety and efficacy of orally administered ATR-101 in subjects with classic congenital adrenal hyperplasia (CAH). Treatment duration will range from a minimum of approximately 2 months to 6 months per subject. A subject may receive a minimum of one dose level or up to a maximum of 5 dose levels, in sequentially increasing dose strengths. Each dose level will last 28 days.

Detailed description:

Arms: arm 1: Ascending dose levels of ATR-101 beginning with 125 mg by mouth twice per day up to 1000 mg twice per day.
Interventions: intervention 1: ATR-101
Intervention descriptions: intervention 1: 125-1000 mg twice per week

Protocol documents:
Prot_000.pdf: 
Millendo Therapeutics, Inc. 
ATR-101-201 
Clinical Study Protocol 
Study Title: A Phase 2, Multicenter  Study of ATR-101 for the Treatment of 
Congenital Adrenal Hyperplasia  
Study Number: ATR-101-201 
Study Phase: 2 
Product Name: ATR-101 
IND Number: 122745 
NCT Number: NCT02804178
Indication: Congenital Adrenal Hyperplasia  
Sponsor: Millendo Therapeutics, Inc. 
Sponsor Medical Contact: Pharis Mohideen, M.D.
Amendment 1 
January 14, 2016 
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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SYNOPSIS   
Compound Name/No. 
ATR-101 
Study Number  
ATR-101-201 
Study Title 
A Phase 2, Multicenter, Study of ATR-101 for the Treatment 
of Congenital Adrenal Hyperplasia  
Phase of Clinical 
Development 
2 
Objective(s) 
Primary: The primary objective of this study is to evaluate the 
efficacy and safety of orally administered ATR-101 in subjects 
with classic congenital adrenal hyperplasia (CAH). 
Secondary:  
 To evaluate the changes in adrenal cortical steroids and 
steroid intermediates   
 To evaluate the changes to the hypothalamic-pituitary-
adrenal axis (via ACTH) 
 To evaluate the pharmacokinetics (PK) of ATR-101 
Study Design 
This is a multicenter, single-blind, multiple dose study of ATR-
101 with a placebo washout component. The Screening Period 
will be followed by a placebo, Baseline Lead-in Period. 
Subjects will then receive the lowest dose of ATR-101 for 14 
days followed by a single-blind placebo Washout Period of 14 
days. Safety and efficacy assessments will occur at the end of 
ATR-101 treatment and following the Washout Period. If the 
primary outcome measure (17-OHP ≤ 2x ULN) is not 
achieved, the subject will proceed to the next higher dose level.  
ATR-101 treatment will stop once the primary outcome 
measure is met. A total of 5 ATR-101 dose levels are possible.  
Duration of Study  
Approximately 12 months  
Number of Centers 
5-8 in United States 
Number/Type of 
Subjects  
Minimum of 9 with a maximum of 17. Classic CAH due to 21-
hydroxylase deficiency (21-OHD). 
Study Treatments  
ATR-101 tablets twice daily by mouth. ATR-101 tablets will 
be available in 125, 250 and 500 mg doses with matching 
placebo tablets. Five dose levels are planned: 125 mg BID, 250 
mg BID, 500 mg BID, 750 mg BID and 1000 mg BID.  
Duration of Treatment 
Treatment duration will range from a minimum of 
approximately 2 months to 6 months per subject. Subjects will 
have a Screening Period of up to 21 days and then enter a 
placebo Baseline Lead-in Period of 14 days.  Each dose level 


 
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Compound Name/No. 
ATR-101 
Study Number  
ATR-101-201 
will last 28 days and consist of ATR-101 treatment for 14 days 
followed immediately by 14 days of matching placebo. A 
subject may receive a minimum of one dose level or up to a 
maximum of 5 dose levels, in sequentially increasing dose 
strengths. 
Key Inclusion Criteria 
Subjects meeting the following criteria may be included in the 
study: 
 Subjects aged 18 to 80 years at the time of signing the 
informed consent form (ICF) 
 Men or women with classic CAH due to 21-OHD   
 Subject must have a documented historical diagnosis of 
CAH due to 21-OHD based on any one of the following 
criteria: 
o Documented genetic mutation in the CYP21A2 
enzyme consistent with a diagnosis of classic CAH 
o Historical documentation of elevated 17-OHP (e.g. 
in infancy or following a cosyntropin (ACTH) 
stimulation test) 
 Biochemical marker of disease status at Screening and 
Baseline Lead-in Period 
o 17-OHP >  4 x ULN  
 Chronic glucocorticoid replacement therapy for at least 
6 consecutive months prior to signing ICF 
 Stable glucocorticoid and mineralocorticoid regimen for at 
least 1 month prior to signing ICF (per Investigator 
discretion) 
 Female subjects of childbearing potential must consent to 
use two medically acceptable methods of contraception 
throughout the study period and for 30 days after the last 
dose of study treatment 
 Males must be sterile (e.g. status-post vasectomy) for 
6 months prior to informed consent or agree to use two 
approved methods of contraception where one method must 
include a barrier method 
 


 
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Compound Name/No. 
ATR-101 
Study Number  
ATR-101-201 
Key Exclusion Criteria 
Subjects will be excluded from participation in the study if any 
of the following criteria are met: 
 Non-classic CAH 
 Other causes of adrenal insufficiency such as Addison’s 
disease; adrenalectomy, etc. 
 Surgery within the previous 3 months prior to screening or 
planned surgery during study participation. Minor 
procedures are permitted (e.g. removal of skin tags or other 
minor dermatological procedures) 
 Abnormal laboratory tests at Screening: 
o ALT or AST > 2 x ULN 
o Bilirubin > 1.5 x ULN  
o Serum Creatinine >1.5 x ULN  
 History of active cancer requiring medical or surgical 
therapy within the past 6 months (with the exception of 
successfully treated non-metastatic basal cell or squamous 
cell carcinoma of the skin and carcinoma in-situ of the 
cervix) 
 Significant comorbid medical condition(s) that may 
preclude compliance with the study protocol or such that 
study participation may not be in the subject’s best medical 
interest. Medical conditions may include (but are not 
limited to) those of the cardiovascular, respiratory, 
gastrointestinal, renal, hepatic, central nervous system 
(CNS) or immune system (e.g., human immunodeficiency 
virus), Myocardial infarction (MI) or cerebrovascular 
accident/transient ischemic attack (CVA/TIA) within the 
past 6 months. 
 Psychiatric illness such that comprehension of the informed 
consent or compliance with the study protocol may be 
impaired 
 Treatment with another investigational drug or device 
within 3 months prior to Screening 


 
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Compound Name/No. 
ATR-101 
Study Number  
ATR-101-201 
Criteria for Evaluation 
Pharmacokinetics:  ATR-101 (and its metabolites) 
pharmacokinetic parameters will be assessed. 
 
Pharmacodynamics:  Changes in adrenal cortical steroids and 
steroid intermediates (e.g. 17-OHP, androstenedione, 
testosterone, free testosterone, sex hormone binding globulin 
(SHBG), dehydroepiandrosterone (DHEA), DHEA-S, 
aldosterone, PRA); Changes in ACTH 
 
Safety:  Safety assessment will consist of monitoring and 
recording: adverse events (AE) and serious adverse events 
(SAE); changes in physical examinations, vital signs, 
electrocardiograms (ECGs); regular monitoring of hematology, 
prothrombin time (PT)/activated partial thromboplastin time 
(aPTT), INR, blood chemistry, steroid hormones and urine 
analysis values. 
Stopping Criteria 
Investigational Medicinal Product (IMP) may be discontinued 
due to a safety event. Once a subject has met the efficacy 
endpoint, no further administration of study drug will be 
permitted. 
Study Endpoints 
Primary Efficacy Endpoint: The primary efficacy endpoint 
will be the overall response rate defined by the percentage of 
subjects meeting the primary outcome measure as follows: 
 17-OHP < 2 x ULN 
Safety Endpoints: Safety parameters (AEs, vital signs, 
physical examination, laboratory measures, ECG) 
Pharmacokinetic Endpoints:   
 Area under the curve (AUC0-4 hr) 
 Maximum plasma concentration (Cmax) 
 Time to maximum concentration (Tmax) 
Statistical Methods 
Qualitative statistical analyses will be performed for both 
safety and efficacy parameters. 


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Schedule of Assessments for ATR-101  
 
Procedure 
Screening 
(Day -21 to 
Day -1)a 
Baseline 
Lead-Inb 
 
Dose Level 1c 
 
Dose Levels 2 - 5 
Final Study 
Visit or 
Early 
Termination 
Visit  
(Day 29) 
Follow-up Visit 
(Telephone) 
Placebo 
(Day 1) 
ATR-101 
Treatment 
(Day 1-14) 
Placebo 
Washout 
(Day 15-
28) 
ATR-101 
Treatment 
(Day 1-14) 
Placebo 
Washout 
(Day 15-28) 
(Final Study 
Visit/Early 
Termination Visit  
+ 2 weeks) 
Informed Consent  
X 
 
 
 
 
 
 
 
Dose Assessmentd 
 
 
 
 
X 
 
 
 
Inclusion/Exclusion Criteria  
X 
X 
Xe 
 
 
 
 
 
Medical History & Demographics  
X 
 
 
 
 
 
 
 
Physical Examinationf 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signsg and Weight 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECGh 
X 
 
X 
X 
X 
X 
X 
 
Hematology Panel 
X 
Xq 
X 
X 
X 
X 
X 
 
Serum Chemistry Panel 
X 
Xq 
X 
X 
X 
X 
X 
 
PT, aPTT, INR 
X 
Xq 
X 
X 
X 
X 
X 
 
Urinalysis 
X 
 
 
 
 
 
X 
 
Serology (HBsAg, Hepatitis C 
antibody, HIV) 
X 
 
 
 
 
 
 
 
Steroid Hormonesi 
X 
X 
X 
X 
X 
X 
X 
 
Exogenous Glucocorticoid Levelsj 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy Testk 
X 
 
X 
 
X 
 
X 
 
PK ATR-101 Plasma Levelsl 
 
 
X 
X 
X 
X 
X 
 
Prior/Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense IMPm 
 
X 
X 
X 
X 
X 
 
 
Collect IMPn/Drug Accountability 
 
 
X 
X 
X 
X 
X 
 
Assess IMP Complianceo 
 
 
X 
X 
X 
X 
X 
 
Adverse Eventsp 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 


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a Day -21 to Day -1 will be used to collect data from the Screening assessments.  
b Baseline Lead-In with placebo will be a  minimum of 14 days but an additional 3 days is allowed. 
c For each Dose Level there will be 14 days of treatment with ATR-101 and 14 days of treatment with placebo.  For each portion there should be a 
minimum of 11 days of treatment and a maximum of +3 days is allowed beyond the scheduled 14 days. 
d Dose assessment will be performed prior to dosing on Day 1 of Dose Levels 2, 3, 4 and 5 as needed.  The PI or SI will review the 17-OHP results 
obtained on Day 15 and determine whether the Final Study Visit will be conducted (17-OHP ≤2 x ULN on Day 15) or whether the next Dose 
Level, Day 1 Visit will be conducted (17-OHP > 2 x ULN on Day 15).   
e 17-OHP results from Screening and Baseline Lead-In Period will be used in this evaluation of inclusion criteria. 
f Complete physical examinations will be performed at Screening and the Final Study Visit or Early Termination Visit. An abbreviated (brief) 
physical exam will be performed at Day 1 of Baseline Lead-In Period, pre-dose on Day 1 and Day 15 of each dose level.   
g Vital signs (blood pressure, pulse, respiration rate, and temperature) and body weight will be measured at Screening, Day 1 of the Baseline Lead-
In Period, pre-dose and 1, 2, and 4 hour post-dose on Day 1 of each dose level, Day 15 for each dose level, and at the Final Study Visit or 
Early Termination Visit.  Height will be measured at Screening. 
h All subjects will have 12-lead ECG assessments at Screening, Day 1 pre-dose and 2 hours post-dose for each dose level, Day 15 pre-dose for 
each dose level, and at the completion of the Placebo Washout Period on Day 29. 
i Blood samples for steroid hormones and steroid intermediates including 17-OHP, androstenedione, cortisol, testosterone, ACTH, free 
testosterone, SHBG, aldosterone, 11-DOC, PRA, DHEA and DHEAS will be obtained at Screening, Day 1 of Baseline Lead-In Period, pre-
dose on Day 1 and Day 15 of each dose level and at the Final Study Visit or Early Termination Visit.  All samples will be collected prior to 10 
AM. 
j Blood samples for exogenous glucocorticoid levels (Betamethasone, Budesonide, Dexamethasone, Fludrocortisone, Flunisolide, 
Fluorometholone, Hydrocortisone, Megestrol acetate, Methylprednisolone, Prednisolone, Prednisone, Triamcinolone, Triamcinolone 
acetonide) will be obtained as appropriate for each subject.  
k Obtained for females of childbearing potential who are not surgically sterile or who have not been naturally postmenopausal for at least 12 
consecutive months (i.e., who have had menses any time in the preceding 12 consecutive months).  A serum pregnancy test will be performed 
at Screening. A urine pregnancy test will be performed prior to dosing on Day 1 of each Dose Level and at the Final Study Visit or Early 
Termination Visit.  
l Blood for PK analysis of ATR101 and its metabolites in plasma will be obtained on Day 1 of each Dose Level at pre-dose and 1, 2, 3, and 4 hours 
post-dose; on Day 15 of each Dose Level at pre-dose and at the Final Study Visit or Early Termination Visit. A window of ± 10 minutes is 
permitted around each sampling time-point. 
m The first dose will be administered on site on Day 1 and Day 15 of each dose level. 
n All bottles and unused tablets must be returned to the study site on Day 1 and Day 15 of each dose level and at the Final Study Visit or Early 
Termination Visit. 
o IMP compliance will be assessed by counting the number of tablets returned and determining if the correct number were taken within the 
window of 80% to 120%. 
p AEs will be collected from the time the subject signs the informed consent form until 30 days after the last dose of IMP. 
q Tests do not need to be repeated on Day 1 of Baseline Lead-In if the subject’s clinical condition has not changed and these tests were done < 14 
days prior to Day 1 
 


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TABLE OF CONTENTS 
Synopsis .................................................................................................................................... 2 
Table Of Contents ..................................................................................................................... 8 
LIST OF IN-TEXT TABLES ................................................................................................. 11 
LIST OF IN-TEXT FIGURES................................................................................................ 11 
LIST OF APPENDICES ......................................................................................................... 12 
List of Abbreviations .............................................................................................................. 13 
1 
Introduction ................................................................................................................... 15 
1.1 Description of Congenital Adrenal Hyperplasia ........................................................... 15 
1.2 Rationale for Use of ATR-101 in Congenital Adrenal Hyperplasia ............................. 16 
2 
Study Objectives ........................................................................................................... 17 
2.1 Primary Objective ......................................................................................................... 17 
2.2 Secondary Objectives ................................................................................................... 17 
3 
Investigational Plan ....................................................................................................... 18 
3.1 Overall Study Design and Plan ..................................................................................... 18 
3.1.1 
Screening Period ................................................................................................. 20 
3.1.2 
Baseline Lead-in Period ...................................................................................... 20 
3.1.3 
Dose Level 1 (ATR-101 125 mg BID and matching placebo) ........................... 20 
3.1.4 
Dose Levels 2, 3, 4 and 5 .................................................................................... 21 
3.1.5 
Final Study Visit ................................................................................................. 21 
3.1.6 
Follow-up Visit ................................................................................................... 21 
3.2 Rationale for Study Design and Dose Levels ............................................................... 21 
3.3 Efficacy Assessment ..................................................................................................... 23 
3.4 Safety Assessment ........................................................................................................ 23 
4 
Study Population Selection ........................................................................................... 24 
4.1 Study Population ........................................................................................................... 24 
4.2 Inclusion Criteria .......................................................................................................... 24 
4.3 Exclusion Criteria ......................................................................................................... 25 
5. 
Study Treatment ............................................................................................................ 26 
5.1 Assignment of Subject Identification Numbers ............................................................ 26 
5.2 Description of Treatment .............................................................................................. 26 
5.3 Treatments Administered .............................................................................................. 27 


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5.3.1  Timing and Administrative Dosing Conditions ...................................................... 28 
5.3.2 
Advancement to the Next Dose Level ................................................................ 28 
5.3.3 
Changes in Daily Dose are Not Permitted .......................................................... 29 
5.3.4 
Missed Doses ...................................................................................................... 29 
5.3.5 
Withholding IMP ................................................................................................ 29 
5.3.6 
Compliance with IMP ......................................................................................... 29 
5.3.7 
Blinding............................................................................................................... 30 
5.3.8 
Concomitant Therapies ....................................................................................... 30 
5.3.9 
Glucocorticoid and Mineralocorticoid Replacement for CAH ........................... 30 
5.3.10 
Prohibited Medications ................................................................................... 30 
5.4 Restrictions, Precautions and Warnings ....................................................................... 31 
5.5 Packaging and Labeling ................................................................................................ 31 
5.6 Storage and Accountability ........................................................................................... 32 
5.7 Investigational Product Retention at Study Site ........................................................... 32 
6 
Study Procedures .......................................................................................................... 33 
6.1 Allowable Variation in Study Visits ............................................................................. 33 
6.2 Informed Consent ......................................................................................................... 33 
6.3 Eligibility ...................................................................................................................... 34 
6.4 Medical History ............................................................................................................ 34 
6.5 Physical Examination ................................................................................................... 34 
6.6 Vital Signs ..................................................................................................................... 34 
6.7 Electrocardiography and Determination of QTc .......................................................... 35 
6.8 Prior and/or Concomitant Medication Assessments ..................................................... 35 
6.9 Pharmacokinetic Assessments ...................................................................................... 35 
6.10 
Pharmacodynamic Assessments ............................................................................. 36 
6.11 
Timing of Pharmacodynamic Blood Samples and Dosing of Replacement Steroids
 
36 
6.12 
Adverse Events, Serious Adverse Events, and Reporting ...................................... 37 
6.12.1 
Adverse Events, Severity, and Relationship ................................................... 37 
6.12.2 
Assessing Severity of Adverse Events ............................................................ 38 
6.12.3 
Assessing Relationship to Study Treatment ................................................... 38 
6.12.4 
Classification of Causality .............................................................................. 38 
6.12.5 
Serious Adverse Events .................................................................................. 39 


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6.12.5..1 
Definition of Serious Adverse Events ......................................................... 39 
6.12.5..2 
Reporting Serious Adverse Events (SAEs) ................................................. 39 
6.12.5..3 
Pregnancy Reporting ................................................................................... 40 
6.12.6 
Regulatory Reporting of Adverse Events ....................................................... 41 
6.13 
Clinical Laboratory Tests ........................................................................................ 41 
6.13.1 
Sample Collection, Storage, and Shipping ..................................................... 43 
6.14 
Blood Sample Collection ........................................................................................ 43 
6.15 
Removal of Subjects from the Study or Study Drug .............................................. 44 
7 
Study Activities ............................................................................................................. 45 
7.1 Screening Visit (Day -21 to Day -1) ............................................................................. 45 
7.2 Baseline Lead-in Period ................................................................................................ 45 
7.3 Dose Level 1, Days 1-28 ............................................................................................... 46 
7.4 Final Study Visit or Next Dose Level, Day 1 ............................................................... 47 
7.5 Dose Levels 2, 3, 4 and 5 .............................................................................................. 48 
7.6 Final Study Visit ........................................................................................................... 48 
7.7 Early Termination Visit ................................................................................................ 48 
7.8 Follow-up Visit ............................................................................................................. 49 
8 
Quality Control and Assurance ..................................................................................... 50 
9 
Planned Statistical Methods .......................................................................................... 51 
9.1 General Considerations ................................................................................................. 51 
9.2 Analysis Populations ..................................................................................................... 51 
9.3 Patient Demographics and Baseline Characteristics ..................................................... 51 
9.4 Treatment ...................................................................................................................... 52 
9.5 Primary Efficacy Endpoint ........................................................................................... 52 
9.6 Secondary Endpoints .................................................................................................... 52 
9.7 Safety ............................................................................................................................ 52 
9.8 Pharmacokinetic and Pharmacodynamic Analyses ...................................................... 52 
9.9 Interim Analysis ............................................................................................................ 52 
10 
Administrative Considerations ..................................................................................... 53 
10.1 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) .............. 53 
10.2 
Ethical Conduct of the Study .................................................................................. 53 
10.3 
Subject Information and Consent............................................................................ 53 
10.4 
Subject Confidentiality ........................................................................................... 54 


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10.5 
Study Monitoring .................................................................................................... 54 
10.6 
Case Report Forms and Study Records .................................................................. 54 
10.7 
Data Safety Monitoring Board ................................................................................ 55 
10.8 
Protocol Deviations ................................................................................................. 55 
10.9 
Access to Source Documentation ........................................................................... 55 
10.10 
Data Generation and Analysis ............................................................................ 56 
10.11 
Retention of Data ................................................................................................ 56 
10.12 
Financial Disclosure ............................................................................................ 56 
10.13 
Premature Termination of the Study ................................................................... 56 
10.14 
Clinical Study Report .......................................................................................... 57 
10.15 
Subject Insurance and Indemnity ........................................................................ 57 
10.16 
Amendments to the Protocol ............................................................................... 57 
11 
Reference List ............................................................................................................... 58 
 
LIST OF IN-TEXT TABLES 
Table 1 
ATR-101 Dose Levels. ..............................................................................20 
Table 2 
Tablet Formulations ...................................................................................27 
Table 3 
ATR-101 Dose Levels and Tablet Doses. ..................................................28 
Table 4 
Pharmacokinetic Sampling Time Points ....................................................36 
Table 5 
List of Clinical Laboratory Tests ...............................................................42 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study Design ..............................................................................................18 
Figure 2 
28 Day Sequence for Each Dose Level ......................................................19 
 


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LIST OF APPENDICES 
Appendix 1 
Sponsor Signature ......................................................................................59 
Appendix 2 
Investigator’s Signature .............................................................................60 
Appendix 3 
Drugs that Prolong the QT/QTc interval ...................................................61 
Appendix 4 
Drugs Known to Interact with CYP3A4 ....................................................64 
Appendix 5 
Drugs that may Interact with P-glycoprotein .............................................70 
 


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LIST OF ABBREVIATIONS 
11-DOC 
11-deoxycorticosterone 
17-OHP 
17-hydroxyprogesterone 
21-OHD 
21-hydroxylase deficiency 
21-OHP 
21-hydroxyprogresterone 
ACC 
Adrenal cortical carcinoma 
ACTH 
Adrenocorticotropic hormone 
ACAT1 
Acyl-CoA: cholesterol acyltransferase 1 
AE 
Adverse event 
ALB 
Albumin 
ALK-P 
Alkaline phosphatase 
ALT; SGPT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST; SGOT 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
β-hCG 
Beta human chorionic gonadotropin 
BID 
Twice daily 
BUN 
Blood urea nitrogen 
Ca 
Calcium 
CAH 
Congenital adrenal hyperplasia 
CE 
Cholesterol ester 
CFR 
Code of Federal Regulations 
Cmax 
Maximum plasma concentration 
CNS 
Central nervous system 
CQA 
Clinical quality assurance 
CRA 
Clinical research associate 
CS 
Cushing's syndrome 
CSR 
Clinical study report 
CVA 
Cerebrovascular accident 
CYP 
Cytochrome P450 enzymes 
DHEA 
Dehydroepiandrosterone 
DHEA-S 
Dehydroepiandrosterone sulfate 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
eCRF 
Electronic case report form 
FC 
Free cholesterol 
FDA 
Food and Drug Administration 
GC 
Glucocorticoid 
GCP 
Good clinical practices 
HBsAg 
Hepatitis B surface antigen 
Hct 
Hematocrit 


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HEENT 
Head, eyes, ears, nose, and throat 
Hgb 
Hemoglobin 
HIPPA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HPA 
Hypothalamic pituitary adrenal 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
ID 
Identification number 
IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 
INR 
International normalizedrRatio 
IRB 
Institutional Review Board 
mg 
Milligram 
MC 
Mineralocorticoid 
MI 
Myocardial Infarction 
MTD 
Maximum tolerated dose 
PCOS 
Polycystic ovarian syndrome 
PI 
Principal investigator 
PD 
Progressive disease 
PK 
Pharmacokinetics 
PRA 
Plasma Renin Activity 
PT 
Prothrombin time 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SI 
Sub-investigator 
StAR 
Steroidogenic acute regulatory protein 
TIA 
Transient ischemic attack 
Tmax 
Time to maximum concentration 
TMF 
Trial master file 
ULN 
Upper limit of normal 
UPT 
Urine pregnancy test 
US 
United States 
WBC 
White blood cell 
WHO 
World Health Organization 


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1 INTRODUCTION 
1.1 
Description of Congenital Adrenal Hyperplasia 
Congenital adrenal hyperplasia (CAH) consists of genetic disorders affecting the 
synthesis of cortisol from the adrenal glands.  More than 90% of all CAH cases are due to 
defects in the cytochrome P450 enzyme steroid 21-hydroxylase, also known as 
21-hydroxylase or CYP21A2.1  The enzyme 21-hydroxylase facilitates the conversion of 
17-hydroxyprogesterone (17-OHP) to 11-deoxycortisol, the immediate precursor of 
cortisol. Additionally, 21-hydroxylase is responsible for the conversion of progesterone 
to 11-deoxycorticosterone, the precursor of aldosterone.1 Depending on the severity of 
the enzyme defect, partial or complete glucocorticoid (GC) and mineralocorticoid (MC) 
deficiency may exist. Two forms of 21-hydroxylase deficiency (21-OHD) have been 
defined: “classic” 21-OHD is associated with cortisol insufficiency and “nonclassic” 21-
OHD is associated with mild subclinical impairment of cortisol synthesis.2  The 
remaining cases (<10%) of CAH are mainly due to four other enzyme deficiencies (i.e. 
P450scc, P450c17, 11-hydroxylase, 3-hydroysteroid dehydrogenase), a cholesterol 
protein defect (StAR) and one electron-transfer protein.3 
In the US, Newborn screening for CAH began in the late 1970’s with the ability to 
readily measure 17-OHP.4  Elevated 17-OHP, the hallmark of CAH due to 21-OHD, 
occurs in the setting of impaired ability to convert 11-deoxycortisol to cortisol and 
progesterone to deoxycorticosterone. Prior to screening measures to identify CAH 
patients and treatment with GC therapy, undiagnosed/untreated CAH was associated with 
significant morbidity and mortality.   
Replacement GC and MC therapy are the mainstays of CAH treatment. In spite of many 
decades of GC replacement therapy and CAH patients surviving into adulthood, CAH 
remains a challenging and difficult disease to manage. Lack of cortisol feedback 
inhibition results in markedly increased ACTH production which over time results in 
enlarged adrenal glands. The adrenals of adult patients with CAH produce a large amount 
of only a few steroids: progesterone, 17-OHP, dehydroepiandrosterone (DHEA) and its 
sulfate (DHEA-S).5   Management of classic CAH entails a difficult balance between GC 
replacement required for survival versus higher, supra-physiologic (pharmacologic) doses 
needed to suppress ACTH levels and decrease androgen production without causing 
iatrogenic Cushing’s syndrome (CS). Women have the added challenges of androgen 
excess (e.g., hirsutism, acne and alopecia) and potentially the inability to conceive.5 
Women may also develop a secondary polycystic ovary syndrome (PCOS) since 
androgens and 17-OHP also derive from the ovaries and may persist even after adrenal 
suppression.6   Men may have complications of androgen excess manifesting as 
suppression of gonadotropins leading to testicular atrophy and infertility.7  Additionally, 
up to 50% of men may have testicular adrenal rest tumors which can become quite large 
and painful along with causing testicular dysfunction.8  Thus, there are three major 
concerns for the management of adults with 21-OHD: (1) prevention of adrenal and 
gonadal hyperplasia and neoplasia, (2) prevention of long-term consequences of adrenal 
replacement therapies, and (3) restoration of fertility in those who desire to have 
children.5  


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1.2 Rationale for Use of ATR-101 in Congenital Adrenal Hyperplasia  
ATR-101 inhibition of adrenal steroid and steroid intermediate synthesis may provide an 
extremely valuable tool for the clinician managing CAH. Inhibition of adrenal 
steroidogenesis across the androgen pathway would negate the need to suppress ACTH 
with supra-physiologic doses of GC and prevent the risk of iatrogenic CS. CAH patients 
may then require only physiologic doses of GC replacement. Use of ATR-101 in the 
treatment of CAH 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.   
The mechanism of action of ATR-101 has been studied extensively in vitro and in vivo. 
ACAT1, the molecular target of ATR-101, is highly expressed in the adrenal glands 
compared with other tissues9 and ATR-101 is found at higher levels in the adrenal glands 
compared to other sites in the body,10 both of which are likely to contribute to the 
selectivity of ATR-101’s effects on the adrenal glands. ATR-101 disrupts adrenal 
cholesterol homeostasis via ACAT1, an enzyme that catalyzes the esterification of free 
cholesterol (FC) to cholesterol ester (CE). In the adrenal glands, CE serves as a substrate 
reservoir for steroid biosynthesis. At low doses/exposures, ATR-101 treatment results 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. 
Two proof of concept dog studies have been conducted which validate the mechanism of 
action studies.10  The first study in 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 CS. Ten dogs with 
confirmed CS (three adrenal and seven 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. 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 30/20 mg/kg BID and three of eight animals (one male, two females) at 
10/7.5 mg/kg BID exhibited clinical signs consistent with adrenal insufficiency. The 
earliest presentation occurred on Day 17. Replacement glucocorticoid (GC) and 
mineralocorticoid (MC) therapy with subcutaneous prednisone and fludrocortisone 


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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 decreases in 
adrenal function (decreases in basal and ACTH-stimulated cortisol measurements), 
decreased adrenal weights and histologic changes, were all anticipated based upon 
published studies.11, 12  
In addition to the nonclinical development program, ATR-101 is currently being tested in 
a Phase 1, first-in-human, maximum tolerated dose (MTD) study, in ACC. ACC is a rare, 
but highly malignant and aggressive cancer. ATR-101 doses for this indication are 
markedly higher (i.e. currently approximately 97.9 mg/kg/day) and are targeted for 
apoptotic effects. Mean AUC0-24 values as high as ~45,000 nghr/mL have been observed 
with acceptable toxicity (i.e. MTD has yet to be defined).   
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. The use of ATR-101 for the treatment of CAH presents a novel 
therapeutic approach. 
2 STUDY OBJECTIVES 
2.1 Primary Objective  
The primary objective of this study is to evaluate the efficacy and safety of orally 
administered ATR-101 in subjects with CAH. 
2.2 Secondary Objectives  
The secondary objectives of this study are: 
 To evaluate the changes in adrenal cortical steroids and steroid intermediates   
 To evaluate the changes to the hypothalamic-pituitary-adrenal axis (via ACTH) 
 To evaluate the pharmacokinetics (PK) of ATR-101 
 


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3 INVESTIGATIONAL PLAN 
3.1 Overall Study Design and Plan 
This is a multicenter, single-blind, multiple dose study of ATR-101 with a placebo washout 
component. A minimum of nine subjects will be enrolled with the potential to add an 
additional eight subjects.  The study design is presented in Figure 1.  
Figure 1 Study Design 
 
 
          
 
 
Each subject will complete a Screening Period of up to 21 days to assess inclusion and 
exclusion criteria. Baseline status will be established with a 14 day single-blind, placebo 
Lead-in Period.  Exogenous GC and MC replacement therapy must be maintained 
Dose Levels 2, 3, 4 and 5 follow 
the same 28 day period as     
Dose Level 1 
Screening Period    
(up to 21 days) 
Placebo Baseline Lead-in 
Period (14 days) 
Dose Level 1 (28 days)
ATR-101 125 mg BID          
(14 days) 
Placebo washout              
(14 days) 
Efficacy 
endpoint is 
met 
Efficacy 
endpoint is 
NOT met
STOP 
LEVEL 2 
Efficacy 
endpoint is 
met
Efficacy 
endpoint is 
NOT met
STOP 
Continue 
         (Assess efficacy and safety) 
 
                (Assess efficacy and safety) 


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throughout the duration of the study. Each dose level will last for a total of 28 days (see 
Figure 2). All subjects will start at Dose Level 1, ATR-101 125 mg BID, for 14 days. 
Efficacy and safety will be assessed after the 14 day ATR-101 treatment period (on the 
morning of day 15). Immediately after the completion of the ATR-101 treatment period, a 
14 day single-blind, placebo Washout Period (placebo matching ATR-101 125 mg) will take 
place. The efficacy assessment obtained on day 15 will be reviewed by the Principal 
Investigator (PI) or Sub-investigator (SI) to determine if the subject has met the primary 
outcome measure or whether the subject should continue to the next dose level (if there are 
no safety issues).   
Figure 2 28 Day Sequence for Each Dose Level 
 
 
 
Subjects will return to the study center after completion of the 14 day placebo Washout 
Period and will follow one of two actions based upon day 15 efficacy results: 
 If the primary outcome measure is met (i.e. 17-OHP < 2 x ULN) the subject completes 
the Final Study Visit  
 If the primary outcome measure is not met (i.e. 17-OHP > 2 x ULN) the subject 
continues to the next dose level  
Table 1 presents the 5 ATR-101 Dose Levels. Dose Levels 2, 3, 4 and 5 will follow the 
same procedures as Dose Level 1 (i.e. treatment with ATR-101 for 14 days, followed by the 
placebo Washout Period of 14 days).  A subject may receive a minimum of one dose level 
(Level 1) or a maximum of 5 dose levels (Level 1-5), along with the corresponding placebo 
Washout Periods.  
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
 Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
ATR-101 
BID 
Placebo 
BID 


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Table 1 
ATR-101 Dose Levels. 
Dose Level 
ATR-101 Dose 
Total Daily Dose 
1 
125 mg BID 
250 mg 
2 
250 mg BID 
500 mg 
3 
500 mg BID 
1000 mg 
4 
750 mg BID 
1500 mg 
5 
1000 mg BID 
2000 mg 
 
3.1.1 Screening Period 
Each subject will have a Screening Period of up to 21 days. The Screening Period will 
assess whether a subject is eligible to participate in the study. All Inclusion and Exclusion 
criteria will be assessed during this period. The 21 day period provides flexibility to 
complete laboratory tests and clinical assessments.     
 
3.1.2 Baseline Lead-in Period 
Eligible subjects will enter a placebo Baseline Lead-in Period.  This 14 day period allows 
subjects to get accustomed to being in a clinical trial (e.g. avoiding prohibited medications) 
and taking investigational medicinal product (IMP) on a regular basis. This period also 
provides an opportunity to develop a more accurate assessment of adrenal steroids and 
steroid intermediates and documentation of exogenous steroid replacement therapy (GC and 
MC).  
 
In order to obtain unbiased information, the subjects will not know that the tablets received 
are placebo and do not contain active drug substance (ATR-101). Placebo tablets for this 
period will look identical to ATR-101 125 mg tablets (i.e. Dose Level 1). However, the 
study center personnel will be aware that the tablets are placebo.  
 
At the conclusion of the Baseline Lead-in Period, subjects will be assessed for protocol 
compliance, including IMP compliance (tablet counts) and whether it is appropriate to 
proceed in the study.   
 
3.1.3 Dose Level 1 (ATR-101 125 mg BID and matching placebo) 
All subjects will start at Dose Level 1 which uses ATR-101 125 mg tablets dosed twice per 
day (BID). ATR-101 will be taken for 14 consecutive days.  
 
Efficacy and safety (including laboratory measures and clinical assessment) will be assessed 
during a study visit after the completion of the 14 day ATR-101 treatment period (i.e. 
morning of day 15). Subjects should take the last dose of ATR-101 Dose Level 1 on the 
evening of day 14.  
 
Day 15 (of the dosing period) will be the start of the single-blind, placebo Washout Period. 
The morning dose for day 15 should be taken from the new bottle dispensed at the day 15 


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visit. Processing of laboratory tests obtained on day 15 will take place during the fourteen 
day placebo Washout Period.    
 
Subjects will take a placebo tablet BID. Study site personnel will know that this is a placebo 
period, but subjects should remain blinded (i.e. not know when they are receiving ATR-101 
and when they are receiving placebo). 
 
At the end of the 28 day period (i.e. 14 days of ATR-101 and 14 days of single-blind 
placebo washout), subjects will return to the study center. Laboratory tests and safety 
assessments will be conducted at this visit. Prior to this visit, the PI or SI will have reviewed 
the efficacy and safety laboratory values taken at the end of the ATR-101 treatment period 
(i.e. day 15). If the primary outcome measure is met (i.e. 17-OHP < 2 x ULN) this visit will 
be designated the Final Study Visit and the subject will not continue to Dose Level 2. 
However, if the primary outcome measure is not met (i.e. 17-OHP > 2 x ULN) and there are 
no safety concerns, the subject will continue to Dose Level 2.  
 
3.1.4 Dose Levels 2, 3, 4 and 5  
Dose Levels 2, 3, 4 and 5 will follow the same procedures as Dose Level 1. Dose Level 2, 
(ATR-101 250 mg BID) will be taken for 14 consecutive days. At the completion of the 
14 day treatment period, subjects will return to the study center for assessment of efficacy 
and safety (including laboratory measures and clinical assessment).  The 14 day single-
blind, placebo Washout Period will then start. After completion of the placebo Washout 
Period, subjects will return to the study center (laboratory testing and safety assessment will 
occur) and either a Final Study Visit will take place or the subjects will continue to Dose 
Level 3. Dose Levels 3, 4 and 5 will follow the same course of action.  
 
3.1.5 Final Study Visit 
The Final Study Visit will take place once a subject has met the primary outcome measure at 
the completion of Dose Levels 1-4 or at the completion of Dose Level 5. This visit will be 
the final visit to the study center. 
3.1.6 Follow-up Visit 
Two weeks after the Final Study Visit or Early Termination Visit, a Follow-up Visit will 
take place. This will consist of a telephone interview with the subject to determine if any 
safety events need to be reported and to record concomitant medications, especially GC and 
MC. 
3.2 
Rationale for Study Design and Dose Levels 
CAH is a rare disease with a limited number of potential subjects. Therefore, the study 
design must derive as much information as possible from each subject while simultaneously 
presenting as little risk as possible. This study protocol provides the potential for each 
subject to achieve the primary outcome measure at the lowest possible dose with a minimum 
duration of exposure (i.e. 14 days per dose level). In addition, the placebo Washout Period 


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ensures that each subject has returned to baseline status prior to receiving the next highest 
dose of ATR-101. This period also serves to verify that changes in adrenal steroids and 
steroid intermediates are due to ATR-101 effects. Thus, this protocol design will generate a 
robust dataset with a limited number of subjects which can establish proof of concept for the 
use of ATR-101 in CAH. 
 
The starting dose for all subjects will be ATR-101 125 mg taken BID orally with food. This 
dose corresponds to approximately 3 mg/kg/day for a 75 kg individual and is intended to be 
a non-effective dose. While the 3 mg/kg/day dose was efficacious in dog studies, the 
exposures (i.e. AUC0-24 hr mean ~4700 nghr/mL) were much higher relative to the projected 
corresponding exposures in humans.  Based on pharmacokinetic modeling from the 
available human data (ACC subjects and healthy volunteer food effect study13), the 125 mg 
BID dose will provide a steady-state AUC0-24 hr of ~2308 nghr/mL. Dose Level 2 (250 mg 
BID) will provide an AUC0-24 hr of ~4616 nghr/mL. Each subsequent dose level (3, 4 and 5) 
will increase the ATR-101 dose by 500 mg per day, with projected steady-state AUC0-24 hr 
values of ~9234, 13850 and 18467 nghr/mL, respectively. Thus, the projected exposures 
span a non-effective range up to approximately 4-times the effective exposure observed in 
the dog studies which allows for potential pharmacokinetic/pharmacodynamic differences 
between dogs and humans.  
 
The Phase 1 ACC study provides tremendous reassurance for the safety of the doses 
proposed for this protocol in that AUC0-24 hr exposures as well as the duration of treatment 
have already far surpassed those being proposed. The highest exposures observed (to date) 
in the ACC study have been ~45,000 nghr/mL. These exposures have been well-tolerated 
and the study will continue to dose escalate until the maximum tolerated dose (MTD) or 
Phase 2/3 dose has been identified.10  In addition, the average duration of exposure was 60 
days across the 11 dose cohorts. ATR-101 has been extremely well tolerated in a patient 
population that is markedly less robust (all have advanced stage cancer and most have 
undergone multiple prior treatment regimens) relative to the CAH patient population. 
 
The dosing rationale is further supported by the 13-week dog toxicity study with AUC0-24 hr 
margins relative to the dog No Observed Adverse Effect Level (NOAEL) of 4.0 to 31.9 for 
the highest (1000 mg BID)  and lowest (125 mg BID) ATR-101 doses planned, respectively.  
 
CAH patients will enter the study with elevated 17-OHP values indicating clinical 
challenges in obtaining optimal GC replacement therapy. CAH patients can have extremely 
high 17-OHP levels, >300 nmol/L (10,000 ng/dL), relative to reference laboratory normal 
ranges (<6 nmol/L; <200 ng/dL)14. However, complete normalization of 17-OHP is not the 
therapeutic goal, as this typically results in overtreatment with GC.14   Acceptably treated 
CAH patients generally have mildly elevated steroid levels.14  Thus, the overall goal of the 
study is to show clinically meaningful decreases in 17-OHP that are aligned with clinical 
practice goals and to demonstrate similar decreases in the androgen pathway (i.e. 
androstenedione, testosterone, DHEA, DHEA-S). The study design and dose levels are 
appropriately supported by existing clinical and nonclinical data. 
 


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3.3 
Efficacy Assessment 
 
Efficacy will be assessed by changes in adrenal steroids and steroid intermediates. 17-OHP 
will serve as the primary outcome measure as this adrenal steroid intermediate is used 
diagnostically and to aid in the management of exogenous GC replacement therapy in 
clinical practice. However, absolute target values for 17-OHP or androgens do not currently 
exist in treatment guidelines put forth by any of the medical societies.  The entry criteria for 
17-OHP is set at > 4 x ULN which is intended to enroll subjects that are not optimally 
controlled while on exogenous steroid replacement therapy. It is anticipated that most 
subjects will enter with 17-OHP levels markedly higher than 4 x ULN. The primary efficacy 
outcome measure will be aligned to the clinical goal of achieving a mildly elevated 17-OHP 
level which for this study is defined as < 2 x ULN.  However, other key efficacy parameters 
in the androgen pathway (androstenedione, testosterone, DHEA, DHEA-S) will also serve to 
define efficacy. 
 
The majority of CAH subjects will enter the study on both GC and MC replacement (75% of 
classic CAH subjects have deficiencies in both pathways). However, plasma renin activity 
(PRA) and aldosterone will be assessed to determine the potential impact on the MC 
pathway.  
 
ACTH levels will be assessed to determine potential effects on the hypothalamic-pituitary-
adrenal (HPA)-axis. Glucocorticoid replacement doses are expected to remain unchanged so 
no significant changes in ACTH are anticipated. Confirmation of stable ACTH levels 
associated with decreases in 17-OHP and androgens will help to establish the ATR-101 
pharmacodynamic effects.  Increased GC levels, secondary to decreased hepatic metabolism 
(ATR-101 CYP3A effect; see Section 5.4), could potentially lead to decreased ACTH and 
subsequently decreased 17-OHP levels. This could potentially confound assessment of 
direct ATR-101 effects on adrenal steroid and steroid intermediate synthesis. Therefore, 
assessment of GC levels will also be done during the study. 
 
3.4 Safety Assessment 
 
Safety will be assessed by monitoring adverse events, changes in physical examination 
(including vital signs), changes in electrocardiograms (ECGs), and changes in laboratory 
parameters. Safety assessment will take place every 2 weeks during study participation. 
 
CAH subjects will have entered the study on stable GC and MC regimens. Monitoring and 
management of replacement steroids should continue per usual clinical practice.    
 
 


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4 STUDY POPULATION SELECTION 
4.1 Study Population 
The study population will consist of adult men and women with a documented history of 
CAH due to classic 21-OHD. Historical documentation of molecular genetic testing for 
CYP21A2 deficiency or other appropriate documentation of diagnosis (e.g. elevated 17-
OHP) should be provided. The documentation of chronic GC and/or MC replacement 
therapy should also be provided. The historical biochemical profile for adrenal steroid and 
steroid intermediates, along with ACTH levels may also provide supportive documentation.  
Newly diagnosed CAH subjects are not eligible since participation in a clinical study may 
not be consistent with optimal medical management. 
 
 
4.2 Inclusion Criteria 
Each subject must meet all of the following criteria to be enrolled in this study: 
1. Aged 18 to 80 years at the time of signing the informed consent form 
2. Men or women with classic CAH due to 21-OHD   
3. Documented historical diagnosis of CAH due to 21-OHD based on any one of the 
following criteria: 
a. Documented genetic mutation in the CYP21A2 enzyme consistent with a 
diagnosis of classic CAH 
b. Historical documentation of elevated 17-OHP (e.g. in infancy or following a 
cosyntropin/ACTH stimulation test) 
4. Biochemical marker of disease status at Screening and Baseline Lead-in Period 
a. 17-OHP ≥4 x ULN  
(Note:  The test may be repeated one time at the Investigator’s discretion if there 
is reason to suspect the results are inaccurate.) 
5. Chronic glucocorticoid replacement therapy for at least 6 consecutive months prior to 
signing Informed Consent 
6. Stable glucocorticoid and mineralocorticoid regimen for at least one month prior to 
signing Informed Consent (per Investigator discretion) 
7. Female subjects of childbearing potential (who are not surgically sterile or who have not 
been naturally postmenopausal for at least 12 consecutive months) must test negative in 
the urine pregnancy test prior to the initiation of IMP 
8. Female subjects of childbearing potential must consent to use two medically acceptable 
methods of contraception throughout the study period and for 30 days after the last dose 
of study treatment 
9. Males must be sterile (e.g. status-post vasectomy) for 6 months prior to informed 
consent or agree to use two approved methods of contraception where one method must 
include a barrier method 
10. Females must have negative serum pregnancy test at Screening 


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11. Able and willing to sign the informed consent form prior to Screening and be willing to 
comply with all aspects of the study protocol 
4.3 Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from participation in the 
study: 
1. Non-classic CAH 
2. Other causes of adrenal insufficiency such as Addison’s disease; adrenalectomy etc. 
3. Surgery within the previous three months prior to screening or planned surgery during 
study participation. Minor procedures are permitted (e.g. removal of skin tags or other 
minor dermatological procedures) 
4. Abnormal laboratory tests at Screening: 
 ALT or AST >2 x ULN 
 Bilirubin >1.5 x ULN  
 Serum Creatinine >1.5 x ULN  
5. History of active cancer requiring medical or surgical therapy within the past 6 months 
(with the exception of successfully treated non-metastatic basal cell or squamous cell 
carcinoma of the skin and carcinoma in-situ of the cervix) 
6. Significant comorbid medical condition(s) that may preclude compliance with the study 
protocol or such that study participation may not be in the subject’s best medical 
interest. Medical conditions may include (but are not limited to) those of the 
cardiovascular, respiratory, gastrointestinal, renal, hepatic, central nervous system 
(CNS) or immune system [(e.g., human immunodeficiency virus (HIV)], Myocardial 
infarction (MI) or cerebrovascular accident/transient ischemic attack (CVA/TIA) within 
the past 6 months 
7. An average QTc value (Fridericia correction) of > 470 msec at Screening 
8. Psychiatric illness such that comprehension of the informed consent or compliance with 
the study protocol may be impaired 
9. Positive screen for HIV, Hepatitis B surface antigen or Hepatitis C antibody at 
Screening 
10. Pregnant or lactating females 
11. Current or ongoing use of any prohibited concomitant medications (Section 5.3) 
12. History of substance abuse within the past 2 years prior to informed consent 
13. Positive toxicology screening test for substances of abuse 
14. Known allergy to ATR-101 
15. Treatment with another investigational drug or device within 3 months prior to 
Screening 


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5. STUDY TREATMENT 
5.1 Assignment of Subject Identification Numbers 
Once the subject has signed the ICF at Screening, site personnel will assign a subject 
identification number (ID). The subject ID will include the site number (3 digits), and 
3 digit subject number, assigned sequentially starting with 001. This number and the 
subject’s initials will be utilized to identify the subject throughout the study period.  Subject 
identification numbers will only be assigned to one subject, i.e., if a subject discontinues 
study treatment early, their subject identification number will not be used for a new subject. 
5.2 Description of Treatment 
ATR-101 Drug Product Tablets are supplied, in doses of 125 mg, 250 mg and 500 mg and 
ATR-101 Drug Product Placebo Tablets which are identical in size shape and color to the 
125 mg, 250 mg and 500 mg ATR-101 Drug Product Tablets. 
Each bottle will contain sufficient ATR-101 Drug Product Tablets or ATR-101 Drug 
Product Placebo Tablets (i.e. 38 tablets) to provide dosing for a 2-week period with extra 
tablets to account for scheduling visit windows. The tablet formulations are described in 
Table 2. 
 


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Table 2 
Tablet Formulations. 
ATR-101 Drug Product Tablets 
Study Product: 
ATR-101 Drug Product Tablets 
Drug Product: 
ATR-101 with mannitol, microcrystalline cellulose, 
croscarmellose sodium, pregelatinized starch, 
hypromellose, magnesium stearate, and Opadry II white. 
Strengths: 
125 mg, 250 mg, and 500 mg 
Route of 
administration: 
Oral 
Manufacturer: 
Corealis Pharma, Inc. 
ATR-101 Drug Product Placebo Tablets 
Study Product: 
ATR-101 Drug Product Placebo Tablets 
Drug Product Placebo: 
 Microcrystalline cellulose, lactose monohydrate, 
croscarmellose sodium, magnesium stearate, and 
Opadry II white in a film-coated tablet 
Images: 
Exact matching image to ATR-101 Drug Product 
125 mg, 250 mg, and 500 mg Tablets  
Route of administration: Oral 
Manufacturer: 
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 most recent version of the 
Investigator’s Brochure.10 
5.3 Treatments Administered 
The Baseline Lead-in Period will administer placebo tablets for 14 days. The tablets will 
match the ATR-101 125 mg tablets and be administered BID.  
Starting with Dose Level 1, each dose level will consist of a 28 day dosing regimen 
consisting of 14 days of ATR-101 treatment followed immediately by 14 days of matching 
placebo washout. Bottles containing 38 tablets will be supplied for each 14 day dosing 
period which allows for 5 extra days of dosing to accommodate visit windows (see 
Pharmacy Manual). Table 3 presents the tablets and dosing regimen by Dose Levels. 
 
 


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Table 3 
ATR-101 Dose Levels and Tablet Doses. 
 
14 day Treatment Period  
14 day Washout Period 
Dose 
Level 
ATR-101 
Tablet 
Strength 
Dispensed 
ATR-101 
Dosing 
Placebo 
Tablet 
Dispensed 
Placebo 
Dosing 
1 
125 mg 
1 tablet BID 
Matching 
125 mg tablet  
1 tablet BID 
2 
250 mg  
1 tablet BID 
matching  
250 mg tablet 
1 tablet BID 
3 
500 mg 
1 tablet BID 
matching  
500 mg tablet 
1 tablet BID 
4 
250 mg and    
500 mg 
1 tablet each 
BID 
matching  
250 mg and  
500 mg tablets 
1 tablet each 
BID 
5 
500 mg 
 2 tablets BID 
matching  
500 mg tablet 
 2 tablets 
BID 
 
Only the doses presented in Table 3 will be permitted. No other doses will be allowed.   
 
 
5.3.1 Timing and Administrative Dosing Conditions 
IMP should be taken approximately 12 hours 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 8AM and 
every evening at 8PM).  
 
IMP 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 IMP.  
 
The first dose of each bottle will be administered at the site prior to PK sampling.  Subjects 
will be provided with food to consume prior to dose administration. See Pharmacy Manual 
for more details. 
 
Grapefruit, grapefruit juice and other foods containing grapefruit should be avoided to 
prohibit possible interactions in the metabolism of ATR-101 or other concomitant 
medications. 
 
5.3.2 Advancement to the Next Dose Level 
If a subject does not meet the primary outcome measure (i.e. 17-OHP <2 x ULN) at the 
completion of a given dose level, advancement to the next higher dose level should take 


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place if there are no safety issues. There is the possibility of receiving a maximum of 5 dose 
levels (Levels 1-5).  
 
A subject must follow the dose levels in numerical sequence (i.e. Dose Level 1 followed by 
Dose Level 2 etc.). Skipping a dose level is prohibited and may result in termination from 
the study.  
 
5.3.3 Changes in Daily Dose are Not Permitted 
Subjects must adhere to the daily dose of IMP according to each dose level. Deviation from 
the protocol regimen is not permitted. Specifically, lower daily doses are not permitted for 
any reason. If a subject cannot tolerate a given dose due to a safety issue then early 
termination from the study is the recommended course of action. Decreasing to a lower dose 
(e.g., once per day dosing or taking fewer tablets at each AM or PM dose) or to the previous 
dose level is not permitted. Additionally, increased doses are not permitted at any time other 
than those associated with the protocol design (i.e. advancing to the next dose level). Taking 
more tablets at a given dose is not permitted under any circumstances.  
 
5.3.4 Missed Doses 
If a subject forgets to take a dose on a given day (e.g. the AM dose was not taken), a “make 
up” dose should not be taken. In general, if more than 4 hours have passed beyond the usual 
time of day when the dose is taken, that particular dose should not be taken.   
5.3.5 Withholding IMP 
A “drug holiday” or “dosing break” is not recommended due to the relatively short 28 day 
period per dose level. However, withholding IMP may be possible under specific 
conditions. For example, a subject may have a medical event (e.g., dental emergency) that is 
considered to be transient or reversible within a few days that may potentially have a 
preferred outcome by withholding IMP. Depending on the specific circumstances, additional 
days of dosing may be possible to complete a 14 day dosing cycle. The PI or SI should 
discuss potential events of this nature with the study medical monitor and Sponsor prior to 
the event if at all possible.  
 
5.3.6 Compliance with IMP 
The IMP is to be dispensed by qualified personnel at the study center and only to subjects 
enrolled in the study.  Subject compliance to therapy will be assessed at scheduled study 
visits by counting the number of tablets returned. Treatment compliance is defined as the 
subject taking 80% to 120% of the study tablets to be taken during the dosing period for a 
given dose level.  Subjects found to be outside of the definition of compliance may be 
discontinued from the study at the discretion of the PI or SI. 
 


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5.3.7 Blinding 
Subjects will be blinded to treatment beginning with the Baseline Lead-in Period that will 
use placebo tablets that appear identical to ATR-101 125 mg. Dose levels 1 to 5 are split 
into two weeks of active treatment (ATR-101) followed by two weeks of treatment with 
matching placebo (Washout Period).  
 
5.3.8 Concomitant Therapies 
Use of concomitant treatments should be kept to a minimum during the study.  Any 
therapies given other than IMP (including blood transfusions, parental fluids, and other 
medications) are to be considered a concomitant medication and must be documented on the 
electronic case report form (eCRF).   
 
GC and MC are critical concomitant medications used in CAH and will be captured on a 
separate eCRF from other concomitant therapies. 
 
5.3.9 Glucocorticoid and Mineralocorticoid Replacement for CAH 
Subjects must continue to receive GC and MC according to individual regimens established 
prior to entering the study. The regimen should remain as stable and unchanged as possible 
to minimize potential confounding effects on efficacy outcome measures. However, changes 
are permitted to ensure subject safety. It is not expected that ATR-101 will have a direct 
effect on GC replacement therapy as the GC synthetic pathway is already compromised in 
CAH. Therefore, decreasing cortisol precursors (i.e. 17-OHP) should have no effect on 
glucocorticoid requirements over the 14 day ATR-101 treatment period.  
 
The timing of glucocorticoid replacement therapy may have an impact on the measurement 
of 17-OHP. Replacement steroids (GC and MC) must not be taken on the mornings when 
adrenal steroids/steroid intermediates are being assessed (i.e. Day 15) as this could confound 
efficacy endpoint measures. GC and MC replacement doses may be given after blood 
samples are obtained for laboratory assessments.  
 
Approximately 75% of CAH subjects have deficiency in the mineralocorticoid pathway in 
addition to the GC pathway.5  Thus, the majority of subjects in this study are anticipated to 
be on MC replacement. ATR-101 inhibition of the MC pathway for these subjects should 
not have an effect on MC replacement therapy. Subjects that enter the study with 
sufficiently intact endogenous MC production may be impacted by suppression of this 
pathway by ATR-101. However, pharmacological doses of GC, especially shorter acting 
ones such as hydrocortisone, also confer MC activity and the need for replacement MC is 
not usually required.14  
 
5.3.10 Prohibited Medications 
ATR-101 is metabolized by several cytochrome P450 enzymes (CYPs) including CYP3A4.  
Concurrent use of drugs known to be metabolized by this pathway should be avoided. 
(Appendix 4).   


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ATR-101 is most soluble in acidic conditions.  Proton pump inhibitors are prohibited and 
calcium preparations and antacids should not be used 2 hours before to 2 hours after 
ATR-101 administration. 
Grapefruit and grapefruit juice are known to inhibit CYP3A4.  Grapefruit products should 
be avoided. 
Concurrent use of medications that are known to prolong the QT/QTc interval at therapeutic 
exposures are not permitted while on this protocol (Appendix 3, List A).  Drugs that only 
cause prolonged QT intervals in unusual circumstances (e.g., overdosage) may be used with 
caution (Appendix 3, Lists B and C). 
Preclinical data indicate that ATR-101 may compete with certain drugs for P-glycoprotein 
in the intestinal lumen.  The drugs listed in Appendix 5 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 3 or 4, and may be contraindicated by those properties. 
 
5.4 Restrictions, Precautions and Warnings 
Preclinical studies have identified adrenal suppression with apoptotic histologic changes. 
Such changes were associated with exposure levels much higher than what is anticipated for 
this study. 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.10  
 
ATR-101 is metabolized by CYP enzymes and is an inhibitor and inducer of CYP enzymes, 
and as a consequence, ATR-101 may interfere with the metabolism of other medicines also 
metabolized by CYP, especially CYP3A4.  The metabolism of ATR-101 may be affected by 
other medicines or foods such as grapefruit products that inhibit CYP3A4.  Such medicines 
and grapefruit products must be avoided.  ATR-101 is an inhibitor of P-gp and OATP1B1. 
Glucocorticoids are CYP substrates so there is the potential for increased GC levels. 
Glucocorticoid levels will be measured during the course of the study. 
 
5.5 Packaging and Labeling  
The formulation and bulk packaging of ATR-101 will be conducted according to standard 
procedures.  The IMP will be packaged and labeled by the Sponsor’s designated contract 
packager and labelled according to regulatory requirements.  IMP will be provided to sites 
as kits containing a total of 15 bottles. Each kit will provide both ATR-101 and matching 
placebo for the Baseline Lead-in Period as well as Dose Levels 1-5. 


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5.6 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 PI/SI 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 PI (or delegate) 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 PI/SI (or delegate) 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. 
5.7 Investigational Product Retention at Study Site 
At the time of study close-out, the Sponsor will direct the site regarding the disposition of 
any unused IMP whether it is to be destroyed or be returned to the Sponsor’s designated 
location.  The Sponsor will assure that a final report of drug accountability is prepared and 
maintained by the investigative site.  Additional details on the inventory of IMP will be 
provided in the Pharmacy Manual. 


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6 STUDY PROCEDURES 
6.1 Allowable Variation in Study Visits 
Visits and the protocol defined days for each specific period/procedure should be adhered to 
as much as possible. However, there is flexibility to allow for logistical considerations and 
to accommodate scheduling conflicts.  Variations to the protocol defined visit dates (i.e. 
study days) may be allowed depending upon the specific circumstances. 
 Screening Visit.  Up to 21 days.   
 Baseline Lead-in Period. A minimum of 14 days must be completed but an additional 3 
days beyond the 14 day period is allowed. 
 Dose Levels 1-5 
o ATR-101 Treatment Period 
 A minimum of 11 days (22 doses) of ATR-101 must be taken prior to 
drawing blood samples for an assessment of efficacy and safety.  Therefore, 
sample collection cannot occur earlier than the 12th day of dosing for a given 
dose level.  
 A maximum of + 3 days is allowed beyond the scheduled 14 day ATR-101 
treatment period.  
o Placebo Washout Period  
 A minimum of 11 days (22 doses) of placebo must be taken prior to drawing 
blood samples for an assessment of efficacy and safety.  Therefore, sample 
collection cannot occur earlier than the 12th day of dosing for a given dose 
level.  
 A maximum of + 3 days is allowed beyond the scheduled 14 day placebo 
treatment period.  
 Follow-up visit. A window of + 3 days is permitted. 
 
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/Independent Ethics Committee (IRB/IEC) approved 
ICF.  Potential subjects will be informed in detail about the study product to be 
administered, and the nature of the clinical investigation with its risks and discomforts to be 
expected.  The subjects will also be instructed that they are free to withdraw their consent 
and discontinue participation in the clinical trial at any time.  The PI/SI 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.   


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6.3 Eligibility 
Review of study inclusion/exclusion criteria will be done at the Screening visit, at the start 
of the Baseline Lead-in Period and reconfirmed prior to receiving the first dose of IMP 
(Dose Level 1). Noncompliance with IMP (i.e., not meeting 80-120%) during the Baseline 
Lead-in Period will result in Early Termination from the Study. 
6.4 Medical History  
A complete medical history will be obtained at the Screening visit.  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 Physical Examination 
A complete physical examination will be obtained at Screening and the Final Study visit or 
Early Termination Visit.   
An abbreviated (brief) physical exam will be completed as follows: 
 Prior to the start of the Baseline Lead-in Period 
 Prior to dosing on the first day of every Dose Level  (active treatment) 
 Prior to starting the placebo Washout Period at each Dose Level 
 
The following systems will be examined for a complete physical examination: HEENT, 
respiratory, cardiovascular, gastrointestinal/hepatobiliary (specifically the presence of 
hepatomegaly or splenomegaly will be assessed), genitourinary/ reproductive, 
musculoskeletal, neurological, psychiatric, endocrine/metabolic, blood/lymphatic, 
dermatologic, and immunologic.  On a brief physical examination, the following systems 
will be examined: respiratory, cardiovascular, gastrointestinal/hepatobiliary and any areas 
pertinent to any adverse events.   
6.6 Vital Signs 
Vital signs, including oral or tympanic temperature, systolic and diastolic blood pressure, 
pulse, respiratory rate, and body weight will be measured at Screening, at the start of the 
Baseline Lead-in Period, at Day 1 pre-dose and at 1, 2 and 4 hours post-dose for each dose 
level, at Day 15 pre-dose for each dose level and at the Final Study Visit or Early 
Termination Visit.  Height will be measured at Screening. 


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6.7 Electrocardiography and Determination of QTc 
All subjects will have 12-lead ECG assessments at Screening, Day 1 pre-dose and 2 hours 
post-dose for each dose level, Day 15 pre-dose for each dose level, and at the completion of 
the Placebo Washout Period on Day 29 (this ECG could serve as the pre-dose ECG, Day 1, 
if the subject is moving to the next dose level or as the ECG for the Final Study Visit or 
Early Termination Visit). ECGs will be stored for later analysis if needed. 
If the QTc is greater than 470 msec on the Screening 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.  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.15 
6.8 Prior and/or Concomitant Medication Assessments 
Prior and concomitant therapies will be documented throughout the study and include any 
treatments that have been taken within 30 days prior to the first placebo dose in the Baseline 
Lead-in Period until the Follow-up Visit.  Any treatments given during the clinical trial 
other than IMP, including blood transfusions, parental fluids, herbal preparations, and all 
pre-medications are considered concomitant therapy and must be recorded on the eCRF.  
Following completion of the Final Study Visit, only concomitant medications related to 
follow-up of an AE should be recorded on the eCRF.  All prior and concomitant 
medications will be coded to the latest version of the World Health Organization (WHO) 
Drug Dictionary.   
  
6.9 Pharmacokinetic Assessments 
Blood samples will be collected to profile the levels of ATR-101 and its metabolites at 
multiple days and times throughout the study.  Assessment of ATR-101 levels may help to 
determine or establish pharmacokinetic and pharmacodynamic relationships. ATR-101 
exposure levels may also help in the assessment of safety events. Sampling time points are 
presented for each of the applicable study days in Table 4. Samples for PK analysis will be 
taken prior to the first dose of ATR-101 (for each dose level) and up to 4 hours, post-dose. 
This time period is designed to capture the Cmax (Tmax is approximately 2 hours) and a few 
additional time points. Following the completion of the 14 day ATR-101 dosing period a 
single PK sample will be collected to assess trough levels of ATR-101 (morning of day 15). 
Subjects will then enter the 14 day placebo Washout Period.  After completion of the 
placebo Washout period, subjects will either proceed to the next Dose Level and perform 
the same PK sampling as Day 1, or subjects will complete the Final Study Visit and do the 
same PK sampling as Day 15. 
PK results will not be used to determine dose escalation. 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 Point 
Dose Level N, Day 1 
Pre-dose, post-dose at 1, 2, 3, and 4 hours 
Dose Level N, Day 15 
Pre-dose, single blood draw 
N=Dose Levels 1-5 
 
 
6.10 Pharmacodynamic Assessments 
The effects of ATR-101 on adrenal steroid synthesis will be assessed at each study visit by 
measuring steroids and steroid intermediates across the mineralocorticoid, glucocorticoid 
and androgen pathways. Plasma renin activity (PRA) is not an adrenal steroid, but it will be 
measured as an assessment of mineralocorticoid activity. In addition, ACTH levels will be 
assessed to determine the potential impact on the HPA-axis.  
 
Pharmacodynamic measures: 
 
 Glucocorticoid pathway: 17-OHP, progesterone 
 Mineralocorticoid pathway: 11-deoxycorticosterone (11-DOC); PRA; aldosterone 
 Androgens: androstenedione, total testosterone, free testosterone, DHEA, DHEA-S  
 HPA-axis: ACTH 
 
 
6.11 Timing of Pharmacodynamic Blood Samples and Dosing of Replacement 
Steroids 
Adrenal steroids and steroid intermediates have a diurnal rhythmicity with peak 17-OHP 
occurring at around 8:00 AM. Thus, it is extremely critical that the timing of sample 
collection for efficacy endpoints and dosing of replacement steroids be precise and 
consistent. Every attempt should be made to collect the sample between 8:00-9:00 AM, but 
no later than 10:00AM. Study visits that require blood sample collection for steroid 
hormones, must adhere to the following: 
 Morning dose of replacement GC and MC must not be given until after the blood sample 
is collected 
 Blood sample collection must be done prior to 10:00 AM   
 
If both of these conditions are not met, the blood sample for steroid hormones must not 
be collected; the visit procedures should not be performed and the study visit must be 
rescheduled for the next day or as soon as feasible.  The subject should continue taking 
study drug with the last dose occurring the evening prior to the rescheduled visit. 
 
Dosing of GC and MC may take place after collection of blood samples for adrenal steroids 
and steroid intermediates.   
 


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Approximately 20 mL of blood will be collected for steroid hormone testing and 
approximately 10 mL of blood will be collected for testing synthetic glucocorticoid levels.  
If exogenous GC levels are suspected of confounding the efficacy outcome measures, 
additional testing may be performed.  Further details on sample collection and handling are 
provided in the Laboratory Manual. 
 
6.12 Adverse Events, Serious Adverse Events, and Reporting 
6.12.1 Adverse Events, Severity, and Relationship 
 
Adverse Event (AE):  Any untoward medical occurrence in a subject or clinical 
investigation subject administered an investigational product.  An AE does not necessarily 
have a causal relationship with IMP.   
 All AEs reported for enrolled subjects during the clinical study will be recorded on the 
eCRF.  All AEs, regardless of relationship to study drug or procedure, should be 
collected beginning from the time the subject signs the study consent.  AEs in clinical 
investigation subjects include any change in the subject’s condition.  This includes 
symptoms, physical findings, or clinical syndromes. 
 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 PI/SI 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 alanine aminotransferase (ALT), hepatitis and not the 
elevated ALT should be listed as the AE). 
 Examples of laboratory abnormalities that should be considered AEs include those that 
result in withdrawal of the study treatment, withholding study treatment pending some 
investigational outcome, or additional concomitant treatment.  All laboratory 
abnormalities considered to constitute an AE should be recorded on the appropriate AE 
page of the eCRF.  Laboratory abnormalities do not need to be listed as separate AEs if 
they are considered to be part of a clinical syndrome that is being reported as an AE.  It 
is the responsibility of the Investigator to review all 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. 
 AEs will be collected from the time the subject signs informed consent until 30 days 
after last dose of IMP.     
 Every effort must be made by the PI/SI to categorize each AE according to its severity 
and its relationship to IMP. 
 Subjects who develop toxicity on study will be followed until the event resolves, 
stabilizes or returns to baseline. 
 


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6.12.2 
Assessing Severity of Adverse Events 
The assessment of severity must be based on the Investigator’s clinical judgement.  
Maximum severity should be assigned to one of the following categories: 
 
 Mild: An AE which is easily tolerated by the subject, causing minimal discomfort and 
not interfering with everyday activities. 
 Moderate: An AE which is sufficiently discomforting to interfere with normal everyday 
activities. 
 Severe: An AE which prevents normal everyday activities. 
 
An AE which is assessed as severe should not be confused with a serious AE.  Refer to 
Section 6.12.5 for the definition of a serious AE. 
 
6.12.3 
Assessing Relationship to Study Treatment 
Items to be considered when assessing the relationship of an AE to the study treatment are 
as follows:  
 Temporal relationship of the onset of the event to the initiation of the study treatment 
 The course of the event, considering especially the effect of discontinuation of study 
treatment or reintroduction of study treatment, as applicable 
 Whether the event is known to be associated with the study treatment or with other 
similar treatments 
 The presence of risk factors in the study subject known to increase the occurrence of the 
event 
 The presence of non-study treatment related factors which are known to be associated 
with the occurrence of the event 
 
Only AEs thought to be caused by IMP should be recorded as “related to IMP”.    
6.12.4 
Classification of Causality 
The relationship of an adverse event to the administration of the study drug is to be assessed 
according to the following definitions: 
 No (unrelated, not related, no relation) – The time course between the administration of 
study drug and the occurrence or worsening of the adverse event rules out a causal 
relationship and another cause (concomitant drugs, therapies, complications, etc.) is 
suspected. 
 Yes (related) – 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. 


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Not Related:  A causal relationship between the study treatment and the AE is not a 
reasonable possibility. 
Related:  A causal relationship between the study treatment and the AE is a reasonable 
possibility.  The Investigator must further qualify the degree of certainty as “possible,” 
“probable”, or “definite.” 
6.12.5 
Serious Adverse Events 
6.12.5..1 Definition of Serious Adverse Events 
A serious adverse event (experience; SAE) or reaction is any untoward medical occurrence 
which: 
 Results in death 
 Is life-threatening (Note:  The term “life-threatening” in the definition of “serious” refers 
to an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it were more severe.) 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 
NOTE: Any hospital admission with at least one overnight stay will be considered an 
inpatient hospitalization. An emergency room visit without hospital admission will not 
be recorded as a serious adverse event (SAE) under this criterion, nor will 
hospitalization for a 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. 
 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly/birth defect.  
 Is determined to be an important medical event (at the discretion of the Investigator) 
 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the 
definition above.  These should also usually be considered serious. 
The following hospitalizations are not considered to be SAEs because there is no “AE” 
(i.e., no untoward medical occurrence) associated with the hospitalization: 
 Planned hospitalizations required by the protocol 
 Hospitalization planned prior to informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration) 
 
6.12.5..2 Reporting Serious Adverse Events (SAEs) 
Initial Reports 


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All SAEs occurring from the time of informed consent through the early termination/final 
visit and for 30 days following study drug discontinuation, whichever is longer, must be 
reported to Medpace Clinical Safety within 24 hours of the knowledge of the occurrence 
(this refers to any adverse event that meets any of the aforementioned serious criteria). All 
serious adverse events that the investigator considers related to study drug occurring after 
the 30-day follow-up period must be reported to the Sponsor. 
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 serious 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 the completed paper SAE form to Medpace (fax number listed below) 
within 24 hours of awareness. When the EDC system becomes available, the SAE 
information must be entered within 24 hours of the system becoming available. 
Safety Contact Information: 
Medpace Clinical Safety 
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 
 
Follow-Up Reports 
The investigator must continue to follow the subject until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment) or the 
subject dies. 
Within 24 hours of receipt of follow-up information, the investigator must update the SAE 
form electronically in the EDC system for the study and submit any supporting 
documentation (e.g., subject discharge summary or autopsy reports) to Medpace Clinical 
Safety via fax or e-mail. If 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/ IEC of the occurrence of the SAE, in writing, in 
accordance with local requirements.  A copy of this communication must be forwarded to 
the clinical research associate (CRA) and filed in the trial master file (TMF). 
6.12.5..3 Pregnancy Reporting 
Any pregnancy 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 pregnancy must 
be reported to Medpace Clinical Safety within 24 hours (from the time the pregnancy is 
detected). Medpace Clinical Safety will then forward the Exposure In Utero form to the PI or SI 
for completion.  


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If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported, regardless of the length of time that has passed since the exposure to study 
treatment. 
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 PI or SI until completion of the pregnancy. If the 
pregnancy ends for any reason before the anticipated date, the PI or SI should notify Medpace 
Clinical Safety.  At the completion of the pregnancy, the PI or SI will document the outcome of 
the pregnancy. If the outcome of the pregnancy meets the criteria for immediate classification as 
an SAE (i.e., postpartum complication, spontaneous abortion, stillbirth, neonatal death, or 
congenital anomaly), the PU or SI should follow the procedures for reporting an SAE. 
6.12.6 
Regulatory Reporting of Adverse Events 
AEs will be reported to the regulatory authorities in compliance with local and regional law and 
established guidance by the Sponsor or by a third party acting on behalf of the Sponsor.  The 
format of these reports will be dictated by the local and regional requirements. 
6.13 Clinical Laboratory Tests 
Blood samples for steroids and steroid intermediate testing, synthetic glucocorticoid levels, 
hematology, serum chemistry, coagulation and urinalysis will be obtained at Screening, at the 
start of the Baseline Lead-in Period, at the start of every dose level (Day 1), at the start of every 
placebo Washout Period (Day 15) and at the Final Study Visit or the Early Termination Visit 
(Day 29). 
Study visits that require blood sample collection for steroid hormones, must adhere to the 
following: 
 Morning dose of replacement GC and MC must not be given until after the blood sample is 
collected 
 Blood sample collection must be done prior to 10:00AM   
 
If both of these conditions are not met, the blood sample for efficacy endpoints must not 
be collected and another study visit must be scheduled for the next day or as soon as 
feasible. 
Approximately 7 mL of blood will be collected for serum chemistry, 3 mL of blood for 
hematology and 3 mL of blood for PT/aPTT/INR.  Approximately 20 mL of blood will be 
collected for steroid hormone testing and approximately 10 mL of blood will be collected for 
synthetic glucocorticoid testing. (See Table 5). Testing will be carried out by a central 
laboratory per the laboratory manual. 
Subjects do not need to fast before the blood tests and will be in a seated or supine position 
during blood collection. Sampling time will be recorded on the eCRF. 
For female subjects who are not surgically sterile or who have not been naturally post-
menopausal for at least 12 consecutive months (i.e., who has had menses any time in the 


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preceding 12 consecutive months), serum pregnancy tests (ß-hCG) will be performed at 
Screening.  A urine pregnancy test (UPT) will be obtained prior to the first dose at each dose 
level on Day 1.  A UPT will also be obtained at the Final Study Visit or Early Termination 
Visit. Sampling time will be recorded on the eCRF.  
Blood samples for serology (HBsAg, Hepatitis C antibody and HIV) will be obtained at 
Screening.  Approximately 4 mL of blood will be collected for serology. 
Abnormal, clinically significant results may be verified to rule out laboratory error.  Persistent 
relevant abnormal values must be followed up until the cause is determined or until they return 
to the previous values.  Abnormal laboratory findings that are considered clinically significant 
by the PI/SI should be recorded as AEs (see Section 6.12.1). 
Table 5 
List of Clinical Laboratory Tests. 
Hematology 
Hematocrit (Hct), Hemoglobin (Hgb), Platelet count, Red blood cell 
(RBC) count,  White blood cell (WBC) count with differential, 
Hemoglobin A1c 
Serum Chemistry 
Albumin (ALB), Alkaline phosphatase (ALK-P), Alanine 
aminotransferase (ALT; SGPT), Aspartate aminotransferase (AST; 
SGOT), Blood urea nitrogen (BUN), Calcium (Ca), Creatinine, 
Glucose, Total bilirubin, Total protein, Serum electrolytes 
(magnesium, sodium, potassium, chloride, bicarbonate),  
Coagulation 
PT/aPTT, INR 
Urinalysis 
Appearance, Bilirubin, Color, Glucose, Ketones, Microscopic 
examination of sediment, Nitrite, Occult blood, pH, Protein, Specific 
gravity, Urobilinogen 
Steroid Hormones 
and intermediates 
Glucocorticoid pathway: 17-OHP, progesterone, cortisol 
Mineralocorticoid pathway: 11-DOC; PRA; aldosterone 
Androgens: androstenedione, total testosterone, free testosterone, 
SHBG, DHEA, DHEAS  
Adrenocorticotropic hormone (ACTH) 
Synthetic 
Glucocorticoid 
Screen 
Betamethasone, Budesonide, Dexamethasone, Fludrocortisone, 
Flunisolide, Fluorometholone, Hydrocortisone, Megestrol acetate, 
Methylprednisolone, Prednisolone, Prednisone, Triamcinolone, 
Triamcinolone acetonide 
Pregnancy Testing Serum and Urine Pregnancy Tests (ß-hCG) 
Serology 
Hepatitis B surface antigen (HBsAg), Hepatitis C antibody, Human 
immunodeficiency virus (HIV) 
 


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6.13.1 
Sample Collection, Storage, and Shipping 
Sample collection, storage and shipment procedures for clinical laboratory samples will be 
provided in the laboratory manual. 
6.14 Blood Sample Collection  
In total, approximately 687 mL of blood will be collected during the study from each subject 
enrolled that continues through all five dose levels.  This consists of approximately 173 mL for 
safety, 124 mL for PK, 390 mL for pharmacodynamic sampling.   


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6.15 Removal of Subjects from the Study or Study Drug 
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 PI/SI 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 PI or SI’s judgment, administration of study drug would be detrimental to the 
subject’s health. 
2. The subject withdraws consent for continued participation or refuses further treatment with 
the investigational product. 
3. The subject is noncompliant with the protocol. 
4. The subject becomes pregnant. 
5. The subject dies.  
6. The subjects experiences an SAE or medically important event that would preclude further 
treatment with study drug 
7. Need to initiate therapy with an excluded medication 
 
Subjects should return to the investigational site for a Final Study Visit or Early Termination 
Visit after withdrawal/removal from the clinical trial.  The reason for and date of 
withdrawal/removal from the clinical trial will be documented in the subject’s medical records.  
Investigational site personnel must attempt to determine whether the reason for withdrawal was 
an AE, and if so, this must be reported in accordance with the procedures provided in Section 
6.12.  For all subjects who do not complete the clinical trial, regardless of the duration of 
treatment, all relevant information related to the withdrawal/removal will be entered into the 
eCRF. 
Subjects who withdraw or are removed from the clinical trial may be replaced at the discretion 
of the Sponsor.   All enrolled subjects will be fully accounted for and documented in the final 
clinical study report (CSR). 


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7 STUDY ACTIVITIES 
Visit time points are intended as targets, and variations may be made to allow for logistical 
considerations and to accommodate scheduling conflicts.   Refer to Section 6.1. 
7.1 Screening Visit (Day -21 to Day -1) 
Prior to any screening evaluations, written informed consent must be obtained.  All Screening 
procedures are to be completed within a 21 day window. 
The following procedures are to be performed at the Screening Visit: 
 Review and signature of the ICF 
 Review of inclusion/exclusion criteria 
 Recording of medical history, demographics data, prior and concomitant medication history 
 Complete physical examination  
 Vital signs (including blood pressure, pulse, respiration, height, body weight and 
temperature) 
 12-lead ECG  
 Blood sampling for hematology, serum chemistry, PT/aPTT/INR 
 Urinalysis 
 Blood sampling for serology 
 Blood sampling for steroids/steroid intermediates (before 10 AM) only if the 
replacement steroids (GC/MC) have not been dosed that morning  
Note:  The test may be repeated one time at the Investigator’s discretion if there is reason to 
suspect the results are inaccurate. 
 Blood sampling for exogenous glucocorticoid levels. 
 Serum pregnancy testing (-hCG) for females who are not surgically sterile or who have not 
been naturally postmenopausal for at least 12 consecutive months (i.e., who have had 
menses any time in the preceding 12 consecutive months) 
 AE reporting, if applicable 
 Scheduling of next visit (Baseline Lead-in Period) 
 Provide instructions to hold GC and MC morning dose prior to the next visit. 
 
7.2 Baseline Lead-in Period  
The following procedures are to be performed on Day 1 of the Baseline Lead-In Period: 
 Vital signs (including blood pressure, pulse, respiration, body weight and temperature) 
 Brief physical examination 
 Review concomitant medications 
 Review inclusion/exclusion criteria to confirm eligibility 
 Blood sampling for hematology, serum chemistry, PT/aPTT/INR (subjects do not need to 
fast) 
 AE reporting, if applicable 


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 Blood sampling for steroids/steroid intermediates (before 10 AM) only if the 
replacement steroids (GC/MC) have not been dosed that morning  
 Blood sampling for exogenous glucocorticoid levels. 
 Dispense IMP  (Important Reminder: Subject is to remain blinded as to whether treatment is 
ATR-101 or placebo) 
 Provide instructions to hold GC and MC morning dose prior to the next visit. 
 
7.3 Dose Level 1, Days 1-28 
ATR-101 Treatment Period, Days 1-14 
 
The following procedures are to be performed on Day 1 of the ATR-101 dosing period: 
Prior to dosing on Day 1 
 Re-confirm eligibility based on inclusion/exclusion criteria   (Note: Screening and Baseline 
visit 17-OHP level must be > 4x ULN) 
 Confirm that the morning dose of replacement steroids (GC/MC) was not taken  
Note:  If the morning dose of replacement GC and MC was taken the visit cannot be 
performed.  The visit must be rescheduled for the next day or as soon as possible.  
Instruct the subject to continue taking their study drug with the last dose occurring the 
evening prior to the rescheduled visit. 
 
 Confirm the day and time of the last dose of IMP 
 Perform drug accountability and confirm compliance with IMP 
 Review of  concomitant medication 
 Assess AEs 
 Abbreviated physical examination 
 Vital signs (including blood pressure, pulse, respiration, body weight and temperature) 
 12-lead ECG 
 Urine pregnancy testing (-hCG) for females who are not surgically sterile or who have not 
been naturally postmenopausal for at least 12 consecutive months (i.e., who have had 
menses any time in the preceding 12 consecutive months)  
 Blood sampling for hematology, serum chemistry, PT/aPTT/INR  (subjects do not need to 
be fasting) 
 Blood sampling for steroids/steroid intermediates (before 10 AM)  
 Blood sampling for exogenous glucocorticoid levels.  
 Blood sampling for ATR-101 PK assessment (pre-dose)  
 
Administer first dose ATR-101 125 mg (after consumption of food) 
 
 Blood sampling for PK assessment at 1, 2, 3, and 4 hours post-dose 
 12-lead ECG 2 hours post-dose 
 Dispense IMP for Days 1-14 
 Recheck vital signs at 1, 2 and 4 hours post-dose 
 Scheduling of next visit  (Dose Level 1,  Day 15) 


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 Provide instructions to hold GC and MC morning dose prior to the next visit. 
 
Placebo Washout Period, Days 15-28 
 
The following procedures are to be performed on Day 15 after the completion of the 14 day 
ATR-101 dosing period. 
Prior to dosing on Day 15 
 Confirm that the morning dose of replacement steroids (GC/MC) was not taken 
Note:  If the morning dose of replacement GC and MC was taken the visit cannot be 
performed.  The visit must be rescheduled for the next day or as soon as possible.  
Instruct the subject to continue taking their study drug with the last dose occurring the 
evening prior to the rescheduled visit. 
 
 Confirm the day and time of the last dose of IMP 
 Perform drug accountability and confirm compliance with IMP from Days 1-14 
 Review of  concomitant medication 
 Assess AEs 
 Abbreviated physical examination 
 Vital signs (including blood pressure, pulse, respiration, body weight and temperature) 
 12-lead ECG 
 Blood sampling for hematology, serum chemistry, PT/aPTT/INR  (subjects do not need to 
be fasting) 
 Blood sampling for steroids/steroid intermediates (before 10 AM)  
 Blood sampling for exogenous glucocorticoid levels. 
 Blood sampling for ATR-101 PK assessment (trough levels) 
 
Administer first dose of placebo (after consumption of food) 
 
 Dispense IMP for Days 15-28 
 Scheduling of next visit (Day 29) 
 Provide instructions to hold GC and MC morning dose prior to the next visit. 
 
 
7.4 Final Study Visit or Next Dose Level, Day 1 
Subjects will return to the clinic immediately after the completion of the 14 day Placebo 
Washout Period (i.e. 29 days after starting the Dose Level). The PI or SI will review the 17-
OHP results obtained on Day 15 and determine whether this visit will be conducted as the Final 
Study Visit or Dose Level 2, Day 1 Visit: 
 If 17-OHP <2 x ULN, complete the Final Study Visit (see Section 7.6), or 
 If 17-OHP >2 x ULN, proceed to Dose Level 2, Day 1 
 
The PI or SI must assess overall safety (i.e. brief physical exam, laboratory test results and AE 
reporting) prior to proceeding to Dose Level 2, Day 1. 


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7.5 Dose Levels 2, 3, 4 and 5 
Dose Levels 2, 3, 4, and 5 will follow the same visit schedule and procedures as Dose Level 1 
(Section 7.3 and 7.4). However, Dose Level 5 is the final dose level and the visit immediately 
following completion of the Level 5 Placebo Washout Period will be the Final Study Visit 
regardless of the Day 15 laboratory results. 
7.6 Final Study Visit 
The Final Study Visit will take place if the primary outcome measure is met (17-OHP <2 x 
ULN) or at the completion of Dose Level 5. The following procedures will be performed. 
 Confirm that the morning dose of replacement steroids (GC/MC) was not taken or if 
taken confirm the day and time of the last dose 
Note: If the morning dose of replacement steroids (GC/MC) was taken, it is acceptable 
to complete the Final Study Visit 
 Confirm the day and time of the last dose of IMP 
 Perform drug accountability and confirm compliance with IMP  
 Review of  concomitant medication 
 Assess AEs 
 Complete physical examination  
 Vital signs (including blood pressure, pulse, respiration, body weight and temperature) 
 12-lead ECG  
 Blood sampling for hematology, serum chemistry, PT/aPTT/INR  
 Urinalysis 
 Urine pregnancy testing (-hCG) for females who are not surgically sterile or who have 
not been naturally postmenopausal for at least 12 consecutive months (i.e., who have 
had menses any time in the preceding 12 consecutive months)  
 Blood sampling for steroids/steroid intermediates (before 10 AM)   
 Blood sampling for exogenous glucocorticoid levels 
 Blood sampling for ATR-101 PK assessment (trough levels) 
 
7.7 Early Termination Visit 
The Early Termination Visit will occur if a subject is not able to complete the study procedures 
as detailed in the protocol for any reason.  The schedule of events for the Early Termination 
Visit is identical to the Final Study Visit (See Section 7.6). 
 Confirm that the morning dose of replacement steroids (GC/MC) was not taken or if 
taken confirm the day and time of the last dose 
Note: If the morning dose of replacement steroids (GC/MC) was taken, it is acceptable 
to complete the Final Study Visit 
 Confirm the day and time of the last dose of IMP 
 Perform drug accountability and confirm compliance with IMP  
 Review of  concomitant medication 


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 Assess AEs 
 Complete physical examination  
 Vital signs (including blood pressure, pulse, respiration, body weight and temperature) 
 12-lead ECG  
 Blood sampling for hematology, serum chemistry, PT/aPTT/INR  
 Urinalysis 
 Urine pregnancy testing (-hCG) for females who are not surgically sterile or who have 
not been naturally postmenopausal for at least 12 consecutive months (i.e., who have 
had menses any time in the preceding 12 consecutive months)  
 Blood sampling for steroids/steroid intermediates (before 10 AM)   
 Blood sampling for exogenous glucocorticoid levels 
 Blood sampling for ATR-101 PK assessment (trough levels) 
 
7.8 Follow-up Visit   
Two weeks after completion of the Final Study Visit or Early Termination Visit, the PI, SI or 
other qualified medical personnel from the study center will contact the subject. A telephone 
interview will take place to confirm the status of the subject. Any safety events will be reported 
and concomitant medications, including replacement steroids will be recorded. This telephone 
interview will conclude the subject’s study participation. 
 


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8 
QUALITY CONTROL AND ASSURANCE 
Before any subjects can be enrolled at an investigational site and prior to the conduct of any 
protocol-specific procedures, formal training of investigational site personnel will be conducted.  
The PI/SI and all relevant investigational site staff are to be trained on all aspects of the trial for 
which they are responsible.  Site personnel may be trained at a formal initiation visit, at an 
Investigator’s Meeting, or by another means as necessary.  Monitoring and auditing procedures 
will be conducted in compliance with the International Conference on Harmonisation (ICH) 
Guidelines for Good Clinical Practice (GCP).  Onsite verification of the eCRFs for 
completeness and clarity, crosschecking with source documents, and clarification of 
administrative matters will be performed on a regular basis.  The investigational site will be 
monitored immediately following enrollment of the first subject at the site (i.e., within 
approximately 2 weeks) to verify that inclusion/exclusion criteria have been fulfilled.  
Subsequent 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 clinical trial are provided in Section 
10.5.  During the course of the clinical trial, investigational sites, the clinical trial database, and 
all associated clinical trial documentation may be subject to quality assurance audits by the 
Sponsor, or their appointed representatives, on a planned or as-needed basis.  In addition, 
representatives of associated regulatory bodies may conduct inspections at their discretion.  The 
Investigator is responsible for ensuring direct access to all protocol-specific materials for the 
purpose of these activities. 


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9 PLANNED STATISTICAL METHODS 
9.1 General Considerations 
 
Sample size considerations are based on a Simon 2-stage Minimax design with 1-sided alpha of 
5% and 80% power.  
 
Stage 1 consists of 9 completed subjects. The study will stop at Stage 1 if either of the following 
conditions are met: 
 Futility criteria: defined as  <2 of 9 (22%) subjects meeting the primary outcome 
measure (17-OHP <2 x ULN) 
 Success criteria: defined as  >7 of 9 (78%) subjects meeting the primary outcome 
measure (17-OHP <2 x ULN) 
 
Stage 2 will commence if 3, 4, 5 or 6 of the 9 subjects meet the primary outcome measure. In 
this scenario, accrual will continue with up to 8 additional subjects for a total of no more than 
17 subjects. Accrual may stop earlier with sufficient evidence for further development if a total 
of 7 or more subjects respond (minimum observed response rate of 7/17, 41%). 
 
The study medical monitor along with the Sponsor may determine if a subject will be replaced 
in order to have a minimum of 9 evaluable subjects for Stage 1. Possible reasons for 
replacement may be due to extreme noncompliance with IMP not related to an adverse event, 
noncompliance with the protocol such as the use of prohibited medications that could confound 
results. 
 
9.2 Analysis Populations 
 
An intent to treat population is not deemed necessary for this study given the relatively small 
number of subjects.   
 
The per protocol population will include all subjects that have taken at least 11 days of ATR-
101 treatment at Dose Level 1 (the lowest dose level) and have at least one post-baseline 
efficacy assessment (i.e.17-OHP) without having a significant protocol deviation.  
 
The safety population will include all subjects that received at least one dose of IMP. 
 
9.3 Patient 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. 
 


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9.4 Treatment 
 
A frequency distribution will be generated for the dose levels administered. Any deviations to 
the dose escalation criteria will also be noted.   
 
9.5 Primary Efficacy Endpoint 
 
The primary efficacy endpoint will be the percentage of responders. A responder is defined as 
a subject that meets the primary outcome measure of 17-OHP <2 x ULN at any dose level. 
Subjects will enter the study with 17-OHP > 4 x ULN. The 17-OHP level associated with the 
primary outcome measure is aligned to clinical management practices for classic CAH. 
 
9.6 Secondary Endpoints 
 
Descriptive statistics and graphical summaries within each cohort, and for each dose as 
appropriate, will be utilized to present the pharmacokinetic and pharmacodynamics parameters 
assessed. 
 
9.7 Safety 
 
Safety parameters, including adverse events, treatment discontinuations, laboratory changes and 
abnormalities, and changes in ECG parameters will be tabulated and each dose, as appropriate.  
 
9.8 Pharmacokinetic and Pharmacodynamic Analyses 
 
Pharmacokinetic (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, Area Under 
the Curve (AUC0-4 hr), and trough levels. 
Individual subject PK data will be analyzed along with pooling of subjects’ data at each dose 
level.  
PK/PD analyses will be detailed in the Statistical Analysis Plan.   
9.9 Interim Analysis 
 
No interim analysis is planned for this study as neither the efficacy nor the safety results will be 
blinded to the PI/SI, study medical monitor or the Sponsor.   
 
 
 
 


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10 ADMINISTRATIVE CONSIDERATIONS 
10.1 Institutional Review Board (IRB)/Independent Ethics Committee (IEC)  
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/IEC.  A letter from the IRB/IEC indicating approval of the Investigator and study site must 
be submitted to the study Sponsor.  All reviews and approval by the IRB/IEC will be in 
accordance with Title 21 of the Code of Federal Regulations (CFR), Part 56. 
The PI/SI will promptly report any new information that may adversely affect the safety of 
subjects or the conduct of the study to the IRB/IEC.  Similarly, the PI/SI will submit written 
summaries of the study status to the IRB/IEC annually, or more frequently if requested.  Upon 
completion of the study, the Investigator will provide the IRB/IEC 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 PI/SI 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 PI/SI will inform the subject of the aims, methods, anticipated benefits, and potential 
hazards of the study, including any discomfort it may entail.  The subject must be given every 
opportunity to clarify any points he/she does not understand and must be provided with more 
information if requested.  At the end of the interview, the subject may be given time to reflect 
and can request more time if needed.  The subject and/or legal guardian will be required to sign 
and date the informed consent form.  After completion, informed consent forms will be kept and 
archived by the PI in the PI study file. 
It should be emphasized to the subject that he or she is at liberty to either discontinue IMP 
and/or withdraw consent to participate at any time, without penalty or loss of benefits to which 
he or she is otherwise entitled.  Subjects who refuse to give or withdraw written informed 
consent may not be included or continued in this study, but this will not affect their subsequent 
care. 


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Please refer to Title 21 of the CFR, Part 50 – Protection of Human Subjects for specific details 
on this regulation. 
10.4 Subject Confidentiality 
Personal and sensitive data will be treated as confidential.  The results of the clinical trial will 
be made available for review by authorized representatives of the Sponsor and/or submitted to 
the IRB/IEC, and regulatory authorities.   
Prior to the subject’s enrollment in the clinical trial, 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 PI/SI 
regularly for monitoring purposes.  The CRA will be allowed, on request, to inspect the various 
records of the clinical trial (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 clinical 
trial, 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 PI/SI (or a designee) agrees to cooperate with the CRA to ensure 
that problems detected during these monitoring visits are resolved. 
In addition, the Sponsor may perform a Clinical Quality Assurance (CQA) audit randomly at a 
sample of clinical sites, or for cause as warranted.  The CQA audit will examine the accuracy of 
source documentation, record retention, data management, and compliance.  These audits will 
be independent of routine monitoring by the CRA with prior written notification provided to the 
site. 
10.6 Case Report Forms and Study Records 
This clinical trial 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 


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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 clinical trial 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 clinical trial.  
The system and procedures for electronic database set-up, entry, review, access, security, and 
auditing are designed in specific compliance with 21 CFR 11 and the Food and Drug 
Administration's (FDA’s) Part 11 Guidance for Industry supplement “Computerized Systems 
Used in Clinical Investigations” dated May 2007.  Any additional electronic systems that may 
be used by vendors (e.g., PK) or clinical sites (e.g., electronic medical records used as source 
documents) should comply with these same regulatory standards.  
As a final step in the data management process, a 100% quality control review will be 
performed on the key efficacy and safety parameters.  In addition, a random subject sample 
(approximately 10%) will be selected to perform a database audit.  The purpose of this audit is 
to detect systematic and random errors.   
10.7 Data Safety Monitoring Board 
A Data Safety Monitoring Board (DSMB) is not planned for this study since treatment is 
unblinded to study personnel and the overall small size of the study generally limits the value of 
pooling data across the study population. All study PI/SI will have the ability to assess 
benefit:risk for each subject in almost real time.  The study 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 duration and assesses safety every 2 weeks.   
10.8 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.    
10.9 Access to Source Documentation 
The PI/SI 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 the Sponsor and of 
the regulatory agencies have direct access to source documents (e.g., subject medical records, 


Millendo Therapeutics, Inc. 
ATR-101-201 
Confidential; 14 January 2016 
Page 56 of 66 
 
charts, laboratory reports) for the purpose of quality assurance audits either by Millendo or their 
appointed representatives.  Subject confidentiality will be protected at all times. 
10.10 Data Generation and Analysis 
Data processing and management will be performed by the Sponsor or its designee.  Data will 
be promptly entered into the study database 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 Sponsor and/or submitted to 
the IRB/IEC, and regulatory authorities.  Prior to the subject’s enrollment in the study, 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. 
10.11 Retention of Data 
Copies of all study documents should be retained by the PI for at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least two years have elapsed since 
the formal discontinuation of clinical development of the investigational product, in accordance 
with 21 CFR 312.62.  These documents should be retained for a longer period, however, if 
required by regulatory requirements or by agreement with the Sponsor.  It is the responsibility 
of the Sponsor to inform the Investigator/institution as to when these documents no longer need 
to be retained.  The final database will be archived by the Sponsor according to the regulatory 
requirements. 
10.12 Financial Disclosure 
PI and SI are required to provide full disclosure of any financial relationship to the Sponsor or 
its designee(s) prior to participation in any trial-related activities.  Additionally, PI/SI 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 clinical trial and 
for 1 year after completion of the clinical trial.  For additional guidance, refer to 21 CFR 
312.53(c) (4), 312.64(d), 812.43(c) (5), 812.110(d). 
 
10.13 Premature Termination of the Study 
If the study is prematurely terminated or suspended, the Sponsor will promptly inform the PI/SI 
/institutions and the regulatory authority(s) of the termination or suspension and the reason(s) 
for the termination or suspension.   


Millendo Therapeutics, Inc. 
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Page 57 of 66 
 
10.14 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”. 
10.15 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. 
10.16 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/IEC 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 PI/SI 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 IEC, except where it is necessary to 
eliminate an immediate hazard to study subjects or where the change(s) involves only logistical 
or administrative aspects of the study (e.g., change in monitor or change of telephone number). 
Protocol amendments will be submitted to the appropriate authority(s) as required by the applicable 
regulatory requirement(s). 


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Confidential; 14 January 2016 
Page 58 of 66 
 
11 REFERENCE LIST 
1. Dauber A, Kellogg M, Majzoub A. Monitoring of Therapy in Congenital Adrenal 
Hyperplasia. Clinical Chemistry. 2010: 56(8):1245-1251. 
2. Auchus  R, Arlt W. Approach to the Patient: The Adult with Congenital Adrenal 
Hyperplasia. J Clin Endocrinol Metab. 2013: 98(7):2645-2655. 
3. Sahakitrungruang T. Clinical and Molecular Review of Atypical Congenital Adrenal 
Hyperplasia. Ann Pediatr Endocrinol Metab. 2015: 20: 1-7. 
4. Trapp  CM, Speiser  PW, Oberfield SE. Congenital Adrenal Hyperplasia: An Update in 
Children. Curr Opin Endocrinol Diabetes Obes. 2011:18(3):166-170. 
5. Auchus R. Management of the Adult with Congenital Adrenal Hyperplasia. Internat J of 
Pediatr Endocrinol. 2010:614107:1-9. 
6. Barnes RB, Rosenfield RL, Ehrmann DA, Cara JF, Cuttler L, Levitsky LL, Rosenthal IM. 
Ovarian Hyperandrogenism as a Result of Congenital Adrenal Virilizing Disorders: 
Evidence for Perinatal Masculinization of Neuroendocrine Function in Women. J Clin 
Endocrionol Metab. 1994: 79(5):1328-1333. 
7. Tiitinen A, Valimaki M. Primary Infertility in 45-year-old Man with Untreated 21-
Hydroxylase Deficiency: Successful Outcome with Glucocorticoid Therapy. J Clin 
Endocrinol Metab. 2002: 87(6): 2442-2444. 
8. Cabrera MS, Vogiatzi MG, New MI. Long Term Outcome in Adult Males with Classic 
Congenital Adrenal Hyperplasia. J Clin Endocrinol Metab. 2001: 86(7): 3070-3078. 
9. 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 
10. ATR-101 Investigator Brochure 
11. Dominick MA, McGuire EJ, Reindel JR, Bobrowski WF, Bocan TMA, Gough 
AW.  Subacute toxicity of a novel inhibitor of acyl-CoA:cholesterol acyltransferase in 
beagle dogs.  Fund Appl Toxicol. 1993;20:217-24. 
12. Reindel JF, Dominick MA, Bocan TMA, Gough AW, McGuire EJ.  Toxicologic effects of a 
novel acyl-CoA:cholesterol acyltransfease inhibitor in cynomolgus monkeys.  Toxicol 
Pathol. 1994;22:510-8. 
13. Food Effect CSR 
14. Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, Meyer-Bahlburg 
HFL, Miller WL, Montori VM, Oberfield SE, Ritzen M, White PC. Congenital Adrenal 
Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical 
Practice Guideline. J Clin Endocrinol Metab. 2010: 95(9): 4133-4160. 
15. Rautaharju PM, Zhang ZM, Prineas R, Heiss G. Assessment of Prolonged QT and JT 
Intervals in Ventricular Conduction Defects. Am J Cardiol. 2004; 93:1017-1021. 
 




Millendo Therapeutics, Inc. 
 
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Confidential; 14 January 2016 
Page 60 of 66 
 
Appendix 2 
Investigator’s Signature 
 
Study Title:  A Phase 2, Multicenter, Study of ATR-101 for the Treatment of Congenital 
Adrenal Hyperplasia 
STUDY INVESTIGATOR SIGNATURE 
I have read the protocol described above.  I agree to comply with all applicable regulations 
and to conduct the study as described in the protocol.  
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 the Sponsor.  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, the Sponsor must be promptly notified. 
 
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 The Sponsor or 
designee the subject’s medical chart specifically for the purposes of this clinical study.  I am 
fully conversant with Good Clinical Practices 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: 
_________________________________ 
 
 
________________________________ 
 
 
_______________________________ 
 
 
 


Millendo Therapeutics, Inc. 
 
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Confidential; 14 January 2016 
Page 61 of 66 
 
Appendix 3 
Drugs that Prolong the QT/QTc interval 
 
List A. Drugs that prolong the QT Interval that are prohibited. 
 
 
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 U.S. 
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 U.S.  
Citalopram 
Celexa® 
Anti-depressant/depression 
 
Clarithromycin 
Biaxin® 
Antibiotic/bacterialinfection 
 
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 U.S.  
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® 
Anti-depressant/Major depression/Anxiety disorders 
 
Escitalopram 
Lexapro® 
Anti-depressant/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 I.V. or excess 
dosage 
Ibutilide 
Corvert® 
Anti-arrhythmic/abnormal heart rhythm 
Females>Males 
Levomethadyl 
Orlaam® 
Opiate agonist/pain control, narcotic dependence 
Not available in U.S.  
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® 
Antilipemic/Hypercholesterolemia 
No longer available in U.S.  
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 U.S.  
Terfenadine 
Seldane® 
Antihistamine/Allergic rhinitis 
No longer available in U.S.  
Thioridazine 
Mellaril® 
Anti-psychotic/schizophrenia 
 
Vandetanib 
Caprelsa® 
Anti-cancer/Thyroid cancer 
 


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Page 62 of 66 
 
LIST B.  Drugs with conditional risk of QT prolongation, to be used with caution 
 
Generic Name 
Brand Name 
Class/Clinical Use 
Comments 
Amisulpride 
Solian® and others 
Antipsychotic, atypical 
Risk of TdP with overdose - 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 in overdosages 
Diphenhydramine 
Nytol® 
Antihistamine/Allergic rhinitis, insomnia 
Risk of QT increase/TdP in overdosages 
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® 
Anti-depressant/ depression 
 
Fluoxetine 
Prozac® 
Anti-depressant/ depression 
 
Galantamine 
Reminyl® 
Cholinesterase inhibitor /Dementia, 
Alzheimer's 
 
Imipramine 
Norfranil® 
Tricyclic Antidepressant /depression 
TdP risk with excess dosage 
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® 
Anti-depressant/ depression 
 
Protriptyline 
Vivactil® 
Tricyclic Antidepressant /depression 
 
Ritonavir 
Norvir® 
Protease inhibitor/HIV 
 
Sertraline 
Zoloft® 
Anti-depressant/ depression 
 
Solifenacin 
VESIcare® 
muscarinic receptor anatagonist/treatment 
of overactive bladder 
 
Trazodone 
Desyrel® 
Anti-depressant/ Depression, insomnia 
 
Trimethoprim-
Sulfa 
Septra® or 
Bactrim® 
Antibiotic/bacterial infection 
Also available in DS (double strength) 
Trimipramine 
Surmontil® 
Tricyclic Antidepressant /depression 
 
 
 
 


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Page 63 of 66 
 
LIST C.   Drugs with possible risk of QT prolongation, to be used with caution 
 
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 U.S. 
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/I.V. forms no longer 
available in U.S. and Canada, 
only ophthalmic 
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 
Anti-depressant  
 
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 c 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 U.S. 
Sertindole 
Serdolect® 
Antipsychotic, atypical/ Anxiety, Schizophrenia 
Not available in U.S. 
Sertindole 
Serlect® 
Antipsychotic, atypical/ Anxiety, Schizophrenia 
Not available in U.S. 
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® 
Anti-depressant/depression 
 
Voriconazole 
VFend® 
Anti-fungal/anti-fungal 
 
Ziprasidone 
Geodon® 
Anti-psychotic/schizophrenia 
 
 
 
 


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Appendix 4 
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_TMU 
cilostazol 
cocaine 
codeine- 
Ndemethylation 
dapsone 
dexamethasone 
dextromethorphan 
docetaxel 
domperidone 
eplerenone 
fentanyl 
finasteride 
gleevec 
haloperidol 
irinotecan 
LAAM 
lidocaine 
methadone 
nateglinide 
ondansetron 
pimozide 
propranolol 
quetiapine 
quinine 
risperidone 
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 
 
 


Millendo Therapeutics, Inc. 
 
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Confidential; 14 January 2016 
Page 65 of 66 
 
INDUCERS 3A4,5,7 
HIV Antivirals: 
efavirenz 
nevirapine 
 
 
 
Miscellaneous 
barbiturates 
carbamazepine 
glucocorticoids 
modafinil 
oxcarbazepine 
phenobarbital 
phenytoin 
pioglitazone 
rifabutin 
rifampin 
St. John's wort 
troglitazone 
 
© Cytochrome P450 Drug Interaction Table 
www.drug-interactions.com 
 
 


Millendo Therapeutics, Inc. 
 
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Confidential; 14 January 2016 
Page 66 of 66 
 
Appendix 5 
Drugs that may Interact 
with P-glycoprotein  
 
Transporter  
MDR1/PgP  
 Gene 
ABCB1  
 Amiodarone  
S/Inhib  
 Amitriptyline  
Inhib  
 Amprenavir  
Induc  
 Astemizole  
Inhib  
 Atorvastatin  
S/Inhib  
 Boceprevir  
S/Inhib  
 Bromocriptine  
Inhib  
 Carvedilol  
Inhib  
 Chlorpromazine  
Inhib  
 Clarithromycin  
Inhib  
 Clotrimazole  
Induc  
 Cyclosporine  
S/Inhib  
 Desipramine  
Inhib  
 Dexverapamil  
Inhib  
 Diltiazem  
S/Inhib  
 Dipyridamole  
Inhib  
 Disulfiram  
Inhib  
 Doxepin  
Inhib  
 Erythromycin  
S/Inhib  
 Fluphenazine  
Inhib  
 Glibenclamide  
Inhib  
 Haloperidol  
Inhib  
 Imipramine  
Inhib  
 Indinavir  
S/Induc  
 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  
 Ofloxacin  
Inhib  
 Pentazocine  
Inhib  
 Prazosin  
Induc  
 Prochlorperazine  
Inhib  
 Progesterone  
Inhib/Induc  
 Propafenone  
Inhib  
 Propranolol  
S/Inhib  
 Quercetin  
Induc  
 Quinidine  
S/Inhib  
 Quinine  
Inhib  
 Reserpine  
inhib  
 Retinoic acid  
Induc  
 Rifampin  
S/Induc  
 Ritonavir  
S/inhib  
 Saquinavir  
S/Inhib  
 Simvastatin  
 S/Inhib 
 St. Johns Wort  
Induc  
 Tacrolimus  
S/Inhib  
 Tamoxifen  
Inhib  
 Telaprevir  
S/Inhib  
 Temsirolimus  
S/Inhib  
 Testosterone  
Inhib  
 Trimipramine  
Inhib  
 Vaspodar  
Inhib  
 Verapamil  
S/Inhib  
 
Inhib = Inhibition;  
Induc = Induction;  
S = Substrate;  
MDR = multidrug resistance protein 
 
Source: Pharmacology Weekly 
http://www.pharmacologyweekly.com/content/pag
es/medications-drugs-substrates-inhibitors-
inducers-efflux-transporters 
 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
A PHASE 2, MULTICENTER STUDY OF ATR-101 FOR THE 
TREATMENT OF CONGENITAL ADRENAL HYPERPLASIA 
Protocol Number: 
Study Phase:  
Product Name:  
IND Number: 
NCT Number:
Sponsor: 
Current Protocol: 
SAP: 
ATR-101-201 
2 
ATR-101 
122745 
NCT02804178
Millendo Therapeutics, Inc. 
Amendment 1 / January 14, 2016 
V2.0 / September 6, 2017 




Millendo Therapeutics, Inc. 
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TABLE OF CONTENTS 
1 
SUMMARY OF CHANGES ........................................................................................................... 5 
2 
INTRODUCTION ........................................................................................................................... 5 
3 
STUDY OBJECTIVES .................................................................................................................... 5 
3.1 
Primary Objective .................................................................................................................. 5 
3.2 
Secondary Objectives ............................................................................................................. 5 
4 
STUDY ENDPOINTS ..................................................................................................................... 5 
4.1 
Efficacy Assessment .............................................................................................................. 6 
4.2 
Safety Assessment .................................................................................................................. 6 
5 
STUDY OVERVIEW ...................................................................................................................... 7 
5.1 
Study Design .......................................................................................................................... 7 
5.2 
Treatments Administered and Blinding ................................................................................. 8 
6 
STATISTICAL METHODOLOGY ................................................................................................ 9 
6.1 
Sample Size Determination .................................................................................................... 9 
6.2 
General Considerations .......................................................................................................... 9 
6.3 
Analysis Populations ............................................................................................................ 10 
6.3.1 
Enrolled Population ................................................................................................. 10 
6.3.2 
Safety Population .................................................................................................... 10 
6.3.3 
Per Protocol Population ........................................................................................... 10 
6.3.4 
Pharmacokinetic Population .................................................................................... 10 
6.4 
Subject Disposition .............................................................................................................. 10 
6.5 
Demographic and Baseline Characteristics .......................................................................... 10 
6.6 
Prior and Concomitant Medications ..................................................................................... 11 
6.7 
Exposure and Compliance .................................................................................................... 11 
6.8 
Primary Efficacy Analyses ................................................................................................... 12 
6.9 
Pharmacodynamic Analyses ................................................................................................ 13 
6.10  Pharmacokinetic Analyses ................................................................................................... 13 
6.10.1  Sample Collections for Pharmacokinetic Analyses ................................................. 13 
6.10.2  Pharmacokinetic Variables ...................................................................................... 13 
6.10.3  Pharmacokinetic Variables Calculation .................................................................. 14 
6.10.4  Pharmacokinetic Summary and Analysis ................................................................ 15 
6.10.5  Handling Missing or Non-Quantifiable Data .......................................................... 15 
6.11  Safety Analyses .................................................................................................................... 16 
6.11.1  Adverse Events ........................................................................................................ 16 
6.11.2  Clinical Laboratory Evaluations .............................................................................. 17 
6.11.3  Vital Signs ............................................................................................................... 17 
6.11.4  Electrocardiogram ................................................................................................... 17 
6.11.5  Physical Examination .............................................................................................. 18 
6.11.6  Other Safety Parameters .......................................................................................... 18 


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7 
CHANGES FROM THE PLANNED ANALYSIS ....................................................................... 18 
8 
GENERAL INFORMATION ........................................................................................................ 18 
8.1 
Statistical Software............................................................................................................... 18 
 


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1 
SUMMARY OF CHANGES 
SAP Version History 
Version Date 
Description of Changes 
1.0 
June 19, 2017 
Original Document 
2.0 
September 6, 2017 
Modify TEAE to include all AEs starting on or after dosing 
by removing “or exist before but get worse in severity or 
relationship to study drug after first dose.” 
Also urinalysis is only collected at Screening and Final 
Study Visit. Remove summaries by dose level for Day 1 and 
Day 15. 
2 
INTRODUCTION 
This Statistical Analysis Plan (SAP) provides a description of the statistical and 
pharmacokinetic (PK) methods and procedures to be implemented for the analyses of data 
from Millendo Therapeutics Protocol ATR-101-201.  Any deviations from this analysis plan 
will be substantiated by sound statistical/PK rationale and will be documented in the final 
clinical study report. 
3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective of this study is to evaluate the efficacy and safety of orally 
administered ATR-101 in subjects with congenital adrenal hyperplasia (CAH). 
3.2 
Secondary Objectives 
The secondary objectives of this study are: 
 To evaluate the changes in adrenal cortical steroids and steroid intermediates 
 To evaluate the changes to the hypothalamic-pituitary-adrenal axis (via 
adrenocorticotropic hormone [ACTH]) 
 To evaluate the PK of ATR-101 
4 
STUDY ENDPOINTS 


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4.1 
Efficacy Assessment 
Efficacy will be assessed by changes in adrenal steroids and steroid intermediates. 
17-hydroxyprogesterone (17-OHP) will serve as the primary outcome measure as this 
adrenal steroid intermediate is used diagnostically and to aid in the management of 
exogenous glucocorticoid (GC) replacement therapy in clinical practice. However, absolute 
target values for 17-OHP or androgens do not currently exist in treatment guidelines put forth 
by any of the medical societies. The entry criterion for 17-OHP is set at ≥4x upper limit of 
normal (ULN) (ULN adjusted as needed for the menstrual cycle phase of subjects who are 
premenopausal women), which is intended to enroll subjects who are not optimally 
controlled while on exogenous steroid replacement therapy. It is anticipated that most 
subjects will enter with 17-OHP levels markedly higher than 4xULN. The primary efficacy 
outcome measure will be aligned to the clinical goal of achieving a mildly elevated 17-OHP 
level, which for this study is defined as ≤2xULN. However, given the high baseline 17-OHP 
levels anticipated, the percentage change in 17-OHP and changes in other key efficacy 
parameters in the androgen pathway (androstenedione, testosterone, dehydroepiandrosterone 
[DHEA], dehydroepiandrosterone sulfate [DHEA-S]) will also serve to define efficacy. 
The majority of CAH subjects will enter the study on both GC and mineralocorticoid (MC) 
replacement (75% of classic CAH subjects have deficiencies in both pathways). Direct renin 
and aldosterone will be assessed to determine the potential impact on the MC pathway. 
ACTH levels will be assessed to determine potential effects on the hypothalamic-pituitary-
adrenal (HPA)-axis. GC replacement doses are expected to remain unchanged. Confirmation 
of low GC levels associated with decreases in 17-OHP and androgens with ATR-101 dosing 
will help to establish the pharmacodynamic effects of ATR-101. Increased GC levels, 
secondary to decreased hepatic metabolism (ATR-101 CYP3A effect), could potentially lead 
to decreased ACTH and subsequently decreased 17-OHP levels. This could potentially 
confound assessment of direct ATR-101 effects on adrenal steroid and steroid intermediate 
synthesis. Therefore, assessment of GC levels will also be done during the study. 
4.2 
Safety Assessment 
Safety will be assessed by monitoring adverse events (AEs), changes in physical examination 
(including vital signs), changes in electrocardiograms (ECGs), and changes in laboratory 
parameters. Safety assessments will take place every 2 weeks during study participation. 


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5 
STUDY OVERVIEW 
5.1 
Study Design 
This is a multicenter, single-blind, multiple dose study of ATR-101 with a placebo washout 
component. A minimum of nine subjects will be enrolled with the potential to add an 
additional eight subjects. The study design is presented in Figure 1 below. 
Figure 1. ATR-101-201 Study Design 
 
Each subject will complete a Screening Period of up to 21 days to assess inclusion and 
exclusion criteria. Baseline status will be established with a 14-day single-blind, placebo 
Lead-in Period. Exogenous GC and MC replacement therapy must be maintained throughout 
the duration of the study. Each dose level, comprised of ATR-101 administered for 14 days 
followed by a 14-day placebo washout, will last for a total of 28 days (see Figure 2 below). 
All subjects will start at Dose Level 1, ATR-101 125 mg twice daily (BID), for 14 days. 
Efficacy and safety will be assessed after the 14-day ATR-101 treatment period (on the 
morning of Day 15). Immediately after the completion of the ATR-101 treatment period, a 
14-day single-blind, placebo Washout Period (placebo matching ATR-101 125 mg) will take 
place. The efficacy assessment obtained on Day 15 will be reviewed by the Principal 
Investigator (PI) or Sub-investiagor (SI) to determine whether the subject has met the 


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primary outcome measure or whether the subject should continue to the next dose level (if 
there are no safety issues).  
Figure 2. Dosing Regimen per Dose Level 
 
Subejcts will return to the study center after completion of the 14-day placebo Washout 
Period and will follow one of two actions based upon Day 15 efficacy results: 
 If the primary outcome measure is met (i.e., 17-OHP ≤ 2xULN) the subject 
completes the Final Study Visit 
 If the primary outcome measure is not met (i.e., 17-OHP > 2xULN) the subject 
continues to the next dose level. 
Table 1 below presents the 5 ATR-101 Dose Levels. Dose Levels 2, 3, 4, and 5 will follow 
the same procedures as Dose Level 1 (i.e., treatment with ATR-101 for 14 days, followed by 
the placebo Washout Period of 14 days). A subject may receive a minimum of one dose level 
(Level 1) or a maximum of 5 dose levels (Level 1-5), along with the corresponding placebo 
Washout Periods. 
Table 1. ATR-101 Doses for Each Dose Level 
 
5.2 
Treatments Administered and Blinding 
During the 14-day Baseline Lead-in Period, placebo tablets that match the ATR-101 125 mg 
tablets will be administered BID. 
Starting with Dose Level 1, each dose level will consist of a 28-day dosing regimen 
consisting of 14 days of ATR-101 treatment followed immediately by 14 days of matching 
placebo washout.  


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Subjects will be blinded to treatment beginning with the Baseline Lead-in Period, which will 
use placebo tablets that appear identical to ATR-101 125 mg. Dose levels 1 to 5 are split into 
two weeks of active treatment (ATR-101) followed by two weeks of treatment with matching 
placebo (Washout Period).  
6 
STATISTICAL METHODOLOGY 
6.1 
Sample Size Determination 
Sample size considerations are based on a Simon 2-stage Minimax design with 1-sided alpha 
of 5% and 80% power. 
Stage 1 consists of 9 completed subjects. The study will stop at Stage 1 if either of the 
following conditions are met: 
 Futility criteria: defined as ≤2 of 9 (22%) subjects having a Day 15 17-OHP 
≤ 2xULN or a negative mean percentage change (i.e., decrease) in 17-OHP from Day 
1 to Day 15 for Dose Levels 1-5 
 Success criteria: defined as ≥7 of 9 (78%) subjects having a Day 15 17-OHP 
≤ 2xULN or a negative mean percentage change (i.e., decrease) in 17-OHP from Day 
1 to Day 15 for Dose Levels 1-5  
Stage 2 will commence if 3, 4, 5, or 6 of the 9 subjects meet the primary outcome measure. 
In this scenario, accrual will continue with up to 8 additional subjects for a total of no more 
than 17 subjects. Accrual may stop earlier with sufficient evidence for further development if 
a total of 7 or more subjects respond (minimum observed response rate of 7/17, 41%). 
The study medical monitor along with the Sponsor may determine if a subject will be 
replaced in order to have a minimum of 9 evaluable subjects for Stage 1. Possible reasons for 
replacement include extreme noncompliance with study drug not related to an AE, and 
noncompliance with the protocol such as the use of prohibited medications that could 
confound results. 
6.2 
General Considerations 
Unless otherwise specified, summaries will be presented by dose level where the first dose of 
ATR-101 defines the start of each dose level. In other words, each dose level consists of 
Day 1 – Day 28 (2 weeks of ATR-101 and 2 weeks of Placebo). Subjects may be counted in 
more than one dose level. Each subject will be counted once in each dose level according to 
sequential participation and once in the overall column. 
In addition, summaries will be provided by last dose level. In other words, the results from 
the subject’s last completed dose level will be carried forward. 


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6.3 
Analysis Populations 
6.3.1 
Enrolled Population 
The Enrolled Population will include all subjects who receive at least one dose of placebo 
during the Lead-in Period. 
6.3.2 
Safety Population 
The Safety Population will include all subjects who receive at least one dose of ATR-101. 
For summaries by dose level, only subjects receiving at least one dose in the specified dose 
level will be included. For summaries by dose level and treatment, only subjects receiving at 
least one dose in the specified dose level treatment will be included. 
6.3.3 
Per Protocol Population 
The Per Protocol Population will include all subjects who take at least 11 days of ATR-101 
treatment at Dose Level 1 (the lowest dose level) and have at least one post-baseline efficacy 
assessment (i.e. 17-OHP) without having a significant protocol deviation. The Per Protocol 
Population will be identified per dose level. All subjects excluded from the Per Protocol 
Population will be identified after database lock.  
6.3.4 
Pharmacokinetic Population 
The PK Population will include all subjects who receive at least one dose of ATR-101 and 
have any measurable level of ATR-101 or its metabolites.  
6.4 
Subject Disposition 
Counts of subjects in each population, as well as counts and percentages of subjects who 
completed the study and who withdraw early from the study, with the reason for early 
withdrawal, will be presented by ATR-101 dose level and overall. 
6.5 
Demographic and Baseline Characteristics 
Descriptive summaries of demographic and baseline characteristics will be presented by dose 
level and overall. Baseline measurements refer to data collected at Dose Level 1 Day 1 
pre-dose.  If a value at Dose Level 1 Day 1 pre-dose is not available, the last measurement 
prior to the first dose of study drug will be used as the baseline value.  
Demographic and baseline characteristics include, but are not limited to: age at informed 
consent, sex, race, ethnicity, baseline glucocorticoids, baseline glucocorticoid dose, baseline 
mineralocorticoid dose, body weight, height, body mass index (BMI), body surface area, 
steroid hormones, and steroid intermediates.  Continuous variables (age, glucocorticoid dose, 
mineralocorticoid dose, body weight, BMI, steroid hormones, and steroid intermediates) will 
be summarized by subject count, mean, standard deviation, median, minimum, and 


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maximum.  Categorical variables (race, sex, ethnicity, and glucocorticoids) will be 
summarized by the number and percentage of subjects in the corresponding categories.  
Body surface area will be calculated as: 
  
Weight in kg × Height in cm 
 
  
3600 
 
 
Demographics and baseline characteristics will be summarized based on the Safety 
Population. If the Per Protocol Population and the PK Population differ from the Safety 
Population, the demographics and baseline characteristics will also be summarized based on 
these populations. Demographics and baseline characteristics will also be summarized for 
male and female subgroups and for men and postmenopausal women (excludes females <50 
years in age). 
All medical history will be listed. 
6.6 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded with the World Health Organization Drug 
Dictionary and listed.  All concomitant medications taken after first dosing of study drug will 
be summarized for the Safety Population by dose level, treatment, and overall. All 
concomitant medications during the Placebo Lead-in Period will be summarized overall. All 
prior and concomitant medications will be listed. 
6.7 
Exposure and Compliance 
Treatment duration within each dose level will be summarized with descriptive statistics for 
ATR-101 and placebo separately and overall. Treatment duration will be calculated as 
follows: 
Treatment duration in days = last dose date – first dose date +1. 
If the last dose date is not available within a dose level, the date prior to the first dose date of 
the next dose level will be used. 
The number of tablets administered will be summarized within each dose level with 
descriptive statistics for ATR-101 and placebo separately and overall.  
Number of tablets administered = number of tablets dispensed – number of tablets returned 
Compliance within each dose level and overall will be summarized with descriptive statistics 
for ATR-101 and placebo separately. The percentage of subjects with compliance <80%, 
80-120%, and >120% will also be tabulated.  


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Dose Levels 1, 2, and 3: 
Compliance (%) = 100 x number of tablets administered / (treatment duration x 2). 
Dose Levels 4 and 5: 
Compliance (%) = 100 x number of tablets administered / (treatment duration x 4). 
6.8 
Primary Efficacy Analyses 
The percentage of responders will be tabulated for the Safety Population overall. A responder 
is defined as a subject who meets the primary outcome measure of Day 15 17-OHP ≤ 2xULN 
(ULN adjusted as needed for the menstrual cycle phase of subjects who are premenopausal 
women) at any dose level.  
The percentage of subjects showing “drug effect” will be tabulated for the Safety Population 
overall. A subject showing “drug effect” is defined as a subject who is a responder or who 
has a negative mean percentage change in 17-OHP from Day 1 to Day 15 for Dose Levels 
1-5. 
The percentage of responders and percentage of subjects showing “drug effect” will also be 
tabulated for the Per Protocol Population overall as a sensitivity analysis to test the 
robustness of the primary result. 
The change and percentage change in 17-OHP will also be calculated from Day 15 to Day 1 
of the next dose level as follows: 
 Change and percentage change from Dose Level 1 Day 15 to Dose Level 2 Day 1 
 Change and percentage change from Dose Level 2 Day 15 to Dose Level 3 Day 1 
 Change and percentage change from Dose Level 3 Day 15 to Dose Level 4 Day 1 
 Change and percentage change from Dose Level 4 Day 15 to Dose Level 5 Day 1 
 Change and percentage change from Dose Level 5 Day 15 to Final Study Visit (Visit 
Day 29) 
The percentage of placebo responders will be tabulated for the Safety Population overall. A 
placebo responder is defined as a subject who meets Day 1/Final Study Visit 17-OHP 
≤ 2xULN at any dose level, i.e. the 17-OHP at the italicized visit above is ≤ 2xULN.  
The percentage of subjects showing “placebo effect” will be tabulated for the Safety 
Population overall. A subject showing “placebo effect” is defined as a subject who is a 
placebo responder or who has a negative mean percentage change in 17-OHP from Day 15 to 
Day 1 of the next dose level. 


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6.9 
Pharmacodynamic Analyses 
All steroid hormones and steroid intermediates will be summarized for Day 1 and Day 15 by 
dose level. The change and percentage change from Day 1 to Day 15 within each dose level 
will be summarized. The change and percentage change from Day 15 to Day 1 of the next 
dose level will also be summarized. Summaries will also be provided for male and female 
subgroups and for men and postmenopausal women (excludes females <50 years in age). 
Pharmacodynamic measures include: 
 GC pathway: progesterone, cortisol 
 MC pathway: 11-deoxycorticosterone (11-DOC), direct renin, aldosterone 
 Androgens: androstenedione, free testosterone, DHEA, DHEA-S 
 HPA-axis: ACTH 
6.10 
Pharmacokinetic Analyses 
6.10.1 
Sample Collections for Pharmacokinetic Analyses 
Blood samples will be collected to profile the levels of ATR-101 and its metabolites on 
Day 1 of each Dose Level at pre-dose and 1, 2, 3, and 4 hours post-dose; on Day 15 of each 
Dose Level at pre-dose, and at the Final Study Visit or Early Termination Visit. A window of 
±10 minutes is permitted around each sampling time point. 
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.  
6.10.2 
Pharmacokinetic Variables 
The PK parameters listed below will be calculated from the individual plasma concentration 
profiles by standard non-compartmental methods: 
Table 2. PK Parameters to be Calculated 
Cmax  
Maximum observed concentration  
tmax  
Time to reach the maximum observed concentration  
AUC0-last  
Area under the concentration-time curve calculated from time zero to the 
last measurable concentration  
AUC0-4 
Area under the concentration-time curve calculated from time zero to 4 


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hours 
Lambda z (λz)  Apparent first-order terminal elimination rate constant calculated by 
linear regression of the terminal linear portion of the log concentration 
vs. time curve (data permitting) 
t½  
Apparent terminal half-life (data permitting) 
AUC0-inf  
Area under the concentration-time curve from time zero to infinity 
(extrapolated) (data permitting) 
6.10.3 
Pharmacokinetic Variables Calculation 
Actual collection times will be used in PK parameter calculations. The Linear Trapezoidal 
Linear Interpolation method will be used in the computation of all AUC values. The PK 
parameters λz, t½, and AUC0-inf will not be presented for those subjects who do not exhibit a 
terminal elimination phase in their concentration versus time profiles. In order to estimate the 
apparent first-order terminal elimination constant, λz, linear regression of concentration in 
logarithm scale vs. time will be performed using at least 3 data points. Uniform weighting 
will be selected to perform the regression analysis to estimate λz. The constant λz will not be 
assigned if:  
 the terminal elimination phase is not linear (as it appears on a semi-logarithmic scale)  
 the terminal elimination rate constant indicates a positive slope (λz > 0)  
 tmax is one of the 3 last data points  
 the regression coefficient (R2) is less than 0.8  
If the percent extrapolated AUC0-inf is greater than 20%, the PK parameters will be reported 
but flagged in the appropriate listing.  In cases where the λz interval is not assigned, the 
values of associated parameters (λz, t½, AUC0-inf) will not be calculated.  
For the calculation of AUC0-4 if the nominal (planned) time of the last observed measurable 
concentration is at 4 hours but the actual time of the last observed measurable concentration 
(tlast) is less than 4 hours (such as actual time = 3.9 hours), the concentration at 4 hours will 
be imputed. The imputed concentration is calculated using the linear extrapolation of the 
previous two records. If the extrapolated concentration is less than 0, then a value of 0 will be 
used. If the nominal time of the last observed measurable concentration is less than 4 hours, 
then AUC0-4 will not be calculated. A visual aide for the imputation of the concentration at 4 
hours is provided below in Figure 3. 


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Figure 3. Illustration of Imputation of Concentration at 4 Hours for Calculation of 
AUC0-4 
 
6.10.4 
Pharmacokinetic Summary and Analysis 
Day 1 PK concentration data, within the acceptable sampling window, will be summarized 
for each time point using descriptive statistics from the PK Population (i.e., Mean, SD, Min, 
Max, Median, %CV, Geometric Mean, Geometric %CV) for each dose level. Plots of mean 
Day 1 concentrations of plasma ATR-101 and its metabolites (with standard deviation bars) 
versus nominal time will be generated for each dose level. Individual ATR-101 and 
metabolite concentration versus actual time plots will also be provided. 
The Day 1 PK parameters will be summarized by dose level using the PK Population.  Actual 
sampling times will be used.  Geometric mean and geometric coefficient of variation (CV%) 
will be added to the descriptive statistics for Cmax and all AUCs.  
PK/PD relationships may be explored graphically. 
6.10.5 
Handling Missing or Non-Quantifiable Data 
Concentrations below the lower limit of quantitation (BLLOQ) before the first measurable 
concentration will be assigned a value of zero. A single BLLOQ 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. BLLOQ 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. 


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6.11 
Safety Analyses 
Safety data includes AEs, physical examinations, vital signs, ECGs, and clinical laboratory 
assessments. Safety data will be summarized and listed. No formal statistical analysis of the 
safety data will be conducted.  All safety summaries will be based on the Safety Population. 
Safety summaries will be based on observed values only. 
6.11.1 
Adverse Events 
AEs will be coded and classified by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA). All AEs reported for enrolled subjects 
during the clinical study will be recorded on the electronic case report form (eCRF). All AEs, 
regardless of relationship to study drug or procedure, should be collected beginning from the 
time the subject signs the study consent. AEs in clinical investigation subjects include any 
change in the subject’s condition. This includes symptoms, physical findings, or clinical 
syndromes. 
TEAEs are defined as adverse events that happen for the first time on or after the first dose 
date (Dose Level 1 Day 1) of ATR-101.  
An overview with counts of events and subjects will be provided by dose level and treatment 
at AE onset and overall for the incidence of AEs in the following categories:  
 Any TEAE  
 Maximum severity of TEAE  
 Any study drug related TEAE  
 Maximum severity of study drug related TEAE  
 Any serious treatment-emergent SAE (TESAE) 
 Any study drug related SAE  
 Death due to AE  
 AE leading to discontinuation from study  
 Study drug related AE leading to discontinuation from study  
The incidence of TEAEs will be summarized by dose level and treatment at AE onset and 
overall by system organ class and preferred term. System organ class will be sorted 
alphabetically and preferred term will be sorted by descending total frequency within system 
organ class. Similar summaries will be provided for TEAEs by maximum severity. The same 
summaries will be done for study drug related TEAEs.   
The AE summaries will be provided by dose level and treatment at AE onset. In other words, 
AEs starting on or after ATR-101 and prior to the subsequent Placebo dose will be attributed 


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to ATR-101. AEs starting on or after Placebo and prior to the subsequent ATR-101 dose will 
be attributed to Placebo. 
Listings will be provided for any SAEs, AEs leading to discontinuation from study, and AEs 
beginning in the Placebo Baseline Lead-In Period. 
6.11.2 
Clinical Laboratory Evaluations 
Safety laboratory data (chemistry, hematology, and coagulation) will be summarized by dose 
level for Day 1 and Day 15 visits. Change from Day 1 to Day 15 will be summarized within 
each dose level. The change from Day 15 to Day 1 of the next dose level will also be 
summarized. 
The number and frequency of subjects with laboratory abnormalities will be summarized by 
dose level. Shift tables from Day 1 to Day 15 will be presented for ALT and AST (>1xULN 
to ≤2xULN, >2xULN to ≤3xULN, >3xULN) and CK (>1xULN to ≤5xULN, >5xULN to 
≤10xULN, >10xULN). Shift tables from Day 15 to Day 1 of the next dose level will also be 
presented. 
Urinalysis will be summarized overall at Screening and the Final Study Visit. 
6.11.3 
Vital Signs  
Vital signs including oral or tympanic temperature, systolic and diastolic blood pressure, 
pulse, and respiratory rate will be measured at Screening, at the start of the Baseline Lead-in 
Period, at Day 1 pre-dose and at 1, 2, and 4 hours post-dose for each dose level, at Day 15 
pre-dose for each dose level, and at the Final Study Visit or Early Termination Visit. Body 
weight will be measured at Screening, at the start of the Baseline Lead-in Period, at Day 1 
pre-dose for each dose level, at Day 15 pre-dose for each dose level, and at the Final Study 
Visit or Early Termination Visit. 
Vital signs will be summarized by dose level for Day 1 pre-dose, 1, 2, and 4 hours post-dose 
and Day 15 visits. Change from Day 1 pre-dose will be summarized.  
6.11.4 
Electrocardiogram 
All subjects will have 12-lead ECG assessments at Screening, Day 1 pre-dose and 2 hours 
post-dose for each dose level, Day 15 pre-dose for each dose level, and at the completion of 
the Placebo Washout Period on Day 29 (this ECG could serve as the pre-dose ECG, Day 1, if 
the subject is moving to the next dose level or as the ECG for the Final Study Visit or Early 
Termination Visit).  
ECG measurements (heart rate, PR, QRS, QT, RR, QTcB, and QTcF) will be summarized by 
dose level for Day 1 pre-dose, 2 hours post-dose and Day 15 visits. Change from Day 1 pre-
dose will be summarized.  


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ECG interpretations (normal, abnormal not clinically significant, abnormal clinically 
significant) will be tabulated by dose level for each time point. 
6.11.5 
Physical Examination 
A complete physical examination will be obtained at Screening and the Final Study visit or 
Early Termination Visit. A targeted brief physical exam will be completed prior to the start 
of the Baseline Lead-in Period, prior to dosing on the first day of every Dose Level (active 
treatment), and prior to starting the placebo Washout Period at each Dose Level. Physical 
exam findings (normal, abnormal not clinically significant, abnormal clinically significant) 
will be tabulated by dose level for each visit. 
6.11.6 
Other Safety Parameters 
All other safety data will be listed, such as urine pregnancy tests. 
7 
CHANGES FROM THE PLANNED ANALYSIS 
Per Protocol, the study was to have been stopped at Stage 1 if either of the following 
conditions were met: 
 Futility criteria: defined as ≤2 of 9 (22%) subjects meeting the primary outcome 
measure (17-OHP ≤ 2xULN) 
 Success criteria: defined as ≥7 of 9 (78%) subjects meeting the primary outcome 
measure (17-OHP ≤ 2xULN) 
From medical considerations, this has been modified as follows: 
 Futility criteria: defined as ≤2 of 9 (22%) subjects having a Day 15 17-OHP 
≤ 2xULN or a negative mean percentage change (i.e., decrease) in 17-OHP from Day 
1 to Day 15 for Dose Levels 1-5 
 Success criteria: defined as ≥7 of 9 (78%) subjects having a Day 15 17-OHP 
≤ 2xULN or a negative mean percentage change (i.e., decrease) in 17-OHP from Day 
1 to Day 15 for Dose Levels 1-5  
8 
GENERAL INFORMATION 
The mock-ups for SAS-generated tables/figures/listings will be prepared in a separate 
document and finalized before database lock for the study. 
8.1 
Statistical Software 
The creation of analysis datasets and all statistical analyses will be done using SAS® version 
9.3.  The PK parameters will be determined using Phoenix™ WinNonlin® version 6.4 or 


Millendo Therapeutics, Inc. 
ATR-101-201 Statistical Analysis Plan 
Page 19 of 19 
 
higher. The Medpace standard operating procedures will be followed for the validation of all 
SAS programs and outputs.