A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of SPR001 (Tildacerfont) in Reducing Supraphysiologic Glucocorticoid Use in Adult Subjects With Classic Congenital Adrenal Hyperplasia
Phase: PHASE2
Conditions: Congenital Adrenal Hyperplasia
Sponsor: Spruce Biosciences

SPR001-204 
CLINICAL STUDY PROTOCOL 
Spruce Biosciences, Inc. 
Global Version 8; EU Version 9, 15 April 2024 
 
 
CONFIDENTIAL 
Page 1 of 108 
 
 
 
 
A Randomized, Double-Blind, Placebo-Controlled Study  
to Evaluate the Efficacy and Safety of SPR001 (Tildacerfont) 
in Reducing Supraphysiologic Glucocorticoid Use  
in Adult Subjects with Classic Congenital Adrenal Hyperplasia 
 
US IND Number: 131761 
Study Number: SPR001-204 
Document Type: Clinical study protocol  
Global Protocol Version: 8.0 (amends Version 7.0) 
EU Protocol Version:  9.0 (amends Version 8.0) 
Protocol Date: 15 April 2024 
Investigational Medicinal Product: SPR001 (tildacerfont) 
Indication: Classic congenital adrenal hyperplasia (CAH) 
Sponsor: Spruce Biosciences, Inc. 
611 Gateway Blvd. Suite 740 
South San Francisco, CA 94080 
United States 
Registries: ClinicalTrials.gov: NCT04544410 
 EudraCT #: 2019-004765-40 
EU CT#: 2023-503771-13-00 
 
Statement of Confidentiality 
This document contains proprietary and confidential information of Spruce Biosciences, Inc. Acceptance of this 
document constitutes agreement by the recipient that no previously unpublished information contained herein 
will be published or disclosed without the prior written approval of Spruce Biosciences, Inc., with the exception 
that this document may be disclosed to study personnel under your supervision who need to know the contents 
for conducting the study and to appropriate Institutional Review Boards (IRBs) or Ethics Committees (ECs) under 
the condition that the personnel have agreed to keep this information confidential. The foregoing shall not apply 
to disclosure required by governmental regulations or laws; however, Spruce Biosciences, Inc. shall be promptly 
notified of any such disclosure. 

SPR001-204 
Spruce Biosciences, Inc. 
CLINICAL STUDY PROTOCOL 
Global Version 8; EU Version 9, 15 April 2024 
SPONSOR APPROVAL PAGE 
A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of 
SPR001 (Tildacerfont) in Reducing Supraphysiologic Glucocorticoid Use in Adult Subjects with 
Classic Congenital Adrenal Hyperplasia 
Study Number: SPR001-204 
Protocol Version: 8.0 (Global) 
Protocol Version: 9.0 (EU) 
Protocol Date: 15 April 2024 
This protocol has been reviewed and approved by Spruce Biosciences, Inc.: 
Saba Sile, MD 
Vice President, Clinical Development 
Date 
Abe Castro 
Executive Director, Clinical Development Operations 
Date 
CONFIDENTIAL 
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DocuSign Envelope ID: 8B9B985D-A0E7-4334-B46F-4814EDE83D04
16-Apr-2024
16-Apr-2024

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INVESTIGATOR PROTOCOL AGREEMENT PAGE 
A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of 
SPR001 (Tildacerfont) in Reducing Supraphysiologic Glucocorticoid Use in Adult Subjects with 
Classic Congenital Adrenal Hyperplasia 
Study Number: SPR001-204 
Protocol Version: 8.0 (Global) 
Protocol Version: 9.0 (EU) 
Protocol Date:  15 April 2024 
I have reviewed the protocol and the attachments, and I agree to conduct this trial in 
accordance with all stipulations of the protocol, including all statements regarding 
confidentiality. I will ensure that no deviation from, or changes to, the protocol will take place 
without prior agreement from the Sponsor and documented approval from the Institutional 
Review Board (IRB)/ Ethics Committee (EC), except where necessary to eliminate an immediate 
hazard(s) to the trial participants or when change(s) involves only logistical or administrative 
aspects of the study. 
I agree to conduct this trial in accordance with International Council for Harmonisation Good 
Clinical Practice (ICH GCP), the most recent version of the Declaration of Helsinki, and all 
applicable local and federal legal and regulatory requirements.  
I agree to provide sufficient time and adequate numbers of qualified staff and facilities for the 
foreseen duration of the clinical study to conduct the study properly, ethically, and safely. All 
personnel involved in the conduct of this study have completed Human Subjects Protection and 
ICH GCP Training. 
I agree to permit periodic site monitoring of case report forms and source documents by the 
Sponsor or designee and by appropriate regulatory authorities. 
I agree to supply the Sponsor with any information regarding ownership interest and financial 
ties with the Sponsor for the purpose of complying with regulatory requirements. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB/EC for review and approval. Approval of both the protocol and the 
consent form must be obtained before any participant is enrolled. Any amendment to the 
protocol will require review and approval by the IRB/EC before the changes are implemented to 
the study. All changes to the consent form will be IRB/EC approved; a determination will be 
made regarding whether participants who provided previous consent need to be re-consented 
using the updated consent form. 
Site Name:  __________________________________________________________________ 
Principal Investigator Name: ____________________________________________________  
___________________________________________________    _______________________ 
Principal Investigator’s Signature 
 
 
 
 
Date 

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TABLE OF CONTENTS 
SPONSOR APPROVAL PAGE ................................................................................................... 2 
INVESTIGATOR PROTOCOL AGREEMENT PAGE ....................................................................... 3 
LIST OF ABBREVIATIONS ........................................................................................................ 9 
1 
PROTOCOL SUMMARY.............................................................................................. 13 
1.1 
Protocol Synopsis .............................................................................................................. 13 
1.2 
Schema .............................................................................................................................. 26 
1.3 
Schedules of Activities ...................................................................................................... 28 
1.3.1 Optional A4 Screening Visit .............................................................................................. 28 
1.3.2 Schedule of Screening Activities ....................................................................................... 28 
1.3.3 Schedule of Glucocorticoid Conversion Period Activities ................................................. 30 
1.3.4 Schedule of Treatment Period and Follow-up Activities .................................................. 32 
1.3.5 Schedule of Optional Open-Label Extension Period Activities ......................................... 36 
2 
INTRODUCTION ........................................................................................................ 38 
2.1 
Study Rationale ................................................................................................................. 38 
2.2 
Background ....................................................................................................................... 39 
2.2.1 Congenital Adrenal Hyperplasia ....................................................................................... 39 
2.2.2 Current Treatment for CAH .............................................................................................. 40 
2.2.3 Tildacerfont for the Treatment of CAH ............................................................................. 41 
2.2.4 Nonclinical Studies of Tildacerfont ................................................................................... 41 
2.2.5 Clinical Experience with Tildacerfont ................................................................................ 42 
2.3 
Risk/Benefit Assessment ................................................................................................... 43 
2.3.1 Observed Potential Risks .................................................................................................. 43 
2.3.2 Observed Potential Benefits ............................................................................................. 44 
2.3.3 Assessment of Potential Risks and Benefits ..................................................................... 45 
3 
OBJECTIVES AND ENDPOINTS ................................................................................... 46 
4 
STUDY DESIGN ......................................................................................................... 49 
4.1 
Overall Design ................................................................................................................... 49 
4.1.1 Study Periods .................................................................................................................... 49 
4.1.2 Study Visits and Telephone Contacts ................................................................................ 50 
4.1.3 Study Diary/Drug Adherence Data Collection .................................................................. 51 
4.1.4 Procedures for Glucocorticoids ........................................................................................ 52 
4.2 
Scientific Rationale for Study Design ................................................................................ 56 
4.3 
Justification for Dose ........................................................................................................ 58 

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4.4 
End of Study ...................................................................................................................... 59 
4.4.1 End of Study Definition ..................................................................................................... 59 
4.4.2 Optional Open-Label Extension Period ............................................................................. 59 
5 
STUDY POPULATION ................................................................................................. 59 
5.1 
Eligibility Criteria ............................................................................................................... 59 
5.1.1 Inclusion Criteria ............................................................................................................... 59 
5.1.2 Exclusion Criteria............................................................................................................... 60 
5.2 
Lifestyle Considerations .................................................................................................... 61 
5.2.1 Shift Work and Time Zone Changes .................................................................................. 61 
5.2.2 Meals and Dietary Restrictions ......................................................................................... 62 
5.2.3 Caffeine, Alcohol, and Tobacco ........................................................................................ 62 
5.2.4 Activity .............................................................................................................................. 62 
5.2.5 Contraception Guidelines ................................................................................................. 62 
5.3 
Screen Failures .................................................................................................................. 64 
6 
STUDY INTERVENTION .............................................................................................. 65 
6.1 
Study Intervention Administration ................................................................................... 65 
6.1.1 Study Intervention Description ......................................................................................... 65 
6.1.2 Treatment Assignment, Dosing, and Administration ....................................................... 65 
6.2 
Preparation/Handling/Storage/Accountability ................................................................ 66 
6.2.1 Acquisition and Accountability ......................................................................................... 66 
6.2.2 Formulation, Appearance, Packaging, and Labeling ......................................................... 66 
6.2.3 Product Storage and Stability ........................................................................................... 66 
6.3 
Measures to Minimize Bias: Randomization and Blinding ............................................... 66 
6.4 
Study Intervention Compliance ........................................................................................ 67 
6.5 
Concomitant Therapy ....................................................................................................... 67 
6.5.1 Prohibited Concomitant Medications ............................................................................... 67 
7 
STUDY DRUG DISCONTINUATION AND PARTICIPANT WITHDRAWAL ......................... 69 
7.1 
Study Drug Discontinuation .............................................................................................. 69 
7.1.1 Liver Chemistry Stopping Criteria ..................................................................................... 69 
7.1.2 QT Stopping Criteria .......................................................................................................... 70 
7.1.3 Suicidality Stopping Criteria .............................................................................................. 70 
7.1.4 Depression or Anxiety Stopping Criteria ........................................................................... 71 
7.1.5 Adrenal Insufficiency Stopping Criteria ............................................................................ 71 
7.1.6 Reproductive Hormone Stopping Criteria ........................................................................ 72 

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7.1.7 Clinically Significant Adverse Event Stopping Criteria ...................................................... 72 
7.2 
Participant Withdrawal from the Study ............................................................................ 72 
7.3 
Lost to Follow-up .............................................................................................................. 73 
8 
STUDY ASSESSMENTS AND PROCEDURES .................................................................. 74 
8.1 
Efficacy Assessments ........................................................................................................ 74 
8.1.1 Hormone Assessments ..................................................................................................... 74 
8.1.2 Quality of Life Assessments .............................................................................................. 74 
8.1.3 Metabolic Assessments .................................................................................................... 75 
8.1.4 Bone Biomarker Assessments ........................................................................................... 75 
8.1.5 Hyperandrogenic Symptoms ............................................................................................ 75 
8.2 
Safety Assessments ........................................................................................................... 76 
8.2.1 Physical Examination ........................................................................................................ 76 
8.2.2 Vital Signs .......................................................................................................................... 76 
8.2.3 Body Weight, Height, BMI, Fat Mass, and Waist Circumference ..................................... 77 
8.2.4 Electrocardiogram ............................................................................................................. 77 
8.2.5 Clinical Laboratory and Urinalysis ..................................................................................... 77 
8.2.6 Psychiatric Evaluations ...................................................................................................... 78 
8.3 
Adverse Events and Serious Adverse Events .................................................................... 78 
8.3.1 Definition of Adverse Event .............................................................................................. 78 
8.3.2 Definition of Serious Adverse Event ................................................................................. 79 
8.3.3 Classification of an Adverse Event .................................................................................... 80 
8.3.4 Time Period and Frequency for Event Assessment and Follow-up .................................. 83 
8.3.5 Adverse Event Reporting .................................................................................................. 83 
8.3.6 Serious Adverse Event Reporting...................................................................................... 84 
8.3.7 Reporting of Pregnancy .................................................................................................... 84 
8.3.8 Adverse Events of Special Interest .................................................................................... 85 
8.4 
Pharmacokinetic Assessments .......................................................................................... 86 
9 
STATISTICAL CONSIDERATIONS ................................................................................. 86 
9.1 
Statistical Hypotheses ....................................................................................................... 86 
9.2 
Sample Size Determination ............................................................................................... 87 
9.3 
Populations for Analyses ................................................................................................... 87 
9.4 
Statistical Analyses ............................................................................................................ 87 
9.4.1 General Considerations..................................................................................................... 87 
9.4.2 Analysis of the Primary Efficacy Endpoint ........................................................................ 88 

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9.4.3 Analysis of the Secondary Efficacy Endpoints .................................................................. 88 
9.4.4 Analysis of the Exploratory Efficacy Endpoints ................................................................. 89 
9.4.5 Analysis of the Exploratory Efficacy Endpoints in the Optional Extension Period ........... 90 
9.4.6 Analysis Evaluation Periods .............................................................................................. 90 
9.4.7 Safety Analyses ................................................................................................................. 90 
9.4.8 Baseline Descriptive Statistics........................................................................................... 91 
9.4.9 Subgroup Analyses ............................................................................................................ 91 
9.5 
Primary and Final Analyses ............................................................................................... 92 
9.6 
Multiplicity Control ........................................................................................................... 92 
9.7 
Data Monitoring Committee ............................................................................................. 92 
10 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS .......................... 92 
10.1 
Informed Consent ............................................................................................................. 92 
10.2 
Study Discontinuation and Closure ................................................................................... 93 
10.3 
Confidentiality and Privacy ............................................................................................... 93 
10.4 
Future Use of Stored Specimens and Data ....................................................................... 94 
10.5 
Key Roles and Study Governance ..................................................................................... 94 
10.5.1 Sponsor ............................................................................................................................. 94 
10.5.2 Investigators ...................................................................................................................... 94 
10.5.3 Institutional Review Board/Ethics Committee ................................................................. 94 
10.6 
Safety Oversight ................................................................................................................ 94 
10.7 
Clinical Monitoring ............................................................................................................ 95 
10.8 
Quality Assurance and Quality Control ............................................................................. 95 
10.9 
Data Handling and Record Keeping .................................................................................. 95 
10.9.1 Data Collection and Management Responsibilities .......................................................... 95 
10.9.2 Study Records Retention .................................................................................................. 96 
10.10 Protocol Deviations ........................................................................................................... 96 
10.11 Publication and Data Sharing Policy ................................................................................. 96 
10.12 Amendments ..................................................................................................................... 96 
11 
COVID-19 RISK MITIGATION ..................................................................................... 97 
11.1 
Risk/Benefit Assessment in the Context of COVID-19 or Other Logistical 
Challenges .................................................................................................................. 97 
11.2 
Study Conduct in the Context of COVID-19 or Other Logistical Challenges ..................... 97 
11.2.1 Mode of Study Visits in the Context of COVID-19 or Other Logistical Challenges ........... 98 
11.3 
Subject Disposition in the Context of COVID-19 or Other Logistical Challenges .............. 99 

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11.4 
Regulatory and Study Oversight Considerations in the Context of COVID-19 or 
Other Logistical Challenges ........................................................................................ 99 
12 
REFERENCES ............................................................................................................ 100 
13 
APPENDICES ............................................................................................................ 103 
13.1 
Appendix of Prohibited Concomitant Medications ........................................................ 103 
13.2 
Appendix of Liver Safety ................................................................................................. 104 
13.2.1 Suggested Actions, Follow-up Assessments, and Monitoring When Liver 
Chemistry Stopping Criteria Are Met ...................................................................... 104 
13.2.2 Increased Liver Chemistry Monitoring While Continuing Study Drug ............................ 105 
13.2.3 Restart Following Transient Resolving Liver Chemistry Events Not Related to 
Study Drug ............................................................................................................... 106 
13.3 
Appendix of Clinical Laboratory and Urinalysis Tests ..................................................... 107 
13.4 
Appendix Regarding Genetic Sample Collection and Testing ......................................... 108 
 
LIST OF TABLES 
Table 1. 
Glucocorticoid Dose Conversion to Hydrocortisone Equivalents (HCe) .................... 53 
Table 2. 
Sick Day Guidelines for Stress Dosing of Hydrocortisone ......................................... 55 
Table 3. 
Stopping Criteria and Increased Monitoring for Liver Chemistry Elevations ............ 70 
Table 4. 
Severity of Adverse Events ........................................................................................ 81 
Table 5. 
Relatedness of Adverse Event to Study Drug or Study Glucocorticoid ..................... 82 
Table 6. 
Outcome of Adverse Event ........................................................................................ 83 
Table 7. 
Secondary Efficacy Endpoints .................................................................................... 89 
 

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LIST OF ABBREVIATIONS 
17-OHP 
17-hydroxyprogesterone 
A4 
androstenedione 
ACTH 
adrenocorticotropic hormone, corticotropin 
ADL 
activities of daily living 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase  
AUC 
area under the concentration-time curve 
BCRP 
breast cancer resistance protein 
BID 
twice daily 
BMD 
bone mineral density 
BMI 
body mass index 
BSAP 
bone-specific alkaline phosphatase 
BUN 
blood urea nitrogen 
C-SSRS 
Columbia–Suicide Severity Rating Scale 
CAH 
congenital adrenal hyperplasia 
CGI-I 
Clinical Global Impression – Improvement Scale 
CI 
confidence interval 
CNS 
central nervous system 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
coronavirus disease 2019 
CPK 
creatinine phosphokinase 
CRF 
corticotropin-releasing factor 
CRF1, CRF2  
corticotropin-releasing factor type-1 or type-2 
CTCAE 
Common Terminology Criteria for Adverse Events  
CTX-1 
C-terminal telopeptide of type 1 collagen 
CV 
coefficient of variation 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DXA 
dual-energy X-ray absorptiometry 

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DILI 
drug-induced liver injury 
DSMB 
Data and Safety Monitoring Board 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
EOT 
end of treatment 
FCP 
female of childbearing potential 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GC 
glucocorticoid 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GI 
gastrointestinal 
HADS 
Hospital Anxiety and Depression Scale 
HbA1c 
hemoglobin A1c 
HBcAb 
hepatitis B core antibody 
HbsAg 
hepatitis B surface antigen 
HC 
hydrocortisone 
HCe 
hydrocortisone equivalent(s) 
HDL 
high-density lipoprotein 
HEENT 
head, eyes, ears, neck, and throat 
HIV 
human immunodeficiency virus 
HOMA-IR 
homeostatic model assessment of insulin resistance 
HPA 
hypothalamic-pituitary-adrenal 
HPLC 
high-performance liquid chromatography 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IgG 
immunoglobulin G 
IgM 
immunoglobulin M 
INR 
international normalized ratio 
IQR 
interquartile range 
IRB 
Institutional Review Board 

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ITT 
Intent to Treat (Population) 
IUD 
intrauterine device 
IUS 
intrauterine system 
LDH 
lactate dehydrogenase 
LDL 
low-density lipoprotein 
LFT 
liver function test 
LH 
luteinizing hormone 
LLD 
lower limit of detection 
MCH 
mean corpuscular hemoglobin 
MCV 
mean corpuscular volume 
MCID 
minimum clinically important differences 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified Intent to Treat (Population) 
ms 
millisecond 
OTC 
over the counter 
PBPK 
physiologically based pharmacokinetic (modeling) 
PD 
pharmacodynamic(s) 
PGIC 
Patient Global Impression of Change 
PK 
pharmacokinetic(s) 
PP 
Per Protocol (Population) 
PRN 
as needed 
PRO 
patient-reported outcome (measure) 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
PVC 
polyvinyl chloride 
PVDC 
polyvinylidene chloride 
QD 
once daily 
QoL 
quality of life 
QTcF 
Fridericia-corrected QT interval 
RBC 
red blood cell 
RTSM 
randomization and trial supply management 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SF-36 
Short Form 36 

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SGOT 
serum glutamic-oxaloacetic transaminase 
SGPT 
serum glutamic-pyruvic transaminase 
SHBG 
sex hormone–binding globulin 
SUSAR 
suspected unexpected serious adverse reaction 
TART 
testicular adrenal rest tumor 
TEAE 
treatment-emergent adverse event 
TID 
3 times daily 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
U-NTx 
urinary N-linked telopeptide of type 1 collagen 
WBC 
white blood cell 
wc 
waist circumference 

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1 PROTOCOL SUMMARY 
1.1 Protocol Synopsis 
Study Number:  SPR001-204 
Study Title 
A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of 
SPR001 (Tildacerfont) in Reducing Supraphysiologic Glucocorticoid Use in Adult Subjects with 
Classic Congenital Adrenal Hyperplasia  
Study Phase:  IIb 
Study Rationale 
Congenital adrenal hyperplasia (CAH) is a serious, chronically debilitating, and life-threatening 
genetic disorder characterized by impaired adrenal synthesis of cortisol and consequent 
overproduction of adrenal androgens. Cortisol deficiency disrupts the balance of the 
hypothalamic-pituitary-adrenal (HPA) axis by removing the negative feedback to the 
hypothalamus and pituitary provided by normal levels of cortisol. This leads to the 
compensatory hypersecretion of corticotropin-releasing factor (CRF) by the hypothalamus, 
overproduction of adrenocorticotropic hormone (ACTH) by the pituitary gland, and 
consequent adrenal hyperplasia and overproduction of downstream adrenal hormones such 
as 17-hydroxyprogesterone (17-OHP) and androstenedione (A4), leading to androgen excess. 
Androgen excess may result in irregular menses, amenorrhea, hirsutism, and virilization in 
females; testicular adrenal rest tumors (TARTs) in males; and increased sebum production, 
acne, altered afternoon blood pressure profiles, and impaired fertility in either sex.  
The current standard of care for CAH is the long-term use of supraphysiologic levels of 
glucocorticoids (GCs) to replace the deficient cortisol and suppress androgen overproduction. 
This is a problematic therapy with significant side effects (eg, loss of bone mineral density, 
iatrogenic Cushing’s syndrome, metabolic disorders, and increased cardiovascular risk), a 
narrow therapeutic window, and overall poor treatment effectiveness. A non-steroidal 
treatment option that both controls androgen levels and reduces patient dependence on 
high-dose GCs would be of significant benefit to patients with CAH. Given the serious nature 
of CAH and the limitations and risks of chronic GC therapy, new treatments are urgently 
needed for patients with CAH.  
Tildacerfont, a potent and highly selective small-molecule antagonist of CRF type 1 (CRF1) 
receptors in the pituitary gland, is being studied for the treatment of CAH on the basis of its 
ability to block the CRF signal produced by the hypothalamus, thereby decreasing ACTH 
overproduction by the pituitary and reducing excess accumulation of downstream adrenal 
hormones. This mechanism of action has been validated in CAH in earlier-phase clinical 
studies of tildacerfont. Given its mechanism of action, tildacerfont may enable a CAH patient 
to have normal androgen levels while taking GC at physiologic replacement levels. 

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To date, tildacerfont has shown an acceptable safety profile at effective doses in nonclinical 
toxicology studies, Phase 1 clinical studies in healthy volunteers, and Phase 2 studies in adult 
subjects with classic CAH. Data from 2 previous Phase 2 studies demonstrated proof of 
concept for tildacerfont as a treatment for CAH, with meaningful reductions in ACTH 
(demonstrating target engagement) and 17-OHP and A4 (demonstrating efficacy in decreasing 
downstream adrenal hormones in CAH), and showed continued improvement in biomarker 
levels over a period of 12 weeks. 
SPR001-204 is a randomized, double-blind, placebo-controlled study that will evaluate the 
potential of tildacerfont to reduce GC burden in adult subjects with classic CAH who have 
lower limit of detection (LLD) ≤ A4 ≤ 2.5x upper limit of normal (ULN) and are on 
supraphysiologic doses of GC therapy (≥30 mg/day and ≤60 mg/day in hydrocortisone [HC] 
equivalents [HCe]). SPR001-204 will be the first study of tildacerfont to evaluate GC dose 
reduction. In addition, Study SPR001-204 will characterize clinical outcomes after up to 76 
weeks of treatment with tildacerfont. An optional Open-Label Extension Period will provide 
additional open-label treatment with tildacerfont at 200 mg QD for up to 240 weeks. 
Objectives 
Endpoints 
Efficacy 
 
Primary Efficacy 
 
To evaluate the mean absolute GC change in 
subjects with CAH over the 24-week, Double 
blind, Placebo-Controlled Treatment period 
Absolute change from baseline in GC dose in 
HCe at Week 24  
Secondary Efficacy 
 
To evaluate the effect of tildacerfont in 
reducing GC use to near-physiologic levels 
while maintaining androgen control in 
subjects with CAH 
Proportion of subjects with GC dose ≤11 
mg/m2/day in HCe and A4 ≤ 1.2x baseline or 
A4 ≤ ULN at Week 24 
To evaluate the effect of tildacerfont in 
reducing GC use to near-physiologic levels 
while maintaining androgen control in 
subjects with CAH 
Proportion of subjects with baseline GC dose ≤ 
35mg HCe who achieve GC dose ≤11 
mg/m2/day in HCe and A4 ≤ 1.2x baseline or ≤ 
ULN at Week 24 
To evaluate the effect of tildacerfont in 
reducing cardiovascular risk in subjects with 
CAH  
Proportion of subjects with improvement in at 
least one cardiovascular risk factor at Week 24 
Exploratory Efficacy 
 
To evaluate the percentage change in GC use 
in subjects with CAH 
Percent change from baseline in GC dose at 
Week 24 

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To evaluate the effect of tildacerfont in 
reducing the cumulative HCe dose in subjects 
with CAH 
Change in total cumulative GC dose in HCe at 
Week 24 
To evaluate the effect of tildacerfont in 
improving HOMA-IR in subjects with CAH 
Change from baseline in the HOMA-IR at 
Week 24 
To evaluate the effect of tildacerfont in 
improving HOMA-IR after 52 weeks of 
tildacerfont treatment in subjects with CAH 
Change from baseline in HOMA-IR after 52 
weeks of tildacerfont treatment 
To evaluate the effect of tildacerfont in 
reducing cardiovascular risk in subjects with 
CAH 
Proportion of subjects with improvement in at 
least one cardiovascular risk factor at Week 52 
To evaluate the effect of tildacerfont in 
reducing GC use to near-physiologic levels 
while maintaining androgen control in 
subjects with CAH 
Proportion of subjects with GC dose ≤ 11 
mg/m2/day and A4 ≤ 1.2x baseline or ≤ ULN at 
Week 52 
To evaluate the effect of tildacerfont in 
reducing GC use to near-physiologic levels 
while maintaining androgen control in 
subjects with CAH 
Proportion of subjects with baseline GC dose ≤ 
35mg HCe who achieve GC dose ≤11 
mg/m2/day in HCe and A4 ≤ 1.2x baseline or ≤ 
ULN at Week 52 
To evaluate the effect of tildacerfont in 
improving quality of life (QoL) in subjects with 
CAH 
Change from baseline at Week 24 in the Short 
Form 36 (SF-36) total score 
To evaluate the effect of tildacerfont in 
improving quality of life (QoL) in subjects with 
CAH 
Change from baseline at Week 52 in the SF-36 
total score 
To evaluate the effect of tildacerfont on BMI 
after 24 weeks in subjects with CAH 
Percent change from baseline in BMI at 
Week 24 
To evaluate the effect of tildacerfont on BMI 
after 52 weeks of tildacerfont treatment in 
subjects with CAH 
Percent change from baseline in BMI after 
52 weeks of tildacerfont treatment 
To evaluate the effect of tildacerfont on waist 
circumference (wc) after 24 weeks of 
tildacerfont treatment in subjects with CAH 
Change from baseline in waist circumference 
after 24 weeks of tildacerfont treatment 

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To evaluate the effect of tildacerfont on waist 
circumference (wc) after 52 weeks of 
tildacerfont treatment in subjects with CAH 
Change from baseline in wc after 52 weeks of 
tildacerfont treatment 
To evaluate the effect of tildacerfont in 
improving body composition after 24 weeks 
of tildacerfont treatment in subjects with CAH 
Change from baseline in fat mass and fat/lean 
mass percentage ratio after 24 weeks of 
tildacerfont treatment 
To evaluate the effect of tildacerfont in 
improving body composition after 52 weeks 
of tildacerfont treatment in subjects with CAH 
Change from baseline in fat mass and fat/lean 
mass percentage ratio after 52 weeks of 
tildacerfont treatment 
To evaluate the effect of tildacerfont in 
improving bone mineral density (BMD) after 
52 weeks of tildacerfont treatment in subjects 
with CAH 
Change from baseline in BMD after 52 weeks 
of tildacerfont treatment 
To evaluate the effect of tildacerfont in 
reducing TART(s) in male CAH subjects with 
TART(s) at baseline after 24 weeks of 
tildacerfont treatment in subjects with CAH 
Proportion of male subjects with reduction in 
TART volume at Week 24 who had TART(s) at 
baseline 
To evaluate the effect of tildacerfont in 
reducing TART(s) in male CAH subjects with 
TART(s) at baseline after 52 weeks of 
tildacerfont treatment in subjects with CAH 
Proportion of male subjects with reduction in 
TART volume at Week 52 who had TART(s) at 
baseline 
To evaluate the effect of tildacerfont in 
reducing GC use while maintaining normal A4 
levels at Week 24 in subjects with CAH 
Proportion of subjects with at least a 
5 mg/day HCe reduction from baseline (Day 1) 
in GC dose and A4 ≤ 1.2x baseline or  ≤ ULN at 
week 24 
To evaluate the effect of tildacerfont in 
reducing GC use while maintaining normal A4 
levels at Week 52 in subjects with CAH 
Proportion of subjects with at least a 
5 mg/day HCe reduction from baseline (Day 1) 
in GC dose and A4 ≤ 1.2x baseline o ≤ ULN at 
week 52 
Exploratory Efficacy (Optional Open-Label Extension Period) 
To evaluate the effect of tildacerfont in 
reducing GC use to near-physiologic levels in 
subjects with CAH 
Proportion of subjects with GC dose ≤11 
mg/m2/day in HCe and A4 ≤ULN at end of 
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To evaluate the percentage change in GC use 
in subjects with CAH 
Percent change from baseline in GC dose at 
EOT 
To evaluate the effect of tildacerfont in 
reducing cardiovascular risk in subjects with 
CAH and at least one cardiovascular risk 
factor at baseline 
Proportion of subjects with improvement in at 
least one cardiovascular risk factor at EOT 
To evaluate the effect of tildacerfont in 
improving BMD in subjects with CAH 
Change from baseline in BMD at EOT 
To evaluate the effect of tildacerfont in 
reducing TART(s) in male CAH subjects with 
TART(s) at baseline 
Proportion of male subjects with reduction in 
TART volume at EOT who had TART(s) at 
baseline 
Safety 
 
To evaluate the safety of tildacerfont in 
subjects with CAH 
Adverse events (AEs), serious adverse events 
(SAEs) 
Study Design 
This is a study with a 2-part treatment period that will evaluate the potential of tildacerfont to 
reduce GC burden in adult subjects with classic CAH who have LLD ≤ A4 ≤ 2.5x ULN and are on 
supraphysiologic doses of GC therapy (≥30 mg/day and ≤60 mg/day in HCe). The first 
24 weeks of the treatment period will be a randomized, double-blind, placebo-controlled 
study in which subjects are randomized in a 1:1 ratio to receive either placebo or tildacerfont 
at 200 mg once daily (QD). All subjects will receive open-label tildacerfont at 200 mg QD 
during the remaining 52 weeks of the treatment period. An optional Open-Label Extension 
Period will provide an open-label treatment with tildacerfont at 200 mg QD for up to 240 
weeks. 
Refer to the study schematic provided in Section 1.2. 
Study Periods 
This study will consist of the following periods: 
• A ≤45-day Screening Period for confirmation of eligibility 
o Optional A4 Screening Visit 
o Screening information captured within 45 days of the start of Day 1 in this 
study (particularly screening information transferred from Spruce Biosciences 
Study SPR001-203 to this study) will be used to determine eligibility and fulfill 
screening requirements for this study.  
In Germany, screening information from Spruce Biosciences Study SPR001-203 is not 
permitted to be transferred to determine study eligibility. 
 

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• A 6 or 12-week Glucocorticoid Conversion Period (Week -12 to either Week -6 or Week 
-2 [±3 days]) for subjects on dexamethasone at the initial Screening Visit who agree to 
convert to a non-dexamethasone regimen as determined by their physician. 
• A 76-week, 2-part Treatment Period 
o The 24-week Placebo-Controlled Treatment Period (Day 1 to Week 24) will be 
randomized, double-blind, and placebo-controlled. Subjects will be randomized 
in a 1:1 ratio to receive either placebo or tildacerfont at 200 mg QD. 
o The 52-week Open-Label Period (day after Week 24 to Week 76) will provide 
subjects who complete the Placebo-Controlled Treatment Period with 
52 weeks of open-label treatment with tildacerfont 200 mg QD. 
o Beginning at Week 2 (based on the Day 1 A4 measurement), subjects with an 
A4 measurement ≤ULN at a study visit will begin to reduce their daily GC dose 
in increments of no more than 5 mg/day HCe each time, down to a minimum of 
15 mg HCe per day. Beginning at Week 6 (based on Week 6 A4 measurement), 
subjects with an A4 >1.25x ULN will begin to increase their daily GC dose by 
increments of no more than 5 mg/day HCe each time. More details on GC dose 
adjustments are provided in Section 4.1.4.3. 
o Subsequent GC dose adjustments are based on A4 measurements at Weeks 12, 
18, 24, 32, 40, 52 and 64. 
• For subjects continuing into the optional Open-Label Extension Period: 
o The Open-Label Extension Period will provide subjects with up to 240 weeks of 
treatment with tildacerfont 200 mg QD.  
o Subjects will be eligible to adjust GC dose level at each visit (see 
Section 4.1.4.3). 
• A 30-day Follow-up Period at EOT 
o Subjects who do not continue to the Open-Label Extension Period upon 
completion of Treatment Period will enter a 30-day Follow-up Period. 
o Upon completion of the Open-Label Extension Period, subjects will enter a 30-
day Follow-up Period. 
o At the end of study treatment, subjects will maintain the GC regimen and 
mineralocorticoid regimen (as applicable) established during the course of the 
study until the 30-day follow-up visit unless the Investigator determines that 
the subject’s clinical status necessitates a dosing change. After completion of 
the study, GC therapy will be managed at the discretion of the subject’s 
treating physician. 
Study Visit Schedule 
• During the Screening Period:  
o Optional A4 Screening Visit 
o Screening Visit at ≤45 days before Day 1  

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• During the Glucocorticoid Conversion Period (for subjects on dexamethasone at 
Screening): visits at Weeks -12 and -8 (and -2, if applicable); scheduled telephone 
contacts at Weeks -11 and -6 (and -5, if applicable) 
• During the 24-week Placebo-Controlled Treatment Period: visits on Day 1 (Baseline) 
and at Weeks 3, 6, 12, 18, and 24 
• During the 52-week Open-Label Period: visits at Weeks 32, 40, 52, 64, and 76; 
scheduled telephone contacts at Weeks 27 and 46 
• During the optional Open-Label Extension Period: Visits every 3 to 6 months at Weeks 
88, 100, 124, 148, 172, 196, 220, 244, 268, 292 and 316 
• At 30 days after the last dose of study drug for final safety follow-up 
• As needed (PRN) telephone contacts are detailed under Telephone Contacts 
Mode of Study Visits in the Context of Coronavirus Disease 2019 (COVID-19) or Other 
Logistical Challenges 
All efforts should be made to conduct all visits in the clinic. Since the COVID-19 pandemic is 
expected to continue during the conduct of this trial, study visits can be adapted into a 
combination of in-clinic and telemedicine activities, with optional at-home visits, to mitigate 
the risk of COVID-19 infection associated with study participation and to accommodate local 
and individual circumstances while maintaining participant access to healthcare resources. 
Some of the clinic activities of the Screening Visit may be conducted remotely (at the subject’s 
home) if approved by the site’s Institutional Review Board (IRB)/Ethics Committee (EC). 
The electronic data capture (EDC) system will capture the mode by which data are collected 
for each visit/activity.  
If home visits are conducted, the qualified medical professionals who will perform the study’s 
home visits are defined as individuals who meet national/local licensing requirements needed 
to perform the procedures required at the home visits. Their national/local licensure will be 
verified, and they will complete training on the study protocol and Good Clinical Practice 
(GCP). If the medical professional does not meet the national/local licensing requirements 
needed to perform the optional home visit activities (physical examination), the Investigator 
or Investigator-delegated study personnel must complete these activities for each visit. 
Refer to Section 11 for more information on study conduct in the context of COVID-19 or 
other logistical challenges.  
Telephone Contacts  
Sites will make scheduled telephone contacts during the Glucocorticoid Conversion Period at 
Weeks -11 and -6 (and -5, if applicable) and during the Treatment Period at Weeks 27 and 46 
to record any AEs and concomitant medications. 
After receiving A4 results from the Day 1 (dose reduction only) and Week 6, 12, 18, 24, 32, 40, 
52, and 64 study visits, as well as visits in the optional Open-Label Extension Period, sites will 
make telephone contacts to subjects who are eligible for a GC dose adjustment. Sites will 
contact these subjects within 2 weeks after each applicable study visit. The site will direct the 

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subject to adjust his/her GC dose at that time if the subject has not experienced any change in 
clinical status since the previous study visit. If a subject’s GC dose is adjusted, the site will 
telephone the subject again 7 days after the GC dose adjustment to assess for the occurrence 
of AEs and the initiation of new concomitant medications. 
Subjects should be instructed to telephone sites if they have any concerns about their health.  
PRN telephone contacts initiated by sites and telephone contacts initiated by subjects should 
be captured in the EDC system as “unscheduled” telephone contacts. 
Study Diary/Drug Adherence Data Collection 
During the Glucocorticoid Conversion and Treatment Periods, subjects will use an electronic 
study diary to document study drug and background GC adherence. Female subjects will also 
use the study diary to record menstrual information (including start and stop dates of 
menses). 
Study Population 
This study will randomize approximately 90 subjects with classic CAH currently receiving GC at 
a supraphysiologic dose (defined under Eligibility Criteria). The study will enroll subjects at 
approximately 130 investigative sites globally. 
Eligibility Criteria 
Inclusion Criteria 
1. Male and female subjects ≥18 years old at screening 
2. Has a known childhood diagnosis of classic CAH due to 21-hydroxylase deficiency based 
on genetic mutation in CYP21A2 and/or documented (at any time) elevated 17-OHP and 
currently treated with HC, HC acetate, prednisone, prednisolone, methylprednisolone, 
dexamethasone (or a combination of the aforementioned GCs) 
3. Has LLD ≤ A4 ≤ 2.5x ULN at screening measured before AM GC dose 
4. Has been on a stable, supraphysiologic dose of GC replacement (defined as ≥30 mg/day 
and ≤60 mg/day in HCe) for ≥1 month before screening  
5. For subjects with the salt-wasting form of CAH, subject has been on a stable dose of 
mineralocorticoid replacement for ≥1 month before screening 
6. Agrees to follow contraception guidelines (Section 5.2.5). Male subjects must also agree 
to refrain from donating sperm throughout the Treatment Period and for 90 days after 
the last dose of study drug 
7. Is able to understand all study procedures and risks involved and provides written 
informed consent indicating willingness to comply with all aspects of the protocol 
Exclusion Criteria 
1. Has a known or suspected diagnosis of any other known form of classic CAH (not due to 
21-hydroxylase deficiency) 
2. Has a history that includes bilateral adrenalectomy or hypopituitarism 

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3. Has a history of allergy or hypersensitivity to tildacerfont, any of its excipients, or any 
other CRF1 receptor antagonist 
4. Shows clinical signs or symptoms of adrenal insufficiency 
5. Has had a clinically significant unstable medical condition, medically significant illness, or 
chronic disease occurring within 30 days of screening, including but not limited to: 
a. An ongoing malignancy or <3 years of remission history from any malignancy, other 
than successfully treated localized skin cancer 
b. Estimated glomerular filtration rate (eGFR) of <45 mL/min/1.73 m2 
c. Current or history of liver disease (with the exception of Gilbert’s syndrome) 
d. History of alcohol or substance abuse within the last year, or any significant history of 
alcohol or substance abuse that would likely prevent the subject from reliably 
participating in the study, based on the opinion of the Investigator 
e. Active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) at screening 
f. Subjects who plan to undergo bariatric surgery during the study are excluded 
g. Any other condition that would impact subject safety or confound interpretation of 
study results  
6. Psychiatric conditions, including but not limited to bipolar disorder, schizophrenia, or 
schizoaffective disorders that are not effectively controlled on medication and may have 
an adverse impact on study compliance. Symptoms including hallucinations, delusions, 
and psychosis are exclusionary. Additionally: 
a. Increased risk of suicide based on the Investigator’s judgment or the results of the 
Columbia–Suicide Severity Rating Scale (C-SSRS) conducted at screening and baseline 
(eg, C-SSRS Type 3, 4, or 5 ideation within the past 6 months or any suicidal behavior 
within the past 12 months)  
b. Hospital Anxiety and Depression Scale (HADS) score >12 for either depression or 
anxiety at screening or baseline 
7. Has clinically significant abnormal electrocardiogram (ECG) or clinical laboratory results. 
Abnormal results that must be reviewed and discussed with the Medical Monitor to 
determine eligibility for this study include but are not limited to: 
a. Any clinically meaningful abnormal ECG results, including Fridericia-corrected QT 
interval (QTcF) >450 milliseconds (ms) for male participants or >470 ms for female 
participants 
b. Alanine aminotransferase (ALT) >2x ULN 
c. Total bilirubin >1.5x ULN  
d. Total bile acids >5x ULN 
8. Routinely works overnight shifts 
9. Subjects with travel plans/work schedules that result in significant and frequent changes 
in time zones (>2 hours) will require Medical Monitor approval for enrollment. 
10. Females who are pregnant or nursing 

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11. Use of any other investigational drug from 30 days or 5 half-lives (whichever is longer) 
before screening to the end of the study 
12. Use of the following drugs from 30 days or 5 half-lives (whichever is longer) before the 
start of the Treatment Period to the end of the study: 
a. Rosiglitazone, aromatase inhibitors, testosterone, growth hormones, or any other 
medication or supplement that could impact subject safety or confound 
interpretation of study results 
b. The drugs listed in Section 13.1, which are: 
i. Moderate to strong inhibitors and/or inducers of cytochrome P450 3A4 (CYP3A4) 
ii. Sensitive substrates or narrow-therapeutic-range substrates of CYP3A4 (except 
hormonal contraception containing ≤35 µg ethinyl estradiol) 
iii. Sensitive substrates or narrow-therapeutic-range substrates of breast cancer 
resistance protein (BCRP) (except those that can be administered QD in the 
morning, separated by approximately 10 hours from evening administration of 
study drug) 
13. Donation or receipt of blood from 90 days before Screening to the end of the study; 
donation or receipt of platelets, white blood cells, or plasma from 30 days before 
Screening to the end of the study 
Investigational Drug 
The drug product is a small-molecule CRF1 receptor antagonist and will be supplied as yellow, 
round, convex tablets containing 50 mg of drug substance. 
Placebo will be supplied as tablets that look identical to drug product but contain no drug 
substance. 
Dose, Route, Regimen 
At the beginning of the Placebo-Controlled Treatment Period, subjects will be randomized in a 
1:1 ratio to receive either placebo or tildacerfont at 200 mg QD for 24 weeks. During the 
Open-Label Period, all subjects will receive open-label tildacerfont at 200 mg QD for 52 weeks. 
During the optional Open-Label Extension Period, subjects will continue to receive tildacerfont 
at 200 mg QD. Study drug will be taken orally each day between 6 PM and midnight, with an 
evening meal. The evening meal should contain approximately 25-50% fat content. Study drug 
may be consumed up to 30 minutes after completing the evening meal, if necessary. 
Subjects entering the study under protocol version 7.0 will use a Principal 
Investigator-prescribed supply of GCs. Subjects who entered the study under prior protocol 
versions will continue to use the GCs provided by the Sponsor through Week 24. After Week 
24, subjects will use Principal Investigator-prescribed supply of GCs. Subjects will continue to 
use the same type of GC throughout the study. Please see important details on GC use in 
Section 4.1.4.1. 
On the evenings before scheduled laboratory assessments, subjects should take their evening 
GC dose before 10 PM. On the mornings of scheduled laboratory assessments, subjects should 

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delay taking any morning dose of GC medication until after the 8 AM (±1 hour) laboratory 
assessments have been completed. On all other days during the study, subjects should take 
their GC medication at the usual time(s). Mineralocorticoid may be taken at any time of day, 
but its timing relative to laboratory assessments should be consistent throughout the study. 
During times of clinically significant physical stress such as intercurrent illness with fever, 
surgical procedures, or significant trauma, stress dosing with extra GC (in the form of HC) for 
prevention of adrenal crisis will be allowed according to “sick day guidelines” (see 
Section 4.1.4.4). The Sponsor will provide GC for periods of stress dosing. 
Study drug will be discontinued in subjects who meet individual treatment-stopping criteria 
(see Section 7.1).  
Study Duration 
The expected duration of study participation for each subject is up to approximately 
86 weeks. This includes a screening period of ≤45 days, a Placebo-Controlled Treatment 
Period of 24 weeks, an Open-Label Period of 52 weeks, and a safety follow-up period of 
approximately 30 days. Subjects who require the GC Conversion Period will participate for an 
additional 6 or 12 weeks. Subjects who continue in the optional Open-Label Extension Period 
will participate for up to an additional 240 weeks.   
Statistical Analyses 
Statistical Hypotheses 
Efficacy endpoints at Week 24 will be evaluated using the following hypothesis-testing 
schema: The tildacerfont treatment group will be compared with the placebo treatment 
group. The null hypothesis is that there is no difference in the mean change from baseline to 
Week 24 in GC dose in HCe. The alternative hypothesis will be that there is a difference 
between the treatment groups. 
Efficacy endpoints after 52 weeks of tildacerfont treatment will be evaluated using the 
following hypothesis-testing schema: The Week 52 value will be compared with the baseline 
value. The null hypothesis will be that there is no difference between the Week 52 and 
baseline values. The alternative hypothesis will be that there is a difference. 
Sample Size 
A sample size of N=45 subjects per group will provide at least 90% power to detect a between 
group difference in the proportion of subjects with at least a 5 mg/day HCe reduction from 
baseline in GC dose at Week 24 with A4 ≤ULN of at least 33% assuming the placebo group has 
a response of 30% and the two-sided type I error is 0.05. 
Analysis Populations 
• The Intent-to-Treat (ITT) Population will include all randomized subjects. 
• The modified ITT (mITT) Population will include all randomized subjects who receive at 
least 1 dose of study drug (tildacerfont or placebo). 

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• The Per Protocol (PP) Population will include all randomized subjects who have no major 
protocol violations that would affect the analysis of efficacy data. 
• The Safety Population will include all subjects who receive at least 1 dose of study drug 
(tildacerfont or placebo). 
• The Pharmacokinetics (PK) Population will include all subjects who receive at least 1 dose 
of tildacerfont and have at least 1 evaluable PK sample. 
Refer to Section 9.3 for further information on analysis populations. 
General Statistical Considerations 
Unless otherwise specified, continuous adrenal biomarkers (A4, 17-OHP, ACTH) will be 
summarized using a 11-point descriptive statistics (i.e., n, mean, standard deviation [SD], 
median, 25% quartile [Q1], 75% quartile [Q3], minimum, maximum, geometric mean, 
geometric coefficient of variance [CV%], 95% confidence interval [CI] for geometric mean 
[including geometric mean ratio and its 95% CI]). Continuous data aside from (A4, 17-OHP and 
ACTH) will be summarized using an 8-point descriptive summary (n, mean, SD, median, Q1, 
Q3, minimum, and maximum). Categorical data will be summarized using the frequency of 
events and percentage of total events. 
For missing data, a retrieved dropout approach will be used in which missing endpoint data 
for subjects who discontinued early will be imputed using data collected from subjects after 
discontinuation of study drug. 
Efficacy Analyses 
All efficacy analyses will be conducted using the ITT Population as the primary analysis set. 
The primary analysis and secondary analyses conducted at Week 24 will compare the 
tildacerfont treated group to the placebo group. Additional secondary and exploratory 
analyses that evaluate the change from baseline in all subjects after 52 weeks of tildacerfont 
treatment will combine the subjects randomized to tildacerfont Day 1 to Week 52 data with 
subjects randomized to placebo tildacerfont treatment data from Week 24 to Week 76.  
The primary efficacy endpoint is the absolute change from baseline in GC dose in HCe at 
Week 24. The analysis of the primary endpoint will be summarized using an exact score test 
for binomial proportions, as appropriate, or a chi-square–based test. Subjects with missing 
data will be assumed to be failure for the primary endpoint.  
GC dose endpoints will be summarized using an analysis of covariance (ANCOVA) model with 
fixed covariates for baseline GC dose and treatment group. Sensitivity analyses that use 
multiple imputation will be conducted for missing GC dose data. The factors impacting the 
multiple imputation will include, but not be limited to, sex and baseline HCe group 
(<40 mg/day and ≥40 mg/day). 
The proportion of subjects meeting various responder definitions will be summarized in a 
similar manner as the primary endpoint. 
Metabolic endpoints (HOMA-IR, body weight, and wc), QoL endpoint (SF-36), and BMD will be 
analyzed using a repeated measure mixed effects model with treatment and visit as fixed 
effects, subject as a random effect, and baseline score as a covariate if >2 timepoints are 

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assessed. If only the baseline timepoint and a single post-baseline timepoint are assessed for 
the endpoint, an ANCOVA model with baseline as a covariate will be used. There will be no 
imputation of missing data.  
Endpoints during the optional Open-Label Extension Period will be summarized descriptively. 
Safety Analyses 
Safety analyses will be conducted on the Safety Population. All safety data will be presented in 
listings. Summary tables will be provided for concomitant medications, AEs, hematology and 
chemistry laboratory results, vital signs, and ECG findings. Safety data will be summarized by 
treatment group using frequency of event or descriptive statistics, as appropriate. 

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1.2 Schema 
 
The 6or 12-week GC conversion only applies to subjects on dexamethasone at the initial Screening Visit who agree to convert to a non-
dexamethasone regimen as determined by their physician. 
 

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1.3 Schedules of Activities 
1.3.1 Optional A4 Screening Visit 
For subjects with unknown A4 levels, prior to a morning GC dose, an optional A4 Screening Visit 
may be conducted up to 45 days prior to Day 1 to test A4 levels prior to further screening 
evaluations. An informed consent form (ICF) specific to this visit will be signed by the subject. 
Retesting of A4 levels will not be required at the SPR001-204 Screening Visit if eligible A4 results 
have been obtained within 45 days prior to the Day 1 visit. 
1.3.2 Schedule of Screening Activities 
Screening will be conducted in-clinic. Some activities of the Screening Visit may be conducted 
remotely (at the subject’s home) if approved by the site’s IRB/EC. Screening activities to be 
performed at the subject’s home will be conducted after activities to be performed in the clinic 
for each study visit.  
In Germany, Italy, and Poland the Screening Visit will be completed in the clinic ≤45 days 
before Day 1 of the study. 
 
On the evening before screening laboratory samples will be collected, subjects should take their 
evening GC dose before 10 PM. Screening laboratory samples will be collected at 8 AM (±1 hour), 
after the subject has fasted overnight (nothing to eat after midnight), and before the subject 
takes any morning dose of GC medication. 
Screening information from the parallel Spruce Biosciences Study SPR001-203 may be used to 
determine eligibility and fulfill screening requirements for this study if the information was 
captured within 45 days before Day 1 in this study. 
In Germany, screening information from Spruce Biosciences Study SPR001-203 is not 
permitted to be transferred to determine study eligibility. 
 
 
Screening Period 
STUDY VISIT NUMBER 
1a 
Optional A4 Screening 
1b 
Screening 
 
In-Clinic Screening Visit 
In-Clinic Screening Visit 
STUDY DAY 
≤45 days before 
Day 11 
≤45 days before 
Day 11 
Informed consent 
X 
X 
Inclusion/exclusion criteria 
 
X 
Demography 
 
X 
Medical history 
 
X 
Prior medications from past year 
 
X 
Concomitant medications 
 
X 

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Screening Period 
STUDY VISIT NUMBER 
1a 
Optional A4 Screening 
1b 
Screening 
 
In-Clinic Screening Visit 
In-Clinic Screening Visit 
STUDY DAY 
≤45 days before 
Day 11 
≤45 days before 
Day 11 
Prior and current GC regimens2 
 
X 
Vital signs3, body weight 
 
X 
Height 
 
X 
Waist circumference 
 
X 
Full physical examination 
 
X 
C-SSRS 
 
X 
HADS 
 
X 
Hepatitis B & C and HIV tests 
 
X4 
Urine drug screen 
 
X4 
Serum pregnancy test for FCP 
 
X4 
Hormones from blood 
X5 
X4, 6 
Clinical laboratory7 
 
X4 
Urinalysis 
 
X4 
HbA1c 
 
X4 
12-lead ECG 
 
X4 
Report subject’s status to site 
 
X4 
Abbreviations:  17-OHP, 17-hydroxyprogesterone; A4, androstenedione; ACTH, adrenocorticotropic hormone; ALP, alkaline 
phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; C-SSRS, Columbia–Suicide Severity Rating Scale; 
ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; FCP, female of childbearing potential; FSH, follicle-
stimulating hormone; GC, glucocorticoid; GGT, gamma-glutamyl transferase; HADS, Hospital Anxiety and Depression Scale; 
HbA1c, hemoglobin A1c; HCe, hydrocortisone equivalents; HIV, human immunodeficiency virus; INR, international normalized 
ratio; LH, luteinizing hormone; PT, prothrombin time; PTT, partial thromboplastin time; SHBG, sex hormone–binding globulin. 
 
1 Screening information captured within 45 days of the start of Day 1 in this study (particularly screening information transferred from 
Spruce Biosciences Study SPR001-203) will be used to determine eligibility and fulfill screening requirements for this study. (In 
Germany, screening information from Spruce Biosciences Study SPR001-203 is not permitted to be transferred to determine study 
eligibility.) 
2 Subjects must be on a stable, supraphysiologic dose of GC replacement (defined as ≥30 mg/day and ≤60 mg/day in HCe) for ≥1 month 
before the Screening Visit. Information to be collected at screening about a subject’s current and historical GC therapy during the past 
year include the type(s) of GC, the regimen(s), reason(s) that the subject is/was on a particular GC regimen, and any GC stress dosing 
during the past year. 
3 Vital signs consist of systolic and diastolic blood pressure, pulse rate, body temperature, and respiration rate and will be measured 
after a 5-min rest period. 
4 These clinic activities of the Screening Visit may be conducted remotely (at the subject’s home) if approved by the site’s IRB/EC. (In 
Germany, Italy, and Poland, the Screening Visit will be performed in the clinic.) 
5 A4 and 17-OHP will be measured. The blood draw for sample will be obtained at 8 AM (± 1 hour) prior to a morning GC dose. 
6 A4, 17-OHP, ACTH, and testosterone will be measured prior to a morning GC dose. 
7 Clinical laboratory assessments include hematology, clinical chemistry (including liver function tests such as ALT, AST, ALP, GGT, total 
and direct bilirubin, and total bile acids), coagulation (PT/INR, and PTT), lipid panel, thyroid panel, LH, FSH, SHBG, renin, aldosterone, 
inhibin B for males only, and estradiol, prolactin, and progesterone for females only. eGFR for screening will be calculated from blood 
creatinine measured as part of screening clinical chemistry. 

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1.3.3 Schedule of Glucocorticoid Conversion Period Activities 
The Glucocorticoid Conversion Period is required for subjects who require conversion from 
dexamethasone to a non-dexamethasone GC regimen. 
 
Glucocorticoid Conversion Period 1 
 
1st 6 weeks 
2nd 6 weeks,  
if GC dose adjustment necessary 
STUDY VISIT NUMBER 
2 
 
3 
 
GC dose 
adjustment 
 
4 
STUDY WEEK 
-12 
-11 
-8 
-6 
-5 
-2 
STUDY DAY 2 
-84 
-77 
-56 
-42 
-35 
-14 
Visit Window (days) 
 
±3 
 ±3 
±3 
±3  
±3 
Study Visit (V)/  
Telephone Contact (T) 
V 
T 
V 
T 
T 
V 
Urine pregnancy test for FCP 
X 
 
 
 
 
 
 
Hormones from blood 3,4 
X 
 
X 
 
 
 
X 
Hematology 3 
 
 
X 
 
 
 
X 
Clinical chemistry 3 
X 5 
 
X 
 
 
 
X 
Renin 3 
X 
 
X 
 
 
 
X 
Vital signs 6, body weight 
X 
 
X 
 
 
 
X 
GC accountability and return of 
used GC to site 
X 
 
X 
 
 
 
X 
Report subject’s status to site 
X 
 
X 
 
 
 
X 
Concomitant medications 
X 
X 
X 
X 
 
X 
X 
Monitor background GC dosing 
X 7 
X 
X 
X 
 
X 
X 
Determine whether subject requires 
GC dose adjustment/2nd 6 weeks OR 
can proceed to Treatment Period 
 
 
 
X 
 
 
 
Background GC accountability 
 
 
X 
 
 
 
X 
Dispense HC for stress dosing and 
perform accountability 8 
X 
 
X 
 
 
 
X 
Review study diary/GC adherence 9 
X 
X 
X 
X 
 
X 
X 
Review adverse events 
X 
X 
X 
X 
 
X 
X 
Physical examination (abbreviated) 
X 
 
X 
 
 
 
X 
Abbreviations: 17-OHP, 17 hydroxyprogesterone; A4, androstenedione; ACTH, adrenocorticotropic hormone; EDC, electronic 
data capture; ET, early termination; FCP, female of childbearing potential; GC, glucocorticoid; T, telephone contact; V, study 
visit.  
 
1 If a subject fails to meet eligibility criteria or cannot tolerate the non-dexamethasone GC regimen during or at the end of the 
Glucocorticoid Conversion Period, the investigational site will schedule an abbreviated ET Visit to review AEs and concomitant 
medications and perform an abbreviated physical examination (preferably in the clinic but also permissible via home visit). (In 
Italy and Poland, the physical exam will not be performed at the subject’s home and must be performed in the clinic). 
 

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2 Study days are numbered relative to Day 1 (Week 0), the first day of the Treatment Period, when the subject will take the first 
dose of study drug. There is no Day 0 (ie, study days go directly from Day -1 to Day 1). 
3 Samples for these lab assessments will be obtained at 8 AM (± 1 hour), after an overnight fast (nothing to eat since the 
previous midnight) and before any morning dose of GC medication. On the evenings before scheduled laboratory assessments, 
subjects should take their evening GC dose before 10 PM. 
4 A4, 17-OHP, ACTH, testosterone, and background GC levels will be measured. 
5 Total bile acids will not be included in clinical chemistry at the Week -12 visit. 
6 Vital signs consist of systolic and diastolic blood pressure, pulse rate, body temperature, and respiration rate and will be 
measured after a 5-min rest period. 
7 On the first day of the Glucocorticoid Conversion Period, subjects will discontinue their dexamethasone GC regimen and begin 
taking a non-dexamethasone GC regimen. 
8 Bottles of HC for stress dosing (see Section 4.1.4.4) will be dispensed starting at the beginning of the Glucocorticoid 
Conversion Period and thereafter as needed to replace opened bottles. Accountability for bottles of HC will be performed at 
every study visit. 
9 Subjects will use an electronic study diary to document background GC adherence. Female subjects will also use the study 
diary to record menstrual information (including start and stop dates of menses). 
 

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1.3.4 Schedule of Treatment Period and Follow-up Activities 
 
Treatment Period 
Follow-
up1 
ET 
Placebo-Controlled Treatment Period 
Open-Label Period 
STUDY VISIT NUMBER 
5 
Base 
line 
6 
7 
8 
9 
10 
 
11 
12 
 
13 
14 
15 
16 
 
STUDY WEEK 
0 
3 
6 
12 
18 
24 
27 
32 
40 
46 
52 
64 
762 
80 
 
STUDY DAY3 
1 
22 
43 
85 
127 
169 
190 
225 
281 
323 
365 
449 
533 
Last dose  
+30 days 
 
Study Visit (V) /  
Telephone Contact (T)4 
V 
V5 
V 
V 
V 
V 
T 
V 
V 
T 
V 
V 
V 
V 
V 
Urine pregnancy test for FCP 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
Hormones from blood6,7 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
Clinical laboratory6,8 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
Urinalysis6 
X 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
HbA1c, fasting glucose and insulin, 
HOMA-IR6 
X 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
BSAP, P1NP, CTX-1, U-NTx, Osteocalcin 
X 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
PK6,9 
 
X 
X 
X 
 
X 
 
 
 
 
X 
 
X 
X 
X 
Genetic sample10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs11, body weight 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
Waist circumference 
X 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
12-lead ECG 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
X 
X 
HADS 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
SF-36 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
PGIC 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
Study treatment accountability and 
return of used treatment to site 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
 
 
Scrotal ultrasound for males 
X12 
 
 
 
 
X13 
 
 
 
 
 
 
X13 
 
X13 

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Treatment Period 
Follow-
up1 
ET 
Placebo-Controlled Treatment Period 
Open-Label Period 
STUDY VISIT NUMBER 
5 
Base 
line 
6 
7 
8 
9 
10 
 
11 
12 
 
13 
14 
15 
16 
 
STUDY WEEK 
0 
3 
6 
12 
18 
24 
27 
32 
40 
46 
52 
64 
762 
80 
 
STUDY DAY3 
1 
22 
43 
85 
127 
169 
190 
225 
281 
323 
365 
449 
533 
Last dose  
+30 days 
 
Study Visit (V) /  
Telephone Contact (T)4 
V 
V5 
V 
V 
V 
V 
T 
V 
V 
T 
V 
V 
V 
V 
V 
DXA scan for body composition and 
bone mineral density14 
X 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
CGI-I 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
Randomization to study drug 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense study drug15 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
 
 
Study drug accountability 
 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
 
X 
Monitor background GC dosing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
GC dose adjustment telephone 
contacts16 
X  
 
X  
X  
X  
X  
 
X  
X  
 
X  
X  
 
 
 
Dispense HC for stress dosing and 
perform accountability17 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
Review study diary/drug adherence18 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination19  
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
Abbreviations: 17-OHP, 17hydroxyprogesterone; A4, androstenedione; ACTH, adrenocorticotropic hormone; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, 
aspartate aminotransferase; BSAP, bone-specific alkaline phosphatase; CGI-I; Clinical Global Impression – Improvement Scale; C-SSRS, Columbia–Suicide Severity Rating Scale; 
CTX-1, C-terminal telopeptide of type 1 collagen; DXA, dual-energy x-ray absorptiometry (scan); EC, Ethics Committee; ECG, electrocardiogram; EDC, electronic data capture; ET, 
early termination; FCP, female of childbearing potential; FSH, follicle-stimulating hormone; GC, glucocorticoid; GGT, gamma-glutamyltransferase; HADS, Hospital Anxiety and 
Depression Scale; HbA1c, hemoglobin A1c; HC(e), hydrocortisone (equivalents); HOMA-IR, homeostatic model assessment of insulin resistance; INR, international normalized 
ratio; IRB, Institutional Review Board; LH, luteinizing hormone; LLD, lower limit of detection; P1NP, procollagen type 1 N terminal propeptide; PGIC, Patient Global Impression of 

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Change; PK, pharmacokinetics; PRN, as needed; PROs, patient-reported outcome measures; PT, prothrombin time; PTT, partial thromboplastin time; SF-36, Short Form 36; SHBG, 
sex hormone–binding globulin; T, telephone contact; TART, testicular adrenal rest tumor; ULN, upper limit of normal; U-NTx, urinary N-linked telopeptide of type 1 collagen; V, 
study visit. 
1 Subjects who do not continue to the optional Open-Label Extension Period upon completion of the Treatment Period will enter a 30-day Follow-up Period. 
2 For subjects who continue to the optional Open-Label Extension Period, Week 76 will be considered Study Visit 1 for optional Open-Label Extension Period. 
3 All study visits and telephone contacts should be performed on the indicated study days. In cases where adherence to the foregoing schedule is not possible, all activities for 
study visits and telephone contacts must be completed within a ±33+6-day window after the indicated study days. The day of the baseline visit (and first dose of study drug) 
will be considered Day 1 (Week 0), and all other study days are counted relative to Day 1. There is no Day 0 (ie, study days go directly from Day -1 to Day 1). 
4 During scheduled telephone contacts, sites will record any AEs and concomitant medications. After receiving A4 results during the Treatment Period, sites will make telephone 
contacts to applicable subjects regarding GC dose adjustment (detailed later in this Schedule of Activities). Subjects should be instructed to telephone sites if they have any 
concerns about their health. Telephone contacts initiated by sites and telephone contacts initiated by subjects should be captured in the EDC system as “unscheduled” 
telephone contacts. 
5 This visit for safety assessments may be scheduled for any day of Week 3, for any time of day, at the subject’s convenience. Clinical laboratory can be measured at any time of 
day for this visit and need not occur before the morning dose of GC. 
6 Samples for these lab assessments will be obtained at 8 AM (± 1 hour), after an overnight fast (nothing to eat after midnight) and before any morning dose of GC medication. 
On the evenings before scheduled laboratory assessments, subjects should take their evening GC dose before 10 PM. 
7 A4, 17-OHP, ACTH, and testosterone will be measured. 
8 Clinical laboratory assessments include hematology, clinical chemistry (including liver function tests such as ALT, AST, ALP, GGT, total and direct bilirubin, and total bile acids), 
coagulation (PT/INR, and PTT), lipid panel, thyroid panel, LH, FSH, SHBG, renin, aldosterone, inhibin B for males only, and estradiol, prolactin, and progesterone for females 
only. 
9 A single blood sample will be drawn for PK measurement at each specified visit.  
10 Where local regulations permit and subject to discretionary approval from each site’s IRB/EC and to subject consent, a voluntary blood sample may be collected for DNA 
analysis. See Section 13.4 for specifics on genetic testing that may be performed. 
11 Vital signs consist of systolic and diastolic blood pressure, pulse rate, body temperature, and respiration rate and will be measured after a 5-min rest period. 
12 The initial scrotal ultrasound may be scheduled for any time before the first dose of study drug and will be considered the baseline measurement for TART.  
13 Scrotal ultrasounds will only be conducted in subjects who had TART(s) at baseline. 
14 DXA scans should be performed for all subjects as indicated. The initial DXA scan may be scheduled for any time before the first day of study drug and will be considered the 
baseline measurement for the bone mineral density endpoint and body composition assessments. Subjects should not take calcium supplements within the 24 hours before a 
DXA scan. 
15 Either the subject will pick up study drug in the clinic or the clinic will ship study drug will be shipped directly to the subject. Study drug will be taken daily between 6 PM and 
midnight, with an evening meal. The evening meal should contain approximately 25- <50% fat content. Study drug may be consumed up to 30 minutes after completing the 
evening meal, if necessary. (In Denmark, UK, Ireland, Romania, Estonia or Turkey shipping of study drug directly from clinic to subject’s home is not permitted)  
16 During the Treatment Period, sites will make telephone contacts to subjects who are eligible for a GC dose adjustment within 2 weeks after each applicable study visit and 
based on their A4 level at that visit. Subjects who are not eligible for a GC change will not be telephoned. The site will direct the subject to adjust his/her GC dose by no more 
than 5 mg/day HCe increments if the subject has not experienced any change in clinical status since the previous study visit. If a subject’s GC dose is adjusted, the site will 
telephone the subject again 7 days after the GC dose adjustment to assess for the occurrence of AEs and the initiation of new concomitant medications. GC reductions may 

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begin at Week 2 (based on the Day 1 A4 measurement) and increases in GC dose may begin based on the A4 measurement at Week 6. GC dose may be reduced to a minimum 
of 15 mg HCe per day (approximately physiologic replacement level). 
17 Bottles of HC for stress dosing (see Section 4.1.4.4) will be dispensed starting at Day 1 and thereafter as needed to replace opened bottles. Accountability for bottles of HC will 
be performed at every study visit. 
18 Subjects will use an electronic study diary to document study drug and background GC adherence. Female subjects will also use the study diary to record menstrual 
information (including start and stop dates of menses). 
19 A full physical examination will be conducted at Baseline (Day 1), Week 24, and Week 76. The full physical examination may exclude rectal, genitourinary, and breast exams. 
An abbreviated physical examination will be conducted at all other visits indicated. If the physical exam is performed at the subject’s home, the qualified medical professional 
will report any changes to the subject’s health to the site to determine whether further evaluation is needed via an unscheduled visit. (In Italy and Poland, the physical exam 
will not be performed at the subject’s home and must be performed in the clinic). 
 
 
 

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1.3.5 Schedule of Optional Open-Label Extension Period Activities 
Extension Treatment Period 
Follow-up 
ET
STUDY VISIT NUMBER 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
STUDY WEEK 
88
100
124
148 
172 
196 
220 
244 
268 
292 
316 
320 
STUDY DAY1
617 701
869
1037
1205
1373
1541
1709
1877
2046
2213 
Last dose 
+30 days
Study Visit (V) 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
Urine pregnancy test for FCP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hormones from blood2,3
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs4, body weight, waist circumference 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SF-365
X 
X 
X 
X 
X 
X 
C-SSRS5
X 
X 
X 
X 
X 
X 
Scrotal ultrasound for males 6 
X 
X 
X 
X 
X 
X6 
DXA scan for body composition and bone mineral density7 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviated physical examination 
X 
X 
X 
X 
X 
X 
Dispense study drug8
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug accountability 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
GC dose adjustment telephone contacts9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense HC for stress dosing and perform accountability10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: 17-OHP, 17-hydroxyprogesterone; A4, androstenedione; C-SSRS, Columbia–Suicide Severity Rating Scale; DXA; dual-energy x-ray absorptiometry (scan); ET, early 
termination; FCP, female of childbearing potential; GC, glucocorticoid; HC(e), hydrocortisone (equivalents); SF-36, Short Form 36; V, study visit
1 For subjects who continue to the optional Open-Label Extension Period, Week 76 visit (as reflected in Table 1.3.4) will be considered as Study Visit 1 for the optional Open-
Label Extension Period and will be performed within ±3-day window. All visits starting Week 88 should be performed within a +30-day window. 
2 Samples for these lab assessments will be obtained at 8 AM (± 1 hour), after an overnight fast (nothing to eat after midnight) and before any morning dose of GC medication. 
On the evenings before scheduled laboratory assessments, subjects should take their evening GC dose before 10 PM. 
3 A4 and 17-OHP and testosterone will be measured. 

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4 Vital signs consist of systolic and diastolic blood pressure, pulse rate, body temperature, and respiration rate and will be measured after a 5-min rest period. 
5 SF-36 and C-SSRS are paper based during the optional Open-Label Extension Period. 
6 Scrotal ultrasounds will only be conducted in subjects who had TART(s) at baseline. 
7 DXA scans should be performed for all subjects as indicated. Subjects should not take calcium supplements within the 24 hours before a DXA scan. 
8 Either the subject will pick up study drug in the clinic or the clinic will ship study drug will be shipped directly to the subject. Study drug will be taken daily between 6 PM and 
midnight, with an evening meal. The evening meal should contain approximately 25-<50% fat content. Study drug may be consumed up to 30 minutes after completing the 
evening meal, if necessary. (In Denmark, UK, Ireland, Romania, Estonia or Turkey shipping of study drug directly from clinic to subject’s home is not permitted.) 
9 During the Treatment Period, sites will make telephone contacts to subjects who are eligible for a GC dose adjustment within 2 weeks after each applicable study visit and 
based on their A4 level at that visit. Subjects who are not eligible for a GC change will not be telephoned. The site will direct the subject to adjust his/her GC dose by no more 
than 5 mg/day HCe increments if the subject has not experienced any change in clinical status since the previous study visit. If a subject’s GC dose is adjusted, the site will 
telephone the subject again 7 days after the GC dose adjustment to assess for the occurrence of AEs and the initiation of new concomitant medications. GC dose may be 
reduced to a minimum of 15 mg HCe per day (approximately physiologic replacement level). 
10 Bottles of HC for stress dosing (see Section 4.1.4.4) will be dispensed as needed. Accountability for bottles of HC will be performed at every study visit. 
 

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2 INTRODUCTION 
2.1 Study Rationale 
CAH is a serious, chronically debilitating, and life-threatening genetic disorder characterized by 
impaired adrenal synthesis of cortisol and overproduction of adrenal androgens. Cortisol 
deficiency disrupts the balance of the HPA axis by removing the negative feedback to the 
hypothalamus and pituitary provided by normal levels of cortisol. This leads to the 
compensatory hypersecretion of CRF by the hypothalamus, overproduction of ACTH by the 
pituitary gland, and consequent adrenal hyperplasia and overproduction of downstream 
adrenal hormones such as 17-OHP and A4, leading to androgen excess. Androgen excess may 
result in irregular menses, amenorrhea, hirsutism, and virilization in females; TARTs in males; 
and increased sebum production, acne, altered afternoon blood pressure profile, and impaired 
fertility in either sex.  
The current standard of care for CAH is the long-term use of supraphysiologic levels of GCs to 
replace the deficient cortisol and suppress androgen overproduction. This is a problematic 
therapy with significant side effects (eg, loss of bone mineral density, iatrogenic Cushing’s 
syndrome, metabolic disorders, and increased cardiovascular risk), a narrow therapeutic 
window, and overall poor treatment effectiveness. A non-steroidal treatment option that both 
controls androgen levels and reduces patient dependence on high-dose GCs would be of 
significant benefit to patients with CAH. Given the serious nature of CAH and the limitations 
and risks of chronic GC therapy, new treatments are urgently needed for patients with CAH.  
Tildacerfont, a potent and highly selective small-molecule antagonist of CRF1 receptors in the 
pituitary gland, is being studied for the treatment of CAH on the basis of its ability to block the 
CRF signal produced by the hypothalamus, thereby decreasing ACTH overproduction by the 
pituitary and reducing excess accumulation of downstream adrenal hormones. This mechanism 
of action has been validated in CAH in earlier-phase clinical studies of tildacerfont. Given its 
mechanism of action, tildacerfont may enable a CAH patient to have normal androgen levels 
while taking GC at physiologic replacement levels. 
To date, tildacerfont has shown an acceptable safety profile at effective doses in nonclinical 
toxicology studies, Phase 1 clinical studies in healthy volunteers, and Phase 2 studies in adult 
subjects with classic CAH. Data from 2 previous Phase 2 studies demonstrated proof of concept 
for tildacerfont as a treatment for CAH, with meaningful reductions in ACTH (demonstrating 
target engagement) and 17-OHP and A4 (demonstrating efficacy in decreasing downstream 
adrenal hormones in CAH), and showed continued improvement in biomarker levels over a 
period of 12 weeks. 
In CAH, a goal of chronic GC replacement therapy is to administer a GC dose that suppresses 
adrenal androgen overproduction due to ACTH stimulation. Serum A4 is a biochemical marker 
of adrenal androgen production. A goal of GC therapy is to suppress adrenal androgen 
production to a level that is at or slightly above the age and sex adjusted normal range (eg, A4 
>ULN but <1.25x ULN). An A4 level substantially above the age and sex adjusted ULN is 

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consistent with the GC dose being insufficient to appropriately suppress ACTH-driven adrenal 
androgen production. An A4 level substantially below the age and sex adjusted ULN is 
consistent with over-suppression of ACTH-driven adrenal androgen production due to too high 
of a GC dose.  
By modulating ACTH release, it is postulated that tildacerfont will allow a lower daily GC 
replacement dose, while maintaining control of adrenal androgen production. To evaluate this 
hypothesis, A4 levels will be used to monitor the impact of glucocorticoid replacement therapy 
on adrenal androgen production.   
SPR001-204 is a randomized, double-blind, placebo-controlled study that will evaluate the 
potential of tildacerfont to reduce GC burden in adult subjects with classic CAH who have 
LLD ≤ A4 ≤ 2.5x ULN and are on supraphysiologic doses of GC therapy (≥30 mg/day and 
≤60 mg/day HCe). SPR001-204 will be the first study of tildacerfont to evaluate GC dose 
reduction. In addition, Study SPR001-204 will characterize clinical outcomes after up to 76 
weeks of treatment with tildacerfont. An optional Open-Label Extension Period will provide an 
open-label treatment with tildacerfont at 200 mg QD for up to 240 weeks. 
2.2 Background 
2.2.1 Congenital Adrenal Hyperplasia 
CAH is a serious and chronically debilitating autosomal recessive genetic disorder characterized 
by impaired adrenal synthesis of the corticosteroids, cortisol and aldosterone and consequent 
overproduction of adrenal androgens (Merke and Bornstein 2005). Approximately 95% of CAH 
patients have a mutation in the CYP21A2 gene, which encodes the cytochrome P450c21 
enzyme, commonly known as 21-hydroxylase (Arlt 2010; Speiser 2018). Mutations in other 
genes that encode enzymes critical in adrenal steroidogenesis (CYP17A1, HSD3B2, CYP11B1, 
and POR) contribute to the remaining approximately 5% of CAH cases (Turcu and Auchus 2015). 
21-hydroxylase catalyzes the conversion of progesterone to 11-deoxycorticosterone (a 
precursor to aldosterone) and the conversion of 17-OHP to 11-deoxycortisol (the precursor to 
cortisol) (White and Speiser 2000; Bachelot 2008; Doleschall 2014; Auchus 2015). A deficiency 
in 21-hydroxylase thus results in a critical blockade in the adrenal steroid synthesis pathways 
that produce cortisol (and aldosterone in some individuals) and an accumulation of the 
precursors to these steroids (mostly 17-OHP, since accumulating progesterone is converted to 
17-OHP). These steroid precursors are then diverted into the synthetic pathway for adrenal 
androgens, resulting in overproduction of A4 and downstream adrenal androgens. 
Impaired cortisol production also disrupts the balance of the HPA axis by removing the negative 
feedback to the hypothalamus and pituitary gland provided by normal levels of cortisol. This 
leads to the compensatory hypersecretion of CRF by the hypothalamus and overproduction of 
ACTH by the pituitary. High levels of ACTH stimulate the adrenal gland to produce even greater 
quantities of 17-OHP, A4, and downstream adrenal androgens, resulting in adrenal hyperplasia.  
The clinical manifestations of CAH are the direct result of cortisol and aldosterone deficiencies 
and of androgen overproduction (Merke and Bornstein 2005; Arlt 2010; Reisch 2019). Cortisol 
deficiency can result in adrenal insufficiency and life-threatening adrenal crises. Overproduction 

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of adrenal androgens may result in advanced skeletal maturation, diminished height potential, 
premature pubarche, and precocious puberty in children; irregular menses, amenorrhea, 
hirsutism, and virilization in females; TARTs in males; and increased sebum production, acne, 
altered afternoon blood pressure profiles, and impaired fertility in either sex. 
CAH is typically classified as either classic (the more severe form that usually presents with 
adrenal crisis in infancy or virilization during early childhood) or nonclassic (the milder form that 
may not become evident until later childhood or early adulthood). Classic CAH can be further 
sub-classified as salt-wasting or simple virilizing. Approximately 75% of classic CAH patients 
have the salt-wasting form of CAH characterized by the loss of large amounts of sodium via 
urine (hyponatremia), hyperkalemia, and elevated plasma renin activity indicating hypovolemia, 
leading to dehydration and hypotension that can be life threatening in early infancy 
(Speiser 2018). Salt-wasting CAH is caused by severe aldosterone deficiency resulting from 
severe mutations that completely ablate 21-hydroxylase activity. Milder mutations that result 
in even 1% to 2% residual 21-hydroxylase activity enable sufficient aldosterone production to 
avoid neonatal adrenal crisis and produce the simple virilizing form of CAH in the remaining 
25% of CAH patients. 
Numerous studies have documented diminished quality of life in patients with CAH (Han 2013; 
Aulinas and Webb 2014; Gilban 2014; Hummel 2016). CAH patients commonly experience sleep 
disturbances, concentration problems, and challenges with social interactions (Malouf 2010). 
Severe fatigue is experienced by nearly half of CAH patients (Giebels 2014), and diminished 
memory performance has also been reported (Browne 2015). Psychiatric disorders and 
substance-use disorders are common, particularly among those with the most severe genotype 
(Engberg 2015). Faced with the debilitating effects of the disease itself, ineffective treatment, 
and/or the severe side effects of long-term high-dose GC treatment, CAH patients may develop 
depression and anxiety. Patients with CAH have increased mortality, with one study 
documenting a mean age of death of 41.2 years in patients with 21-hydroxylase deficiency, 
6.5 years earlier than matched controls (Falhammar 2014). The causes of death were adrenal 
crisis (42%), cardiovascular disease (32%), cancer (16%), and suicide (10%). 
Refer to the Investigator’s Brochure (IB) for additional information on CAH. 
2.2.2 Current Treatment for CAH 
There are no approved therapies for CAH. The current standard of care for CAH is lifelong 
treatment with GCs (eg, HC, prednisone, prednisolone, dexamethasone) to replace cortisol and 
suppress adrenal androgen overproduction (Speiser 2018). In patients with salt-wasting CAH, 
mineralocorticoids (eg, fludrocortisone) are also used to replace aldosterone; before weaning, 
NaCl supplements are also provided to prevent a potentially lethal salt-losing crisis 
(Padidela and Hindmarsh 2010). Evidence-based treatment guidelines for CAH are only 
beginning to be developed (Reisch 2015; Speiser 2018), and current overall treatment 
effectiveness for CAH patients is poor (Mnif 2012; Bachelot 2015). 
Treatment of CAH with chronic GCs is a problematic therapy with a narrow therapeutic window 
and significant side effects. The challenge in using GC therapy to manage CAH lies in striking the 
difficult balance between hyperandrogenism and hypercortisolism (Merke 2008; Arlt 2010; 

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Reisch 2019). Treating CAH patients with lower, physiologic doses of GC (≤10 mg/m2 of HCe per 
day, Lukert 2006) may be sufficient to prevent adrenal insufficiency but does not suppress 
androgen overproduction. Hyperandrogenic sequelae include hirsutism, female virilization, 
TARTs, acne, and infertility (Merke 2008; Reisch 2019). In contrast, treating patients with 
higher, supraphysiologic doses of GCs may suppress androgen overproduction but often results 
in iatrogenic hypercortisolism. Hypercortisolism leads to bone loss, Cushing’s syndrome, 
metabolic disorders and increased cardiovascular risk (hypertension, greater body mass index 
[BMI], obesity, hypercholesterolemia, insulin resistance), psychological and cognitive changes, 
musculoskeletal effects, gastrointestinal (GI) effects, and other effects (Merke 2008; 
Moghadam-Kia and Werth 2010; Reisch 2019). Thus, the ideal dose, which reduces excess 
androgen without supplying excess GC, is often difficult to find in the individual patient, and 
patients often experience hyperandrogenism, hypercortisolism, or a combination of these 
states (Falhammar 2007; Merke 2008). Despite the availability of GCs as a treatment for CAH, 
approximately two-thirds of CAH patients are considered outside the acceptable bounds of 
biochemical control based on 17-OHP and A4 levels (Han 2014). Among patients with 
21-hydroxylase deficiency treated with GCs, normal serum A4 has been shown to be achieved 
in only 36% of patients (Arlt 2010).  
Over a lifetime, the treatment of patients with CAH shifts from an emphasis on normal 
childhood growth to pubertal development to adult fertility and long-term health concerns, 
including metabolic abnormalities, cardiovascular disease, osteoporosis, and overall diminished 
quality of life (Arlt 2010; Auchus 2015). 
Given the serious nature of CAH and the lack of satisfactory available therapies, new 
treatments are urgently needed for patients with CAH. 
2.2.3 Tildacerfont for the Treatment of CAH 
Tildacerfont is an oral small-molecule antagonist of the CRF1 receptors on the pituitary gland. In 
vitro studies show that tildacerfont binds to CRF1 receptors with high affinity and specificity and 
blocks CRF-stimulated receptor function. In CAH, tildacerfont is intended to block the CRF signal 
produced by the hypothalamus, thereby decreasing CRF1 receptor–mediated ACTH 
overproduction by the pituitary and reducing excessive accumulation of downstream adrenal 
hormones such as 17-OHP and A4. This mechanism of action has been validated in CAH in 
earlier-phase clinical studies of tildacerfont (see Section 2.2.5). Given its mechanism of action, 
tildacerfont may enable a CAH patient to have normal androgen levels while taking GC at 
physiologic replacement levels. 
Nonclinical studies of tildacerfont are summarized in Section 2.2.4. Clinical experience with 
tildacerfont is summarized in Section 2.2.5. 
2.2.4 Nonclinical Studies of Tildacerfont 
A comprehensive nonclinical development program has been conducted to support clinical 
development of tildacerfont. 
In vitro membrane- and cell-based radioligand binding assays have demonstrated that 
tildacerfont is a potent CRF1 receptor antagonist that is highly selective for the human CRF1 

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over the human CRF2 receptor (6.1 nM vs >100 nM, respectively) and inhibits CRF-stimulated 
human CRF1 receptor function. 
Nonclinical safety pharmacology studies have indicated no undesirable pharmacodynamic (PD) 
effects of tildacerfont on physiological functions. 
Nonclinical PK studies have shown tildacerfont to be quickly absorbed; distributed primarily to 
endocrine, fatty, metabolic/excretory, and GI tract tissues and not to melanin-containing 
tissues; metabolized primarily by CYP3A4; and eliminated to below the quantitation limit in 
most tissues by 168 hours, with the majority of drug substance eliminated from tissues by 
72 hours. Refer to Section 6.5.1 for information on potential drug interactions of tildacerfont. 
Nonclinical toxicology studies to date include completed genotoxicity studies and adult, 
juvenile, and reproductive and developmental toxicology studies.  
• In a standard battery of genotoxicity studies, tildacerfont was found to be neither 
mutagenic nor clastogenic/aneugenic.  
• Chronic repeat-dose toxicity studies have been conducted in adult rats and dogs using the 
clinically relevant route (oral) and schedule (daily) of administration. Tildacerfont doses of 
up to 2000 mg/kg/day have been evaluated in rats and dogs dosed for up to 13 weeks, 
doses of up to 1000 mg/kg/day have been evaluated in rats dosed for 26 weeks, and doses 
of up to 1000/500 mg/kg/day have been evaluated in dogs dosed for 39 weeks. Target 
organs identified histopathologically in rats and/or dogs include the liver, 
testes/epididymides, and thyroid gland. Refer to Section 2.3.1 for a discussion of the 
potential liver, testicular, and thyroid risks associated with tildacerfont. 
• In developmental toxicity studies in juvenile rats administered tildacerfont doses of up to 
1000 mg/kg/day for 7 weeks beginning on postnatal day 45 (comparable to a 12-year-old 
human), adverse effects were limited to microscopic findings in the testes of males at 
1000 mg/kg/day, consistent with the findings in adult rats. 
• In reproductive and developmental toxicity studies, no adverse effects on fertility, early 
embryonic development, embryo-fetal development, or maternal toxicity were noted in 
rats at tildacerfont doses ≤1000 mg/kg/day. In rabbits, maternal toxicity was observed at 
≥30 mg/kg/day, and embryo-fetal developmental toxicity was observed at 
≥100 mg/kg/day. 
Refer to the IB for additional information on nonclinical studies of tildacerfont. 
2.2.5 Clinical Experience with Tildacerfont 
Tildacerfont has been studied in 7 completed interventional clinical studies to date, of which 5 
were Phase 1 studies and 2 were Phase 2 studies. 
To date, tildacerfont has been well tolerated at effective doses with no related SAEs. Two 
subjects in Phase 2 studies experienced transient elevations in liver function tests (LFTs) after 
being administered doses higher than those in this study (see Section 2.3.1 for more details). 
Proof of concept for tildacerfont as a CRF1 receptor antagonist in CAH patients was 
demonstrated in the Phase 2 Study SPR001-201, which showed clinical evidence of CRF1 

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receptor target engagement (reductions in ACTH) and reductions in key adrenal hormones 
(17-OHP and A4) at multiple dose levels tested. In addition, the Phase 2 Study SPR001-202 
showed tildacerfont’s ability to normalize ACTH and adrenal hormones with 12 weeks of 
treatment at a dose of 400 mg QD (see Section 2.3.2 for more details). 
2.3 Risk/Benefit Assessment 
2.3.1 Observed Potential Risks 
2.3.1.1 Liver 
Effects on the liver noted in chronic toxicity animal studies include the following: 
• Increased liver weight (in female rats dosed with 1000 mg/kg/day [~39-fold higher 
exposure in rat than the expected average exposure for the human dose in this study] for 
26 weeks) 
• Hepatocellular hypertrophy (in rats dosed with ≤1000 mg/kg/day [~39-fold higher] for 
26 weeks and in dogs dosed with ≤1000/500 mg/kg/day [>66-fold higher exposure in dog 
than the expected average exposure for the human dose in this study] for up to 39 weeks) 
• Increased liver mRNA expression of CYP2B1 and CYP2B2 (in rats dosed with 300 and 
1000 mg/kg/day [>11-fold higher exposure in rat than the expected average exposure for 
the human dose in this study] for 26 weeks) or of CYP1A1, CYP2B11, and CYP3A12 (in dogs 
dosed with ≤1000/500 mg/kg/day [>66-fold higher] for up to 39 weeks) 
• Hepatocellular degeneration, focal necrosis, vacuolation, bile duct hyperplasia, and/or 
periportal mixed leukocyte infiltration associated with increases in gamma-glutamyl 
transferase (GGT) and ALT activities (in dogs dosed with 300 and 1000/500 mg/kg/day 
[>39-fold higher exposure in dog than the expected average exposure for the human dose 
in this study] for up to 39 weeks) 
Reversible effects on LFTs have been observed in the Phase 2 clinical studies. Two subjects in 
Cohort A of Study SPR001-201 experienced transient elevations in ALT and aspartate 
aminotransferase (AST) after receiving 1000 mg QD for 2 weeks (following 2 weeks on 200 mg 
QD and 2 weeks on 600 mg QD). One subject experienced an ALT elevation of up to 8.6x ULN, 
and the other subject experienced a mild ALT elevation of 2.3x ULN. Concurrent elevations in 
AST were also observed to a lesser extent in these subjects, while bilirubin levels remained 
within normal limits. Both events resolved spontaneously within 2 to 4 weeks without any 
specific medical management. Both subjects were subsequently re-challenged with 
tildacerfont. The first subject was re-challenged in Study SPR001-202 at 400 mg QD, 
experienced a moderate increase in ALT (2.9x ULN), and was subsequently discontinued from 
that study. The other subject was re-challenged in Cohort B of Study SPR001-201 at 200 mg 
twice daily (BID) and did not experience a recurrence of any liver enzyme elevation. 
No treatment-emergent LFT abnormalities were observed in the Phase 1 studies, which treated 
healthy adults with single tildacerfont doses of up to 800 mg and multiple tildacerfont doses of 
up to 200 mg QD for 14 days. No LFT abnormalities have been observed in CAH subjects treated 
with tildacerfont doses of ≤200 mg QD for 2 weeks in the Phase 2 studies. 

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2.3.1.2 Testicular 
Reversible testicular/spermatocyte degeneration/atrophy was consistently observed in chronic 
toxicity studies: in rats and dogs dosed with 2000 mg/kg/day (~79-fold [rat] and >200-fold [dog] 
higher exposure than the expected average exposure for the human dose in this study) for 
13 weeks, in rats dosed with ≤1000 mg/kg/day (~39-fold higher) for 26 weeks, and in dogs 
dosed with 1000/500 mg/kg/day (>66-fold higher) for <20 weeks. Effects included smaller 
testes and/or epididymides, seminiferous tubule degeneration/atrophy, and germ cell debris 
and/or reduced sperm in epididymides. However, male reproductive studies in rats showed no 
impairment in fertility at the highest dose tested (1,000 mg/kg/day [~39-fold higher]). 
Additionally, no meaningful effects on clinical laboratory markers of testicular function 
(luteinizing hormone [LH], follicle-stimulating hormone [FSH], inhibin B, and sex hormone–
binding globulin [SHBG]) have been observed in male subjects in the Phase 1 or Phase 2 clinical 
studies. 
2.3.1.3 Thyroid 
Effects on the thyroid gland noted in chronic toxicity studies include increased weight of the 
thyroid/parathyroid gland (in rats dosed at ≤1000 mg/kg/day [~39-fold higher exposure than 
the expected average exposure for the human dose in this study] for 26 weeks), C-cell adenoma 
of the thyroid (in male rats dosed at 1000 mg/kg/day [~39-fold higher] for 26 weeks), and 
follicular hypertrophy (in dogs dosed at 2,000 mg/kg/day [~262-fold higher] for 13 weeks). The 
follicular hypertrophy was considered secondary to the hepatocellular hypertrophy also noted 
in these animals and not a direct result of tildacerfont administration. Thyroid follicular cell 
hypertrophy can be associated with increased functional hepatocellular mass, with increased 
thyroxine metabolism and increased release of thyroid-stimulating hormone (TSH) from the 
pituitary. The clinical relevance of this secondary finding is presently unclear. Thyroid function 
was not evaluated in the Phase 1 studies, and no meaningful changes in thyroid function have 
been observed in the Phase 2 studies. 
2.3.2 Observed Potential Benefits 
Evidence from nonclinical and available clinical data suggests that tildacerfont is effective as a 
CRF1 receptor antagonist.  
Data from Study SPR001-201 (which tested tildacerfont doses of 200 mg QD, 600 mg QD, 
1000 mg QD, 100 mg BID, and 200 mg BID, all for 2 weeks) showed clinical evidence of CRF1 
receptor target engagement and reductions in key adrenal hormones in adult subjects with 
classic CAH. For example, after 2 weeks of treatment at a total daily dose of 200 mg, subjects 
with elevated ACTH at baseline had a mean reduction in ACTH of approximately 33%, and 
subjects with elevated biomarkers at baseline had mean reductions in both 17-OHP and A4 of 
13%. The higher total daily doses evaluated in Study SPR001-201 demonstrated similar efficacy, 
suggesting that a total daily dose of 200 mg tildacerfont may be at the top of the dose-response 
curve. 
Data from Study SPR001-202 (which tested a tildacerfont dose of 400 mg QD for 12 weeks) 
demonstrated continued improvement in ACTH, 17-OHP, and A4 levels over 12 weeks of 
treatment. Subjects with elevated biomarkers at baseline had a maximum mean percentage 

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reduction of 68% in ACTH, 88% in 17-OHP, and 81% in A4 over 12 weeks of treatment; 
individual maximum reductions exceeded 97% for all of these biomarkers. Additionally, 67% of 
subjects with abnormal ACTH at baseline achieved normalization of ACTH on study, and 40% of 
subjects with abnormal A4 at baseline achieved normalization of A4 on study. 
2.3.3 Assessment of Potential Risks and Benefits 
Multiple study design elements have been incorporated to mitigate the potential risks of LFT 
laboratory abnormalities, testicular injury, and thyroid effects described in Section 2.3.1. First, 
these risks are all associated with higher doses of tildacerfont; in this study, tildacerfont tablets 
will be administered at a total daily dose of 200 mg, lower than the doses at which elevated 
LFTs have been observed and doses that have been well tolerated. Additionally, clinical 
laboratory measures of liver chemistry, testicular function, and thyroid function will be 
assessed at every study visit in this study. Liver chemistry will be monitored by measuring ALT, 
AST, alkaline phosphatase (ALP), GGT, total and direct bilirubin, total bile acids, prothrombin 
time (PT)/international normalized ratio (INR), and partial thromboplastin time (PTT). Testicular 
function will be monitored by measuring LH, FSH, inhibin B, and SHBG and performing scrotal 
ultrasounds. Thyroid function will be monitored via a thyroid panel that measures T3, T4, and 
TSH. Finally, strict individual treatment-stopping criteria for liver chemistry findings and criteria 
for increased liver chemistry monitoring are in place (see Section 7.1.1 and Section 13.2). 
The reversible histopathological effects of tildacerfont on the male reproductive tract in rat and 
dog toxicity studies occurred in the context of animals with normal, rather than elevated, 
baseline hormone function. As a CRF1 receptor antagonist, tildacerfont is intended to reduce 
abnormally elevated ACTH and androgen levels. In healthy animal models where baseline 
hormone levels are within normal ranges, clinical benefits are not expected, and indeed, effects 
on male reproductive tissues may be expected as a result of androgen reduction outside of the 
normal range. However, in patients with CAH, whose baseline ACTH and androgen levels are 
pathologically elevated, androgen reduction would be considered a positive, therapeutic effect. 
The Sponsor believes that the benefit-to-risk profile of this study is favorable. Given the serious 
nature of CAH and the limitations and risks of chronic steroid therapy, new treatment 
modalities are needed for patients with CAH. Given 1) the acceptable overall safety and 
tolerability profile of tildacerfont in healthy volunteers and subjects with CAH; 2) the ability to 
monitor the observed risk of LFT elevation, which is reversible and occurred at higher exposures 
than those expected in this study; and 3) the evidence of reductions in ACTH, 17-OHP, and A4 at 
multiple dose levels tested in previous Phase 2 studies, the Sponsor believes that the 
benefit-to-risk profile favors the continued clinical investigation of tildacerfont, including this 
investigation of tildacerfont’s potential to reduce GC use and of extended treatment with 
tildacerfont for up to 76 weeks in subjects with CAH. An optional Open-Label Extension Period 
will provide an open-label treatment with tildacerfont at 200 mg QD for up to 240 weeks. 

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3 OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Efficacy 
 
Primary Efficacy 
 
To evaluate the mean absolute GC change in 
subjects with classic CAH over the 24 -week, 
Double Blind, Placebo-Controlled Treatment 
Period 
Absolute change from baseline in GC dose in 
HCe at Week 24  
Secondary Efficacy 
 
To evaluate the effect of tildacerfont in 
reducing GC use to near-physiologic levels 
while maintaining androgen control in 
subjects with CAH 
Proportion of subjects with GC dose ≤11 
mg/m2/day in HCe and A4 ≤ 1.2x baseline or A4 
≤ ULN at Week 24 
To evaluate the effect of tildacerfont in 
reducing GC use to near-physiologic levels 
while maintaining androgen control in 
subjects with CAH 
Proportion of subjects with baseline GC dose ≤ 
35mg HCe who achieve GC dose ≤11 
mg/m2/day in HCe and A4 ≤ 1.2x baseline or ≤ 
ULN at Week 24 
To evaluate the effect of tildacerfont in 
reducing cardiovascular risk in subjects with 
CAH  
Proportion of subjects with improvement in at 
least one cardiovascular risk factor at Week 24 
Exploratory Efficacy 
 
To evaluate the percentage change in GC 
use in subjects with CAH 
Percent change from baseline in GC dose at 
Week 24 
To evaluate the effect of tildacerfont in 
reducing the cumulative HCe dose in 
subjects with CAH 
Change in total cumulative GC dose in HCe at 
Week 24 
To evaluate the effect of tildacerfont in 
improving HOMA-IR in subjects with CAH 
Change from baseline in the HOMA-IR at 
Week 24 
To evaluate the effect of tildacerfont in 
improving HOMA-IR after 52 weeks of 
tildacerfont treatment in subjects with CAH 
Change from baseline in HOMA-IR after 
52 weeks of tildacerfont treatment 

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Objectives 
Endpoints 
To evaluate the effect of tildacerfont in 
reducing cardiovascular risk in subjects with 
CAH 
Proportion of subjects with improvement in at 
least one cardiovascular risk factor at Week 52 
To evaluate the effect of tildacerfont in 
reducing GC use to near-physiologic levels 
while maintaining androgen control in 
subjects with CAH 
Proportion of subjects with GC dose ≤ 11 
mg/m2/day and A4 ≤ 1.2x baseline or ≤ ULN at 
Week 52 
To evaluate the effect of tildacerfont in 
improving QoL in subjects with CAH 
Change from baseline at Week 24 in the SF-36 
total score 
To evaluate the effect of tildacerfont in 
improving quality of life in subjects with 
CAH 
Change from baseline at Week 52 in the SF-36 
total score 
To evaluate the effect of tildacerfont on 
BMI after 24 weeks in subjects with CAH 
Percent change from baseline in BMI at 
Week 24 
To evaluate the effect of tildacerfont on 
BMI after 52 weeks of tildacerfont 
treatment in subjects with CAH 
Percent change from baseline in BMI after 
52 weeks of tildacerfont treatment 
To evaluate the effect of tildacerfont on wc 
after 52 weeks of tildacerfont treatment in 
subjects with CAH 
Change from baseline in wc after 24 weeks of 
tildacerfont treatment 
To evaluate the effect of tildacerfont on 
waist circumference after 52 weeks of 
tildacerfont treatment in subjects with CAH 
Change from baseline in waist circumference 
after 52 weeks of tildacerfont treatment 
To evaluate the effect of tildacerfont in 
improving body composition after 52 weeks 
of tildacerfont treatment in subjects with 
CAH 
Change from baseline in fat mass and fat/lean 
mass percentage ratio after 24 weeks of 
tildacerfont treatment 
To evaluate the effect of tildacerfont in 
improving body composition after 52 weeks 
of tildacerfont treatment in subjects with 
CAH 
Change from baseline in fat mass and fat/lean 
mass percentage ratio after 52 weeks of 
tildacerfont treatment 
To evaluate the effect of tildacerfont in 
improving BMD after 52 weeks of 
tildacerfont treatment in subjects with CAH 
Change from baseline in BMD after 52 weeks of 
tildacerfont treatment 

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Objectives 
Endpoints 
To evaluate the effect of tildacerfont in 
reducing TART(s) in male CAH subjects with 
TART(s) at baseline after 24 weeks of 
tildacerfont treatment in subjects with CAH 
Proportion of male subjects with reduction in 
TART volume at Week 24 who had TART(s) at 
baseline 
To evaluate the effect of tildacerfont in 
reducing TART(s) in male CAH subjects with 
TART(s) at baseline after 52 weeks of 
tildacerfont treatment in subjects with CAH 
Proportion of male subjects with reduction in 
TART volume at Week 52 who had TART(s) at 
baseline 
To evaluate the effect of tildacerfont in 
reducing GC use while maintaining normal 
A4 levels at Week 24 in subjects with CAH 
Proportion of subjects with at least a 5 mg/day 
HCe reduction from baseline (Day 1) in GC dose 
and A4 ≤ 1.2x baseline or  ≤ ULN at week 24 
To evaluate the effect of tildacerfont in 
reducing GC use while maintaining normal 
A4 levels at 52 weeks in subjects with CAH 
Proportion of subjects with at least a 5 mg/day 
HCe reduction from baseline (Day 1) in GC dose 
and A4 ≤ 1.2x baseline o ≤ ULN at week 52 
Exploratory Efficacy (Optional Open-Label Extension Period) 
To evaluate the effect of tildacerfont in 
reducing GC use to near-physiologic levels in 
subjects with CAH 
Proportion of subjects with GC dose ≤11 
mg/m2/day in HCe and A4 ≤ULN at EOT  
To evaluate the percentage change in GC 
use in subjects with CAH 
Percent change from baseline in GC dose at EOT 
To evaluate the effect of tildacerfont in 
reducing cardiovascular risk in subjects with 
CAH and at least one cardiovascular risk 
factor at baseline 
Proportion of subjects with improvement in at 
least one cardiovascular risk factor at EOT 
To evaluate the effect of tildacerfont in 
improving BMD in subjects with CAH 
Change from baseline in BMD at EOT 
To evaluate the effect of tildacerfont in 
reducing TART(s) in male CAH subjects with 
TART(s) at baseline 
Proportion of male subjects with reduction in 
TART(s) at EOT who had TART(s) at baseline 
Safety 
 
To evaluate the safety of tildacerfont in 
subjects with CAH 
AEs, SAEs 

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4 STUDY DESIGN 
4.1 Overall Design 
This is a study with a 2-part treatment period that will evaluate the potential of tildacerfont to 
reduce GC burden in adult subjects with classic CAH who have LLD ≤ A4 ≤ 2.5x ULN and are on 
supraphysiologic doses of GC therapy (≥30 mg/day and ≤60 mg/day in HCe). The first 24 weeks 
of the treatment period will be a randomized, double-blind, placebo-controlled study in which 
subjects are randomized in a 1:1 ratio to receive either placebo or tildacerfont at 200 mg QD. 
All subjects will receive open-label tildacerfont at 200 mg QD during the remaining 52 weeks of 
the treatment period. An optional Open-Label Extension Period will provide an open-label 
treatment with tildacerfont at 200 mg QD for up to 240 weeks. 
Refer to the study schematic provided in Section 1.2. 
4.1.1 Study Periods 
This study will consist of the following periods: 
• A ≤45-day Screening Period for confirmation of eligibility 
o Optional A4 Screening Visit. 
o Screening information captured within 45 days of Day 1 in this study (particularly 
screening information transferred from Spruce Biosciences Study SPR001-203 to this 
study) will be used to determine eligibility and fulfill screening requirements for this 
study.  
In Germany, screening information from Spruce Biosciences Study SPR001-203 is 
not permitted to be transferred to determine study eligibility. 
 
A 6- or 12-week Glucocorticoid Conversion Period (Week -12 to either Week -6 or Week -2  [±3 
days]) for subjects on dexamethasone at the initial Screening Visit who agree to convert to a 
non-dexamethasone regimen as determined by their physician (Section 1.3.3)  
• A 76-week, 2-part Treatment Period 
o The 24-week Placebo-Controlled Treatment Period (Day 1 to Week 24) will be 
randomized, double-blind, and placebo-controlled. Subjects will be randomized in a 
1:1 ratio to receive either placebo or tildacerfont at 200 mg QD. 
o The 52-week Open-Label Period (day after Week 24 to Week 76) will provide subjects 
who complete the Placebo-Controlled Treatment Period with 52 weeks of open-label 
treatment with tildacerfont 200 mg QD. 
o Beginning at Week 2 (based on the Day 1 A4 measurement), subjects with an A4 
measurement ≤ ULN at a study visit will begin to reduce their daily GC dose by 
increments of no more than 5 mg/day HCe each time, down to a minimum of 15 mg 
HCe per day. Beginning at Week 6 (based on Week 6 A4 measurement), subjects with 
an A4 >1.25x ULN will begin to increase their daily GC dose by increments of no more 

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than 5 mg/day HCe each time. More details on GC dose adjustments are provided in 
Section 4.1.4.3. 
o Subsequent GC dose adjustments are based on A4 measurements at Weeks 12, 18, 
24, 32, 40, 52 and 64. 
• For subjects continuing into the optional Open-Label Extension Period 
o The Open-Label Extension Period will provide subjects with up to 240 weeks of 
treatment with tildacerfont 200 mg QD.  
o Subjects will be eligible to adjust GC dose level at each visit (see Section 4.1.4.3). 
• A 30-day Follow-up Period at EOT 
o Subjects who do not continue to the Open-Label Extension Period upon completion 
of Treatment Period will enter a 30-day Follow-up Period. 
o Upon completion of the Open-Label Extension Period, subjects will enter a 30-day 
Follow-up Period. 
o At the end of study treatment, subjects will maintain the GC regimen and 
mineralocorticoid regimen (as applicable) established during the course of the study 
until the 30-day follow-up visit unless the Investigator determines that the subject’s 
clinical status necessitates a dosing change. After completion of the study, GC 
therapy will be managed at the discretion of the subject’s treating physician.  
4.1.2 Study Visits and Telephone Contacts 
4.1.2.1 Study Visit Schedule 
• During the Screening Period:  
o Optional A4 Screening Visit 
o Screening Visit at ≤45 days before Day 1  
• During the Glucocorticoid Conversion Period (for subjects on dexamethasone at Screening): 
visits at Weeks -12 and -8 (and -2, if applicable); scheduled telephone contacts at 
Weeks -11 and -6 (and -5, if applicable) 
• During the 24-week Placebo-Controlled Treatment Period: visits on Day 1 (baseline) and at 
Weeks 3, 6, 12, 18, and 24 
• During the 52-week Open-Label Period: visits at Weeks 32, 40, 52, 64, and 76; scheduled 
telephone contacts at Weeks 27 and 46 
• During the optional Open-Label Extension Period: Visits every 3 to 6 months at Weeks 88, 
100, 124, 148, 172, 196, 220, 244, 268, 292 and 316 
• At 30 days after the last dose of study drug for final safety follow-up 
• PRN telephone contacts are detailed in Section 4.1.2.3 
4.1.2.2 Mode of Study Visits in the Context of COVID-19 or Other Logistical Challenges 
 All efforts should be made to conduct visits in the clinic as per the Principal Investigator’s 
clinical judgement or patient’s preference. Since the COVID-19 pandemic is expected to 
continue during the conduct of this trial, study visits can be adapted into a combination of in-

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clinic and telemedicine activities, with optional at-home visits, to mitigate the risk of COVID-19 
infection associated with study participation and to accommodate local and individual 
circumstances while maintaining participant access to healthcare resources. 
Some of the clinic activities of the Screening Visit may be conducted remotely (at the subject’s 
home) if approved by the site’s IRB/EC. 
For post-Screening activities, the investigational site will decide how to conduct these activities 
if alternatives are necessary due to COVID-19 restrictions, taking into consideration subject 
preference and the relevant local public health guidelines and striving to maintain a consistent 
mode for each activity throughout the study. The EDC system will capture the mode by which 
data are collected for each visit/activity.  
If home visits are conducted, the qualified medical professionals who will perform the study’s 
home visits are defined as individuals who meet national/local licensing requirements needed 
to perform the procedures required at the home visits. Their national/local licensure will be 
verified, and they will complete training on the study protocol and GCP. If the medical 
professional does not meet the national/local licensing requirements needed to perform the 
optional home visit activities (physical examination), the Investigator or Investigator-delegated 
study personnel must complete these activities for each visit.  
Refer to Section 11 for more information on study conduct in the context of COVID-19 or other 
logistical challenges. 
4.1.2.3 Telephone Contacts 
Sites will make scheduled telephone contacts during the Glucocorticoid Conversion Period at 
Weeks -11 and -6 (and -5, if applicable) and during the Treatment Period at Weeks 27 and 46 to 
record any AEs and concomitant medications. 
After receiving A4 results from the Day 1 (dose reduction only) and Week 6, 12, 18, 24, 32, 40, 
52, and 64 study visits, or during the optional Open-Label Extension Period, sites will make 
telephone contacts to subjects who are eligible for a GC dose adjustment. Sites will contact 
these subjects within 2 weeks after each applicable study visit. The site will direct the subject to 
adjust his/her GC dose at that time if the subject has not experienced any change in clinical 
status since the previous study visit. If no GC dose adjustment is warranted based on the A4 
level, the site does not need to contact the subject. If a subject’s GC dose is adjusted, the site 
will telephone the subject again 7 days after the GC dose adjustment to assess for the 
occurrence of AEs and the initiation of new concomitant medications.  
Subjects should be instructed to telephone sites if they have any concerns about their health.  
PRN telephone contacts initiated by sites and telephone contacts initiated by subjects should 
be captured in the EDC system as “unscheduled” telephone contacts. 
4.1.3 Study Diary/Drug Adherence Data Collection 
During the Glucocorticoid Conversion and Treatment Periods, subjects will use an electronic 
study diary to document study drug and background GC adherence. Female subjects will also 
use the study diary to record menstrual information (including start and stop dates of menses). 

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4.1.4 Procedures for Glucocorticoids 
4.1.4.1 General Procedures for Glucocorticoids 
Information to be collected at screening about a subject’s current and historical GC therapy 
during the past year include the type(s) of GC, the regimen(s), reason(s) that the subject is/was 
on that particular GC regimen, and any GC stress dosing during the past year. 
To be eligible to enter this study, subjects must be on a stable dose of GC replacement 
≥30 mg/day and ≤60 mg/day in HCe for ≥1 month before screening without any evidence of 
non-adherence to the GC regimen during this period (stress dosing is allowed). For any subject 
whose prescribed total daily GC dose varies from day to day but is stable on a weekly basis, an 
average total daily dose based on the total weekly dose will be calculated to determine 
eligibility.  
Subjects with the salt-wasting form of CAH must also be on a stable dose of mineralocorticoid 
replacement for ≥1 month before screening. A change to a subject’s GC regimen during the 
study could necessitate an adjustment to the subject’s mineralocorticoid regimen. The 
adequacy of a subject’s mineralocorticoid dose should be monitored throughout the study and 
adjusted as needed to adequately maintain standing blood pressure, plasma renin levels, and 
electrolytes (serum potassium in particular) within acceptable ranges (Speiser 2018). 
Please see instructions for administration of GCs through Week 24 and after Week 24 below. 
Administration of GCs through Week 24: 
• Participants who enter the study under protocol versions prior to Protocol Version 7.0 
will receive Sponsor-supplied GCs  
• 
Participants who enter the study under Protocol Version 7.0 and higher will receive 
Principal Investigator-prescribed GCs* 
• Participants should remain on the same GC (not the same dose) through week 24. If a 
change is necessary due to drug shortage, etc., switching within the same type of GC 
(i.e., intermediate – intermediate/prednisone – prednisolone) is allowed. Any such 
changes should be discussed with the Medical Monitor.  
 *In countries where prednisolone 1mg is not commercially available, the Sponsor will provide this GC 
through week 24 
 Administration of GCs after Week 24: 
• Participants who enter the study under any protocol version (1 and higher) will use 
Principal Investigator-prescribed GCs 
• A change in GC type (e.g., prednisone to prednisolone) is acceptable after Week 24 (see 
note on change between types of GC below) 
Subjects should not switch between short-acting and intermediate-acting GCs because it could 
confound interpretation of morning biomarker levels (e.g., if a subject switches from HC to 
prednisolone and the morning A4 decreases, it may be difficult to ascertain if the A4 decrease is 
due to longer GC coverage overnight or study drug effect). Half-lives of intermediate-acting GCs 
are similar enough that confounding interpretation should not be a concern when switching 

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from one intermediate-acting GC to another. For example, after Week 24, subjects could switch 
between prednisone to prednisolone (one intermediate-acting GC for another) but should not 
switch between short-acting and intermediate-acting GCs unless necessary based on GC 
availability. Any such cases should be discussed with the Medical Monitor. 
Sponsor acknowledges that the protocol uses a 1:4 ratio for HC: prednisone and 1:5 for HC: 
prednisolone. Transitioning from prednisolone to prednisone will require the closest 
approximation possible, given the denomination of tablets available. Switching from 1mg 
prednisolone to 1mg prednisone is the closest approximation possible, and therefore is not a 
protocol deviation. 
On the evenings before scheduled laboratory assessments, subjects should take their evening 
GC dose before 10 PM. On the mornings of scheduled laboratory assessments, subjects should 
delay taking any morning dose of GC medication until after the 8 AM (±1 hour) laboratory 
assessments have been completed. On all other days during the study, subjects should take 
their GC medication at the usual times. Mineralocorticoid may be taken at any time of day, but 
its timing relative to laboratory assessments should be consistent throughout the study. 
4.1.4.2 Glucocorticoid Dose Conversion to Hydrocortisone Equivalents 
Table 1 defines the potencies of various GCs relative to HC in treating CAH in HCe. The table 
provides the conversion units for subjects who are converting from dexamethasone to another 
GC and provides the units to convert GC mg to HCe units to conduct GC dose changes.  
Note that fludrocortisone (a mineralocorticoid, not a GC) should not be converted to HCe or 
included in the calculation of a subject’s total daily GC dose. 
Table 1. 
Glucocorticoid Dose Conversion to Hydrocortisone Equivalents (HCe) 
Glucocorticoid 
Potency in CAH (HCe) 
Hydrocortisone 
1 
Prednisone 
41 
Prednisolone or methylprednisolone 
51,2 
Dexamethasone 
60 to 803 
1 Zoorab 1998. 2 Clayton 2002. 3 Rivkees 2010; Speiser 2018. The Investigator may use a conversion factor for 
dexamethasone in the range specified, based on clinical judgment. The protocol uses a 1:4 ratio for HC:prednisone 
and 1:5 for HC:prednisolone. However, transitioning from prednisolone to prednisone will require the closest 
approximation possible given the denomination of tablets available. Switching from 1mg prednisolone to 1mg 
prednisone is the closest approximation possible and therefore is not a protocol deviation. 
 
4.1.4.3 A4-Based Daily Glucocorticoid Dose Adjustment Algorithm 
Any adjustment of GC dose will be based on the A4 level measured at study visits and made in 
increments ≤5 mg/day HCe according to the standardized sets of GC regimens (Table 1).  
The below A4-based algorithm will be used to guide changes to GC replacement therapy. 
Reductions below 15 mg/day should be discussed with the Medical Monitor.  

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A4 Level ≤ULN  
• Reduce GC dose  
• GC dose reductions may begin on Week 2 (based on Day 1 measurement) and 
thereafter at Week 6, 12, 18, 24, 32, 40, 52, and 64 study visits, or during the optional 
Open-Label Extension Period 
A4 Level >1.25x ULN  
• Increase GC dose  
• GC dose increases can occur at Week 6, 12, 18, 24, 32, 40, 52, and 64 study visits, or 
during the optional Open-Label Extension Period 
A4 level >ULN and ≤1.25x ULN 
• Maintain GC Dose 
The Investigator should contact the Medical Monitor if the Investigator does not intend to 
follow A4-based GC dose adjustment algorithm at a visit. 
The daily GC dosing frequency (e.g., BID or 3 times daily [TID]) should remain stable throughout 
the study. The Investigator should contact the Medical Monitor if the Investigator intends a 
change to the GC dosing frequency at a visit. 
If a change in GC is warranted by the A4 algorithm, sites will contact subjects by telephone 
within 2 weeks after each applicable study visit. If no GC dose adjustment is warranted based 
on the A4 level, the site does not need to contact the subject.  
Sites will telephone subjects again 7 days after GC dose adjustment to assess for the occurrence 
of AEs and the initiation of new concomitant medications. 
4.1.4.4 Stress Dosing of Glucocorticoid 
During times of clinically significant physical stress such as intercurrent illness with fever, 
surgical procedures, or significant trauma, subjects may take extra GC (in the form of HC) 
consistent with the “sick day guidelines” for prevention of adrenal crisis shown in Table 2 
(Bornstein 2016). Sites may employ variations on these guidelines, consulting with the Medical 
Monitor, if possible, in non-urgent situations. The Sponsor will provide all subjects with oral HC 
for the purposes of stress dosing (Section 6.2.2). For subjects who are not taking HC as their 
background GC regimen, the stress dose of HC should be estimated based on the relative 
potencies of GCs specified in Table 1. 
The stress doses recommended in Table 2 are meant to replace a subject’s usual daily GC dose; 
they are NOT taken in addition to the subject’s usual daily GC dose. When taking the stress dose 
orally, the subject should take the entire stress dose using HC tablets from the bottle provided 
by the Sponsor. Daily replacement dosing from the subject’s or Sponsor-provided GCs should be 
temporarily held during stress dosing and reinstated as soon as the stress dosing period ends. 
While all GC stress doses should be entered into the EDC, changes to usual daily GC dose only 
need to be entered into EDC when there is a definitive long-term, chronic alteration in the usual 
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Table 2. 
Sick Day Guidelines for Stress Dosing of Hydrocortisone 
Condition 
Stress Dosing of Hydrocortisone 
Home management of fever >38 °C 
(>100.4 °F) or illness requiring bed rest, 
when requiring antibiotics for an 
infection, or before undergoing a minor 
outpatient procedure (eg, dental work) 
• Approximately double the routine oral GC dose (and give 
as HC) until recovery (usually 2 to 3 days) 
• For fever >39 °C (102.2 °F) only, approximately triple the 
routine oral GC dose (and give as HC) until recovery 
(usually 2 to 3 days)1 
• Increase consumption of electrolyte-containing fluids and 
simple and complex carbohydrates (El-Maouche 2018), as 
tolerated 
Unable to tolerate oral medication due 
to gastroenteritis or trauma 
• HC 100 mg IM or SC 
Minor to moderate surgical stress 
• HC 25 to 75 mg/24 hours (usually 1 to 2 days) 
Major surgery with general anesthesia, 
trauma, or disease that requires 
intensive care 
• HC 100 mg IV injection, followed by HC 200 mg/24 hours 
(via continuous IV infusion or 50 mg bolus every 6 hours 
IV or IM) 
• Weight-appropriate continuous IV fluids with 5% 
dextrose and 0.2% or 0.45% NaCl 
• Rapid tapering and switch to oral regimen depending on 
clinical state 
Acute adrenal crisis 
• HC 100 mg IV injection, followed by HC 200 mg/24 hours 
(via continuous infusion or 50 mg every 6 hours IV or IM), 
reduced to HC 100 mg/day the following day 
• Rapid infusion of 1000 mL isotonic saline within the first 
hour or 5% glucose in isotonic saline, followed by 
continuous IV isotonic saline guided by individual patient 
needs 
• For hypoglycemia: 0.5 to 1 g/kg dextrose or 2 to 4 mL/kg 
of D25W (maximum single dose 25 g) infused slowly at 
rate of 2 to 3 mL/min 
• Cardiac monitoring: rapid tapering and switch to oral 
regimen depending on clinical state 
Abbreviations:  D25W, dextrose 25% in water; GC, glucocorticoid; HC, hydrocortisone; IM, intramuscular; IV, 
intravenous; SC, subcutaneous. 
1 When tripling the routine oral GC dose, the HC stress dose should be rounded up to the next highest 10-mg HC 
tablet. 
 
To prevent hypoglycemia, the subject should drink small amounts of clear sugar-containing 
liquids frequently and/or consume carbohydrates if the subject is able, glucose monitoring 
should be considered, and IV sodium and glucose replacement may be required (Clayton 2002; 
Merke and Bornstein 2005; Keil 2010).  
Day-to-day physical or psychological stressors, such as a short-term strenuous activity or school 
examinations, generally do not require increased GC dosing (Clayton 2002; Crown & Lightman 
2005; Merke and Bornstein 2005). 

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Subjects will maintain stress dosing until symptoms subside (or according to the clinical 
judgment of the treating physician), then return to their usual GC regimen. Any scheduled lab 
draws should be delayed until 5 to 7 days after subjects first return to their usual GC regimen. 
Any study visit delayed because of stress dosing will not be considered a protocol deviation. 
Extra unscheduled study visits for safety follow-up may be conducted in the interim. 
4.1.4.5 Post-Treatment Glucocorticoid Dosing 
Upon completion of the Treatment Period, subjects will maintain the GC regimen and 
mineralocorticoid regimen (as applicable) established during the course of the study until the 
30-day follow-up visit unless the Investigator determines that the subject’s clinical status 
necessitates a dosing change. After completion of the study, GC therapy will be managed at the 
discretion of the subject’s treating physician.  
4.2 Scientific Rationale for Study Design 
In previous Phase 2 open-label studies, tildacerfont exhibited an acceptable safety profile and 
proof-of-concept efficacy in reducing ACTH, 17-OHP, and A4 levels in adult subjects with classic 
CAH, which support the continued clinical development of tildacerfont. Study SPR001-204, 
which has a 24-week randomized, double-blind, Placebo-Controlled Treatment Period followed 
by a 52-week Open-Label period and will enroll approximately 90 subjects, will provide a more 
definitive, longer-duration, powered dataset. An optional Open-Label Extension Period will 
provide up to an additional 240 weeks of open-label treatment with tildacerfont at 200 mg QD. 
The placebo treatment group will control for any potential placebo effects in CAH and their 
impact on the overall tildacerfont treatment effect. 
Given the problematic nature and significant side effects of standard-of-care CAH therapy using 
chronic supraphysiologic GC replacement (see Section 2.2.2), an important goal of treatment in 
CAH is the reduction of GC dose requirements (Speiser 2018). To that end, Study SPR001-204 
will be the first clinical study to evaluate the potential GC-sparing effects of tildacerfont in 
subjects with CAH, with change in GC dose after 24 weeks of study drug as its primary endpoint 
and other measures of GC dose reduction as secondary endpoints. To evaluate tildacerfont’s 
potential to reduce GC use in CAH, Study SPR001-204 will enroll subjects who are taking 
supraphysiologic doses of GCs (and have LLD ≤ A4 ≤ 2.5x ULN) and gradually reduce the GC 
regimen in subjects who maintain A4 ≤ULN during the Treatment Period. 
Study SPR001-204 will enroll subjects who are taking supraphysiologic doses of GCs and have 
LLD ≤ A4 ≤ 2.5x ULN. Based on subgroup analyses of data from previous Phase 2 studies, these 
subjects constitute an appropriate subpopulation of CAH patients for evaluating reductions in 
GC dose. Eligibility for the previous Phase 2 Studies SPR001-201 and SPR001-202 was based 
primarily on elevated 17-OHP. This contributed to the recruitment of a heterogeneous 
population of CAH patients that may have obscured the efficacy signal across different dose 
cohorts in these studies. When baseline A4 and ACTH levels were instead used to stratify 
subjects into subgroups, 2 distinct subgroups were revealed that differed by their mean 
background GC dose at study entry and tildacerfont PD response profiles. These 2 subgroups 
had potentially different treatment goals. The subgroup of subjects with elevated A4 and ACTH 

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showed greater, more consistent reductions in key hormones in response to tildacerfont 
treatment and would require reduction of key hormones before any GC dose reduction. In 
contrast, the subgroup of subjects with lower A4 and ACTH were on a higher mean GC dose and 
constitute an appropriate subpopulation of CAH patients for a study of GC reduction. Enrolling 
this subpopulation of CAH patients will provide a more homogeneous study population from 
which to draw more robust conclusions. 
Study SPR001-204 will treat subjects with tildacerfont for up to 76 weeks, significantly longer 
than previous Phase 2 studies. The initial Phase 2 Study SPR001-201 treated subjects with 
tildacerfont for 2 weeks at each dose level ranging from 200 mg to 1000 mg per day. The 
subsequent Phase 2 Study SPR001-202 treated subjects with tildacerfont for 12 weeks at 
400 mg QD. The magnitude of the efficacy response strengthened over 12 weeks of therapy, 
suggesting that the full treatment effect of tildacerfont may only be revealed after longer-term 
therapy. Study SPR001-204 will treat subjects with randomized study drug for 24 weeks during 
the Placebo-Controlled Treatment Period and with open-label tildacerfont for a further 
52 weeks during the Open-Label Period. An optional Open-Label Extension Period will provide 
up to an additional 240 weeks of open-label treatment with tildacerfont at 200 mg QD. This 
duration of treatment will provide much longer-term monitoring of clinical outcomes for this 
chronic drug. The 30-day post-treatment washout period allows for adequate safety follow-up 
and analysis of any HPA axis rebound after the last dose of study drug. 
Subjects cannot be on dexamethasone during this study because dexamethasone may have a 
moderate drug interaction with tildacerfont that would confound efficacy analysis. Based on 
nonclinical and Phase 1 clinical data, tildacerfont is a moderate inhibitor of CYP3A4. 
Dexamethasone is primarily metabolized through CYP3A4, and GC exposure data from Study 
SPR001-201 have shown a potential for drug-drug interaction (DDI) between tildacerfont and 
dexamethasone, with tildacerfont increasing dexamethasone exposures approximately 1.8-fold 
and with the lower bound of the associated 95% confidence intervals (CIs) generally above 1.0. 
In contrast, prednisone/prednisolone and HC are metabolized through multiple pathways, with 
CYP3A4 comprising <18% of its metabolism (Kovacs 2019, Ohno 2008). Based on static 
mechanistic modeling used to predict DDI (FDA 2000), no clinically relevant increase in GC 
exposure is expected with prednisone/prednisolone or HC and tildacerfont. Phase 2 clinical 
data have shown a low likelihood of a DDI with tildacerfont.  
In CAH, a goal of chronic GC replacement therapy is to administer a GC dose that suppresses 
adrenal androgen overproduction due to ACTH stimulation. Serum A4 is a biochemical marker 
of adrenal androgen production. A goal of GC therapy is to suppress adrenal androgen 
production to a level that is at or slightly above the age and sex adjusted normal range (eg, 
A4 >ULN but <1.25x ULN). An A4 level substantially above the age and sex adjusted ULN is 
consistent with the GC dose being insufficient to appropriately suppress ACTH-driven adrenal 
androgen production. An A4 level substantially below the age and sex adjusted ULN is 
consistent with over-suppression of ACTH-driven adrenal androgen production due to too high 
of a GC dose.  
By modulating ACTH release, it is postulated that tildacerfont will allow a lower daily GC 
replacement dose, while maintaining control of adrenal androgen production. To test this 

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hypothesis, A4 levels will be used to monitor the impact of GC replacement therapy on adrenal 
androgen production.   
Another important goal of treatment in CAH is the reduction of adrenal hormone levels. To that 
end, this study will also measure the effect of tildacerfont on key hormones (ACTH, A4, 
17-OHP). Other exploratory efficacy endpoints will assess additional clinical benefit associated 
with reduction in GC dose and hormone control, such as improvements to QoL, metabolic 
parameters, and BMD. 
The schedule of study visits interspersed with telephone contacts provides an appropriate 
balance between minimizing subject burden and closely monitoring subjects for safety and 
response to therapy.  
Study drug will be taken with a meal because Phase 1 clinical studies showed that taking 
tildacerfont in a fed state improves drug absorption. The meal should contain approximately 
25-50% fat content because high fat intake with study drug may increase drug accumulation. 
Individual treatment-stopping criteria and appropriate laboratory and medical assessments 
have been established to ensure subject safety. 
4.3 Justification for Dose 
In Study SPR001-204, tildacerfont tablets will be administered at 200 mg QD for up to 76 weeks. 
Data from previous Phase 1 and Phase 2 studies support the safety and potential PD effects of 
this dose. 
The safety data show that tildacerfont has been generally well tolerated in all clinical studies to 
date, with no related SAEs. Specifically, tildacerfont at a dose of ≤200 mg/day has been well 
tolerated in previous clinical studies. 
The clinical efficacy/PD data show CRF1 receptor target engagement (reductions in ACTH) and 
reductions in key adrenal hormones (17-OHP and A4) in subjects with CAH dosed for 2 weeks 
with 200 mg/day tildacerfont, the lowest dose previously tested in subjects with CAH (see 
Section 2.3.2). 
A 1-compartment PK model with first-order absorption and elimination was fit to PK data from 
Study SPR001-201. This model was then used to estimate the steady-state exposure for each 
subject at each dose. For each of the 3 key hormones of ACTH, 17-OHP, and A4, an apparent 
plateau in response is observed at exposures achieved with the 200 mg/day dose of 
tildacerfont, with no additional benefit at the higher doses. This suggests that a dose of 
≤200 mg/day tildacerfont may provide maximum benefit while minimizing drug exposure. 
The long half-life of tildacerfont, estimated to be approximately 60 hours after single-dose 
administration, supports QD dosing in this study. 
Guided by the safety, efficacy, and exposure-response analyses from available clinical data, 
Spruce has selected a tildacerfont tablet dose of 200 mg QD for testing in Study SPR001-204. 
This dose lies within a clinically precedented dose range that has both been well tolerated and 
produced responses in key hormones. 

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4.4 End of Study  
4.4.1 End of Study Definition 
A subject is considered to have completed study treatment if the subject has completed all 
76 weeks of the Treatment Period. A subject is considered to have completed the study if the 
subject has completed study treatment and the last follow-up visit. The end of the study is 
defined as the date of the last follow-up visit of the last subject in the study. 
4.4.2 Optional Open-Label Extension Period 
Subjects who successfully complete all visits in the Treatment Period will be eligible to 
participate in an optional Open-Label Extension Period for up to 240 weeks of additional study 
treatment. If additional studies are warranted in the clinical development program for adult 
CAH or other unforeseen circumstances arise, the Open-Label Extension Period may be closed 
to further enrollment or discontinued early. 
The end of the study is defined as the date of the last follow-up visit of the last subject in the 
study. 
5 STUDY POPULATION 
This study will randomize approximately 90 subjects with classic CAH currently receiving GC at a 
supraphysiologic dose (defined in Section 5.1.1). The study will enroll subjects at approximately 
130 investigative sites globally. 
All applicable screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria. The Investigator will maintain a screening log to record 
details of all individuals screened and to confirm eligibility or record reasons for screening 
failure, as applicable. 
Screening information from the parallel Spruce Biosciences Study SPR001-203 to this study may 
be used to determine eligibility and fulfill screening requirements for this study if the 
information was captured within 45 days before Day 1 in this study. 
In Germany, screening information from Spruce Biosciences Study SPR001-203 is not 
permitted to be transferred to determine study eligibility. 
 
5.1 Eligibility Criteria  
5.1.1 Inclusion Criteria  
A subject must meet all of the following criteria to be eligible for this study: 
1. Male and female subjects ≥18 years old at screening 
2. Has a known childhood diagnosis of classic CAH due to 21-hydroxylase deficiency based on 
genetic mutation in CYP21A2 and/or documented (at any time) elevated 17-OHP and 

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currently treated with HC, HC acetate, prednisone, prednisolone, methylprednisolone, 
dexamethasone (or a combination of the aforementioned GCs) 
3. Has LLD ≤ A4 ≤ 2.5x ULN at screening measured before an AM GC dose 
4. Has been on a stable, supraphysiologic dose of GC replacement (defined as ≥30 mg/day and 
≤60 mg/day in HCe) for ≥1 month before screening  
5. For subjects with the salt-wasting form of CAH, subject has been on a stable dose of 
mineralocorticoid replacement for ≥1 month before screening 
6. Agrees to follow contraception guidelines (Section 5.2.5). Male subjects must also agree to 
refrain from donating sperm throughout the Treatment Period and for 90 days after the last 
dose of study drug 
7. Is able to understand all study procedures and risks involved and provides written informed 
consent indicating willingness to comply with all aspects of the protocol 
5.1.2 Exclusion Criteria  
A subject will not be eligible for this study if he/she meets any of the following criteria: 
1. Has a known or suspected diagnosis of any other known form of classic CAH (not due to 
21-hydroxylase deficiency) 
2. Has a history that includes bilateral adrenalectomy or hypopituitarism 
3. Has a history of allergy or hypersensitivity to tildacerfont, any of its excipients, or any other 
CRF1 receptor antagonist 
4. Shows clinical signs or symptoms of adrenal insufficiency 
5. Has had a clinically significant unstable medical condition, medically significant illness, or 
chronic disease occurring within 30 days of screening, including but not limited to: 
a. An ongoing malignancy or <3 years of remission history from any malignancy, other 
than successfully treated localized skin cancer 
b. eGFR of <45 mL/min/1.73 m2 
c. Current or history of liver disease (with the exception of Gilbert’s syndrome) 
d. History of alcohol or substance abuse within the last year, or any significant history of 
alcohol or substance abuse that would likely prevent the subject from reliably 
participating in the study, based on the opinion of the Investigator 
e. Active hepatitis B, hepatitis C, or HIV at screening 
f. Subjects who plan to undergo bariatric surgery during the study are excluded 
g. Any other condition that would impact subject safety or confound interpretation of 
study results 
6. Psychiatric conditions, including but not limited to bipolar disorder, schizophrenia, or 
schizoaffective disorders that are not effectively controlled on medication and may have an 
adverse impact on study compliance. Symptoms including hallucinations, delusions, and 
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a. Increased risk of suicide based on the Investigator’s judgment or the results of the 
C-SSRS conducted at screening and baseline (eg, C-SSRS Type 3, 4, or 5 ideation within 
the past 6 months or any suicidal behavior within the past 12 months) 
b. HADS score >12 for either depression or anxiety at screening or baseline 
7. Has clinically significant abnormal ECG or clinical laboratory results. Abnormal results that 
must be reviewed and discussed with the Medical Monitor to determine eligibility for this 
study include but are not limited to: 
a. Any clinically meaningful abnormal ECG results, including QTcF >450 ms for male 
participants or >470 ms for female participants 
b. ALT >2x ULN 
c. Total bilirubin >1.5x ULN  
d. Total bile acids >5x ULN 
8. Routinely works overnight shifts 
9. Subjects with travel plans/work schedules that result in significant and frequent changes in 
time zones (>2 hours) will require Medical Monitor approval for enrollment 
10. Females who are pregnant or nursing 
11. Use of any other investigational drug from 30 days or 5 half-lives (whichever is longer) 
before screening to the end of the study 
12. Use of the following drugs from 30 days or 5 half-lives (whichever is longer) before the start 
of the Treatment Period to the end of the study: 
a. Rosiglitazone, aromatase inhibitors, testosterone, growth hormones, or any other 
medication or supplement that could impact subject safety or confound interpretation 
of study results 
b. The drugs listed in Section 13.1, which are: 
i. Moderate to strong inhibitors and/or inducers of CYP3A4 
ii. Sensitive substrates or narrow-therapeutic-range substrates of CYP3A4 (except 
hormonal contraception containing ≤35 µg ethinyl estradiol) 
iii. Sensitive substrates or narrow-therapeutic-range substrates of BCRP (except those 
that can be administered QD in the morning, separated by approximately 10 hours 
from evening administration of study drug) 
13. Donation or receipt of blood from 90 days before Screening to the end of the study; 
donation or receipt of platelets, white blood cells, or plasma from 30 days before Screening 
to the end of the study 
5.2 Lifestyle Considerations 
5.2.1 Shift Work and Time Zone Changes 
Given the circadian rhythm of HPA axis hormones, the dosing of study drug with an evening 
meal, and early-morning blood draws for laboratory assessments, subjects who routinely work 
overnight shifts are not eligible for this study, and subjects with travel plans/work schedules 

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that result in significant and frequent changes in time zones (>2 hours) require Medical Monitor 
approval for enrollment. 
5.2.2 Meals and Dietary Restrictions 
Study drug must be consumed with food. Study drug will be consumed between 6 PM and 
midnight, with an evening meal. The evening meal should contain approximately 25-50% fat 
content. Study drug may be consumed up to 30 minutes after completing the evening meal, if 
necessary. If a subject has not consumed study drug within 30 minutes after the evening meal, 
the subject should consume study drug with a snack. Guidance on appropriate food content will 
be provided separately. 
Subjects will be advised to refrain from consumption of grapefruit, grapefruit juice, or any fruits 
that are known to be strong CYP3A4 inhibitors from 1 day before the first dose of study drug 
until after the final dose. 
Subjects should not take calcium supplements within the 24 hours before a dual-energy X-ray 
absorptiometry (DXA) scan. 
5.2.3 Caffeine, Alcohol, and Tobacco 
Subjects will abstain from imbibing alcohol within 12 hours before the blood draw (after 8 PM). 
Subjects should not use nicotine-containing products or drink caffeinated beverages within 
30 minutes before any study-related procedure. 
5.2.4 Activity 
Subjects should abstain from strenuous exercise for 8 hours before each study visit. Strenuous 
exercise might cause temporary spikes in biomarkers that could confound analysis of the effect 
of study drug. 
Subjects should not exercise within 30 minutes before any study-related procedure. 
5.2.5 Contraception Guidelines 
5.2.5.1 Contraception Guidelines for Male Subjects 
A male enrolling in this study must meet ONE of the following contraceptive criteria from 
Screening until 90 days after the last dose of study drug: 
1. Is sexually abstinent from penile-vaginal intercourse as his usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agrees to remain abstinent from 
Screening until 90 days after the last dose of study drug 
2. Is vasectomized and the absence of sperm has been confirmed 
3. Agrees to use a male condom AND female partner uses/has in place one of the following 
highly effective contraceptive methods from Screening until 90 days after the last dose of 
study drug: 
a. Combined hormonal contraception (containing estrogen and progestogen) 
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b. Progestogen-only hormonal contraception associated with inhibition of ovulation: 
oral, injectable, or implantable 
c. Intrauterine device (IUD) 
d. Intrauterine system (IUS) 
e. Bilateral tubal occlusion 
5.2.5.2 Contraception Guidelines for Female Subjects 
A female enrolling in this study must meet ONE of the following contraceptive criteria from 
Screening until 30 days after the last dose of study drug: 
1. Is postmenopausal at Screening 
A postmenopausal state is defined as no menses for at least 1 year without an alternative 
medical cause. A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy. However, a single FSH measurement is insufficient to establish a 
postmenopausal state without at least 1 year of amenorrhea. 
2. Has documentation of one of the following performed before Screening: 
a. Hysterectomy 
b. Bilateral salpingectomy 
c. Bilateral oophorectomy 
3. Is sexually abstinent from penile-vaginal intercourse as her usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agrees to remain abstinent from 
Screening until 30 days after the last dose of study drug 
4. Any male sexual partner is vasectomized, and the absence of sperm has been confirmed 
5. Agrees to use one of the following highly effective contraceptive methods, which must be 
in place from at least 1 month before Screening until 30 days after the last dose of study 
drug: 
a. Combined hormonal contraception (containing estrogen and progestogen) 
associated with inhibition of ovulation: oral, intravaginal, or transdermal 
Any hormonal contraception containing ethinyl estradiol must contain ≤35 µg ethinyl 
estradiol, is permitted only for subjects who would not be considered at high risk for 
thromboembolic or cardiovascular complications with estrogen use, and must be 
used simultaneously with a backup method of contraception. Acceptable backup 
methods of contraception include diaphragm with spermicide, cervical cap with 
spermicide, vaginal sponge with spermicide, and male or female condom with or 
without spermicide. Dosing of oral formulations of hormonal contraception 
containing ethinyl estradiol should be offset by approximately 10 hours from the 
evening dose of study drug. The Investigator may consult with the Medical Monitor 
regarding such individuals. 
b. Progestogen-only hormonal contraception associated with inhibition of ovulation: 
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c. IUD 
d. IUS 
e. Bilateral tubal occlusion 
5.3 Screen Failures 
Screen failures are defined as participants who consent to participate but are not subsequently 
randomized in the study. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, and eligibility 
criteria. 
Individuals who do not meet the following criteria for participation in the study may be 
rescreened according to the following guidelines: 
• Individuals who do not meet the screening hormone inclusion criteria may be rescreened 
if their GC dose is adjusted and stable for ≥1 month. The Investigator will first consult with 
the Medical Monitor regarding such individuals. Any morning dose of GC medication 
should be taken after the screening blood draw to allow for an unimpeded assessment of 
hormones. 
• Individuals on incompatible or excluded concomitant medications may be rescreened 
after an appropriate washout period (eg, 30 days or 5 half-lives, whichever is longer). The 
Investigator will first consult with the Medical Monitor regarding such individuals. 
• Individuals who have an exclusionary laboratory value during the screening period may be 
retested before Day 1 if the Investigator believes that the prior laboratory value is not 
consistent with the individual’s overall clinical picture. The Investigator will first consult 
with the Medical Monitor regarding such individuals. 
If appropriate, screening information transferred from Spruce Biosciences Study SPR001-203 to 
this study may be used to determine eligibility and fulfill screening requirements for this study.  
In Germany, screening information from Spruce Biosciences Study SPR001-203 is not 
permitted to be transferred to determine study eligibility. 
 

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6 STUDY INTERVENTION 
6.1 Study Intervention Administration 
6.1.1 Study Intervention Description 
Tildacerfont is a small-molecule CRF1 receptor antagonist.  
Details about the physical, chemical, and pharmaceutical properties of tildacerfont are provided 
in the IB. 
Study drug is defined as either tildacerfont or placebo. 
Study treatment is defined more broadly as study drug, GC regimens, or HC for stress dosing 
provided by the Sponsor. 
6.1.2 Treatment Assignment, Dosing, and Administration 
At the beginning of the Placebo-Controlled Treatment Period, subjects will be randomized in a 
1:1 ratio to receive either placebo or tildacerfont at 200 mg QD for 24 weeks. During the 
Open-Label Period, all subjects will receive open-label tildacerfont at 200 mg QD for 52 weeks. 
During the optional Open-Label Extension Period, subjects will continue to receive tildacerfont 
at 200 mg QD. 
Study drug will be taken orally each day between 6 PM and midnight, with an evening meal. The 
evening meal should contain approximately 25-50% fat content. Study drug may be consumed 
up to 30 minutes after completing the evening meal, if necessary. 
Subjects entering the study under protocol version 7.0 will use a Principal 
Investigator-prescribed supply of GCs. Subjects who entered the study under prior protocol 
versions will continue to use the GCs provided by the Sponsor through Week 24. After Week 24, 
subjects will use a Principal Investigator-prescribed supply of GCs. Subjects will continue to use 
the same type of GC (example: switch between short-acting GC and intermediate acting GC 
shall not be allowed) throughout the study. Please see important details on GC use in Section 
4.1.4.1.  
On the evenings before scheduled laboratory assessments, subjects should take their evening 
GC dose before 10 PM. On the mornings of scheduled laboratory assessments, subjects should 
delay taking any morning dose of GC medication until after the 8 AM (±1 hour) laboratory 
assessments have been completed. On all other days during the study, subjects should take 
their GC medication at the usual times. Mineralocorticoid may be taken at any time of day, but 
its timing relative to laboratory assessments should be consistent throughout the study. 
Only authorized study staff may dispense study treatment. Sites will provide subjects with 
dosing instructions. The Sponsor will provide GC for periods of stress dosing. Sponsor-provided 
HC for stress dosing may be shipped directly to subjects. 
In Denmark, UK, Ireland, Romania, Estonia or Turkey shipping of study drug directly from 
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Criteria for study drug discontinuation are provided in Section 7.1. 
6.2 Preparation/Handling/Storage/Accountability 
6.2.1 Acquisition and Accountability 
The Investigator is responsible for study drug and study GC receipt and accountability, 
reconciliation, and record maintenance. 
6.2.2 Formulation, Appearance, Packaging, and Labeling 
The drug product is formulated as a tablet containing 50 mg of drug substance and the 
following inactive ingredients: lactose monohydrate, hydroxypropyl cellulose, sodium lauryl 
sulfate, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium 
stearate, and Opadry® yellow.  
Placebo will be supplied as tablets that look identical to the drug product but contain no drug 
substance. 
Study drug tablets will be supplied in blister cards.  
HC tablets for stress dosing will be supplied by the Sponsor in bottles. 
In the United States, a 50mg and/or 200 mg of drug substance tablet will be available. The 
tablets may be packaged into HDPE bottles for use in the open label extension portion of the 
study. 
 
6.2.3 Product Storage and Stability 
All study treatment should be stored at room temperature, protected from light. Study 
treatment must be stored in a secure, environmentally controlled area that is monitored 
(manually or automatically) and accessible only to the Investigator and authorized study staff. 
Further details on the acceptable storage range for each study treatment are available in the 
study pharmacy manual. 
6.3 Measures to Minimize Bias: Randomization and Blinding 
At the beginning of the Placebo-Controlled Treatment Period, subjects will be centrally 
randomized in a 1:1 ratio to receive placebo or tildacerfont at 200 mg QD using a randomization 
and trial supply management (RTSM) system. Randomization will be stratified by sex and 
baseline GC dose level (<40 mg/day and ≥40 mg/day in HCe). 
Emergency unblinding to a subject’s treatment assignment should only occur when knowledge 
of the treatment assignment is necessary for immediate medical management of the subject. If 
emergency unblinding is required, the Investigator may use the code provided at the site 
initiation visit to access the subject’s treatment assignment details via the RTSM system. 

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6.4 Study Intervention Compliance 
Subjects will be asked to document study drug and background GC adherence in their electronic 
study diaries (see Section 4.1.3). Subjects will return study treatment at each study visit for a 
pill count. The Investigator is responsible for ensuring that dosing is administered in compliance 
with the protocol. 
Compliance information to be reviewed will include (but not be limited to) adherence to the 
subject’s GC regimen (including consistency in timing of doses), adherence to the study drug 
regimen (including taking as instructed with food), adequate recording of data in the study 
diary. 
6.5 Concomitant Therapy 
Concomitant medication is any medication (including over-the-counter [OTC] medication, 
prescription medication, vaccines, vitamins, and supplements) that the subject is receiving at 
screening or receives during the study. All concomitant medications must be recorded, along 
with: 
• Reason for use 
• Dates of administration, including start and end dates 
• Dosage information, including dose and frequency 
All concomitant medications should be compared against the list of prohibited medications 
(Section 6.5.1) and the list of other medications of concern (Section 13.1). Subjects should be 
instructed to contact the site immediately any time a new medication is required during the 
course of the study, including prescription and OTC medications, even those to be used for only 
a short period of time (e.g., antibiotics, cold and flu remedies, GI therapies, opioids or other 
pain relievers). The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
Information on concomitant GC therapy is presented in Section 4.1.4. 
6.5.1 Prohibited Concomitant Medications 
Other investigational drugs are prohibited during the study. 
Rosiglitazone is prohibited during the study because it could affect the subject’s ACTH levels. 
Aromatase inhibitors, testosterone, and growth hormones are also prohibited because these 
medications could affect the subject’s total androgen levels. In general, subjects who require 
ongoing treatment with these medications should not be screened. 
Any other medication or supplement that could impact subject safety or confound 
interpretation of study results is prohibited during the study. 
6.5.1.1 Inducers or Inhibitors of CYP3A4 
In vitro CYP reaction phenotyping has indicated that tildacerfont is metabolized by CYP3A4. 
Therefore, drugs that are known to be moderate to strong inducers or inhibitors of CYP3A4 are 

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prohibited. Use of dexamethasone is not permitted during the study (see rationale in 
Section 4.2). Subjects will be advised to refrain from consumption of grapefruit, grapefruit juice, 
or any fruits that are known to be strong CYP3A4 inhibitors from 1 day before the first dose of 
study drug until after the final dose. 
6.5.1.2 Substrates of CYP3A4 and/or BCRP 
In vitro drug interaction studies coupled with physiologically based pharmacokinetic (PBPK) 
modeling have indicated that tildacerfont has the potential to inhibit CYP3A4 and BCRP. 
Tildacerfont has also demonstrated the potential to induce CYP3A4 (mRNA), but the net effect 
on CYP3A4 is moderate inhibition. Phase 1 clinical data have also confirmed that tildacerfont is 
a moderate inhibitor of CYP3A4. Therefore, drugs that are sensitive substrates or narrow-
therapeutic-range substrates of CYP3A4 and/or BCRP must be avoided. Sensitive substrates or 
narrow-therapeutic-range substrates of BCRP that are not also metabolized by CYP3A4 and that 
can be administered QD in the morning (separated by approximately 10 hours from evening 
administration of study drug) may be permitted with monitoring for safety. 
Sensitive substrates are drugs whose plasma area under the concentration-time curve (AUC) 
has been shown to increase ≥5-fold when co-administered with a known inhibitor of the 
enzyme and drugs for which the AUC in poor metabolizers is >5-fold the AUC in extensive 
metabolizers. Drugs with narrow therapeutic ranges are those for which even small increases in 
a subject’s exposure to these drugs (potentially induced by the concomitant use of tildacerfont) 
could lead to serious safety concerns (e.g., torsades de pointes). 
Ethinyl estradiol is a CYP3A4 and BCRP substrate, and tildacerfont may increase the level of 
ethinyl estradiol by <1.25-fold. With ethinyl estradiol doses ≤35 µg, exposure to ethinyl 
estradiol is unlikely to reach the threshold associated with increased thromboembolic or 
cardiovascular risk that is observed with higher-dose ethinyl estradiol formulations. Thus, any 
hormonal contraception containing ethinyl estradiol used by female subjects must contain 
≤35 µg ethinyl estradiol, is permitted only for subjects who would not be considered at high risk 
for thromboembolic or cardiovascular complications with estrogen use, and must be used 
simultaneously with a backup method of contraception according to Section 5.2.5.2. Dosing of 
oral formulations of hormonal contraception containing ethinyl estradiol should be offset by 
approximately 10 hours from the evening dose of study drug. 
Section 13.1 provides a non-exhaustive list of medications that are prohibited because of their 
potential for metabolic interactions with tildacerfont. This list shows many commonly used 
medications, including certain antibiotics, antifungal agents (itraconazole, ketoconazole), 
statins (lovastatin, simvastatin), anti-inflammatory agents (felodipine), migraine remedies 
(eletriptan), anxiolytics (buspirone, midazolam), and drugs for erectile dysfunction (avanafil, 
sildenafil, vardenafil). (Many oncology drugs and medications used to treat the hepatitis C virus 
and HIV are strong inhibitors of CYP3A4 but are not listed simply because individuals with active 
cancer, hepatitis C, and/or HIV are excluded from this study.) It is critical that each subject’s 
concomitant medications are carefully compared to the list in Section 13.1. 

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In all cases, if there is a question or concern about a specific medication being used by the 
subject, it is appropriate to review the usage with the Medical Monitor before enrolling the 
subject in the study and/or making a change in concomitant medications. 
7 STUDY DRUG DISCONTINUATION AND PARTICIPANT WITHDRAWAL 
7.1 Study Drug Discontinuation 
Subjects may voluntarily discontinue study drug at any time. The Investigator and/or Sponsor 
may also discontinue a subject’s study drug at any time. Study drug will be discontinued in 
subjects who experience individual treatment-stopping criteria described in this section. The 
Sponsor and Investigator will make efforts (when possible) to continue to collect data 
(according to the Schedule of Treatment Period and Follow-up Activities) on subjects who 
discontinue study drug. 
When feasible, Investigators should discuss any safety concerns with the Medical Monitor as 
soon as possible to determine whether a subject should continue or discontinue study drug.  
If study drug is discontinued, the Investigator will report the discontinuation to the Medical 
Monitor, document the date and reason for study drug discontinuation on the appropriate 
electronic case report form (eCRF), schedule an early termination visit for the subject (see the 
Schedule of Treatment Period and Follow-up Activities in Section 1.3.3), provide or arrange for 
appropriate follow-up, and document the course of the subject’s condition. 
7.1.1 Liver Chemistry Stopping Criteria 
Liver chemistry stopping criteria defined in Table 3 are designed to ensure subject safety and to 
evaluate liver event etiology. The Investigator should notify the Sponsor within 24 hours of 
awareness if any of the criteria defined in Table 3 are met. Further suggested actions, follow-up 
assessments, and monitoring assessments are provided in Section 13.2. A significant change in 
liver chemistry that requires increased monitoring but does not necessarily satisfy stopping 
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Table 3. 
Stopping Criteria and Increased Monitoring for Liver Chemistry Elevations 
Criteria
Action
ALT 5x ULN 
Discontinue study drug and notify Sponsor
ALT 3x ULN 
AND total bilirubin 2x ULN 
(>35% direct bilirubin)1 
Discontinue study drug and notify Sponsor
Possible Hy’s Law case—report as SAE 
AND INR >1.5
Discontinue study drug and notify Sponsor. 
Possible Hy’s Law case—report as SAE 
AND subject has symptoms (new or 
worsening) believed to be related to 
liver injury or hypersensitivity2 
Discontinue study drug and notify Sponsor
AND total bile acids >3x ULN
Withhold study drug and notify Sponsor.
Repeat liver chemistry tests after 1 week and 
discuss with Medical Monitor whether to 
discontinue study drug. 
ALT 3x ULN only 
Monitor weekly for 4 weeks while continuing 
study drug and notify Sponsor (see 
Section 13.2.2) 
AND cannot be monitored weekly 
for 4 weeks 
Discontinue study drug and notify Sponsor
persists for 4 weeks 
Discontinue study drug and notify Sponsor 
Abbreviations:  ALT, alanine aminotransferase; INR, international normalized ratio; SAE, serious adverse event; 
ULN, upper limit of normal. 
1 If serum bilirubin fractionation is not immediately available, discontinue study drug if ALT 3x ULN and 
bilirubin 2x ULN and record the presence/absence of detectable urinary bilirubin on dipstick, which is indicative 
of direct bilirubin elevations suggesting liver injury. 
2 Symptoms related to liver injury include fatigue, nausea, vomiting, right upper quadrant pain or tenderness, and 
jaundice. Symptoms related to hypersensitivity include fever, rash, and eosinophilia. 
7.1.2 QT Stopping Criteria 
Study drug will be discontinued for a subject if either of the following criteria is met: 
QTcF >500 msec OR uncorrected QT >600 msec
Change from screening or baseline in QTcF of >60 msec
One repeat ECG should be performed to confirm the accuracy and persistence of an initial 
result that fulfills the QT stopping criteria. 
7.1.3 Suicidality Stopping Criteria 
Tildacerfont is considered to be a central nervous system (CNS)–active drug. Some CNS-active 
drugs may be associated with an increased risk of suicidal ideation in certain populations. 
Although tildacerfont has not been shown to be associated with an increased risk of suicidal 

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thinking or behavior in past clinical studies, subjects will be monitored for such events during 
this study using the C-SSRS (see Section 8.2.6.1). 
Individuals who answer “yes” to Question 3, 4, or 5 in the suicidal ideation section of the C-SSRS 
at screening or baseline are not eligible for this study. Any subject who exhibits any Suicidal 
Behavior or Suicidal Ideation (eg, answers “yes” to Question 3, 4, or 5 in the suicidal ideation 
section of the C-SSRS) will have study drug immediately discontinued and should be evaluated 
by a psychiatrist. This safety finding will be considered an AESI if it is not an SAE (e.g., requiring 
hospitalization) (see Section 8.3.8). 
7.1.4 Depression or Anxiety Stopping Criteria 
Individuals who score >12 on either the depression or anxiety subscale of the HADS (see 
Section 8.2.6.2) at screening or baseline are not eligible for this study. Any subject who 
develops severe depression or anxiety (Common Terminology Criteria for Adverse Events 
[CTCAE] Grade 3 or higher), as assessed by the Investigator, will require study drug 
discontinuation and appropriate follow-up. This will be considered an AESI if it is not an SAE (eg, 
requiring hospitalization) (see Section 8.3.8). 
7.1.5 Adrenal Insufficiency Stopping Criteria 
Symptoms of adrenal insufficiency include weakness, tiredness, anorexia, nausea, vomiting, 
abdominal pain, orthostasis and muscle and joint aches. Weight loss and hypotension (ie, 
systolic blood pressure <90 mmHg) are also associated with adrenal insufficiency. 
Hyponatremia, hyperkalemia, hypercalcemia, azotemia, anemia and eosinophilia may 
accompany adrenal insufficiency. It is important to note that many of these signs, symptoms 
and laboratory findings are nonspecific and commonly occur in persons without adrenal 
insufficiency. The Investigator should use their clinical judgment when determining whether the 
signs, symptoms or laboratory findings are isolated adverse events or are possibly due to 
adrenal insufficiency.  
The Investigator is strongly encouraged to contact the Medical Monitor to review the 
presentation and discuss the plan for a subject with any potential adverse events of adrenal 
insufficiency.  
If the Investigator deems the sign(s), symptom(s) and/or laboratory finding(s) to be due to 
adrenal insufficiency, the adverse event should be recorded as adrenal insufficiency. The 
sign(s), symptom(s) and laboratory findings resulting in the diagnosis of adrenal insufficiency 
will be collected on separate Adrenal Insufficiency Adverse Event CRF and should not be 
recorded on the Adverse Event CRF. 
If a subject develops an adrenal insufficiency AE meeting the SAE definition (Section 8.3.2) or 
the definition of an adrenal crisis (Section 4.1.4.4, Table 2), the Investigator should discuss with 
Medical Monitor (in cases where a clear explanation for the occurrence of adrenal insufficiency 
or adrenal crisis is identified, discontinuation of the study medication is not necessary).  If there 
is no clear explanation for serious event of adrenal insufficiency, then PI may discuss further 
steps with medical monitors. 
. 

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If the subject develops adrenal insufficiency due to undertreatment (as opposed to an acute 
stressor), the subject’s daily GC dose should be increased by 5 mg HCe and should not be 
reduced again to the GC dose level associated with adrenal insufficiency (per Investigator 
judgment and discussion with the Medical Monitor). Study drug should not be discontinued but 
may be interrupted while GC dose adjustment is made. 
In the absence of any clear explanation for the subject’s acute adrenal insufficiency, the 
Investigator should discontinue study drug. This will be considered an AESI (see Section 8.3.8). 
Adverse events or other conditions that lead to GC stress dosing should not be reported as AEs 
of adrenal insufficiency since the stress dosing is done to prevent, not treat, adrenal 
insufficiency.   
7.1.6 Reproductive Hormone Stopping Criteria 
If a subject experiences significant changes from baseline in reproductive hormone(s), the 
Investigator should determine whether such changes represent clinically significant 
reproductive abnormalities, potential risks to the subject, whether to discontinue study drug, 
and appropriate safety follow-up. These changes include but are not limited to significant 
changes in LH, FSH, or SHBG; significant changes in inhibin B or testicular dysfunction in men; 
and significant changes in estradiol, prolactin, progesterone, or menstrual cyclicity in women. 
Investigators should keep in mind that subjects with CAH can be expected to have abnormal 
reproductive hormone levels because deficient 21-hydroxylase enzyme activity leads 1) to 
elevated levels of cortisol precursors that are shunted into reproductive hormone biosynthetic 
pathways and 2) to low levels of the cortisol that normally provides negative feedback on the 
HPA axis. Standard-of-care therapy with GC and mineralocorticoid replacement does not 
necessarily fully normalize adrenal steroid production pathways and signaling systems, 
including ACTH and CRF levels. Thus, subjects with CAH can be expected to have abnormal 
plasma concentrations of various androgens and progestogens at baseline. Therapy with an 
effective CRF receptor antagonist may in fact shift the balance between various intermediates 
in the steroid biosynthetic pathway. Investigators should inform the Medical Monitor before 
discontinuing study drug. 
7.1.7 Clinically Significant Adverse Event Stopping Criteria 
The Investigator should consider study drug discontinuation and appropriate safety follow-up 
for a subject who experiences a clinically significant AE. When feasible, the Investigator should 
contact the Medical Monitor to discuss the subject’s clinical condition before discontinuing 
study drug. Clinically significant AEs include but are not limited to study drug–related SAEs 
(Section 8.3.2) and study drug–related AESIs (Section 8.3.8). 
7.2 Participant Withdrawal from the Study 
Subjects are free to withdraw from the study at any time upon request. If the subject 
withdraws consent for disclosure of future information, the Sponsor may retain and continue to 
use any data collected before the withdrawal of consent. The subject may request destruction 

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of any samples taken and not tested, and the Investigator must document this in the site study 
records. 
Subjects will be withdrawn from the study by the Investigator and/or Sponsor for either of the 
following: 
• Pregnancy 
• If any clinical AE, laboratory abnormality, or other medical condition or situation occurs 
such that continued participation in the study would not be in the best interest of the 
subject 
A subject may also be withdrawn from the study by the Investigator and/or Sponsor at any time 
for other safety, behavioral, compliance, or administrative reasons such as the following: 
• Significant protocol deviation or noncompliance with study procedures/restrictions 
• If the subject no longer meets eligibility criteria 
• Study termination by the Sponsor  
Subject withdrawal is expected to be uncommon. If possible, an early termination visit (as 
shown in the Schedule of Treatment Period and Follow-up Activities in Section 1.3.3) should be 
conducted before subject withdrawal. The Investigator must document the date and primary 
reason for the withdrawal on the appropriate eCRF. Subjects who withdraw prematurely may 
be replaced at the discretion of the Sponsor to ensure adequate numbers of evaluable subjects.  
7.3 Lost to Follow-up 
A subject will be considered lost to follow-up if the subject repeatedly fails to attend scheduled 
visits and study personnel are unable to reach the subject. 
The following actions must be taken if a subject fails to attend a required study visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible, counsel the subject on the importance of maintaining the assigned visit 
schedule, and ascertain whether the subject wishes to and/or should continue in the 
study. 
• Before a subject is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the subject, including, where possible, making 
3 telephone calls to the subject and, if necessary, sending a certified letter to the 
subject’s last known mailing address (or local equivalent methods). Attempts to contact 
the subject should be documented in the subject’s medical record. 
• If the subject continues to be unreachable, the subject will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 

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8 STUDY ASSESSMENTS AND PROCEDURES 
This section describes what study assessments and procedures will be performed and how they 
will be conducted. The timing of study assessments and procedures is provided in the Schedules 
of Activities in Section 1.3. 
8.1 Efficacy Assessments 
8.1.1 Hormone Assessments 
All blood samples will be collected at 8 AM prior to administering their GC dose after an 
overnight fast (nothing to eat after midnight) unless otherwise specified.  
A4, 17-OHP, ACTH, and testosterone will be measured.  
Detailed instructions for the collection and handling of biological samples will be provided 
separately. 
8.1.2 Quality of Life Assessments 
Quality of life will be measured using the SF-36, the Patient Global Impression of Change (PGIC), 
and the Clinical Global Impression – Improvement Scale (CGI-I), all described in this section. 
Quality of life as reflected by mood will be measured using the HADS, which is also used as a 
measure of safety and is described in Section 8.2.6.2. 
8.1.2.1 Short Form 36 
The SF-36 (Ware and Sherbourne 1992) is a widely used, validated, patient-reported survey that 
assesses subjective health status. The SF-36 consists of 36 items and the following 8 health 
domains: physical functioning, role-physical (limitations in usual role activities because of 
physical health problems), bodily pain, general health perceptions, vitality, social functioning, 
role-emotional (limitations in usual role activities because of emotional problems), and mental 
health. Domain scores range from 0 to 100, with higher scores corresponding to better 
subjective health status. The survey provides summary scores for physical health and mental 
health. 
8.1.2.2 Patient Global Impression of Change 
The PGIC (Guy 1976) is a 1-question survey that asks subjects to evaluate whether there has 
been an improvement in overall subjective health status. Subjects select a response on a 
7-point Likert scale. 
8.1.2.3 Clinical Global Impression – Improvement Scale 
The CGI-I (Guy 1976) is a 1-question survey that requires the clinician to assess how much a 
patient’s illness has improved or worsened relative to a baseline state. Clinicians select a 
response on a 7-point Likert scale. 

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8.1.3 Metabolic Assessments 
A lipid panel (total cholesterol, low-density lipoprotein [LDL], high-density lipoprotein [HDL], 
and triglycerides) and hemoglobin A1c (HbA1c), fasting glucose, and fasting insulin will be 
assessed as part of clinical laboratory (see Section 13.3). HOMA-IR will be calculated from 
fasting glucose and fasting insulin. Blood pressure (systolic and diastolic) will be assessed. Body 
weight, BMI, and wc will be assessed as described in Section 8.2.3.  
DXA is a whole-body scan that measures both total body composition (including the mass of fat, 
bones, and lean tissue) and BMD. One whole-body DXA scan exposes an individual to an 
effective radiation dose of <10 microSieverts, comparable to the normal background radiation 
of 1 day at sea level (Shepherd 2017). DXA scans should be performed for all subjects according 
to the Schedule of Treatment Period and Follow-up Activities. However, DXA scans will be 
optional at study centers that lack access to a DXA scanner. The initial DXA scan may be 
scheduled for any time before the first dose of study drug and will be considered the baseline 
measurement for the BMD endpoint and body composition assessments. Subjects should not 
take calcium supplements within the 24 hours before a DXA scan. 
8.1.4 Bone Biomarker Assessments 
Bone-specific alkaline phosphatase (BSAP), procollagen type 1 N terminal propeptide (P1NP), 
and osteocalcin are markers of bone formation. C-terminal telopeptide of type 1 collagen 
(CTX-1) and urinary N-linked telopeptide of type 1 collagen (U-NTx) are markers of bone 
turnover that will be assessed according to the Schedules of Activities. 
8.1.5 Hyperandrogenic Symptoms 
8.1.5.1 Testicular Adrenal Rest Tumors 
TARTs are a common complication of CAH caused by ACTH-driven overstimulation of aberrant 
adrenal cells within the testes (Olpin and Witt 2014) and may result in pain, discomfort, 
impaired spermatogenesis, and infertility (Chihaoui 2016; Claahsen-van der Grinten 2014; 
Delfino 2012). Complete scrotal ultrasounds will be obtained for male subjects using a real-time 
scanner to detect and to evaluate the size and number of TARTs. Standard images should be 
obtained in the longitudinal and transverse planes. Each potential TART lesion will be measured 
in 3 planes to allow for calculation of TART volume. Detailed instructions for performing the 
scrotal ultrasound will be provided separately.  
The initial scrotal ultrasound may be scheduled for any time before the first dose of study drug 
and will be considered the baseline measurement for the TART assessment. Only subjects with 
a TART at baseline will be followed for TART changes. Scrotal ultrasounds will be read by a 
central radiologist blinded to treatment assignment and to the study timepoints at which 
ultrasounds were taken. 
8.1.5.2 Menstrual Cyclicity 
Female subjects will record menstrual information in their electronic study diaries, including the 
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8.2 Safety Assessments 
Safety assessments will include monitoring and recording all AEs (including SAEs, AEs leading to 
discontinuation/withdrawal, and AESIs), physical examination, vital signs assessment, ECGs, 
clinical laboratory, monitoring for suicide risk, and depression/anxiety. AE procedures are 
described in Section 8.3. 
8.2.1 Physical Examination 
A full physical examination should include assessments of the cardiovascular, respiratory, GI, 
neurological, and musculoskeletal systems; head, eyes, ears, neck, and throat (HEENT); thyroid; 
skin; and extremities. The full physical examination may exclude rectal, genitourinary, and 
breast exams. 
An abbreviated physical examination should include the following components: cardiovascular, 
respiratory, abdomen, musculoskeletal, HEENT, and skin. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
A full physical examination will be performed during the Screening Visit and at Day 1, Week 24, 
and Week 76. If the physical exam is performed at the subject’s home, the qualified medical 
professional will conduct a full physical exam and report any changes to the subject’s health to 
the site to determine whether further evaluation is needed via an unscheduled visit. 
In Germany, only post-screening physical exams are eligible to be conducted at the subject’s 
home. 
In Italy and Poland, home visits are not permitted, and physical examinations must occur in 
the clinic. 
 
8.2.2 Vital Signs 
Vital signs consist of systolic and diastolic blood pressure, pulse rate, respiration rate, and body 
temperature. The subject should rest for at least 5 minutes before vital signs measurement 
without speaking or using a cellphone. The subject should ideally have an empty bladder. Vital 
signs will be measured as specified in the Schedules of Activities and as clinically indicated. 
Blood pressure should be measured with an appropriately sized cuff on a bare arm just above 
the bend of the elbow. An appropriately sized cuff has the inflatable portion covering 
approximately 40% of the arm’s circumference and the width of the cuff covering 
approximately 80% of the area from the elbow to the shoulder. The subject should be sitting in 
an upright position with feet flat on the floor and the measurement arm supported at heart 
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8.2.3 Body Weight, Height, BMI, Fat Mass, and Waist Circumference 
Body weight will be measured at every visit using a calibrated balance. The balance should be 
placed on a hard, flat surface and checked for zero balance before each measurement. The 
subject should stand unassisted, in the center of the platform, and be asked to look straight 
ahead, standing relaxed but still.   
Height needs to be recorded at screening only. 
BMI will be calculated for every visit using height and weight measurements. 
Fat mass will be assessed by DXA. 
Waist circumference will be measured using an appropriate tape measure placed horizontally 
just above the hip bones at the level of the belly button, placed snugly but not compressing the 
skin, and after the subject breathes out. 
8.2.4 Electrocardiogram 
A 12-lead ECG will be obtained using an ECG machine that automatically calculates the heart 
rate, QRS, QT, and QTc intervals, preferably using Fridericia’s formula. Any ECG measurement 
assessed by the Investigator as a clinically significant abnormality should be recorded in the AE 
section of the eCRF and monitored until resolution. 
Refer to Section 7.1.2 for QT individual treatment-stopping criteria and any additional ECGs that 
may be necessary. 
8.2.5 Clinical Laboratory and Urinalysis 
Clinical laboratory assessments include hematology, clinical chemistry, coagulation, lipid panel, 
thyroid panel, LH, FSH, SHBG, renin, aldosterone, inhibin B for males only, and estradiol, 
prolactin, and progesterone for females only. eGFR for screening will be calculated from blood 
creatinine measured as part of screening clinical chemistry. 
A complete list of study-required clinical laboratory and urinalysis tests is provided in 
Section 13.3.  
All study-required clinical laboratory tests must be conducted in accordance with the laboratory 
manual and will be performed by a central laboratory. 
The Investigator must review the laboratory report, document the review, and record any 
clinically significant laboratory findings that occur during the study in the AE section of the 
eCRF. Laboratory reports must be filed with the source documents. Clinically significant 
laboratory findings are those that are not associated with the underlying disease, unless judged 
by the Investigator to be more severe than expected for the subject’s condition. 
All laboratory tests with values considered clinically significantly during the Treatment Period or 
within 30 days after the last dose of study drug should be reported as AEs and repeated at least 
weekly until the values return to normal or baseline or are no longer considered clinically 
significant by the Investigator or Medical Monitor. If such values do not return to 
normal/baseline within a period of time judged reasonable by the Investigator, the etiology 
should be identified, and the Sponsor notified. 

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8.2.6 Psychiatric Evaluations 
8.2.6.1 Columbia–Suicide Severity Rating Scale 
The C-SSRS will be used during the study to monitor suicidal ideation and behavior. The C-SSRS 
is a Food and Drug Administration (FDA)–endorsed questionnaire administered by trained study 
personnel to screen for suicidality in trials of CNS-active compounds. The Baseline/Screening 
Version of the C-SSRS, which assesses both lifetime history and history from the last 12 months, 
will be used at screening to determine subject eligibility. The Since Last Visit Version of the 
C-SSRS will be used at all subsequent visits specified. 
Refer to Section 7.1.3 for suicidality individual treatment-stopping criteria. 
8.2.6.2 Hospital Anxiety and Depression Scale 
Subject anxiety and depression will be monitored during the study using the HADS, assessed at 
baseline and Weeks 12, 24, 52, and 76 (Zigmond and Snaith 1983). The HADS is a widely used 
subject-reported instrument that focuses on subjective disturbances of mood rather than 
physical signs. The scale consists of 14 items, 7 items each for anxiety and depression. Each 
item is rated on a 4-point scale based on the frequency of symptoms over the preceding week 
and ranging from 0 (not at all) to 3 (very often).  
Refer to Section 7.1.4 for depression and/or anxiety individual treatment-stopping criteria. 
8.3 Adverse Events and Serious Adverse Events 
8.3.1 Definition of Adverse Event 
An AE is any untoward medical occurrence in a clinical trial subject who has signed the ICF; the 
event need not necessarily have a causal relationship with the study drug or study GC. 
Examples of AEs include but are not limited to: 
• Clinically significant abnormal test results 
• Clinically significant symptoms and signs 
• Changes in physical examination findings 
• Hypersensitivity 
• Progression/worsening of underlying disease 
A treatment-emergent adverse event (TEAE) is an AE that is temporally associated with 
administration of study drug and is defined as an AE that occurs during or after administration 
of the first dose of study drug until 30 days after the final dose of study drug (safety follow-up 
visit). For AEs that occur on the date of the first dose of study drug, the time of onset (before or 
after intake of study drug) must be specified. 
An abnormal test result should be reported as an AE if any of the following criteria are met: 
• Test result is associated with accompanying symptoms 
• Test result requires additional diagnostic testing or medical/surgical intervention 

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• Test result leads to a change in study drug dosing or study drug discontinuation, 
significant additional concomitant drug treatment, or other therapy 
• Test result is considered to be an AE by the Investigator or Sponsor 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE. Any abnormal test result that is determined to be an error does not require 
reporting as an AE. 
Examples of events that do not meet the definition of an AE include but are not limited to: 
• Clinically significant abnormal test result or other abnormal safety assessment associated 
with the underlying disease, unless it is more severe than expected for the subject’s 
condition 
• The underlying disease and its signs and symptoms, unless they are more severe than 
expected for the subject’s condition 
• Medical and surgical procedures; the condition that leads to the procedure is the AE if it 
meets the definition of an AE. For example, an acute appendicitis that begins during the 
AE reporting period should be reported as the AE, and the resulting appendectomy 
should be recorded as treatment for the AE. 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen 
8.3.2 Definition of Serious Adverse Event 
An SAE or serious adverse drug reaction is any untoward medical occurrence at any dose that 
meets any of the following criteria: 
• Results in death 
• Is life threatening (immediate risk of death) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is an important medical event 
Medical and scientific judgment should be exercised in determining whether an event is an 
important medical event. An important medical event may not be immediately life threatening 
and/or result in death or hospitalization. However, if it is determined that the event may 
jeopardize the subject and may require intervention to prevent one of the other outcomes 
listed in the definition above, the important medical event should be reported as serious. 
Examples of such events include allergic bronchospasm that requires intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
hospitalization, or the development of drug dependency or drug abuse. If either the Sponsor or 
the Investigator believes that an event is serious, the event must be considered serious and 
evaluated by the Sponsor for expedited reporting. 
 
 

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Hospitalization does not include the following: 
• Rehabilitation facilities 
• Hospice facilities 
• Respite care (e.g., caregiver relief) 
• Skilled nursing facilities 
• Nursing homes 
• Same-day surgeries (as outpatient/same day/ambulatory procedures) 
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical AE is 
not in itself an SAE. Examples include the following: 
• Admission for treatment of a pre-existing condition not associated with the development 
of a new AE or with a worsening of the pre-existing condition (e.g., for workup of 
persistent pre-treatment lab abnormality) 
• Social admission (e.g., subject has no place to sleep) 
• Administrative admission (e.g., for yearly physical exam) 
• Protocol-specified admission during a clinical trial (e.g., for a procedure required by the 
trial protocol) 
• Optional admission not associated with a precipitating clinical AE (e.g., for elective 
cosmetic surgery) 
• Pre-planned treatments or surgical procedures should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject. 
8.3.3 Classification of an Adverse Event 
As far as possible, each AE will be described by the following: 
• Duration (start and end dates) 
• Severity (Section 8.3.3.1) 
• Relationship to study drug (Section 8.3.3.2) 
• Action(s) taken and, as relevant, the outcome (Section 8.3.3.3) 
8.3.3.1 Severity 
The Investigator will assess the severity of each AE according to the National Cancer Institute 
CTCAE version 5.0 (CTCAE 2017), which is summarized in Table 4. 
 
 

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Table 4. 
Severity of Adverse Events 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated. 
Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL (preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc). 
Grade 3: Severe or medically significant but not immediately life threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL (bathing, dressing and 
undressing, feeding self, using the toilet, taking medications, and not bedridden). 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
Grade 5: Death related to AE. 
Abbreviations: ADL, activities of daily living; AE, adverse event. 
 
Note the distinction between the severity and the seriousness of an AE. A severe event is not 
necessarily a serious event. Severe is a category used for rating the intensity of an event, and 
both AEs and SAEs can be assessed as severe. For example, a headache may be severe 
(interferes significantly with subject’s usual function) but would not be classified as serious 
unless it met at least one of the criteria for an SAE listed in Section 8.3.2, such as resulting in 
hospitalization. 
If there is a change in the severity of an ongoing AE, it will be recorded as part of the same 
event, with the worst grade of severity for the entire event timeframe being recorded. 
8.3.3.2 Relationship to Study Drug or Study Glucocorticoid (Study Treatment) 
The Investigator will assess the relationship of each AE separately to study drug and to the 
study GC according to the categories in Table 5. This assessment will serve to determine 
whether there exists a reasonable possibility that the study drug or study GC caused or 
contributed to the AE. 
 
 

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Table 5. 
Relatedness of Adverse Event to Study Drug or Study Glucocorticoid 
UNRELATED: This category applies to those AEs that are clearly and incontrovertibly due to extraneous 
causes (disease, environment, etc). 
UNLIKELY RELATED: This category applies to those AEs that are judged to be unrelated to study 
treatment but for which no extraneous cause may be found. An AE may be considered unlikely to be 
related to study treatment if or when it meets two of the following criteria:  
(1) it does not follow a reasonable temporal sequence in relation to administration of study treatment;  
(2) it could readily have been produced by the subject’s clinical state, environmental or toxic factors, 
or other therapies administered to the subject;  
(3) it does not follow a known pattern of response to study treatment; or  
(4) it does not reappear or worsen when study treatment is re-administered. 
POSSIBLY RELATED: This category applies to those AEs for which a connection to study treatment 
administration cannot be ruled out with certainty. An AE may be considered possibly related if or 
when it meets two of the following criteria: 
(1) it follows a reasonable temporal sequence in relation to administration of study treatment; 
(2) it could not readily have been produced by the subject’s clinical state, environmental or toxic 
factors, or other therapies administered to the subject; or  
(3) it follows a known pattern of response to study treatment. 
PROBABLY RELATED: This category applies to those AEs that the Investigator thinks are related to 
study treatment with a high degree of certainty. An AE may be considered probably related if or when 
it meets three of the following criteria: 
(1) it follows a reasonable temporal sequence in relation to administration of study treatment;  
(2) it could not be reasonably explained by the known characteristics of the subject’s clinical state, 
environmental or toxic factors, or other therapies administered to the subject; 
(3) it disappears or decreases on cessation or reduction in dose of study treatment. There are 
exceptions when an AE does not disappear upon discontinuation of study treatment yet 
treatment-relatedness clearly exists (e.g., as in bone marrow depression, fixed drug eruptions, or 
tardive dyskinesia); or  
(4) it follows a known pattern of response to study treatment. 
DEFINITELY RELATED: This category applies to those AEs that the Investigator thinks are 
incontrovertibly related to study treatment. An AE may be assigned an attribution of definitely related 
if or when it meets all of the following criteria:  
(1) it follows a reasonable temporal sequence in relation to administration of study treatment; 
(2) it could not be reasonably explained by the known characteristics of the subject’s clinical state, 
environmental or toxic factors, or other therapies administered to the subject; 
(3) it disappears or decreases upon cessation or reduction in dose of study treatment and recurs with 
re-exposure to study treatment (if rechallenge occurs); and 
(4) it follows a known pattern of response to study treatment. 
Abbreviation: AE, adverse event. 
 
 
 

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The Investigator will use clinical judgment and consult the IB to determine the relationship. 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to study drug or study GC administration will 
be considered and investigated. 
AEs classified as unrelated or unlikely related to study treatment will be considered not related 
to treatment, and AEs classified as possibly, probably, or definitely related to study treatment 
will be considered related to treatment. 
8.3.3.3 Outcome 
The outcome of each AE will be recorded as one of the categories in Table 6. 
Table 6. 
Outcome of Adverse Event 
Not recovered/not resolved: The event has not improved or recuperated. 
Recovered/resolved: The event has improved or recuperated. The subject recovered from the AE. 
Record the AE stop date. 
Recovering/resolving: The event is improving. No AE stop date should be recorded when an AE is 
recovering/resolving. 
Recovered/resolved with sequelae: The subject recuperated but retained pathological conditions 
resulting from the prior disease or injury. Record the AE stop date. The AE stop date will represent the 
date the AE stabilized with no change in event outcome anticipated. 
Unknown: There is an inability to access the subject or the subject’s records to determine the 
outcome (ie, subject withdraws consent or is lost to follow-up). No AE stop date should be recorded. 
Fatal: The AE directly caused death. Record the date of death as the AE stop date. 
Abbreviation: AE, adverse event. 
 
8.3.4 Time Period and Frequency for Event Assessment and Follow-up 
AEs will be recorded from the time the ICF is signed until the end of the follow-up period. AEs 
will be assessed at each study visit, and subjects should be encouraged to contact the study site 
to report AEs that occur between scheduled visits. AEs that occur in the time period between 
informed consent and the first dose of study drug should be recorded but will not be 
considered TEAEs. If the AE occurs on the date of the first dose of study drug, the time of onset 
(before or after intake of study drug) will be captured.  
After the initial AE/SAE report, the Investigator is required to proactively follow each subject at 
subsequent visits/contacts. All AEs/SAEs will be followed until resolution, stabilization, the 
event has been shown to be unrelated to study treatment, or the subject is lost to follow-up (as 
defined in Section 7.3). 
8.3.5 Adverse Event Reporting 
The Investigator is to report all AEs, whether volunteered by the subject, discovered through 
questioning, or directly detected, that occur in the time period specified in Section 8.3.4 and 
according to classifications described in Section 8.3.3.  

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Non-serious AEs that don’t require immediate reporting are to be reported on the AE eCRF. 
SAEs and AESIs will receive special consideration in decisions about continuing, modifying, or 
suspending dosing/enrollment. The Investigator will notify the Sponsor within 1 day of 
awareness for immediate review (see Section 8.3.6). 
8.3.6 Serious Adverse Event Reporting 
Throughout the study, the Investigator is to report all SAEs, regardless of suspected causality, to 
the Sponsor within 24 hours of learning of its occurrence using the SAE Report Form in the EDC 
system. AESIs (see Section 8.3.8) will also be reported on the SAE Report Form in the EDC 
system and must be clearly differentiated from SAEs. Completion guidelines are provided in the 
Investigator Site File. The Investigator must assess and record the relationship of each event to 
study drug. Any SAE experienced after the follow-up period should be reported to the Sponsor 
only if the Investigator suspects a causal relationship to the study drug.  
Recurrent episodes, complications, or progression of the initial SAE, regardless of when they 
occur, must be reported as follow-up to the original episode within 24 hours of the Investigator 
receiving the follow-up information. Follow-up information will also be captured in the EDC 
system and should describe whether the event resolved or continues, if and how it was treated, 
and whether the subject continued or withdrew from study participation. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
SAE should be reported separately as a new event. 
The Sponsor will ensure that all suspected unexpected serious adverse reactions (SUSARs), 
determined based on the Reference Safety Information in the most recent version of the IB at 
the time of the event, will be reported to the competent authorities of all countries where the 
trial is performed and to all IRBs/ECs overseeing the conduct of the study, in accordance with 
FDA 21 CFR 312.32 and European Directive 2001/20/EC. These reports will be unblinded upon 
submission where required. 
8.3.7 Reporting of Pregnancy 
Any subject who becomes pregnant during the study will have study drug discontinued 
immediately and be withdrawn from the study. All pregnancies in female subjects or in the 
female partners of male subjects must be reported to the Sponsor within 24 hours of the site 
learning of the pregnancy. Information about pregnancies will be recorded on the Pregnancy 
Report Form and any follow-up information will be forwarded to the Sponsor. 
For any female subject who becomes pregnant while participating in this study, the Investigator 
will collect information about the pregnancy and follow up with the subject to determine the 
outcome of the pregnancy and the status of mother and child. 
Male subjects will be instructed to notify the site in the event that any female partner becomes 
pregnant. If any female partner of a male subject who received at least 1 dose of study drug 
becomes pregnant within 90 days of the male subject’s last dose of study drug, the Investigator 
will attempt to collect information about the pregnancy. The Investigator must obtain informed 
consent from the pregnant partner before collecting such information. The Investigator will also 

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attempt to follow up with the female partner to determine the outcome of the pregnancy and 
the status of mother and child.  
Generally, follow-up will not be required for longer than 6 to 8 weeks beyond the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 
Pregnancy in itself is not regarded as an AE. However, a pregnancy complication is an AE, and 
congenital abnormalities/birth defects or spontaneous miscarriages should be reported as 
SAEs. Elective termination of a pregnancy is not considered an AE. While the Investigator is not 
obligated to actively seek this information in former study subjects, he or she may learn of such 
an SAE through spontaneous reporting. 
8.3.8 Adverse Events of Special Interest 
AESIs must be monitored on an ongoing basis. These events will be reported with narratives, 
allowing for the collection of additional information, as warranted. The following may be 
considered AESIs for this study: 
• Significant liver chemistry changes that do not satisfy study drug stopping rules (see 
Section 7.1.1 and Section 13.2). Cases of Hy’s Law should be reported as SAEs.  
• Suicidality as indicated by Type 3, 4, or 5 ideation on the C-SSRS (see Section 7.1.3 
regarding study drug stopping criteria for suicidality and Section 8.2.6.1 regarding the 
C-SSRS). This safety finding will be reported as an AESI if it is not considered an SAE 
definition (e.g., resulting in hospitalization).   
• Depression or anxiety that is moderate or severe (CTCAE Grade 2 or higher), as assessed 
by the Investigator (see Section 7.1.4 regarding study drug stopping criteria for 
depression or anxiety). This will be reported as an AESI if it is not considered an SAE (e.g., 
resulting in hospitalization). 
• Adverse events of adrenal insufficiency will be reported on a separate Adrenal 
Insufficiency Form. Additionally, symptoms of adrenal insufficiency will be reported as 
SAE if they necessitate parental GC administration by a health care professional and two 
of the following criteria are met: hypotensive (systolic blood pressure <100 mmHg); 
nausea or vomiting; severe fatigue; documented hyponatremia, hyperkalemia, or 
hypoglycemia. If hospitalization was required or the event of adrenal insufficiency is 
deemed to be an important medical event, life-threatening, results in a persistent or 
significant disability/incapacity or death, it should also be reported as an SAE.   
o 
For SAEs of adrenal insufficiency, records from the office of health care provider, 
emergency facility or hospital the following information should be obtained as 
source documents to provide the following information:  
 
Was stress dosing employed prior to the adrenal insufficiency event? If yes, 
what were the GC dose and duration of dosing and the cause for stress dosing 
prior to seeking medical attention? 
 
What type, dose and route of parental GC was administered and the duration 
of administration? 

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 
What concomitant medications were administered? 
 
What clinical laboratory results are available? 
 
What AEs occurred? 
 
What was the duration of stay if admitted to the hospital? 
 
What was deemed to be the inciting factor leading to adrenal crisis?  
For non-SAEs of adrenal insufficiency, all symptoms and findings on physical examination, 
vital sign collection and/or laboratory assessments leading to the diagnosis of adrenal 
insufficiency will be collected. 
Adverse events or other conditions that lead to GC stress dosing should not be reported 
as AEs of adrenal insufficiency since the stress dosing is done to prevent, not treat, 
adrenal insufficiency. If an AE, such as an infection, results in GC stress dosing, the AE 
should be captured in the Adverse Event CRF. The following additional information will 
be collected in a patient diary during episodes of GC stress dosing: start and stop date, 
concomitant medications, cause for stress dosing (e.g., infection, strenuous exercise, 
emotional stress, pain, surgery) and concurrent AEs. Adverse events resulting in stress 
dosing will be reported on the Adverse Event CRF. 
8.4 Pharmacokinetic Assessments 
A plasma sample will be collected consistently by a qualified medical professional at 8 AM (± 1 
hour) for measurement of tildacerfont concentration at each study visit indicated in the 
Schedule of Treatment Period and Follow-up Activities. Samples will be collected after an 
overnight fast (nothing to eat after midnight) and before subjects take any morning dose of GC. 
Tildacerfont drug concentration will be determined by a bioanalytical laboratory using validated 
methods. 
9 STATISTICAL CONSIDERATIONS 
Statistical considerations are summarized here. A detailed description of statistical methods will 
be provided in the Statistical Analysis Plan (SAP). 
9.1 Statistical Hypotheses 
Efficacy endpoints at Week 24 will be evaluated using the following hypothesis-testing schema: 
The tildacerfont treatment group will be compared with the placebo treatment group. The null 
hypothesis is that there is no difference in the mean change from baseline to Week 24 in GC 
dose in HCe. The alternative hypothesis will be that there is a difference between the treatment 
groups. 
Efficacy endpoints after 52 weeks of tildacerfont treatment will be evaluated using the 
following hypothesis-testing schema: The Week 52 value will be compared with the baseline 
value. The null hypothesis will be that there is no difference between the Week 52 and baseline 
values. The alternative hypothesis will be that there is a difference. 

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9.2 Sample Size Determination 
A sample size of N=45 subjects per group will provide at least 90% power to detect a between 
group difference in the proportion of subjects with at least a 5 mg/day HCe reduction from 
baseline in GC dose at Week 24 with A4 ≤ULN of at least 33%, assuming the placebo group has a 
response of 30% and the two-sided type I error is 0.05. 
9.3 Populations for Analyses  
The ITT Population will include all randomized subjects. The ITT Population will be the primary 
analysis set for analyzing demographics, baseline characteristics, and efficacy. 
The mITT Population will include all randomized subjects who receive at least 1 dose of study 
drug (tildacerfont or placebo). 
The PP Population will include all randomized subjects who have no major protocol deviations 
that would affect the analysis of efficacy data, defined as the following: 
• Subject did not meet efficacy-based inclusion criteria (hormone levels, GC regimen) 
• Subject met efficacy-based exclusion criteria (inadequate adherence to GC regimen, 
night-shift worker) 
• Subject’s adherence to study drug or the subject-specific GC regimen was <80% over the 
Treatment Period 
Additional criteria may be specified in the SAP. The PP Population will be identified prior to 
database lock. 
The mITT and/or PP Populations may be used for secondary analyses of the primary and 
secondary efficacy endpoints. 
The Safety Population will include all subjects who receive at least 1 dose of study drug 
(tildacerfont or placebo), summarized by actual drug received. The Safety Population will be the 
primary analysis set for general and safety analyses. 
The PK Population will include all subjects who receive at least 1 dose of tildacerfont and have 
at least 1 evaluable PK sample.  
9.4 Statistical Analyses 
9.4.1 General Considerations 
All individual data will be listed as measured. All statistical summaries and analyses will be 
performed using SAS software (SAS Institute Inc, Cary, North Carolina, USA). 
Unless otherwise specified, continuous adrenal biomarkers (A4, 17-OHP, ACTH) will be 
summarized using a 11-point descriptive statistics (i.e., n, mean, standard deviation [SD], 
median, 25% quartile [Q1], 75% quartile [Q3], minimum, maximum, geometric mean, geometric 
coefficient of variance [CV%], 95% confidence interval [CI] for geometric mean [including 
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be summarized using an 8-point descriptive summary (n, mean, SD, median, Q1, Q3, minimum, 
and maximum). 
Categorical data will be summarized using the frequency of events and percentage of total 
events. 
Data will be presented by treatment group. Changes in primary, secondary, and exploratory 
endpoints will be analyzed over time, with change from baseline summarized for each 
post-baseline time point measured. 
All efficacy analyses will be conducted using the ITT Population as the primary analysis set and 
using a 2-sided alpha of 0.05.  
For missing data, a retrieved dropout approach will be used in which missing endpoint data for 
subjects who discontinued early will be imputed using data collected from subjects after 
discontinuation of study drug. 
Secondary and exploratory analyses that evaluate the change from baseline in all subjects after 
52 weeks of tildacerfont treatment will combine the subjects randomized to tildacerfont Day 1 
to Week 52 data with subjects randomized to placebo tildacerfont treatment data from Week 
24 to Week 76. 
Any changes to the protocol-specified analyses will be pre-specified in the SAP prior to 
database lock. 
9.4.2 Analysis of the Primary Efficacy Endpoint 
The primary efficacy endpoint is the absolute change from baseline in GC dose in HCe at 
Week 24. The null hypothesis is that there is no difference in the mean change from baseline to 
Week 24 in GC dose in HCe. The alternative hypothesis will be that there is a difference 
between the treatment groups. The ITT Population will be used for the primary analysis of the 
primary efficacy endpoint. The analysis of the primary endpoint will be summarized using an 
exact score test through logistic regression using the randomization strata and treatment group 
in the model specification. Missing values for proportion endpoints will not be imputed and will 
be assumed to be failures. Additional covariates may be specified in the SAP. 
9.4.3 Analysis of the Secondary Efficacy Endpoints 
The analysis population for the Secondary Efficacy Endpoint analyses is the ITT analysis set, 
including all classic CAH subjects who were randomized into the study. 
 
 

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Table 7. 
Secondary Efficacy Endpoints 
Objectives 
Endpoints 
Analysis 
Secondary Efficacy 
 
To evaluate the effect of tildacerfont in 
reducing GC use to near-physiologic levels 
while maintaining androgen control in 
subjects with CAH 
2.1 
Proportion of subjects with GC dose 
≤11 mg/m2/day in HCe and A4 ≤ 1.2x 
baseline or A4 ≤ ULN at Week 24 
Primary 
Analysis 
To evaluate the effect of tildacerfont in 
reducing GC use to near-physiologic levels 
while maintaining androgen control in 
subjects with CAH 
2.2 
Proportion of subjects with baseline GC 
dose ≤ 35mg HCe who achieve GC dose 
≤11 mg/m2/day in HCe and A4 ≤ 1.2x 
baseline or ≤ ULN at Week 24 
Primary 
Analysis 
To evaluate the effect of tildacerfont in 
reducing cardiovascular risk in subjects 
with CAH  
2.3 
Proportion of subjects with 
improvement in at least one 
cardiovascular risk factor at Week 24 
Primary 
Analysis 
 
For Secondary Efficacy Endpoint 2.1 the null hypothesis is that the difference between 
randomized treatment groups in the proportion of subjects achieving GC dose ≤11 mg/m2/day 
in HCe and A4 ≤ 1.2x baseline or A4 ≤ ULN at Week 24 is equal to zero. The alternative 
hypothesis is that the difference is not equal to zero. 
For Secondary Efficacy Endpoint 2.2 the null hypothesis is that in the subset of subjects with a 
baseline GC dose ≤ 35mg the difference between randomized treatment groups in the 
proportion of subjects achieving GC dose ≤11 mg/m2/day in HCe and A4 ≤ 1.2x baseline or A4 ≤ 
ULN at Week 24 is equal to zero. The alternative hypothesis is that the difference is not equal to 
zero. 
Secondary Efficacy Endpoint 2.3 is the proportion of classic CAH subjects who were randomized 
into the study who improve at least one baseline CV risk factor at 24 weeks from 
randomization. This proportion is calculated for each treatment group (e.g., placebo, 
tildacerfont) as the number of subjects at Week 24 who had at least one CV risk factor at 
baseline (i.e subjects without any CV risk factors will not be included in the analysis) and no 
longer meets one or more of the baselines CV risk factors at Week 24, divided by the total 
number of subjects in the ITT analysis who were randomized to that specific treatment and had 
at least one CV risk factor at baseline.   
Additional details on secondary endpoints and analysis may be specified in the SAP.  
9.4.4 Analysis of the Exploratory Efficacy Endpoints 
The analysis population for Exploratory Efficacy Endpoint analyses is the ITT analysis set, 
including all classic CAH subjects who were randomized into the study.  Detailed information 
around the analysis of the exploratory endpoints listed in Section 3 is provided in the Statistical 
Analysis Plan (SAP) Version 1.0. 

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9.4.5 Analysis of the Exploratory Efficacy Endpoints in the Optional Extension Period 
Analysis of the Exploratory Efficacy Endpoints in the Optional Extension Period is not included in 
the SAP Version 1.0, as it will be described in a separate SAP not yet developed and, therefore, 
is not addressed herein. 
9.4.6 Analysis Evaluation Periods 
The primary evaluation period will evaluate baseline to Week 24 comparing the tildacerfont 
group to the placebo group. Select endpoints will also be evaluated using the following periods: 
• After 52 weeks on tildacerfont treatment (Week 52 for the tildacerfont group and Week 
76 for the placebo group compared to baseline) 
• After approximately 24 weeks on tildacerfont treatment (Week 24 for the tildacerfont 
group and Week 52 for the placebo group compared to Week 24 for the placebo group)  
• After 76 weeks on tildacerfont treatment (Week 76 for the tildacerfont group compared 
to baseline) 
• From baseline to Week 76 
• From baseline to EOT   
The baseline for each evaluation period will be defined in the SAP. 
9.4.7 Safety Analyses 
The Safety Population will be used for all safety analyses. All safety data will be presented in 
listings. Summary tables will be provided for concomitant medications, AEs, hematology and 
chemistry laboratory results, vital signs, and ECG findings. Safety data will be summarized by 
treatment group using frequency of event or descriptive statistics, as appropriate.   
9.4.7.1 Extent of Exposure 
Dosing information for individual subjects will be listed. Using dosing data, estimates of 
exposure to tildacerfont will be summarized. Dose discontinuations and reasons for study drug 
discontinuation will be listed and summarized. 
9.4.7.2 Concomitant Medication Data 
Concomitant medications used before and during the Treatment Period will be summarized. 
9.4.7.3 Adverse Event Data 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). AE 
summaries will be presented by System Organ Class, Preferred Term, severity, and frequency 
and percentage of subjects reporting each observed event.  
AEs that occur before the first dose of study drug will be distinguished from TEAEs (defined in 
Section 8.3.1). All AEs and TEAEs will be listed by subject. The frequency of subjects who 
experience TEAEs will be summarized overall and by treatment group. TEAEs will also be 
summarized by relationship to study drug and severity. 
Listings will be provided for subjects who experienced an SAE or discontinued study 
drug/withdrew from the study because of an AE. 

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9.4.7.4 Laboratory Data 
Clinical laboratory test results will be listed by subject. Reference ranges provided by the 
laboratory for each parameter will be used to evaluate the clinical significance of laboratory 
test results. Values outside the relevant reference range will be flagged in the listings. Abnormal 
clinical laboratory test results will be listed in a separate listing.  
Laboratory data will be summarized in terms of observed values, changes from baseline, values 
relative to normal ranges, and changes from baseline relative to normal ranges. Subjects 
meeting specific thresholds for laboratory data will also be summarized as specified in the SAP. 
P-values for change from baseline and change from placebo or differences in proportions 
meeting specific thresholds will be derived using the appropriate statistical test as specified in 
the SAP. 
Additional subgroup analyses based on baseline laboratory data [elevated, normal] will be 
specified in the SAP. 
9.4.7.5 Vital Signs Data 
Vital signs data will be summarized within appropriately defined categories in terms of 
observed values (by time point), changes from baseline (by time point), and counts and 
percentages. Subjects meeting specific thresholds for vital sign data will also be summarized as 
specified the SAP. 
P-values for change from baseline and change from placebo will be derived using t-tests as 
specified in the SAP. 
9.4.7.6 ECG Data 
The QTcF, PR interval, QT interval, QRS duration, and heart rate from standard digital ECGs will 
be summarized within appropriately defined categories in terms of observed values, changes 
from baseline, and counts and percentages. 
9.4.7.7 Psychiatric Evaluations 
C-SSRS and HADS data will be listed. 
9.4.8 Baseline Descriptive Statistics 
Demographics and baseline characteristics (including age, sex, race, ethnicity, height, weight, 
and BMI) will be summarized for the ITT Population. 
Biomarkers at screening and at baseline will be summarized for the Safety Population. 
Baseline clinical characteristics and history will be summarized. 
9.4.9 Subgroup Analyses 
The following pre-defined subgroups will be analyzed: 
• Baseline GC formulation [HC mono therapy, 
prednisolone/prednisone/methylprednisolone monotherapy, combination therapy] 
• Baseline HCe dose [<40 mg/day, ≥40 mg/day], [<35, ≥35 mg/day] 

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• Sex [male, female] 
• A4 ULN at baseline [≤ULN, >ULN] 
The subgroups will be used in supportive analysis of the primary endpoint and secondary 
endpoints, as applicable. Any additional subgroup analyses will be specified in the SAP. 
9.5 Primary and Final Analyses 
The primary efficacy analysis is planned after all subjects have completed Week 24, at the end 
of the double-blind treatment period.  
The final analyses will occur after the last subject has completed the follow-up visit after 
Week 76 or if the study is discontinued by the Sponsor.   
A clinical study report will be completed for the study with results up to Week 76/80. An 
addendum to the clinical study report will be completed to summarize results from Week 76 up 
to Week 316/320.  
9.6 Multiplicity Control 
The primary endpoint (absolute change from baseline in GC dose in HCe at Week 24), 
secondary endpoints (proportion of subjects with GC dose ≤11 mg/m2/day in HCe and A4 ≤ 1.2x 
baseline or A4 ≤ ULN at Week 24, proportion of subjects with baseline GC dose ≤ 35mg HCe 
who achieve GC dose ≤11 mg/m2/day in HCe and A4 ≤ 1.2x baseline or ≤ ULN at Week 24, and 
proportion of subjects with improvement in at least one cardiovascular risk factor at Week 24) 
 will be reported under strict control of the Type I error using a multiplicity algorithm which will 
be detailed in the SAP. 
9.7 Data Monitoring Committee 
Refer to Section 10.6 (Safety Oversight) for information on the Data and Safety Monitoring 
Board (DSMB). 
10 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1 Informed Consent 
For each study subject, written informed consent must be obtained before the subject may be 
enrolled into the study and before any protocol-specified procedures may be conducted. The 
signing of the ICF must also be witnessed where required by law or regulation. The ICF will also 
be signed and dated by the Investigator and/or designee. The process of obtaining informed 
consent should be documented in the subject source documents. Each study subject will be 
provided a copy of his/her signed and dated ICF. 

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As part of the informed consent process, the Investigator or designee must explain to each 
subject the purpose and procedures of the study and the possible risks involved. Subjects 
should be informed that they may withdraw from the study at any time. They should be 
informed that their data will be stored in a confidential manner, in accordance with local data 
protection laws. They should be informed that their records may be viewed by the Sponsor or 
its designee and by regulatory authorities. The ICF and any other materials provided to subjects 
or investigative staff must use vocabulary and language that can be readily understood. 
The Investigator must use the most current IRB/EC-approved ICF. Any changes to the proposed 
ICF suggested by the Investigator must be agreed to by the Sponsor before submission to the 
IRB/EC, and a copy of the approved version must be provided to the Sponsor after IRB/EC 
approval. 
10.2 Study Discontinuation and Closure 
Premature study termination may occur because of a regulatory authority decision, change in 
opinion of the IRB/EC, drug safety problems, or Sponsor decision. In addition, the Sponsor 
retains the right to discontinue development of tildacerfont at any time. 
Premature study termination will occur if the benefit/risk profile becomes unfavorable because 
of a new risk or toxicity that makes the study unjustifiable and/or if new scientific evidence that 
could affect subject safety becomes available during the study (e.g., from other clinical trials). 
When AEs occur, the Sponsor will evaluate the severity, duration, frequency, and nature of the 
AEs relative to the existing safety profile of tildacerfont to determine whether there are any 
substantial changes in risk-benefit considerations. 
If this study is prematurely terminated or discontinued, the Sponsor will promptly notify the 
Investigator. After notification, the Investigator must contact all participating subjects within 
7 business days and have them complete final visit safety assessments (abbreviated early 
termination visits per sponsor guidance). As directed by the Sponsor, all study materials must 
be collected and all eCRFs completed to the greatest extent possible. 
10.3 Confidentiality and Privacy 
All information obtained during the conduct of this study will be regarded as confidential, and 
written permission from the Sponsor is required before disclosing any information related to 
this study. 
All processing of personal data at the site and by the Sponsor must be carried out in accordance 
with any legislation concerning the protection of personal data. The Investigator must ensure 
that the subject’s privacy is maintained. The Sponsor will assign each subject a unique 
identifier. Any subject records or datasets that are transferred from the site to the Sponsor will 
contain this identifier only; subject names or any information which would make the subject 
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10.4 Future Use of Stored Specimens and Data 
Any biological samples collected for this study may be stored for up to 5 years after the last 
study visit of the last subject in the study. These samples may be used in the future for the 
discovery, analysis, verification, and/or validation of other biomarkers or tests related to CAH. 
Samples will not directly identify subjects on the label. Consent from subjects to store the 
samples will be requested, and subjects may elect to opt out of prolonged sample storage at 
any time by indicating so in the ICF. A record of the final disposition of subject samples will be 
maintained by the Sponsor. 
10.5 Key Roles and Study Governance 
10.5.1 Sponsor 
The Sponsor or its designee will provide protocol training to investigative staff as appropriate. 
Clinical monitors will conduct site visits as needed to ensure study procedures are conducted in 
accordance with the protocol, GCP, and all applicable regulatory requirements. Throughout the 
study, a Sponsor representative will be available to address any issues that may arise. 
A list of study contacts will be provided in a separate document. 
10.5.2 Investigators 
Before study start, Investigators are required to sign an Investigator Protocol Agreement Page 
confirming their agreement to conduct the study in accordance with the protocol. It is the 
responsibility of the Investigator to ensure that all investigative personnel are fully informed of 
all relevant aspects of the study, including detailed knowledge of and training in all procedures 
to be followed. 
10.5.3 Institutional Review Board/Ethics Committee 
The protocol and ICF must be reviewed and approved by a properly constituted IRB/EC before 
study start. A signed and dated statement that the protocol and ICF have been approved by the 
IRB/EC must be given to the Sponsor before study initiation. 
10.6 Safety Oversight 
An external, independent DSMB will review the available safety data from this study 
periodically and provide recommendations to the Sponsor if needed. The DSMB will be 
composed of independent reviewers who are not involved in the conduct of the study and will 
include at least 1 endocrinologist, 1 hepatologist, and 1 statistician. The DSMB will review both 
blinded and unblinded safety data and advise the Sponsor of any trends or safety issues that 
may impact the study or study subjects. The Sponsor will make final decisions concerning the 
continuation, modification, or termination of the trial. The DSMB’s scope of responsibility, 
membership, confidentiality, and procedures will be established in a separate DSMB charter. 

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10.7 Clinical Monitoring 
Before study initiation, at a site initiation visit or at an Investigator’s meeting, a Sponsor 
representative will review the protocol and eCRFs with the Investigators and their staff. During 
the study, the field monitor will visit the site regularly to check the completeness of subject 
records, the accuracy of entries on the eCRFs, adherence to the protocol and to GCP, the 
progress of enrollment, and that study drug is being stored, dispensed, and accounted for 
according to specifications. Key study personnel must be available to assist the field monitor 
during these visits. See Section 11.4 for information on monitoring visits in the context of 
COVID-19 or other logistical challenges. 
The Investigator must give the monitor access to all relevant source documents to confirm their 
consistency with eCRF entries. The Sponsor’s monitoring standards require full verification for 
the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and recording of data that will be used for all primary and safety 
variables. Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan. No information in source documents about the 
identity of subjects will be disclosed. 
Refer to Section 10.9.1 for information on eCRFs and source documents. 
10.8 Quality Assurance and Quality Control 
In addition to routine clinical monitoring by the Sponsor, the study may be evaluated by 
Sponsor internal auditors and government inspectors, who must be allowed access to case 
report forms, source documents, and other study files. Sponsor audit reports will be kept 
confidential. The Investigator must notify the Sponsor promptly of any inspections scheduled by 
regulatory authorities and promptly forward copies of inspection reports to the Sponsor. 
10.9 Data Handling and Record Keeping 
10.9.1 Data Collection and Management Responsibilities 
An eCRF must be completed for each enrolled subject. Completed original case report forms are 
the sole property of the Sponsor and should not be made available in any form to third parties, 
except for authorized representatives of the Sponsor or appropriate regulatory authorities, 
without written permission from the Sponsor. It is the Investigator's responsibility to ensure 
completion of and to review and approve all eCRFs. Case report forms must be signed by the 
Investigator. These signatures serve to attest that the information contained on the eCRFs is 
true. At all times, the Investigator has final personal responsibility for the accuracy and 
authenticity of all clinical and laboratory data entered on the eCRFs. 
For each subject in the study, the Investigator must maintain source documents at the trial site 
consisting of the original ICF signed by the subject (a copy of which is given to the subject), the 
hospital/clinic or physician medical records/chart for the subject, case and visit notes, 
laboratory data, ECGs, and the results of any other tests or assessments. All information on 

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eCRFs must be traceable to these source documents in the subject's file. In some cases, certain 
items entered on the eCRF may not require a separate written record, and the eCRF itself may 
serve as the source document. Such items will be prospectively defined between the Sponsor 
and Investigator before study start. 
10.9.2 Study Records Retention 
To enable evaluations and/or audits from regulatory authorities or the Sponsor or its designees, 
the Investigator agrees to keep records that include the identity of all subjects (sufficient 
information to link records [eg, eCRFs and hospital records]), all original signed ICFs, copies of 
all eCRFs, SAE forms, source documents, and treatment disposition. The records should be 
retained by the Investigator for as long as ICH, local regulations, or the Clinical Study Agreement 
dictates, whichever is longer.   
If the Investigator relocates, retires, or for any reason withdraws from the trial, the Sponsor 
should be prospectively notified, and the trial records must be transferred to an acceptable 
designee, such as another Investigator, another institution, or the Sponsor. The Investigator 
must obtain the Sponsor’s written permission before disposing of any records, even if retention 
requirements have been met. 
10.10 Protocol Deviations 
If a protocol deviation occurs that affects a subject’s safety, the Sponsor must be informed as 
soon as possible. 
If a protocol deviation is implemented to eliminate an immediate hazard before a protocol 
amendment can be submitted for IRB/EC review and approval/favorable opinion (see 
Section 10.12), the deviation will be reported as soon as possible to 1) the IRB/EC for review 
and approval/favorable opinion, 2) the Sponsor, and 3) regulatory authority(ies), if required by 
local regulations. Documentation of approval signed by the chairperson or designee of the 
IRB(s)/EC(s) must be sent to the Sponsor. 
Protocol deviations will be included in the Clinical Study Report. 
10.11 Publication and Data Sharing Policy 
Any manuscripts for publication based on data from this study must be submitted to the 
Sponsor for review and comment before submission to a publisher. This requirement should 
not be construed as a means of restricting publication but is intended solely to ensure 
concurrence regarding data, evaluations, and conclusions and to provide an opportunity for the 
Sponsor to share with the Investigator any new or unpublished information of which the 
Investigator may be unaware. 
10.12 Amendments 
The study shall be conducted as described in this protocol. All revisions to the protocol must be 
discussed with and prepared by the Sponsor. The Investigator should not implement any 

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change to the protocol without a prior protocol amendment that has been reviewed by and 
received documented approval/favorable opinion from the IRB/EC, except where necessary to 
eliminate an immediate hazard(s) to study subjects. Any significant protocol deviation must be 
documented (see Section 10.10). 
If a protocol amendment is an Administrative Letter, Investigators must inform their 
IRB(s)/EC(s).   
If a protocol amendment substantially alters the study design or increases the potential risk to 
the subject, 1) the consent form must be revised and submitted to the IRB(s)/EC(s) for review 
and approval/favorable opinion, 2) the revised consent form must be used to obtain re-consent 
from subjects currently enrolled in the study if they are affected by the amendment, and 3) the 
revised consent form must be used to obtain consent from any new subjects prior to 
enrollment. 
11 COVID-19 RISK MITIGATION 
11.1 Risk/Benefit Assessment in the Context of COVID-19 or Other Logistical 
Challenges 
In general, the CAH patient population possesses a higher-than-average risk of serious 
complications from any infection or febrile illness because such conditions can lead to adrenal 
crises in CAH patients if they are not managed appropriately. The emergence of COVID-19 
increases the overall infection risk in affected communities, including CAH patients who reside 
in those communities.  
Participation in a clinical trial provides subjects with increased access to healthcare resources 
and reinforcement of appropriate practices during a time of increased infection risk. Study 
participants will have access to healthcare professionals on a more intensive schedule than in 
normal clinical practice for the management of CAH. The standard of care for a CAH patient 
with an infection or febrile illness is to temporarily increase the patient’s GC dose to 
accommodate the additional stress and prevent an adrenal crisis (see Section 4.1.4.4). The 
Sponsor will provide HC for stress dosing to all subjects during the study, starting at the 
beginning of the Treatment Period. Thus, study participants will have immediate access to 
supplemental GC in the event of COVID-19 or other infection. 
The potential risks of a subject receiving tildacerfont and concomitantly developing COVID-19 
have been considered. Tildacerfont is not expected to increase the risk of contracting a viral 
illness such as COVID-19 or to increase the risk of severe illness with COVID-19. 
11.2 Study Conduct in the Context of COVID-19 or Other Logistical Challenges 
All study activities will be conducted in accordance with relevant local, regional, and national 
guidance around COVID-19. 

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If in-clinic visits are no longer possible, in-clinic–only activities (eg, scrotal ultrasound, DXA) will 
not be conducted. After a site reopens or the shelter-in-place order is lifted, attempts should be 
made to conduct any missed in-clinic activities via an unscheduled visit. 
If a subject or a member of the subject’s household is suspected or confirmed to have COVID-
19, the Investigator must consult with the Medical Monitor to determine the best course of 
action. In this situation, only telemedicine activities can proceed. If the subject misses 
scheduled study activities during this time, an unscheduled visit will be conducted once the 
subject or member of his/her household no longer has suspected or confirmed COVID-19. At a 
minimum, safety labs must be performed at the unscheduled visit. Subjects cannot go more 
than 3 months or 2 consecutive scheduled visits without labs being drawn.  
In Italy and Poland, if necessary due to COVID-19 restrictions, clinical labs may be conducted 
as available at a local laboratory instead of a central laboratory.  
To ensure the quality of data and protection of subjects, remote source data verification may 
be used, if necessary due to COVID-19 restrictions. The Sponsor will determine the extent 
and nature of remote source data verification needed.  
In Italy and Poland, study drug may be shipped to subjects if necessary due to COVID-19 
restrictions. 
 
For scenarios not delineated here or for further clarification, the Investigator should consult 
with the Medical Monitor to determine the best course of action. 
11.2.1 Mode of Study Visits in the Context of COVID-19 or Other Logistical Challenges 
All efforts should be made to conduct visits in the clinic as per the Principal Investigator’s 
clinical judgement or patient’s preference. Since the COVID-19 pandemic is expected to 
continue during the conduct of this trial, study visits can be adapted into a combination of in-
clinic and telemedicine activities, with optional at-home visits, to mitigate the risk of COVID-19 
infection associated with study participation and to accommodate local and individual 
circumstances while maintaining participant access to healthcare resources. 
Some of the clinic activities of the Screening Visit may be conducted remotely (at the subject’s 
home) if approved by the site’s IRB/EC. 
In Germany, the Screening Visit will be performed in the clinic. After the Screening Visit, 
study visits should continue in-clinic, however in the event of COVID-driven challenges, at-
home and telemedicine visits can be used to support patient data collection. 
In Italy, Poland, all visits will be performed in the clinic. If necessary due to COVID-19 
restrictions, the clinic visits may be conducted remotely (via telemedicine) if approved by the 
site’s IRB/EC. 
 

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For post-Screening activities, the investigational site will decide how to conduct these activities 
if alternatives are necessary due to COVID-19 restrictions, taking into consideration subject 
preference and the relevant local public health guidelines and striving to maintain a consistent 
mode for each activity throughout the study. The EDC system will capture the mode by which 
data are collected for each visit/activity.  
If home visits are conducted, the qualified medical professionals who will perform the study’s 
home visits are defined as individuals who meet national/local licensing requirements needed 
to perform the procedures required at the home visits. Their national/local licensure will be 
verified, and they will complete training on the study protocol and GCP. If the medical 
professional does not meet the national/local licensing requirements needed to perform the 
optional home visit activities (physical examination), the Investigator or Investigator-delegated 
study personnel must complete these activities for each visit. 
11.3 Subject Disposition in the Context of COVID-19 or Other Logistical Challenges 
If a subject develops an active COVID-19 infection (whether confirmed or suspected) during the 
course of the study, the Investigator will work with the subject and the Medical Monitor to 
determine the best course of action, taking into consideration the AE and SAE guidelines in 
Section 8.3 and the individual stopping criteria for clinically significant AEs in Section 7.1.7. 
If study drug is discontinued or a subject is withdrawn from the study because of COVID-19, the 
reason for early termination will be captured in the EDC system as such. 
11.4 Regulatory and Study Oversight Considerations in the Context of COVID-19 or 
Other Logistical Challenges 
If planned onsite monitoring visits are not possible because of COVID-19, remote monitoring 
may occur, if allowed by local and federal legal and regulatory requirements. If source data are 
collected at a home health visit, those source documents will be maintained with the home 
healthcare staff until they can be transferred to the trial site. If a protocol deviation is the result 
of COVID-19–related circumstances, this information should be captured. 

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12 REFERENCES 
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cohort study of 203 patients. J Clin Endocrinol Metab. 2010;95(11):5110-5121. 
Auchus RJ. Management considerations for the adult with congenital adrenal hyperplasia. Mol 
Cell Endocrinol. 2015;408:190-197. 
Aulinas A, Webb SM. Health-related quality of life in primary and secondary adrenal 
insufficiency. Expert Rev Pharmacoecon Outcomes Res. 2014;14(6):873-888. 
Bachelot A, Chakthoura Z, Rouxel A, et al. Classical forms of congenital adrenal hyperplasia due 
to 21-hydroxylase deficiency in adults. Horm Res. 2008;69:203-211. 
Bachelot A, Golmard JL, Dulon J, et al. Determining clinical and biological indicators for health 
outcomes in adult patients with childhood onset of congenital adrenal hyperplasia. Eur J 
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Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: 
an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2016;101(2):364-389. 
Browne WV, Hindmarsh PC, Pasterski V, et al. Working memory performance is reduced in 
children with congenital adrenal hyperplasia. Horm Behav. 2015;67:83-88. 
Chihaoui M, Kanoun F, Chaker F, et al. Testicular adrenal rest tumours in young adult males 
with congenital adrenal hyperplasia: prevalence and impact on testicular function. Andrologia. 
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Claahsen-van der Grinten HL, Dehzad F, Kamphuis-van Ulzen K, de Korte CL. Increased 
prevalence of testicular adrenal rest tumours during adolescence in congenital adrenal 
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Delfino M, Elia J, Imbrogno N, et al. Testicular adrenal rest tumors in patients with congenital 
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El-Maouche D, Hargreaves CJ, Sinaii N, Mallappa A, Veeraraghavan P, Merke DP. Longitudinal 
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Giebels V, Repping-Wuts H, Bleijenberg G, et al. Severe fatigue in patients with adrenal 
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Mental Health Administration; 1976. 
Han TS, Stimson RH, Rees DA, et al. Glucocorticoid treatment regimen and health outcomes in 
adults with congenital adrenal hyperplasia. Clin Endocrinol (Oxf). 2013;78(2):197-203. 
Han TS, Walker BR, Arlt W, et al. Treatment and health outcomes in adults with congenital 
adrenal hyperplasia. Nat Rev Endocrinol. 2014;10:115-124. 
Hummel SR, Sadler S, Whitaker MJ, Ara RM, Dixon S, Ross RJ. A model for measuring the health 
burden of classic congenital adrenal hyperplasia in adults. Clin Endocrinol (Oxf). 2016;85(3):361-
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Lukert B. Editorial: Glucocorticoid replacement—How much is enough? J Clin Endocrinol Metab. 
2006;91(3):793-794. 
Malouf MA, Inman AG, Carr AG, Franco J, Brooks LM. Health-related quality of life, mental 
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“growth toxic” glucocorticoid. Int J Pediatr Endocrinol. 2010;2010:569680. 
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White PC and Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. 
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13 APPENDICES 
13.1 Appendix of Prohibited Concomitant Medications 
Refer to Section 6.5.1 for more information on prohibited concomitant medications. 
Because of their potential impact on the metabolism of tildacerfont, strong CYP3A4 inducers 
and inhibitors are prohibited. Subjects will be advised to refrain from consumption of 
grapefruit, grapefruit juice, or any fruits that are known to be strong CYP3A4 inhibitors from 
1 day before the first dose of study drug until after the final dose. 
In addition, drugs that are sensitive substrates or narrow-therapeutic-range substrates of 
CYP3A4 and/or BCRP must be avoided. Sensitive substrates or narrow-therapeutic-range 
substrates of BCRP that are not also metabolized by CYP3A4 and that can be administered QD 
in the morning (separated by approximately 10 hours from evening administration of study 
drug) may be permitted with monitoring for safety. 
Ethinyl estradiol is a CYP3A4 and BCRP substrate, and tildacerfont may increase the level of 
ethinyl estradiol by <1.25-fold. With ethinyl estradiol doses ≤35 µg, exposure to ethinyl 
estradiol is unlikely to reach the threshold associated with increased thromboembolic or 
cardiovascular risk that is observed with higher-dose ethinyl estradiol formulations. Thus, any 
hormonal contraception containing ethinyl estradiol used by female subjects must contain 
≤35 µg ethinyl estradiol, is permitted only for subjects who would not be considered at high risk 
for thromboembolic or cardiovascular complications with estrogen use, and must be used 
simultaneously with a backup method of contraception according to Section 5.2.5.2. Dosing of 
oral formulations of hormonal contraception containing ethinyl estradiol should be offset by 
approximately 10 hours from the evening dose of study drug. 
The following is a non-exhaustive list of medications that are prohibited because of their 
potential for metabolic interactions with tildacerfont. This list is intended to show more 
commonly encountered drugs that subjects may be taking at screening. Any drugs of concern 
should be discussed with the Medical Monitor. 
alfentanil 
darifenacin 
itraconazole 
phenobarbital 
simvastatin 
apixaban 
diltiazem 
ketoconazole 
phenytoin 
St John's wort 
atorvastatin 
elagolix 
lesinurad 
posaconazole 
teneligliptin 
avanafil 
eletriptan 
loperamide 
quetiapine 
ticagrelor 
avasimibe 
ethinyl estradiol 
(>35 mg) 
lovastatin 
repaglinide 
triazolam 
buspirone 
felodipine 
mibefradil 
rifampin 
vardenafil 
carbamazepine 
fluconazole 
midazolam 
rifapentine 
voriconazole 
cenobamate 
glyburide 
nefazodone 
rivaroxaban 
 
ciprofloxacin 
isavuconazole 
oseltamivir 
sildenafil 
 

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Many oncology drugs and medications used to treat the hepatitis C virus and HIV are strong 
inhibitors of CYP3A4 but are not listed above simply because individuals with active cancer, 
hepatitis C, and/or HIV are excluded from this study. 
13.2 Appendix of Liver Safety 
Liver chemistry stopping criteria are presented in Section 7.1.1. 
13.2.1 Suggested Actions, Follow-up Assessments, and Monitoring When Liver Chemistry 
Stopping Criteria Are Met 
13.2.1.1 Actions 
• Immediately discontinue study drug. 
• Within 24 hours, report the event to the Sponsor or designated contract research 
organization and complete the AE eCRF (indicating that it is an AESI). 
• If the event also meets the criteria for an SAE (see Table 3), complete the SAE fields in the 
eCRF. 
• Request list of any medications taken in last 48 hours. Specifically question about 
medications that are known to increase liver enzymes, such as aspirin, acetaminophen, 
ibuprofen, naproxen, diclofenac, phenylbutazone, and any antibiotics. 
• Perform liver chemistry follow-up assessments (see Section 13.2.1.2).   
• Monitor the participant until liver chemistry test abnormalities resolve, stabilize, or return 
to baseline (see Section 13.2.1.3). 
• If restart/rechallenge is not granted, permanently discontinue study drug and continue 
participant in the study for any protocol-specified follow-up assessments. 
13.2.1.2 Follow-up Assessments 
• Perform viral hepatitis serology: hepatitis A immunoglobulin M (IgM) antibody, hepatitis B 
surface antigen (HBsAg) and hepatitis B core antibody (HBcAb), hepatitis C RNA, 
cytomegalovirus IgM antibody, Epstein-Barr viral capsid antigen IgM antibody (or, if 
unavailable, heterophile antibody or monospot testing), and hepatitis E IgM antibody. 
• Obtain blood sample for PK analysis. Record on the eCRF the date/time of the PK blood 
sample draw and the date/time of the last dose of study drug before the blood sample 
draw. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. Instructions for sample handling and shipping will be provided in the 
laboratory manual from the applicable central laboratory. 
• Measure serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH). 
• Obtain complete blood count with differential to assess eosinophilia. 
• Record the appearance or worsening of clinical symptoms of liver injury or hypersensitivity 
on the AE report form. 

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• Record use of concomitant medications (including acetaminophen, herbal remedies, and 
other OTC medications) on the concomitant medications eCRF. 
• Record alcohol use in EDC according to eCRF completion guidelines. 
For a possible Hy’s Law case (ALT ≥3x ULN AND total bilirubin ≥2x ULN or INR >1.5): 
• Fractionate bilirubin, if total bilirubin is ≥2x ULN. 
• Measure anti-nuclear antibody, anti–smooth muscle antibody, type 1 anti-liver kidney 
microsomal antibodies, and quantitative total immunoglobulin G (IgG) or gamma 
globulins. 
• Perform serum acetaminophen adduct high-performance liquid chromatography (HPLC) 
assay (quantifies potential acetaminophen contribution to liver injury) in subjects with 
definite or likely acetaminophen use in the preceding week. 
• Perform liver imaging (ultrasound, magnetic resonance, or computerized tomography) of 
complete liver and/or liver biopsy to evaluate liver disease. 
13.2.1.3 Monitoring 
For a possible Hy’s Law case (ALT ≥3x ULN AND total bilirubin ≥2x ULN or INR >1.5):  
• Repeat liver chemistry tests (include ALT, AST, ALP, GGT, bilirubin, total bile acids, PT/INR, 
and PTT) and perform liver event follow-up assessments within 24 hours. 
• Collect blood samples twice weekly for repeat liver chemistry tests (ALT, AST, ALP, GGT, 
bilirubin, total bile acids, PT/INR, and PTT) until abnormalities resolve, stabilize, or return 
to baseline. 
• A specialist or hepatology consultation is recommended. 
For a non–Hy’s Law case of ALT ≥3x ULN that meets other liver chemistry stopping criteria:  
• Repeat liver chemistry tests (include ALT, AST, ALP, GGT, bilirubin, total bile acids, PT/INR, 
and PTT) and perform liver event follow-up assessments within 24 to 72 hours. 
• Collect blood samples weekly for repeat liver chemistry tests (ALT, AST, ALP, GGT, 
bilirubin, total bile acids, PT/INR, and PTT) until abnormalities resolve, stabilize, or return 
to baseline. 
13.2.2 Increased Liver Chemistry Monitoring While Continuing Study Drug 
If ALT ≥3x ULN and <5x ULN and total bilirubin <2x ULN, without symptoms believed to be 
related to liver injury or hypersensitivity, and the subject can be monitored weekly for 4 weeks, 
perform the following actions: 
• Notify the Medical Monitor within 24 hours of learning of the abnormality to discuss 
subject safety.   
• Subject can continue study drug. 

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• Collect blood samples weekly for repeat liver chemistry tests (ALT, AST, ALP, GGT, 
bilirubin, total bile acids, PT/INR, and PTT) until the abnormalities resolve, stabilize, or 
return to baseline.   
• If at any time the subject meets liver chemistry stopping criteria, proceed as described in 
Section 7.1.1 and Section 13.2.1. 
• If, after 4 weeks of monitoring, ALT <3x ULN and total bilirubin <2x ULN, monitor per 
standard scheduling for remainder of study and follow-up period. 
13.2.3 Restart Following Transient Resolving Liver Chemistry Events Not Related to Study 
Drug 
The Investigator may request the Sponsor to consider restarting study drug in a subject who 
stopped study drug because of a liver chemistry event. Approval for study drug restart can be 
considered under the following circumstances: 
• Liver chemistry events have a clear underlying cause (eg, biliary obstruction, pancreatic 
events, hypotension, acute viral hepatitis), liver chemistry tests have improved to normal 
or are within 1.5x baseline, and ALT <3x ULN. 
• Possible drug-induced liver injury (DILI) has been excluded by the Investigator and the 
study team. This includes the absence of markers of hypersensitivity (otherwise 
unexplained fever, rash, eosinophilia). Where a study medication has an identified genetic 
marker associated with liver injury (eg, lapatinib, abacavir, amoxicillin/clavulanate), the 
presence of the marker should be excluded. If study drug–related liver injury cannot be 
excluded, the guidance on appropriate action and follow-up in the previous sections of 
this Appendix will apply. 
• There is no evidence of alcoholic hepatitis. 
• Medical Monitor approval of study drug restart has been obtained. 
If restart of study drug is approved by the Sponsor in writing:  
• Study drug must be administered at the dose specified by the Sponsor. 
• Subjects approved by the Sponsor for restart of study drug must have twice weekly blood 
draws for liver chemistry tests until stable liver chemistry tests have been demonstrated, 
and then standard laboratory monitoring may resume as per protocol. 
• If the subject meets protocol-defined liver chemistry stopping criteria after study drug 
restart, study drug should be permanently discontinued.   
• The Medical Monitor must be informed of the outcome for the subject following study 
drug restart.   
• The Sponsor must be notified of any AEs. 
 
 

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13.3 Appendix of Clinical Laboratory and Urinalysis Tests 
Refer to Section 8.2.5 for more information on clinical laboratory and urinalysis tests. 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet count  
RBC count 
RBC indices: MCV, MCH, % reticulocytes 
Hemoglobin 
Hematocrit 
WBC count  
Differential: neutrophils, lymphocytes, monocytes, eosinophils, basophils 
Clinical Chemistry1 
Potassium 
Calcium 
Sodium 
BUN 
Creatinine 
Total protein 
ALP 
ALT/SGPT 
AST/SGOT 
GGT 
Total and direct bilirubin  
Total bile acids 
Coagulation 
PT/INR, PTT 
Lipid Panel 
Total cholesterol, LDL, HDL, triglycerides 
Thyroid Panel 
T3 (free and total), T4 (free and total), TSH 
Routine Urinalysis 
Specific gravity 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, by dipstick 
Microscopic examination (if blood or protein is abnormal) 
Other Tests 
LH, FSH, SHBG, renin, aldosterone 
For males only: inhibin B 
For females only: estradiol, prolactin, progesterone 
Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, 
blood urea nitrogen; FSH, follicle-stimulating hormone; GGT, gamma-glutamyltransferase; HDL, high-density 
lipoprotein; INR, international normalized ratio; LDL, low-density lipoprotein; LH, luteinizing hormone; MCH, mean 
corpuscular hemoglobin; MCV, mean corpuscular volume; PT, prothrombin time; PTT, partial thromboplastin time; 
RBC, red blood cell; SAE, serious adverse event; SGOT, serum glutamic-oxaloacetic transaminase; SGPT, serum 
glutamic-pyruvic transaminase; SHBG, sex hormone–binding globulin; TSH, thyroid-stimulating hormone; ULN, 
upper limit of normal; WBC, white blood cell. 
1 Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 7.1.1 and Section 13.2. All events of ALT ³3x ULN plus total bilirubin ³2x ULN 
(>35% direct bilirubin) or ALT ³3x ULN plus INR >1.5 may indicate severe liver injury (possible Hy’s Law) and must 
be reported as SAEs. 

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13.4 Appendix Regarding Genetic Sample Collection and Testing 
Where local regulations permit and subject to discretionary approval from each site’s IRB/EC 
and to subject consent, a voluntary blood sample may be collected for DNA analysis. These 
samples may be tested for CAH genotype, genes related to the mechanism of action of 
tildacerfont, and drug metabolism enzyme and transporter polymorphisms. Drug metabolism 
enzyme and transporter polymorphisms may be evaluated using an analytical methodology that 
comprehensively assesses an array of drug metabolism enzyme and transporter genes from a 
single sample. Alternative genotyping platforms may be used, if appropriate, to confirm initial 
results. Certain genotyping may be omitted at the discretion of the Investigator and/or Sponsor 
(eg, if the subject was previously tested for certain genes using the same platform/technology). 
No additional testing will be performed on these samples. 
Details regarding the collection, processing, storage, and shipping of samples can be found in 
the Laboratory Manual. Samples collected as part of a later analysis will be securely stored in a 
central biorepository selected by the Sponsor for up to 5 years after the last study visit of the 
last subject in the study, or as local regulations allow. Any samples remaining after 5 years will 
be destroyed.