Clinical trial NCT04457336
Conditions: Congenital Adrenal Hyperplasia
Keywords: CAH Adrenal Disorder Congenital Adrenal Hyperplasia
Sponsor: Spruce Biosciences
Start date: 2020-08-26; Completion date: 2024-05-23
Enrollment: 96 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
An investigation of the efficacy and safety of up to 70 weeks of treatment with Tildacerfont in subjects with classic CAH who have elevated biomarkers at baseline on their current GC regimen. Optional open label treatment extension period up to 240 weeks with 200mg Tildacerfont QD.

Detailed description:
This is a study that will test the efficacy and safety of Tildacerfont. The first 12-weeks will be a double-blind, placebo controlled, dose ranging study. The following 58-weeks will assess the long term safety of Tildacerfont. Optional open label treatment extension period up to 240 weeks with 200mg Tildacerfont QD.

Arms: arm 1: Tildacerfont administered daily via oral tablet for 12 weeks at dose level 1 arm 2: Tildacerfont administered daily via oral tablet for 12 weeks at dose level 2 arm 3: Tildacerfont administered daily via oral tablet for 70 weeks at dose level 3 arm 4: Placebo administered daily via oral tablet for 12 weeks.
Interventions: intervention 1: Tildacerfont/Placebo
Intervention descriptions: intervention 1: Tablet, administered daily

Protocol documents:
Prot_000.pdf: 
SPR001-203 
CLINICAL STUDY PROTOCOL 
Spruce Biosciences, Inc. 
Version 8.0, Dated 06 February 2024 
 
 
CONFIDENTIAL 
Page 1 of 101 
 
 
 
 
A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study  
to Evaluate the Eﬃcacy and Safety of SPR001 (Tildacerfont) 
in Adult Subjects with Classic Congenital Adrenal Hyperplasia 
 
US IND Number: 
131761 
Study Number: 
SPR001-203 
Document Type: 
Clinical study protocol  
Protocol Version: 
8.0 (amends Version 7.0) 
Protocol Date: 
06 February 2024 
InvesƟgaƟonal Medicinal Product: 
SPR001 (Ɵldacerfont) 
IndicaƟon: 
Classic congenital adrenal hyperplasia (CAH) 
Sponsor: 
Spruce Biosciences, Inc. 
611 GatewayBlvd, Suite 740 
South San Francisco, CA 94080 
United States 
Registries: 
ClinicalTrials.gov: NCT04457336 
 
EudraCT #: 2019-004764-22 
EU CT #: 2023-503770-21-00 
 
 
 
 
Statement of ConﬁdenƟality 
This document contains proprietary and conﬁdenƟal informaƟon of Spruce Biosciences, Inc. Acceptance of this 
document consƟtutes agreement by the recipient that no previously unpublished informaƟon contained herein will 
be published or disclosed without the prior writen approval of Spruce Biosciences, Inc., with the excepƟon that 
this document may be disclosed to study personnel under your supervision who need to know the contents for 
conducƟng the study and to appropriate InsƟtuƟonal Review Boards (IRBs) or Ethics Commitees (ECs) under the 
condiƟon that the personnel have agreed to keep this informaƟon conﬁdenƟal. The foregoing shall not apply to 
disclosure required by governmental regulaƟons or laws; however, Spruce Biosciences, Inc. shall be promptly 
noƟﬁed of any such disclosure.  


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SPONSOR APPROVAL PAGE 
A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study to Evaluate the Eﬃcacy and 
Safety of SPR001 (Tildacerfont) in Adult Subjects with Classic Congenital Adrenal Hyperplasia 
Study Number: SPR001-203 
Protocol Version: 8.0 
Protocol Date:  06 February 2024 
 
 
This protocol has been reviewed and approved by Spruce Biosciences, Inc.: 
 
 
 
__________________________________________________ 
 
_________________ 
Saba Sile, MD   
 
 
 
 
 
 
Date 
Vice President, Clinical Development  
 
 
 
__________________________________________________ 
 
_________________ 
Vaeling Miller   
 
 
 
 
 
 
Date 
Vice President, Clinical Development OperaƟons 
DocuSign Envelope ID: 95341363-82E5-4593-A863-06D62C156C59
06-Feb-2024
06-Feb-2024


SPR001-203 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE 
A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study to Evaluate the Eﬃcacy and 
Safety of SPR001 (Tildacerfont) in Adult Subjects with Classic Congenital Adrenal Hyperplasia 
Study Number: SPR001-203 
Protocol Version: 8.0 
Protocol Date:  06 February 2024 
I have reviewed the protocol and the atachments, and I agree to conduct this trial in accordance with all 
sƟpulaƟons of the protocol, including all statements regarding conﬁdenƟality. I will ensure that no 
deviaƟon from, or changes to, the protocol will take place without prior agreement from the Sponsor 
and documented approval from the InsƟtuƟonal Review Board (IRB)/Ethics Commitee (EC), except 
where necessary to eliminate an immediate hazard(s) to the trial parƟcipants or when change(s) involves 
only logisƟcal or administraƟve aspects of the study. 
I agree to conduct this trial in accordance with InternaƟonal Council for HarmonisaƟon Good Clinical 
PracƟce (ICH GCP), the most recent version of the DeclaraƟon of Helsinki, and all applicable local and 
federal legal and regulatory requirements.  
I agree to provide suﬃcient Ɵme and adequate numbers of qualiﬁed staﬀ and faciliƟes for the foreseen 
duraƟon 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 ProtecƟon 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 authoriƟes. 
I agree to supply the Sponsor with any informaƟon regarding ownership interest and ﬁnancial Ɵes with 
the Sponsor for the purpose of complying with regulatory requirements. 
The protocol, informed consent form(s), recruitment materials, and all parƟcipant materials will be 
submited to the IRB/EC for review and approval. Approval of both the protocol and the consent form 
must be obtained before any parƟcipant 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 determinaƟon will be made regarding whether parƟcipants who 
provided previous consent need to be re-consented using the updated consent form. 
Site Name:  __________________________________________________________________ 
Principal InvesƟgator Name: ____________________________________________________   
 
___________________________________________________    _______________________ 
InvesƟgator’s Signature  
 
 
 
 
 
Date 


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TABLE OF CONTENTS 
SPONSOR APPROVAL PAGE ..................................................................................................... 2 
INVESTIGATOR PROTOCOL AGREEMENT PAGE ........................................................................ 3 
TABLE OF CONTENTS ............................................................................................................... 4 
LIST OF TABLES ........................................................................................................................ 8 
LIST OF ABBREVIATIONS .......................................................................................................... 9 
1 
PROTOCOL SUMMARY ............................................................................................... 13 
1.1 
Protocol Synopsis ............................................................................................................ 13 
1.2 
Schema ............................................................................................................................ 25 
1.3 
Schedules of Activities ..................................................................................................... 27 
1.3.1 Optional A4 Screening Visit ............................................................................................. 27 
1.3.2 Schedule of Screening Activities ...................................................................................... 27 
1.3.3 Schedule of Post-Screening Activities .............................................................................. 29 
2 
INTRODUCTION .......................................................................................................... 35 
2.1 
Study Rationale ............................................................................................................... 35 
2.2 
Background ..................................................................................................................... 36 
2.2.1 Congenital Adrenal Hyperplasia ...................................................................................... 36 
2.2.2 Current Treatment for CAH ............................................................................................. 37 
2.2.3 Tildacerfont for the Treatment of CAH ............................................................................ 38 
2.2.4 Nonclinical Studies of Tildacerfont .................................................................................. 38 
2.2.5 Clinical Experience with Tildacerfont .............................................................................. 39 
2.3 
Risk/Benefit Assessment ................................................................................................. 39 
2.3.1 Observed Potential Risks ................................................................................................. 39 
2.3.2 Observed Potential Benefits ............................................................................................ 41 
2.3.3 Assessment of Potential Risks and Benefits .................................................................... 41 
3 
OBJECTIVES AND ENDPOINTS ..................................................................................... 42 
4 
STUDY DESIGN ........................................................................................................... 44 
4.1 
Overall Design ................................................................................................................. 44 
4.1.1 Study Periods .................................................................................................................. 44 
4.1.2 Study Visits and Telephone Contacts .............................................................................. 46 
4.1.3 Study Diary/Drug Adherence Data Collection ................................................................. 47 


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4.2 
Scientific Rationale for Study Design ............................................................................... 47 
4.3 
Justification for Dose ....................................................................................................... 49 
4.4 
End of Study .................................................................................................................... 50 
4.4.1 End of Study Definition ................................................................................................... 50 
4.4.2 Optional Open-Label Extension Period ............................................................................ 50 
5 
STUDY POPULATION .................................................................................................. 51 
5.1 
Eligibility Criteria ............................................................................................................. 51 
5.1.1 Inclusion Criteria ............................................................................................................. 51 
5.1.2 Exclusion Criteria ............................................................................................................. 51 
5.2 
Lifestyle Considerations .................................................................................................. 53 
5.2.1 Shift Work and Time Zone Changes ................................................................................. 53 
5.2.2 Meals and Dietary Restrictions ........................................................................................ 53 
5.2.3 Caffeine, Alcohol, and Tobacco ....................................................................................... 54 
5.2.4 Activity ............................................................................................................................ 54 
5.2.5 Contraception Guidelines ................................................................................................ 54 
5.3 
Screen Failures ................................................................................................................ 55 
6 
STUDY INTERVENTION ............................................................................................... 56 
6.1 
Study Intervention Administration .................................................................................. 56 
6.1.1 Study Intervention Description ....................................................................................... 56 
6.1.2 Treatment Assignment, Dosing, and Administration ....................................................... 56 
6.2 
Preparation/Handling/Storage/Accountability ................................................................ 57 
6.2.1 Acquisition and Accountability ........................................................................................ 57 
6.2.2 Formulation, Appearance, Packaging, and Labeling ........................................................ 57 
6.2.3 Product Storage and Stability .......................................................................................... 58 
6.3 
Measures to Minimize Bias: Randomization and Blinding ............................................... 58 
6.4 
Study Intervention Compliance ....................................................................................... 58 
6.5 
Concomitant Therapy ...................................................................................................... 59 
6.5.1 Glucocorticoid Replacement Therapy ............................................................................. 59 
6.5.2 Prohibited Concomitant Medications .............................................................................. 63 
7 
STUDY DRUG DISCONTINUATION AND PARTICIPANT WITHDRAWAL ......................... 64 
7.1 
Study Drug Discontinuation ............................................................................................. 64 


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7.1.1 Liver Chemistry Stopping Criteria .................................................................................... 65 
7.1.2 QT Stopping Criteria ........................................................................................................ 66 
7.1.3 Suicidality Stopping Criteria ............................................................................................ 66 
7.1.4 Depression or Anxiety Stopping Criteria .......................................................................... 66 
7.1.5 Adrenal Insufficiency Stopping Criteria ........................................................................... 66 
7.1.6 Reproductive Hormone Stopping Criteria ....................................................................... 67 
7.1.7 Clinically Significant Adverse Event Stopping Criteria...................................................... 67 
7.2 
Participant Withdrawal from the Study ........................................................................... 68 
7.3 
Lost to Follow-up ............................................................................................................. 68 
8 
STUDY ASSESSMENTS AND PROCEDURES ................................................................... 69 
8.1 
Efficacy Assessments ....................................................................................................... 69 
8.1.1 Hormone Assessments .................................................................................................... 69 
8.1.2 Quality of Life Assessments ............................................................................................. 69 
8.1.3 Metabolic Assessments ................................................................................................... 69 
8.1.4 Hyperandrogenic Symptoms ........................................................................................... 70 
8.2 
Safety Assessments ......................................................................................................... 70 
8.2.1 Physical Examination ....................................................................................................... 71 
8.2.2 Vital Signs ........................................................................................................................ 71 
8.2.3 Body Weight, Height, BMI, and Waist Circumference ..................................................... 71 
8.2.4 Electrocardiogram ........................................................................................................... 71 
8.2.5 Clinical Laboratory and Urinalysis ................................................................................... 72 
8.2.6 Psychiatric Evaluations .................................................................................................... 72 
8.3 
Adverse Events and Serious Adverse Events ................................................................... 73 
8.3.1 Definition of Adverse Event ............................................................................................. 73 
8.3.2 Definition of Serious Adverse Event ................................................................................ 74 
8.3.3 Classification of an Adverse Event ................................................................................... 75 
8.3.4 Time Period and Frequency for Event Assessment and Follow-up .................................. 77 
8.3.5 Adverse Event Reporting ................................................................................................. 77 
8.3.6 Serious Adverse Event Reporting .................................................................................... 78 
8.3.7 Reporting of Pregnancy ................................................................................................... 78 
8.3.8 Adverse Events of Special Interest .................................................................................. 79 


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8.4 
Pharmacokinetic Assessments ........................................................................................ 80 
9 
STATISTICAL CONSIDERATIONS .................................................................................. 80 
9.1 
Statistical Hypotheses ..................................................................................................... 80 
9.2 
Sample Size Determination ............................................................................................. 80 
9.3 
Populations for Analyses ................................................................................................. 80 
9.4 
Statistical Analyses .......................................................................................................... 81 
9.4.1 General Considerations ................................................................................................... 81 
9.4.2 Analysis of the Primary Efficacy Endpoint ....................................................................... 82 
9.4.3 Analysis of the Secondary Efficacy Endpoints .................................................................. 82 
9.4.4 Analysis of the Exploratory Efficacy Endpoints ................................................................ 83 
9.4.5 Analysis of the Exploratory Efficacy Endpoints in the Optional Open-Label 
Extension Period ............................................................................................................. 83 
9.4.6 Safety Analyses................................................................................................................ 84 
9.4.7 Baseline Descriptive Statistics ......................................................................................... 85 
9.4.8 Subgroup Analyses .......................................................................................................... 85 
9.5 
Primary and Final Analyses .............................................................................................. 85 
9.6 
Multiplicity Control ......................................................................................................... 86 
9.7 
Data Monitoring Committee ........................................................................................... 86 
10 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS .......................... 86 
10.1 
Informed Consent ........................................................................................................... 86 
10.2 
Study Discontinuation and Closure ................................................................................. 87 
10.3 
Confidentiality and Privacy .............................................................................................. 87 
10.4 
Future Use of Stored Specimens and Data ...................................................................... 87 
10.5 
Key Roles and Study Governance .................................................................................... 87 
10.5.1 Sponsor ........................................................................................................................... 87 
10.5.2 Investigators .................................................................................................................... 88 
10.5.3 Institutional Review Board/Ethics Committee................................................................. 88 
10.6 
Safety Oversight .............................................................................................................. 88 
10.7 
Clinical Monitoring .......................................................................................................... 88 
10.8 
Quality Assurance and Quality Control ............................................................................ 89 
10.9 
Data Handling and Record Keeping ................................................................................. 89 


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10.9.1 Data Collection and Management Responsibilities ......................................................... 89 
10.9.2 Study Records Retention ................................................................................................. 89 
10.10 Protocol Deviations ......................................................................................................... 89 
10.11 Publication and Data Sharing Policy ................................................................................ 90 
10.12 Amendments ................................................................................................................... 90 
11 
COVID-19 RISK MITIGATION ....................................................................................... 90 
11.1 
Risk/Benefit Assessment in the Context of COVID-19 or Other Logistical 
Challenges ................................................................................................................ 90 
11.2 
Study Conduct in the Context of COVID-19 or Other Logistical Challenges ..................... 91 
11.3 
Subject Disposition in the Context of COVID-19 or Other Logistical Challenges .............. 91 
11.4 
Regulatory and Study Oversight Considerations in the Context of COVID-19 or 
Other Logistical Challenges ...................................................................................... 91 
12 
REFERENCES ............................................................................................................... 92 
13 
APPENDICES ............................................................................................................... 96 
13.1 
Appendix of Prohibited Concomitant Medications ......................................................... 96 
13.2 
Appendix of Liver Safety .................................................................................................. 97 
13.2.1 Suggested Actions, Follow-up Assessments, and Monitoring When Liver 
Chemistry Stopping Criteria Are Met .............................................................................. 97 
13.2.2 Increased Liver Chemistry Monitoring While Continuing Study Drug.............................. 98 
13.2.3 Restart Following Transient Resolving Liver Chemistry Events Not Related to 
Study Drug ....................................................................................................................... 99 
13.3 
Appendix of Clinical Laboratory and Urinalysis Tests .................................................... 100 
13.4 
Appendix Regarding Genetic Sample Collection and Testing ........................................ 101 
LIST OF TABLES 
Table 1. 
Relative Potencies of Glucocorticoids in Hydrocortisone Equivalents (HCe) ............ 60 
Table 2. 
Sick Day Guidelines for Stress Dosing of Hydrocortisone ......................................... 62 
Table 3. 
Stopping Criteria and Increased Monitoring for Liver Chemistry Elevations ............ 65 
Table 4. 
Severity of Adverse Events ....................................................................................... 75 
Table 5. 
Relatedness of Adverse Event to Study Drug (or HC Stress Dosing) ......................... 76 
Table 6. 
Outcome of Adverse Event ....................................................................................... 77 
 


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LIST OF ABBREVIATIONS 
17-OHP 
17-hydroxyprogesterone 
A4 
androstenedione 
ACTH 
adrenocorƟcotropic hormone, corƟcotropin 
ADL 
acƟviƟes 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 concentraƟon-Ɵme curve 
BCRP 
breast cancer resistance protein 
BID 
twice daily 
BMI 
body mass index 
BUN 
blood urea nitrogen 
C-SSRS 
Columbia–Suicide Severity RaƟng Scale 
CAH 
congenital adrenal hyperplasia 
CGI-I 
Clinical Global Impression – Improvement Scale 
CI 
conﬁdence interval 
CMH 
Cochran-Mantel-Haenszel (test) 
CNS 
central nervous system 
CONSORT 
Consolidated Standards of ReporƟng Trials 
COVID-19 
coronavirus disease 2019 
CPK 
creaƟnine phosphokinase 
CRF 
corƟcotropin-releasing factor 
CRF1, CRF2 
corƟcotropin-releasing factor type-1 or type-2 
CRO 
contract research organizaƟon 
CTCAE 
Common Terminology Criteria for Adverse Events  
CV 
coeﬃcient of variaƟon 
CYP 
cytochrome P450 
DDI 
drug-drug interacƟon 
DILI 
drug-induced liver injury 


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DSMB 
Data and Safety Monitoring Board 
EC 
Ethics Commitee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
esƟmated glomerular ﬁltraƟon rate 
EOT 
end of treatment 
FCP 
female of childbearing potenƟal 
FDA 
Food and Drug AdministraƟon 
FSH 
follicle-sƟmulaƟng hormone 
GC 
glucocorƟcoid 
GCP 
Good Clinical PracƟce 
GGT 
gamma-glutamyl transferase 
GI 
gastrointesƟnal 
HADS 
Hospital Anxiety and Depression Scale 
HbA1c 
hemoglobin A1c 
HBcAb 
hepaƟƟs B core anƟbody 
HBsAg 
hepaƟƟs B surface anƟgen 
HC 
hydrocorƟsone 
HCe 
hydrocorƟsone equivalent(s) 
HDL 
high-density lipoprotein 
HEENT 
head, eyes, ears, neck, and throat 
HIV 
human immunodeﬁciency virus 
HOMA-IR 
homeostaƟc model assessment of insulin resistance 
HPA 
hypothalamic-pituitary-adrenal 
HPLC 
high-performance liquid chromatography 
IB 
InvesƟgator’s Brochure 
ICF 
informed consent form 
ICH 
InternaƟonal Council for HarmonisaƟon of Technical Requirements for 
PharmaceuƟcals for Human Use 
IGA 
InvesƟgator’s Global Assessment (of acne severity) 
IgG 
immunoglobulin G 
IgM 
immunoglobulin M 
INR 
internaƟonal normalized raƟo 
IQR 
interquarƟle range 
IRB 
InsƟtuƟonal Review Board 


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ITT 
Intent to Treat (PopulaƟon) 
IUD 
intrauterine device 
IUS 
intrauterine system 
LDH 
lactate dehydrogenase 
LDL 
low-density lipoprotein 
LFT 
liver funcƟon test 
LH 
luteinizing hormone 
MCH 
mean corpuscular hemoglobin 
MCV 
mean corpuscular volume 
MedDRA 
Medical DicƟonary for Regulatory AcƟviƟes 
mFG 
modiﬁed Ferriman-Gallwey (score for hirsuƟsm) 
mITT 
modiﬁed Intent to Treat (PopulaƟon) 
ms 
millisecond 
OTC 
over the counter 
PBPK 
physiologically based pharmacokineƟc (modeling) 
PD 
pharmacodynamic(s) 
PGIC 
PaƟent Global Impression of Change 
PK 
pharmacokineƟc(s) 
PP 
Per Protocol (PopulaƟon) 
PRN 
as needed 
PRO 
paƟent-reported outcome (measure) 
PT 
prothrombin Ɵme 
PTT 
parƟal thromboplasƟn Ɵme 
PVC 
polyvinyl chloride 
PVDC 
polyvinylidene chloride 
QD 
once daily 
QoL 
quality of life 
QTcF 
Fridericia-corrected QT interval 
RBC 
red blood cell 
RTSM 
randomizaƟon and trial supply management 
SAE 
serious adverse event 
SAP 
StaƟsƟcal Analysis Plan 
SD 
standard deviaƟon 
SF-36 
Short Form 36 
SGOT 
serum glutamic-oxaloaceƟc transaminase 


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SGPT 
serum glutamic-pyruvic transaminase 
SHBG 
sex hormone–binding globulin 
SUSAR 
suspected unexpected serious adverse reacƟon 
TART 
tesƟcular adrenal rest tumor 
TEAE 
treatment-emergent adverse event 
TSH 
thyroid-sƟmulaƟng hormone 
ULN 
upper limit of normal 
WBC 
white blood cell 


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1 PROTOCOL SUMMARY 
1.1 Protocol Synopsis 
Study Number:  SPR001-203 
Study Title 
A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study to Evaluate the Eﬃcacy and 
Safety of SPR001 (Tildacerfont) in Adult Subjects with Classic Congenital Adrenal Hyperplasia 
Study Phase:  IIb 
Study RaƟonale 
Congenital adrenal hyperplasia (CAH) is a serious, chronically debilitaƟng, and life-threatening geneƟc 
disorder characterized by impaired adrenal synthesis of corƟsol and consequent overproducƟon of 
adrenal androgens. CorƟsol deﬁciency disrupts the balance of the hypothalamic-pituitary-adrenal 
(HPA) axis by removing the negaƟve feedback to the hypothalamus and pituitary provided by normal 
levels of corƟsol. This leads to the compensatory hypersecreƟon of corƟcotropin-releasing factor (CRF) 
by the hypothalamus, overproducƟon of adrenocorƟcotropic hormone (ACTH) by the pituitary gland, 
and consequent adrenal hyperplasia and overproducƟon 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, hirsuƟsm, and virilizaƟon in females; tesƟcular 
adrenal rest tumors (TARTs) in males; and increased sebum producƟon, acne, altered aŌernoon blood 
pressure proﬁles, and impaired ferƟlity in either sex.  
The current standard of care for CAH is the long-term use of supraphysiologic levels of glucocorƟcoids 
(GCs) to replace the deﬁcient corƟsol and suppress androgen overproducƟon. This is a problemaƟc 
therapy with signiﬁcant side eﬀects (e.g., loss of bone mineral density, iatrogenic Cushing’s syndrome, 
metabolic disorders, and increased cardiovascular risk), a narrow therapeuƟc window, and overall 
poor treatment eﬀecƟveness. A non-steroidal treatment opƟon that both controls androgen levels and 
reduces paƟent dependence on high-dose GCs would be of signiﬁcant beneﬁt to paƟents with CAH. 
Given the serious nature of CAH and the limitaƟons and risks of chronic GC therapy, new treatments 
are urgently needed for paƟents with CAH.  
Tildacerfont, a potent and highly selecƟve 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 overproducƟon by the pituitary and 
reducing excess accumulaƟon of downstream adrenal hormones. This mechanism of acƟon has been 
validated in CAH in earlier-phase clinical studies of Ɵldacerfont. Given its mechanism of acƟon, 
Ɵldacerfont may enable a CAH paƟent to have normal androgen levels while taking GC at physiologic 
replacement levels. 
To date, Ɵldacerfont has shown an acceptable safety proﬁle at eﬀecƟve 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 Ɵldacerfont as a 
treatment for CAH, with meaningful reducƟons in ACTH (demonstraƟng target engagement) and 


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17-OHP and A4 (demonstraƟng eﬃcacy in decreasing downstream adrenal hormones in CAH), and 
showed conƟnued improvement in biomarker levels over a period of 12 weeks. 
In contrast to previously completed Phase 2 studies of Ɵldacerfont, which were smaller, open-label, 
and shorter in duraƟon, Study SPR001-203 is a larger, randomized, double-blind, placebo-controlled, 
dose-ranging study that will invesƟgate the eﬃcacy and safety of up to 70 weeks of treatment with 
Ɵldacerfont in subjects with classic CAH who have elevated biomarkers at baseline on their current GC 
regimen. An opƟonal Open-Label Extension Period will provide addiƟonal open-label treatment with 
Ɵldacerfont at 200 mg QD for up to 240 weeks. 
ObjecƟves 
Endpoints 
Eﬃcacy 
Primary Eﬃcacy 
To evaluate the eﬀect of 
Ɵldacerfont in reducing A4 in 
subjects with classic CAH over 
12 weeks 
Assessment of dose response for change from baseline in log A4 
aŌer 12 weeks on double-blind, placebo-controlled treatment 
(Week 18) 
Secondary Eﬃcacy 
To evaluate the eﬀect of 
Ɵldacerfont on A4 levels in 
subjects with classic CAH over 12 
weeks 
Change from baseline in A4 as assessed on the log scale aŌer 12 
weeks on double-blind, placebo-controlled treatment (Week 18)  
To evaluate the eﬀect of Ɵldacerfont 
in reducing A4 in subjects with classic 
CAH over 12 weeks 
Absolute change from baseline in A4 as determined via applicaƟon of 
the delta theorem to the log scale analysis results aŌer 12 weeks on 
double-blind, placebo-controlled treatment (Week 18) 
To evaluate the eﬀect of 
Ɵldacerfont in reducing 17-OHP 
levels in subjects with classic CAH 
over 12 weeks 
Assessment of dose response for change from baseline in log 17-
OHP aŌer 12 weeks on double-blind, placebo-controlled 
treatment (Week 18)  
To evaluate the eﬀect of Ɵldacerfont 
in reducing 17-OHP in subjects with 
classic CAH over 12 weeks 
Change from baseline in 17-OHP as assessed on the log scale aŌer 
12 weeks on double-blind, placebo-controlled treatment (Week 18) 
To evaluate the eﬀect of Ɵldacerfont 
in reducing 17-OHP in subjects with 
classic CAH over 12 weeks 
Absolute change from baseline in 17-OHP as determined via applicaƟon 
of the delta theorem to the log scale analysis results aŌer 12 weeks on 
double-blind, placebo-controlled treatment (Week 18) 
Exploratory Eﬃcacy 
To evaluate the eﬀect of Ɵldacerfont 
in reducing A4 in subjects with classic 
CAH over 12 weeks 
ProporƟon of subjects who achieve adequate control of A4 (A4 ≤ 1x, 
1.25x, 1.5x, 1.75x and 2x ULN) aŌer 12 weeks on double-blind, placebo-
controlled treatment (Week 18) for each treatment group 


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To evaluate the eﬀect of Ɵldacerfont 
in reducing 17-OHP in subjects with 
classic CAH over 12 weeks 
ProporƟon of subjects who achieve adequate control of 17-OHP 
(17-OHP ≤ 1200 ng/dL) aŌer 12 weeks on double-blind, placebo-
controlled treatment (Week 18) for each treatment group 
To evaluate the eﬀect of Ɵldacerfont 
in reducing tesƟcular adrenal rest 
tumor(s) (TART[s]) in male classic CAH 
subjects with TART(s) at baseline aŌer 
12 weeks on treatment 
Change in the lesion volume of TART(s) from baseline aŌer 12 weeks on 
double-blind, placebo-controlled treatment (Week 18) for each 
treatment group 
To characterize dose-exposure of 
Tildacerfont in CAH 
CorrelaƟon of Tildacerfont plasma concentraƟon vs dose   
To evaluate the eﬀect of Ɵldacerfont 
on biomarkers relaƟve to each other 
in subjects with classic CAH over 12 
weeks 
EsƟmate the within subject correlaƟon of A4 and 17-OHP log scale 
values over Ɵme 
To evaluate the eﬀect of Ɵldacerfont 
in improving QoL in subjects with 
classic CAH 
Change from baseline at Week 76 in SF-36 total score across all ITT 
subjects 
To evaluate the eﬀect of 
Ɵldacerfont in improving acne in 
classic CAH subjects with acne at 
baseline 
Change from baseline at Week 76 in InvesƟgator’s Global 
Assessment (IGA) score of acne severity score across all ITT 
subjects with acne at baseline 
To evaluate the eﬀect of 
Ɵldacerfont in improving hirsuƟsm 
in female classic CAH subjects with 
hirsuƟsm at baseline 
Change from baseline at Week 76 in Modiﬁed Ferriman-Gallwey 
(mFG) score for hirsuƟsm across all female ITT subjects with 
hirsuƟsm at baseline 
To evaluate the proporƟon of 
subjects who can reduce GC use in 
subjects with classic CAH 
ProporƟon of subjects with at least a 5 mg/day hydrocorƟsone 
equivalents (HCe) reducƟon from baseline in GC dose and A4 
≤ULN at Week 76  
To evaluate the eﬀect of 
Ɵldacerfont in reducing TART(s) in 
male classic CAH subjects with 
TART(s) at baseline 
Change in the total lesion volume of TART(s) from baseline at 
Week 76 across all male ITT subjects with TART(s) at baseline 
To evaluate the eﬀect on 
Ɵldacerfont in reducing A4 in 
subjects with classic CAH over 
12 weeks  
Assessment of dose response for change from baseline in log ATCH aŌer 
12 weeks on double-blind, placebo-controlled treatment (Week 18) 
To evaluate the eﬀect of Ɵldacerfont 
in reducing ACTH in subjects with 
classic CAH over 12 weeks 
Absolute change from baseline in ACTH as determined via applicaƟon of 
the delta theorem to the log scale analysis results aŌer 12 weeks on 
double-blind, placebo-controlled treatment (Week 18) 


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To evaluate the eﬀect of Ɵldacerfont 
in reducing ACTH in subjects with 
classic CAH over 12 weeks 
Change from baseline in ACTH as assessed on the log scale aŌer 
12 weeks on double-blind, placebo-controlled treatment (Week 18) 
To characterize dose-exposure of 
Tildacerfont in CAH 
EsƟmate the within subject correlaƟon of A4 and 17-OHP log scale 
values with Ɵldacerfont plasma concentraƟons over Ɵme 
Exploratory Eﬃcacy (Optional Open-Label Extension Period) 
To evaluate the eﬀect of 
Ɵldacerfont in reducing GC use to 
near-physiologic levels in subjects 
with CAH 
ProporƟon of subjects with GC dose ≤25 mg/day in HCe and A4 
≤ULN at end of treatment (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 
Ɵldacerfont in reducing 
cardiovascular risk in subjects with 
CAH and at least one 
cardiovascular risk factor at 
baseline 
ProporƟon of subjects with improvement in at least one 
cardiovascular risk factor at EOT 
To evaluate the eﬀect of 
Ɵldacerfont in reducing TART(s) in 
male CAH subjects with TART(s) at 
baseline 
ProporƟon of male subjects with reducƟon in TART(s) at EOT who 
had TART(s) at baseline 
Safety 
To evaluate the safety of 
Ɵldacerfont in subjects with CAH 
Adverse events (AEs), serious adverse events (SAEs) 
Study Design 
This is a study with a 3-part treatment period that will evaluate the eﬃcacy and safety of up to 70 
weeks of treatment with Ɵldacerfont in subjects with classic CAH who have elevated biomarkers at 
baseline. An opƟonal Open-Label Extension Period will provide addiƟonal open-label treatment with 
Ɵldacerfont at 200 mg QD for up to 240 weeks. 
Refer to the study schemaƟc provided in SecƟon 1.2. 
Study Periods 
This study will consist of the following periods: 
• 
A ≤45-day Screening Period for conﬁrmaƟon of eligibility 
o OpƟonal A4 Screening Visit 
o Screening informaƟon captured within 45 days of Day 1 in this study (parƟcularly 
screening informaƟon transferred from Spruce Biosciences Study SPR001-204) will be 
used to determine eligibility and fulﬁll screening requirements for this study.  


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• 
A 6-week, single-blind, placebo Run-in Period, during which subjects will be assessed for 
adherence to their exisƟng GC therapy and daily ingesƟon of placebo with food 
• 
Subjects who conƟnue to meet all eligibility criteria at the end of the Run-in Period will then 
enter a 3-part Treatment Period: 
• 
Part A:  The ﬁrst 12 weeks of the Treatment Period will be a randomized, double-blind, 
placebo-controlled, dose-ranging study. Subjects will be randomized in a 1:1:1:1 raƟo to 
receive either placebo or Ɵldacerfont at a dose of 50 mg once daily (QD), 100 mg QD, or 200 
mg QD. 
• 
Part B:  During the second 12 weeks of the Treatment Period, all subjects will receive acƟve 
drug (Ɵldacerfont), with possible dose escalaƟon for eligible subjects. Subjects and 
InvesƟgators will remain blinded to previous treatment in Part A and dose level of Ɵldacerfont 
in Part B. 
o Subjects who were randomized to placebo in Part A will receive Ɵldacerfont at 100 mg 
QD at the beginning of Part B. 
o Subjects who were randomized to Ɵldacerfont at 200 mg QD in Part A will conƟnue to 
receive Ɵldacerfont at 200 mg QD in Part B. 
o Subjects who were randomized to Ɵldacerfont at 50 mg QD or 100 mg QD in Part A 
will conƟnue to receive the same dose at the beginning of Part B if they have A4 ≤ULN 
at Week 18. These subjects will be escalated to the next highest dose at the beginning 
of Part B if they have A4 >ULN at Week 18 (i.e., subjects previously on 50 mg QD 
would be escalated to 100 mg QD, and subjects previously on 100 mg QD would be 
escalated to 200 mg QD). 
Based on the results of the Week 24 visit of Part B, subjects will have another opportunity for 
Ɵldacerfont dose escalaƟon if they have A4 >ULN and are toleraƟng their current dose of 
Ɵldacerfont. Speciﬁcally: 
o Subjects currently taking 50 mg QD will be escalated to 100 mg QD. 
o Subjects currently taking 100 mg QD will be escalated to 200 mg QD. 
• 
Part C:  During the last 46 weeks of the Treatment Period, all subjects will be escalated to 200 
mg QD, with periodic opportuniƟes for GC adjustment for eligible subjects. Subjects and 
InvesƟgators will conƟnue to remain blinded to previous treatment in Part A and dose level of 
Ɵldacerfont in Part B. 
o Subjects with A4 ≤ULN at Week 38 or Week 46 will begin to reduce their daily GC dose 
level by increments of approximately 5 mg/day HCe each Ɵme, down to a minimum of 
15 mg/day HCe (see SecƟon 6.5.1.4). 
• 
For subjects conƟnuing into the opƟonal Open-Label Extension Period  
o The Open-Label Extension Period will provide subjects with up to 240 weeks of 
treatment with Ɵldacerfont 200 mg QD.  
o Subjects will be eligible to adjust GC dose level at each visit (see SecƟon 6.5.1.4). 
• 
A 30-day Follow-up Period at EOT 


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o Subjects who do not conƟnue to the Open-Label Extension Period upon compleƟon of 
Treatment Period Part C will enter a 30-day Follow-up Period. 
o Upon compleƟon 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 
mineralocorƟcoid regimen (as applicable) established during the course of the study 
unƟl the 30-day follow-up visit unless the InvesƟgator determines that the subject’s 
clinical status necessitates a dosing change. AŌer compleƟon of the study, GC therapy 
will be managed at the discreƟon of the subject’s treaƟng physician. 
Changes in GC dosing are generally not permited during this study except in Part C, in the Open-Label 
Extension Period, and in the case of stress dosing throughout the study. During Ɵmes 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 hydrocorƟsone [HC]) for prevenƟon of adrenal 
crisis will be allowed according to “sick day guidelines” (see SecƟon 6.5.1.5). 
Study Visit Schedule 
• 
During the Screening Period: 
o OpƟonal A4 Screening Visit 
o Screening Visit at ≤45 days before Day 1  
• 
During the Run-in Period: visits at Day 1 and Week 4; scheduled telephone contact at Week 2 
• 
During the Treatment Period: 
o Part A: visits every 4 weeks, at Week 6 (baseline) and Weeks 10, 14, and 18; scheduled 
telephone contact at Week 8 
o Part B: visits every 6 weeks, at Weeks 24 and 30; scheduled telephone contact at 
Week 21 
o Part C: visits every 6 to 12 weeks, at Weeks 38, 46, 58, 70, and 76; scheduled 
telephone contact at Week 52 
• 
During the opƟonal 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 aŌer 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 LogisƟcal 
Challenges 
All eﬀorts should be made to conduct all visits in the clinic as per the Principal InvesƟgator’s clinical 
judgement or paƟent’s preference. Since the COVID-19 pandemic is expected to conƟnue during the 
conduct of this trial, study visits can be adapted into a combinaƟon of in-clinic and telemedicine 
acƟviƟes, with opƟonal at-home visits, to miƟgate the risk of COVID-19 infecƟon associated with study 
parƟcipaƟon and to accommodate local and individual circumstances while maintaining parƟcipant 
access to healthcare resources. 
The clinic acƟviƟes of the Screening Visit may be conducted remotely (at the subject’s home) if 
approved by the site’s InsƟtuƟonal Review Board (IRB)/Ethics Commitee (EC). 


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The electronic data capture (EDC) system will capture the mode by which data are collected for each 
visit/acƟvity. 
If home visits are conducted, the qualiﬁed medical professionals who will perform the study’s home 
visits are deﬁned as individuals who meet naƟonal/local licensing requirements needed to perform 
the procedures required at the home visits. Their naƟonal/local licensure will be veriﬁed, and they will 
complete training on the study protocol and Good Clinical PracƟce (GCP). If the medical professional 
does not meet the naƟonal/local licensing requirements needed to perform the opƟonal home visit 
acƟviƟes (physical examinaƟon, acne IGA score, and hirsuƟsm mFG score for females), the InvesƟgator 
or InvesƟgator-delegated study personnel must complete these acƟviƟes for each visit. 
Refer to SecƟon 11 for more informaƟon on study conduct in the context of COVID-19 or other 
logisƟcal challenges. 
Telephone Contacts 
Sites will make scheduled telephone contacts to all subjects at Weeks 2, 8, 21, and 52 to record any 
AEs and concomitant medicaƟons. During the Week 2 telephone contact, sites will also conﬁrm 
subject adherence to study acƟviƟes. 
AŌer receiving A4 results, sites will make telephone contacts to applicable subjects concerning 
Ɵldacerfont dose escalaƟon or GC adjustment. 
• 
For subjects who are eligible for GC adjustment following the Week 38 and/or 46 study visits 
as well as visits in the opƟonal Open-Label Extension Period, sites will contact these subjects 
by telephone within 2 weeks aŌer the applicable study visit. The site will direct a subject to 
reduce his/her GC dose at that Ɵme 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 aŌer the dose adjustment to assess for the occurrence 
of AEs and the iniƟaƟon of new concomitant medicaƟons. 
Subjects should be instructed to telephone sites if they have any concerns about their health.  
PRN telephone contacts iniƟated by sites and telephone contacts iniƟated by subjects should be 
captured in the EDC system as “unscheduled” telephone contacts. 
Study Diary/Drug Adherence Data CollecƟon 
During the Run-in and Treatment Periods, subjects will use an electronic study diary to document 
study drug and background GC adherence through Week 18. Female subjects will also use the study 
diary to record menstrual informaƟon (including start and stop dates of menses) across the full 
treatment period up to Week 76. 
Study PopulaƟon 
This study will randomize approximately 72 subjects with classic CAH currently receiving GC therapy 
into the start of the Treatment Period. The study will enroll subjects at approximately 130 invesƟgaƟve 
sites globally. 
Eligibility Criteria 
Inclusion Criteria 


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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 
geneƟc mutaƟon in CYP21A2 and/or documented (at any Ɵme) elevated 17-OHP and currently 
treated with HC, HC acetate, prednisone, prednisolone, methylprednisolone (or a combinaƟon of 
the aforemenƟoned GCs) 
3. Has been on a stable, supraphysiologic dose of GC replacement (deﬁned as ≥15 mg/day and ≤60 
mg/day in HCe) for ≥1 month before screening  
4. Has A4 >ULN at both screening and Week 4 (measured before any AM GC dose) if daily GC dose 
<30 mg OR has A4 >2.5x ULN at both screening and Week 4 (measured before any AM GC dose) 
5. For subjects with the salt-wasƟng form of CAH, subject has been on a stable dose of 
mineralocorƟcoid replacement for ≥1 month before screening 
6. Agrees to follow contracepƟon guidelines (SecƟon 5.2.5). Male subjects must also agree to 
refrain from donaƟng sperm throughout the treatment period and for 90 days aŌer the last dose 
of study drug. 
7. Is able to understand all study procedures and risks involved and provides writen informed 
consent indicaƟng 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 
3. Has a history of allergy or hypersensiƟvity to Ɵldacerfont, any of its excipients, or any other CRF1 
receptor antagonist 
4. Current treatment with dexamethasone as GC therapy for CAH 
a. Prior treatment with dexamethasone is allowed as long as the transiƟon to an alternaƟve GC 
regimen (eg, HC, prednisone, or prednisolone) has resulted in a stable dose of GC 
replacement for ≥1 month before screening. 
5. Is not adherent to GC or study drug dosing regimen during the Run-in Period (deﬁned as taking 
<80% of expected doses based on drug accountability) 
6. Shows clinical signs or symptoms of adrenal insuﬃciency 
7. Has had a clinically signiﬁcant unstable medical condiƟon, 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. EsƟmated glomerular ﬁltraƟon rate (eGFR) of <45 mL/min/1.73 m2 
c. Current or history of liver disease (with the excepƟon 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 parƟcipaƟng in the 
study, based on the opinion of the InvesƟgator 
e. AcƟve hepaƟƟs B, hepaƟƟs C, or human immunodeﬁciency virus (HIV) at screening 


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f. Subjects who plan to undergo bariatric surgery during the study are excluded. 
g. Any other condiƟon that would impact subject safety or confound interpretaƟon of study 
results  
8. Psychiatric condiƟons, including but not limited to bipolar disorder, schizophrenia, or 
schizoaﬀecƟve disorders that are not eﬀecƟvely controlled on medicaƟon and may have an 
adverse impact on study compliance. Symptoms including hallucinaƟons, delusions, and 
psychosis are exclusionary. AddiƟonally: 
a. Increased risk of suicide based on the InvesƟgator’s judgment or the results of the 
Columbia–Suicide Severity RaƟng Scale (C-SSRS) conducted at screening and Week 6 (eg, 
C-SSRS Type 3, 4, or 5 ideaƟon 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 Week 6 
9. 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 parƟcipants or >470 ms for female parƟcipants 
b. Alanine aminotransferase (ALT) >2x ULN 
c. Total bilirubin >1.5x ULN  
d. Total bile acids >5x ULN 
10. RouƟnely works overnight shiŌs  
11. Subjects with travel plans/work schedules that result in signiﬁcant and frequent changes in Ɵme 
zones (>2 hours) will require Medical Monitor approval for enrollment. 
12. Females who are pregnant or nursing 
13. Use of any other invesƟgaƟonal drug from 30 days or 5 half-lives (whichever is longer) before 
screening to the end of the study 
14. Use of the following drugs from 30 days or 5 half-lives (whichever is longer) before Day 1 to the 
end of the study:  
a. Rosiglitazone, aromatase inhibitors, testosterone, growth hormones, or any other 
medicaƟon or supplement that could impact subject safety or confound interpretaƟon of 
study results 
b. The drugs listed in SecƟon 13.1, which are: 
i. Moderate to strong inhibitors and/or inducers of cytochrome P450 3A4 (CYP3A4) 
ii. SensiƟve substrates or narrow-therapeuƟc-range substrates of CYP3A4 (except hormonal 
contracepƟon containing ≤35 µg ethinyl estradiol) 
iii. SensiƟve substrates or narrow-therapeuƟc-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 administraƟon of study drug) 


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15. DonaƟon or receipt of blood from 90 days before Screening to the end of the study; donaƟon or 
receipt of platelets, white blood cells, or plasma from 30 days before Screening to the end of the 
study 
InvesƟgaƟonal 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 idenƟcal to drug product but contain no drug substance. 
Dose, Route, Regimen 
Subjects will use their own physician-prescribed supply of GCs as prescribed during the study, 
including during the Run-in Period. 
Subjects will take placebo (during the Run-in Period) or assigned study drug (during the Treatment 
Period) 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 aŌer 
compleƟng the evening meal, if necessary. 
During Part A (the ﬁrst 12 weeks of the Treatment Period), subjects will be randomized in a 1:1:1:1 
raƟo to receive either placebo or Ɵldacerfont at a dose of 50 mg QD, 100 mg QD, or 200 mg QD. 
During Part B (the second 12 weeks of the Treatment Period) and Part C (the last 46 weeks of the 
Treatment Period), all subjects will receive acƟve drug (Ɵldacerfont). 
• Subjects who were randomized to placebo in Part A will receive Ɵldacerfont 100 mg QD at the 
beginning of Part B. 
• Subjects who were randomized to Ɵldacerfont 200 mg QD in Part A will conƟnue to receive 
Ɵldacerfont at 200 mg QD throughout Parts B and C. 
• Based on A4 results at Weeks 18 and 24 study visits, eligible subjects may undergo a Ɵldacerfont 
dose escalaƟon aŌer each of these study visits. Speciﬁcally: 
o Subjects taking Ɵldacerfont 50 mg QD will either conƟnue to receive the same dose (if A4 
≤ULN) or be escalated to Ɵldacerfont 100 mg QD (if A4 >ULN and the subject is toleraƟng 
his/her current Ɵldacerfont dose) 
o Subjects taking Ɵldacerfont 100 mg QD will either conƟnue to receive the same dose (if A4 
≤ULN) or be escalated to Ɵldacerfont 200 mg QD (if A4 >ULN and the subject is toleraƟng 
his/her current Ɵldacerfont dose). 
• At Week 30, all subjects will be escalated to 200 mg QD. 
Immediately following the Weeks 18 and 24 visits, subjects will conƟnue to take their previously 
assigned study drug unƟl A4 laboratory results are received, the randomizaƟon and trial supply 
management (RTSM) system determines the appropriate Ɵldacerfont doses for the next porƟon of the 
study, and subjects receive their Ɵldacerfont doses for the next porƟon of the study. 
During the opƟonal Open-Label Extension Period, subjects will conƟnue to receive Ɵldacerfont at 
200 mg QD. 
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 


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morning dose of GC medicaƟon unƟl aŌer the 8 AM (±1 hour) laboratory assessments have been 
completed. On all other days during the study, subjects should take their GC medicaƟon at the usual 
Ɵme(s). MineralocorƟcoid may be taken at any Ɵme of day, but its Ɵming relaƟve to laboratory 
assessments should be consistent throughout the study. 
During Ɵmes 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 prevenƟon of 
adrenal crisis will be allowed according to “sick day guidelines” (see SecƟon 6.5.1.5). The Sponsor will 
provide GC for periods of stress dosing. 
Study drug will be disconƟnued in subjects who meet individual treatment-stopping criteria (see 
SecƟon 7.1).  
Study DuraƟon 
The expected duraƟon of study parƟcipaƟon for each subject is up to approximately 86 weeks. This 
includes a Screening Period of ≤45 days, a placebo Run-in Period of 6 weeks, a Treatment Period of 70 
weeks, and a safety follow-up period of approximately 30 days. Subjects who conƟnue in the opƟonal 
Open-Label Extension Period will parƟcipate for up to an addiƟonal 240 weeks.   
StaƟsƟcal Analyses 
StaƟsƟcal Hypotheses 
For the Primary Eﬃcacy Analysis, the null hypothesis is that there is no diﬀerence in the proﬁle of log 
A4 change from baseline through 12 weeks of blinded randomized treatment between Ɵldacerfont 
and placebo. The alternaƟve hypothesis is that there is diﬀerence in the proﬁle of log A4 change from 
baseline through 12 weeks of blinded randomized treatment between Ɵldacerfont and placebo. 
Sample Size 
A sample size of n=15 subjects per group will provide at least 80% power to detect a diﬀerence of at 
least 50% in A4 mean percent change from baseline between a given dose level of Ɵldacerfont and 
placebo, assuming a common standard deviaƟon (SD) of 30%.  
An assumed dropout rate of 15% during the Treatment Period results in a target of 18 subjects per 
group and a total sample size of 72 subjects who enter the Treatment Period. 
Analysis PopulaƟons 
• The Intent-to-Treat (ITT) PopulaƟon will include all randomized subjects regardless of treatment 
period eligibility or compleƟon.  
• The Modiﬁed ITT (mITT) PopulaƟon is deﬁned as all randomized subjects who receive at least 1 
dose of study drug (Ɵldacerfont or placebo), have at least 1 post-baseline A4 assessment, and did 
not change background GC through Week 18. 
• The Per Protocol (PP) PopulaƟon for each part of the Treatment Period will include all eligible 
subjects who have no major protocol deviaƟons that would aﬀect the analysis of eﬃcacy data.  
• The Safety PopulaƟon will include all subjects who receive at least 1 dose of study drug 
(Ɵldacerfont or placebo) during the Treatment Period. 
• The PharmacokineƟcs (PK) PopulaƟon will include all randomized subjects who receive at least 1 
dose of Ɵldacerfont and have at least 1 evaluable PK sample. 
Refer to SecƟon 9.3 for further informaƟon on analysis populaƟons. 


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General StaƟsƟcal ConsideraƟons 
ConƟnuous data will be summarized using an 11-point descripƟve summary (n, mean, SD, median, 
interquarƟle range [IQR; 25% quarƟle, 75% quarƟle], minimum, and maximum, geometric mean, 
geometric coeﬃcient of variance [CV%], 95% conﬁdence interval [CI] for geometric mean [including 
geometric mean raƟo and its 95% CI]) or 8-point descripƟve summary (n, mean, SD, median, Q1, 
Q3minimum, 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 disconƟnued early will be imputed using data collected from subjects aŌer 
disconƟnuaƟon of study drug 
Eﬃcacy Analyses 
All eﬃcacy analyses will be conducted on the ITT PopulaƟon using a 2-sided alpha of 0.05.  
The primary objecƟve of the study is to evaluate the eﬀect of Ɵldacerfont in controlling A4 levels in 
adult subjects with classic CAH who have elevated biomarkers at baseline on their current dose of GC 
replacement therapy over the 12-week, double-blind, placebo-controlled Part A of the Treatment 
Period.   This objecƟve will be achieved via A4 dose response analysis. StaƟsƟcal tesƟng for dose 
response will be performed using the repeated measures random coeﬃcients mixed-eﬀects model. 
The secondary eﬃcacy analyses related to A4 will be achieved as an integral part of the dose response 
modelling. The secondary eﬃcacy analyses related to 17-OHP will be conducted using the same 
methodology as the primary eﬃcacy analysis. 
Quality-of-life endpoints, IGA acne score, mFG hirsuƟsm score, and TART lesion size will be analyzed 
using a repeated measure mixed eﬀects model with treatment and visit as ﬁxed eﬀects, subject as a 
random eﬀect, and the baseline score as a covariate if >2 Ɵmepoints are assessed. If only the baseline 
Ɵmepoint and a single post-baseline Ɵmepoint are assessed for the endpoint, an analysis of covariance 
(ANCOVA) model with the baseline score as a covariate will be used. There will be no imputaƟon of 
missing data.  
Endpoints during the opƟonal Open-Label Extension Period will be summarized descripƟvely. 
Safety Analyses 
Safety analyses will be conducted on the Safety PopulaƟon. All safety data will be presented in lisƟngs. 
Summary tables will be provided for concomitant medicaƟons, AEs, hematology and chemistry 
laboratory results, vital signs, and ECG ﬁndings. Safety data will be summarized by treatment group 
using frequency of event or descripƟve staƟsƟcs, as appropriate. 


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1.2 Schema 
 


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1.3 Schedules of AcƟviƟes 
1.3.1 
OpƟonal A4 Screening Visit  
For subjects with unknown A4 levels, prior to a morning GC dose, an opƟonal A4 Screening Visit may be 
conducted up to 45 days prior to Day 1 to test A4 levels prior to further screening evaluaƟons. An 
informed consent form (ICF) speciﬁc to this visit will be signed by the subject. RetesƟng of A4 levels will 
not be required at the SPR001-203 Screening Visit if eligible A4 results have been obtained within 
45 days prior to the Day 1 visit. 
1.3.2 
Schedule of Screening AcƟviƟes 
Screening will be conducted in-clinic. Some acƟviƟes of the Screening Visit may be conducted remotely 
(at the subject’s home) if approved by the site’s IRB/EC. Screening acƟviƟes to be performed at the 
subject’s home will be conducted aŌer acƟviƟes to be performed in the clinic for each study visit. 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), aŌer the subject has 
fasted overnight (nothing to eat aŌer midnight), and before the subject takes any morning dose of GC 
medicaƟon. 
Screening informaƟon from the parallel Spruce Biosciences Study SPR001-204 may be used to determine 
eligibility and fulﬁll screening requirements for this study if the informaƟon was captured within 45 days 
before Day 1 in this study.  
 
Screening Period 
STUDY VISIT NUMBER 
1a 
OpƟonal A4 Screening 
1b 
Screening 
 
In-Clinic Screening Visit 
In-Clinic Screening Visit 
STUDY DAY 
≤45 days before Day 1 1 
≤45 days before Day 1 1 
Informed consent 
X 
X 
Inclusion/exclusion criteria 
 
X 
Demography 
 
X 
Medical history 
 
X 
Prior medicaƟons from past year 
 
X 
Concomitant medicaƟons 
 
X 
Prior and current GC regimens 2 
 
X 
Vital signs 3, body weight 
 
X 
Height 
 
X 
Full physical examinaƟon 
 
X 
C-SSRS 
 
X 
HADS 
 
X 
HepaƟƟs B & C and HIV tests 
 
X 4 


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Screening Period 
STUDY VISIT NUMBER 
1a 
OpƟonal A4 Screening 
1b 
Screening 
 
In-Clinic Screening Visit 
In-Clinic Screening Visit 
STUDY DAY 
≤45 days before Day 1 1 
≤45 days before Day 1 1 
Urine drug screen 
 
X 4 
Serum pregnancy test for FCP 
 
X 4  
Hormones from blood  
X5 
X 4, 6 
Clinical laboratory 7 
 
X 4 
Urinalysis 
 
X 4 
HbA1c 
 
X 4 
12-lead ECG 
 
X 4 
Report subject’s status to site 
 
X 4 
AbbreviaƟons:  17-OHP, 17-hydroxyprogesterone; A4, androstenedione; ACTH, adrenocorƟcotropic hormone; 
ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; C-SSRS, Columbia–
Suicide Severity RaƟng Scale; ECG, electrocardiogram; eGFR, esƟmated glomerular ﬁltraƟon rate; FCP, female 
of childbearing potenƟal; FSH, follicle-sƟmulaƟng hormone; GC, glucocorƟcoid; GGT, gamma-glutamyl 
transferase; HADS, Hospital Anxiety and Depression Scale; HbA1c, hemoglobin A1c; HCe, hydrocorƟsone 
equivalents; HIV, human immunodeﬁciency virus; INR, internaƟonal normalized raƟo; LH, luteinizing 
hormone; PT, prothrombin Ɵme; PTT, parƟal thromboplasƟn Ɵme; SHBG, sex hormone–binding globulin.
 
1 Screening informaƟon captured within 45 days of the start of Day 1 in this study (parƟcularly screening 
informaƟon transferred from Spruce Biosciences Study SPR001-204) will be used to determine eligibility and fulﬁll 
screening requirements for this study.  
2 Subjects must be on a stable, supraphysiologic dose of GC replacement (deﬁned as ≥15 and ≤60 mg HCe per day) 
for ≥1 month before the Screening Visit. InformaƟon 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 parƟcular 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 respiraƟon rate and 
will be measured aŌer a 5-min rest period. 
4 These clinic acƟviƟes of the Screening Visit may be conducted remotely (at the subject’s home) if approved by the 
site’s IRB/EC. 
5 A4 and 17-OHP will be measured. The blood draw for the A4 and 17-OHP 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 funcƟon tests such as ALT, 
AST, ALP, GGT, bilirubin, and total bile acids), coagulaƟon (PT/INR and PTT), lipid panel, thyroid panel, LH, FSH, 
SHBG, renin, aldosterone, inhibin B for males only, and estradiol, prolacƟn, and progesterone for females only. 
eGFR for screening will be calculated from blood creaƟnine measured as part of screening clinical chemistry. 
 


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1.3.3 
Schedule of Post-Screening AcƟviƟes  
 
Placebo  
Run-in 
Period 
Treatment Period 
Follow-
up1 
ET 
Part A 
Part B 
Part C 
STUDY VISIT NUMBER 
2 
 
3 
4 
Base 
line 
 
5 
6 
7 
 
8 
9 
10 
11 
 
12 
13 
14 
15 
 
STUDY WEEK 
0 
2 
4 
6 
8 
10 
14 
18 
21 
24 
30 
38 
46 
52 
58 
70 
762 
80 
 
STUDY DAY 3 
1 
15 29 
43 
57 
71 
99 
127 148 169 
211 267 
323 
365 
407 
491 
533 
Last dose 
 +30 days 
 
Study Visit (V)/ 
Telephone Contact (T) 4 
V 
T 
V 
V 
T 
V 
V 
V 
T 
V 
V 
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 
X 
X 
X 
Hormones from blood 5,6 
X 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Clinical laboratory 5,7 
 
 
 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Urinalysis 5 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
HbA1c, fasƟng glucose and insulin, 
HOMA-IR 5 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
PK 5,8 
 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
GeneƟc sample 9 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 10, body weight 
X 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Waist circumference 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
12-lead ECG 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
X 
X 
HADS 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
 
X 
SF-36 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
PGIC 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Scrotal ultrasound for males 
 
 
X11 
 
 
 
 
X12 
 
 
 
 
 
 
 
 
X12 
 
X12 
Inclusion/exclusion criteria 13 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medicaƟons 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
GC monitoring 14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Placebo  
Run-in 
Period 
Treatment Period 
Follow-
up1 
ET 
Part A 
Part B 
Part C 
STUDY VISIT NUMBER 
2 
 
3 
4 
Base 
line 
 
5 
6 
7 
 
8 
9 
10 
11 
 
12 
13 
14 
15 
 
STUDY WEEK 
0 
2 
4 
6 
8 
10 
14 
18 
21 
24 
30 
38 
46 
52 
58 
70 
762 
80 
 
STUDY DAY 3 
1 
15 29 
43 
57 
71 
99 
127 148 169 
211 267 
323 
365 
407 
491 
533 
Last dose 
 +30 days 
 
Study Visit (V)/ 
Telephone Contact (T) 4 
V 
T 
V 
V 
T 
V 
V 
V 
T 
V 
V 
V 
V 
T 
V 
V 
V 
V 
V 
C-SSRS 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
CGI-I 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
RandomizaƟon to treatment in Part 
A 15/DeterminaƟon of Ɵldacerfont 
dose in Parts B and C 16 
 
 
 
X 
 
 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
Dispense study drug 17 
X 
 
 
X 
 
X 
X 
X18,19 
 
X18,19 X20 
X 
X  
 
X 
X20 
 
 
 
Study drug accountability 
 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
Dispense HC for stress dosing and 
perform accountability 21 
X 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
PRN telephone contact to follow up 
aŌer possible Ɵldacerfont dose 
escalaƟon 22 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
PRN telephone contacts regarding 
GC adjustment 23 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
Review study diary/drug 
adherence24 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examinaƟon 25 
X 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Acne IGA score 26 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
HirsuƟsm mFG score for females 26 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 


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AbbreviaƟons: 17-OHP, 17-hydroxyprogesterone; A4, androstenedione; ACTH, adrenocorƟcotropic hormone; AE, adverse event; ALP, alkaline phosphatase; ALT, 
alanine aminotransferase; AST, aspartate aminotransferase; CGI-I, Clinical Global Impression – Improvement Scale; C-SSRS, Columbia–Suicide Severity RaƟng 
Scale; EC, Ethics Commitee; ECG, electrocardiogram; EDC, electronic data capture; ET, early terminaƟon; FCP, female of childbearing potenƟal; FSH, follicle-
sƟmulaƟng hormone; GC, glucocorƟcoid; GGT, gamma-glutamyl transferase; HADS, Hospital Anxiety and Depression Scale; HbA1c, hemoglobin A1c; HC(e), 
hydrocorƟsone (equivalents); HIV, human immunodeﬁciency virus; HOMA-IR, homeostaƟc model assessment of insulin resistance; IGA, InvesƟgator’s Global 
Assessment (score for acne); INR, internaƟonal normalized raƟo; IRB, InsƟtuƟonal Review Board; LH, luteinizing hormone; mFG, modiﬁed Ferriman-Gallwey 
(score for hirsuƟsm); PGIC, PaƟent Global Impression of Change; PK, pharmacokineƟcs; PRN, as needed; PROs, paƟent-reported outcome measures; PT, 
prothrombin Ɵme; PTT, parƟal thromboplasƟn Ɵme; RTSM, randomizaƟon and trial supply management (system); SF-36, Short Form 36; SHBG, sex hormone–
binding globulin; T, telephone contact; TART, tesƟcular adrenal rest tumor; V, study visit. 
Footnotes from 1.3.3 
Schedule of Post-Screening Activities: 
1 Subjects who do not continue to the optional Open-Label Extension Period upon completion of Treatment Period Part C 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 Number 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 after the Week 0 visit must be completed within a ± 3-day window after the indicated study days. 
4 During scheduled telephone contacts, sites will record any AEs and concomitant medications. After receiving A4 results, sites will make telephone contacts to 
applicable subjects concerning study drug dose escalation and GC adjustment (detailed later in this Schedule of Post-Screening Activities). 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. 
5 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. 
6 A4, 17-OHP, ACTH, and testosterone will be measured. 
7 Clinical laboratory assessments include hematology, clinical chemistry (including liver function tests such as ALT, AST, ALP, GGT, 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. 
8 A single blood sample will be drawn for PK measurement at each specified study visit. 
9 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. 
10 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. 
11 The initial scrotal ultrasound can be performed anytime during screening up to Week 4 of run-in and will be considered the baseline measurement for TART. 
12 Scrotal ultrasounds will only be conducted in subjects who had TART(s) at baseline. 
13 If a subject fails to meet eligibility criteria during or at the end of the Run-in Period, the investigational site will schedule an abbreviated early termination 
visit to review AEs and concomitant medications and perform an abbreviated physical examination (preferably in the clinic, but also permissible via home visit). 


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14 Subjects must be on a stable regimen of GC replacement ≥15 and ≤60 mg HCe per day throughout the Run-in Period, Part A, and Part B. Subjects will confirm 
whether their GC regimen was followed each day in a study diary. 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 laboratory assessments have been completed.  
15 In Part A, subjects will be randomized to tildacerfont 50 mg QD, tildacerfont 100 mg QD, tildacerfont 200 mg QD, or placebo.  
16 In Parts B and C, all subjects will receive tildacerfont. Subjects who were randomized to placebo in Part A will receive tildacerfont 100 mg QD at the 
beginning of Part B. Subjects who were randomized to tildacerfont 200 mg QD in Part A will continue to receive tildacerfont 200 mg QD throughout Parts B and 
C. Based on A4 results from the Weeks 18 and 24 study visits, eligible subjects may undergo a tildacerfont dose escalation after each of these study visits. 
Specifically, subjects taking tildacerfont 50 mg QD will either continue to receive the same dose (if A4 ≤ULN) or be escalated to tildacerfont 100 mg QD (if 
A4 >ULN and the subject is tolerating his/her current tildacerfont dose); subjects taking tildacerfont 100 mg QD will either continue to receive the same dose (if 
A4 ≤ULN) or be escalated to tildacerfont 200 mg QD (if A4 >ULN and the subject is tolerating his/her current tildacerfont dose). At Week 30, all subjects will be 
escalated to 200 mg QD. 
17 Either the subject will pick up study drug in the clinic or the 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. 
18 Immediately following each indicated study visit, subjects will continue to take their previously assigned study drug until subjects receive their tildacerfont 
doses for the next portion of the study. 
19 IRT order assigned to specific participant. The shipment does not need to be accepted in IRT. Blister Cards will be assigned when the "Confirm A4 Value" 
action is recorded for Week 18 and week 24. 
20 IRT order assigned to specific participant. The shipment does not need to be accepted in IRT. Blister Cards will be assigned when the "Record Study Visit" 
action is recorded for Week 30 - Week 70 since no A4 value is needed to determine the dose at these visits. 
21 Bottles of HC for stress dosing (see Section 6.5.1.5) will be dispensed starting at Day 1 and thereafter as needed to replace opened bottles. Accountability for 
HC will be performed at every study visit. 
22 For subjects who are eligible for blinded tildacerfont dose escalation following the indicated study visits (i.e., subjects with A4 >ULN who have not reduced 
GC), the site will telephone the subject again 7 days after the dose adjustment to assess for the occurrence of AEs and the initiation of new concomitant 
medications. Subjects who were not eligible for study drug dose escalation will not be telephoned. 
23 In Part C, subjects with A4 ≤ULN at Week 38 or Week 46 will begin to adjust their daily GC dose level by increments of approximately 5 mg/day HCe each 
time, down to a minimum of 15 mg/day HCe. Sites will contact subjects who are eligible for a GC adjustment by telephone within 2 weeks after each applicable 
study visit. Subjects who are not eligible for a GC adjustment will not be telephoned. 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 a subject’s GC dose is adjusted, the site will telephone the subject 
again 7 days after the dose adjustment to assess for the occurrence of AEs and the initiation of new concomitant medications.  
24 Subjects will use an electronic study diary to document study drug and background GC adherence through Week 18. Female subjects will also use the study 
diary to record menstrual information (including start and stop dates of menses) across the full treatment period up to Week 76. 


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25 A full physical examination will be conducted at Day 1, Week 18, 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. 
26 At Week 6, acne will be evaluated in all subjects and hirsutism in all female subjects. After Week 6, acne/hirsutism will only be evaluated in subjects who had 
acne/hirsutism at Week 6. 
 
1.3.4 
Schedule of OpƟonal Open-Label Extension Period AcƟviƟes  
 
Extension Treatment Period1 
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 blood 2,3 
 
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-36  
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
C-SSRS 5 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Scrotal ultrasound for males 6 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X6 
Concomitant medicaƟons  
 
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 examinaƟon 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Dispense study drug 7 
 
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 contacts 8 
 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Dispense HC for stress dosing and perform accountability 9 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 


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AbbreviaƟons: 17-OHP, 17-hydroxyprogesterone; A4, androstenedione; C-SSRS, Columbia–Suicide Severity RaƟng Scale; ET, early terminaƟon; FCP, female of 
childbearing potenƟal; GC, glucocorƟcoid; HC(e), hydrocorƟsone (equivalents); SF-36, Short Form 36; V, study visit 
Footnotes from 1.3.4 
Schedule of Optional Open-Label Extension Period Activities: 
1 For subjects who conƟnue to the opƟonal Open-Label Extension Period, Week 76 visit (as reﬂected in Table 1.3.3) will be considered as Study Visit 1 for the 
opƟonal Open-Label Extension Period and will be performed within ±3-day window. All visits starƟng Week 88 should be performed within a +30-day window. 
2 Samples for these lab assessments will be obtained at 8 AM (± 1 hour), aŌer an overnight fast (nothing to eat aŌer midnight) and before any morning dose of 
GC medicaƟon. 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. 
4 Vital signs consist of systolic and diastolic blood pressure, pulse rate, body temperature, and respiraƟon rate and will be measured aŌer a 5-min rest period. 
5 SF-36 and C-SSRS are paper based during the opƟonal Open-Label Extension Period. 
6 Scrotal ultrasounds will only be conducted in subjects who had TART(s) at baseline. 
7 Subject will pick up study drug in the clinic. 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 aŌer compleƟng the evening meal, if necessary. 
8 During the Treatment Period, sites will make telephone contacts to subjects who are eligible for a GC dose adjustment within 2 weeks aŌer 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 approximately 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 aŌer the GC dose adjustment to assess for the occurrence of AEs and the iniƟaƟon 
of new concomitant medicaƟons. GC dose may be reduced to a minimum of 15 mg HCe per day (approximately physiologic replacement level). 
9 Botles of HC for stress dosing (see SecƟon 6.5.1.5) will be dispensed as needed. Accountability for botles of HC will be performed at every study visit. 
 
 


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2 INTRODUCTION 
2.1 Study RaƟonale 
CAH is a serious, chronically debilitaƟng, and life-threatening geneƟc disorder characterized by impaired 
adrenal synthesis of corƟsol and overproducƟon of adrenal androgens. CorƟsol deﬁciency disrupts the 
balance of the HPA axis by removing the negaƟve feedback to the hypothalamus and pituitary provided 
by normal levels of corƟsol. This leads to the compensatory hypersecreƟon of CRF by the hypothalamus, 
overproducƟon of ACTH by the pituitary gland, and consequent adrenal hyperplasia and overproducƟon 
of downstream adrenal hormones such as 17-OHP and A4, leading to androgen excess. Androgen excess 
may result in irregular menses, amenorrhea, hirsuƟsm, and virilizaƟon in females; TARTs in males; and 
increased sebum producƟon, acne, altered aŌernoon blood pressure proﬁle, and impaired ferƟlity in 
either sex.  
The current standard of care for CAH is the long-term use of supraphysiologic levels of GCs to replace the 
deﬁcient corƟsol and suppress androgen overproducƟon. This is a problemaƟc therapy with signiﬁcant 
side eﬀects (eg, loss of bone mineral density, iatrogenic Cushing’s syndrome, metabolic disorders, and 
increased cardiovascular risk), a narrow therapeuƟc window, and overall poor treatment eﬀecƟveness. A 
non-steroidal treatment opƟon that both controls androgen levels and reduces paƟent dependence on 
high-dose GCs would be of signiﬁcant beneﬁt to paƟents with CAH. Given the serious nature of CAH and 
the limitaƟons and risks of chronic GC therapy, new treatments are urgently needed for paƟents with 
CAH.  
Tildacerfont, a potent and highly selecƟve 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 overproducƟon by the pituitary and reducing 
excess accumulaƟon of downstream adrenal hormones. This mechanism of acƟon has been validated in 
CAH in earlier-phase clinical studies of Ɵldacerfont. Given its mechanism of acƟon, Ɵldacerfont has the 
potenƟal to eﬀect normalizaƟon of androgen levels while allowing for GC replacement at physiologic 
dose levels. 
To date, Ɵldacerfont has shown an acceptable safety proﬁle at eﬀecƟve 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 Ɵldacerfont as a 
treatment for CAH, with meaningful reducƟons in ACTH (demonstraƟng target engagement) and 17-OHP 
and A4 (demonstraƟng eﬃcacy in decreasing downstream adrenal hormones in CAH), and showed 
conƟnued improvement in biomarker levels over a period of 12 weeks. 
In contrast to previously completed Phase 2 studies of Ɵldacerfont, which were smaller, open-label, and 
shorter in duraƟon, Study SPR001-203 is a larger, randomized, double-blind, placebo-controlled, 
dose-ranging study that will invesƟgate the eﬃcacy and safety of up to 70 weeks of treatment with 
Ɵldacerfont in subjects with classic CAH who have elevated biomarkers at baseline. An opƟonal Open-
Label Extension Period will provide addiƟonal open-label treatment with Ɵldacerfont at 200 mg QD for 
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2.2 Background 
2.2.1 
Congenital Adrenal Hyperplasia 
CAH is a serious and chronically debilitaƟng autosomal recessive geneƟc disorder characterized by 
impaired adrenal synthesis of the corƟcosteroids, corƟsol and aldosterone and consequent 
overproducƟon of adrenal androgens (Merke and Bornstein 2005). Approximately 95% of CAH paƟents 
have a mutaƟon in the CYP21A2 gene, which encodes the cytochrome P450c21 enzyme, commonly 
known as 21-hydroxylase (Arlt 2010; Speiser 2018). MutaƟons in other genes that encode enzymes 
criƟcal 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-deoxycorƟcosterone (a precursor to aldosterone) and the conversion of 17-OHP to 
11-deoxycorƟsol (the precursor to corƟsol) (White and Speiser 2000; Bachelot 2008; Doleschall 2014; 
Auchus 2015). A deﬁciency in 21-hydroxylase thus results in a criƟcal blockade in the adrenal steroid 
synthesis pathways that produce corƟsol (and aldosterone in some individuals) and an accumulaƟon of 
the precursors to these steroids (mostly 17-OHP, since accumulaƟng progesterone is converted to 17-
OHP). These steroid precursors are then diverted into the syntheƟc pathway for adrenal androgens, 
resulƟng in overproducƟon of A4 and downstream adrenal androgens. 
Impaired corƟsol producƟon also disrupts the balance of the HPA axis by removing the negaƟve 
feedback to the hypothalamus and pituitary gland provided by normal levels of corƟsol. This leads to the 
compensatory hypersecreƟon of CRF by the hypothalamus and overproducƟon of ACTH by the pituitary. 
High levels of ACTH sƟmulate the adrenal gland to produce even greater quanƟƟes of 17-OHP, A4, and 
downstream adrenal androgens, resulƟng in adrenal hyperplasia.  
The clinical manifestaƟons of CAH are the direct result of corƟsol and aldosterone deﬁciencies and of 
androgen overproducƟon (Merke and Bornstein 2005; Arlt 2010; Reisch 2019). CorƟsol deﬁciency can 
result in adrenal insuﬃciency and life-threatening adrenal crises. OverproducƟon of adrenal androgens 
may result in advanced skeletal maturaƟon, diminished height potenƟal, premature pubarche, and 
precocious puberty in children; irregular menses, amenorrhea, hirsuƟsm, and virilizaƟon in females; 
TARTs in males; and increased sebum producƟon, acne, altered aŌernoon blood pressure proﬁles, and 
impaired ferƟlity in either sex. 
CAH is typically classiﬁed as either classic (the more severe form that usually presents with adrenal crisis 
in infancy or virilizaƟon during early childhood) or nonclassic (the milder form that may not become 
evident unƟl later childhood or early adulthood). Classic CAH can be further sub-classiﬁed as salt-wasƟng 
or simple virilizing. Approximately 75% of classic CAH paƟents have the salt-wasƟng form of CAH 
characterized by the loss of large amounts of sodium via urine (hyponatremia), hyperkalemia, and 
elevated plasma renin acƟvity indicaƟng hypovolemia, leading to dehydraƟon and hypotension that can 
be life threatening in early infancy (Speiser 2018). Salt-wasƟng CAH is caused by severe aldosterone 
deﬁciency resulƟng from severe mutaƟons that completely ablate 21-hydroxylase acƟvity. Milder 
mutaƟons that result in even 1% to 2% residual 21-hydroxylase acƟvity enable suﬃcient aldosterone 
producƟon to avoid neonatal adrenal crisis and produce the simple virilizing form of CAH in the 
remaining 25% of CAH paƟents. 


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Numerous studies have documented diminished quality of life in paƟents with CAH (Han 2013; Aulinas 
and Webb 2014; Gilban 2014; Hummel 2016). CAH paƟents commonly experience sleep disturbances, 
concentraƟon problems, and challenges with social interacƟons (Malouf 2010). Severe faƟgue is 
experienced by nearly half of CAH paƟents (Giebels 2014), and diminished memory performance has 
also been reported (Browne 2015). Psychiatric disorders and substance-use disorders are common, 
parƟcularly among those with the most severe genotype (Engberg 2015). Faced with the debilitaƟng 
eﬀects of the disease itself, ineﬀecƟve treatment, and/or the severe side eﬀects of long-term high-dose 
GC treatment, CAH paƟents may develop depression and anxiety. PaƟents with CAH have increased 
mortality, with one study documenƟng a mean age of death of 41.2 years in paƟents 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 InvesƟgator’s Brochure (IB) for addiƟonal informaƟon 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 corƟsol and suppress adrenal 
androgen overproducƟon (Speiser 2018). In paƟents with salt-wasƟng CAH, mineralocorƟcoids 
(eg, ﬂudrocorƟsone) are also used to replace aldosterone; before weaning, NaCl supplements are also 
provided to prevent a potenƟally 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 eﬀecƟveness for CAH paƟents is poor (Mnif 2012; Bachelot 2015). 
Treatment of CAH with chronic GCs is a problemaƟc therapy with a narrow therapeuƟc window and 
signiﬁcant side eﬀects. The challenge in using GC therapy to manage CAH lies in striking the diﬃcult 
balance between hyperandrogenism and hypercorƟsolism (Merke 2008; Arlt 2010; Reisch 2019). 
TreaƟng CAH paƟents 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 overproducƟon. 
Hyperandrogenic sequelae include hirsuƟsm, female virilizaƟon, TARTs, acne, and inferƟlity (Merke 2008; 
Reisch 2019). In contrast, treaƟng paƟents with higher, supraphysiologic doses of GCs may suppress 
androgen overproducƟon but oŌen results in iatrogenic hypercorƟsolism. HypercorƟsolism 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 
cogniƟve changes, musculoskeletal eﬀects, gastrointesƟnal (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 oŌen diﬃcult to ﬁnd in the individual paƟent, and paƟents oŌen 
experience hyperandrogenism, hypercorƟsolism, or a combinaƟon of these states (Falhammar 2007; 
Merke 2008). Despite the availability of GCs as a treatment for CAH, approximately two-thirds of CAH 
paƟents are considered outside the acceptable bounds of biochemical control based on 17-OHP and A4 
levels (Han 2014). Among paƟents with 21-hydroxylase deﬁciency treated with GCs, normal serum A4 
has been shown to be achieved in only 36% of paƟents (Arlt 2010).  
 
 


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Over a lifeƟme, the treatment of paƟents with CAH shiŌs from an emphasis on normal childhood growth 
to pubertal development to adult ferƟlity and long-term health concerns, including metabolic 
abnormaliƟes, cardiovascular disease, osteoporosis, and overall diminished quality of life (Arlt 2010; 
Auchus 2015). 
Given the serious nature of CAH and the lack of saƟsfactory available therapies, new treatments are 
urgently needed for paƟents 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 Ɵldacerfont binds to CRF1 receptors with high aﬃnity and speciﬁcity and blocks CRF-
sƟmulated receptor funcƟon. In CAH, Ɵldacerfont is intended to block the CRF signal produced by the 
hypothalamus, thereby decreasing CRF1 receptor–mediated ACTH overproducƟon by the pituitary and 
reducing excessive accumulaƟon of downstream adrenal hormones such as 17-OHP and A4. This 
mechanism of acƟon has been validated in CAH in earlier-phase clinical studies of Ɵldacerfont (see 
SecƟon 2.2.5). Given its mechanism of acƟon, Ɵldacerfont may enable a CAH paƟent to have normal 
androgen levels while taking GC at physiologic replacement levels. 
Nonclinical studies of Ɵldacerfont are summarized in SecƟon 2.2.4. Clinical experience with Ɵldacerfont 
is summarized in SecƟon 2.2.5. 
2.2.4 
Nonclinical Studies of Tildacerfont 
A comprehensive nonclinical development program has been conducted to support clinical development 
of Ɵldacerfont. 
In vitro membrane- and cell-based radioligand binding assays have demonstrated that Ɵldacerfont is a 
potent CRF1 receptor antagonist that is highly selecƟve for the human CRF1 over the human CRF2 
receptor (6.1 nM vs >100 nM, respecƟvely) and inhibits CRF-sƟmulated human CRF1 receptor funcƟon. 
Nonclinical safety pharmacology studies have indicated no undesirable pharmacodynamics (PD) eﬀects 
of Ɵldacerfont on physiological funcƟons. 
Nonclinical PK studies have shown Ɵldacerfont to be quickly absorbed; distributed primarily to 
endocrine, faty, metabolic/excretory, and GI tract Ɵssues and not to melanin-containing Ɵssues; 
metabolized primarily by CYP3A4; and eliminated to below the quanƟtaƟon limit in most Ɵssues by 
168 hours, with the majority of drug substance eliminated from Ɵssues by 72 hours. Refer to 
SecƟon 6.5.2 for informaƟon on potenƟal drug interacƟons of Ɵldacerfont. 
Nonclinical toxicology studies to date include completed genotoxicity studies and adult, juvenile, and 
reproducƟve and developmental toxicology studies.  
• In a standard batery of genotoxicity studies, Ɵldacerfont 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 administraƟon. 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 


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1000/500 mg/kg/day have been evaluated in dogs dosed for 39 weeks. Target organs idenƟﬁed 
histopathologically in rats and/or dogs include the liver, testes/epididymides, and thyroid gland. 
Refer to SecƟon 2.3.1 for a discussion of the potenƟal liver, tesƟcular, and thyroid risks associated 
with Ɵldacerfont. 
• In developmental toxicity studies in juvenile rats administered Ɵldacerfont 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 reproducƟve and developmental toxicity studies, no adverse eﬀects on ferƟlity, early embryonic 
development, embryo-fetal development, or maternal toxicity were noted in rats at Ɵldacerfont 
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 addiƟonal informaƟon on nonclinical studies of Ɵldacerfont. 
2.2.5 
Clinical Experience with Tildacerfont 
Tildacerfont has been studied in 7 completed intervenƟonal clinical studies to date, of which 5 were 
Phase 1 studies and 2 were Phase 2 studies. 
To date, Ɵldacerfont has been well tolerated at eﬀecƟve doses with no related SAEs. Two subjects in 
Phase 2 studies experienced transient elevaƟons in liver funcƟon tests (LFTs) aŌer being administered 
doses higher than those in this study (see SecƟon 2.3.1 for more details). 
Proof of concept for Ɵldacerfont as a CRF1 receptor antagonist in CAH paƟents was demonstrated in the 
Phase 2 Study SPR001-201, which showed clinical evidence of CRF1 receptor target engagement 
(reducƟons in ACTH) and reducƟons in key adrenal hormones (17-OHP and A4) at mulƟple dose levels 
tested. In addiƟon, the Phase 2 Study SPR001-202 showed Ɵldacerfont’s ability to normalize ACTH and 
adrenal hormones with 12 weeks of treatment at a dose of 400 mg QD (see SecƟon 2.3.2 for more 
details). 
2.3 Risk/Beneﬁt Assessment 
2.3.1 
Observed PotenƟal 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 at the highest 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 at the highest 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 at the highest 


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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 degeneraƟon, focal necrosis, vacuolaƟon, bile duct hyperplasia, and/or periportal 
mixed leukocyte inﬁltraƟon associated with increases in gamma-glutamyl transferase (GGT) and ALT 
acƟviƟes (in dogs dosed with 300 and 1000/500 mg/kg/day [>39-fold higher exposure in dog than 
the expected average exposure at the highest 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 elevaƟons in ALT and aspartate aminotransferase (AST) aŌer 
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 elevaƟon of up to 8.6x ULN, and the other subject experienced a mild ALT 
elevaƟon of 2.3x ULN. Concurrent elevaƟons 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 Ɵldacerfont. 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 disconƟnued 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 elevaƟon. 
No treatment-emergent LFT abnormaliƟes were observed in the Phase 1 studies, which treated healthy 
adults with single Ɵldacerfont doses of up to 800 mg and mulƟple Ɵldacerfont doses of up to 200 mg QD 
for 14 days. No LFT abnormaliƟes have been observed in CAH subjects treated with Ɵldacerfont doses of 
≤200 mg QD for 2 weeks in the Phase 2 studies. 
2.3.1.2 
Testicular 
Reversible tesƟcular/spermatocyte degeneraƟon/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 at the highest 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 degeneraƟon/atrophy, and germ cell debris and/or reduced sperm in epididymides. However, 
male reproducƟve studies in rats showed no impairment in ferƟlity at the highest dose tested 
(1,000 mg/kg/day [~39-fold higher]). AddiƟonally, no meaningful eﬀects on clinical laboratory markers of 
tesƟcular funcƟon (luteinizing hormone [LH], follicle-sƟmulaƟng 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 in rat than the 
expected average exposure at the highest 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 Ɵldacerfont administraƟon. Thyroid follicular cell hypertrophy can be 


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associated with increased funcƟonal hepatocellular mass, with increased thyroxine metabolism and 
increased release of thyroid-sƟmulaƟng hormone (TSH) from the pituitary. The clinical relevance of this 
secondary ﬁnding is presently unclear. Thyroid funcƟon was not evaluated in the Phase 1 studies, and no 
meaningful changes in thyroid funcƟon have been observed in the Phase 2 studies. 
2.3.2 
Observed PotenƟal Beneﬁts 
Evidence from nonclinical and available clinical data suggests that Ɵldacerfont is eﬀecƟve as a CRF1 
receptor antagonist.  
Data from Study SPR001-201 (which tested Ɵldacerfont 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 reducƟons in key adrenal hormones in adult subjects with classic CAH. For example, 
aŌer 2 weeks of treatment at a total daily dose of 200 mg, subjects with elevated ACTH at baseline had a 
mean reducƟon in ACTH of approximately 33%, and subjects with elevated biomarkers at baseline had 
mean reducƟons in both 17-OHP and A4 of 13%. The higher total daily doses evaluated in Study SPR001-
201 demonstrated similar eﬃcacy, suggesƟng that a total daily dose of 200 mg may be at the top of the 
dose-response curve. 
Data from Study SPR001-202 (which tested a Ɵldacerfont dose of 400 mg QD for 12 weeks) 
demonstrated conƟnued improvement in ACTH, 17-OHP, and A4 levels over 12 weeks of treatment. 
Subjects with elevated biomarkers at baseline had a maximum mean percentage reducƟon of 68% in 
ACTH, 88% in 17-OHP, and 81% in A4 over 12 weeks of treatment; individual maximum reducƟons 
exceeded 97% for all of these biomarkers. AddiƟonally, 67% of subjects with abnormal ACTH at baseline 
achieved normalizaƟon of ACTH on study, and 40% of subjects with abnormal A4 at baseline achieved 
normalizaƟon of A4 on study. 
2.3.3 
Assessment of PotenƟal Risks and Beneﬁts 
MulƟple study design elements have been incorporated to miƟgate the potenƟal risks of LFT laboratory 
abnormaliƟes, tesƟcular injury, and thyroid eﬀects described in SecƟon 2.3.1. First, these risks are all 
associated with higher doses of Ɵldacerfont; in this study, Ɵldacerfont tablets will be administered at a 
range between 50 mg and 200 mg QD, lower than the doses at which elevated LFTs have been observed 
and doses that have been well tolerated. AddiƟonally, clinical laboratory measures of liver chemistry, 
tesƟcular funcƟon, and thyroid funcƟon 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 Ɵme (PT)/internaƟonal normalized raƟo (INR), and parƟal thromboplasƟn Ɵme 
(PTT). TesƟcular funcƟon will be monitored by measuring LH, FSH, inhibin B, and SHBG and performing 
scrotal ultrasounds. Thyroid funcƟon 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 SecƟon 7.1.1 and SecƟon 13.2). 
The reversible histopathological eﬀects of Ɵldacerfont on the male reproducƟve tract in rat and dog 
toxicity studies occurred in the context of animals with normal, rather than elevated, baseline hormone 
funcƟon. As a CRF1 receptor antagonist, Ɵldacerfont 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 reproducƟve Ɵssues may be expected as a 


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result of androgen reducƟon outside of the normal range. However, in paƟents with CAH, whose 
baseline ACTH and androgen levels are pathologically elevated, androgen reducƟon would be considered 
a posiƟve, therapeuƟc eﬀect. 
The Sponsor believes that the beneﬁt-to-risk proﬁle of this study is favorable. Given the serious nature of 
CAH and the limitaƟons and risks of chronic steroid therapy, new treatment modaliƟes are needed for 
paƟents with CAH. Given 1) the acceptable overall safety and tolerability proﬁle of Ɵldacerfont in healthy 
volunteers and subjects with CAH; 2) the ability to monitor the observed risk of LFT elevaƟon, which is 
reversible and occurred at higher exposures than those expected in this study; and 3) the evidence of 
reducƟons in ACTH, 17-OHP, and A4 at mulƟple dose levels tested in previous Phase 2 studies, the 
Sponsor believes that the beneﬁt-to-risk proﬁle favors the conƟnued clinical invesƟgaƟon of Ɵldacerfont, 
including this randomized, double-blind, placebo-controlled invesƟgaƟon of extended treatment with 
Ɵldacerfont for up to 70 weeks in subjects with CAH. An opƟonal Open-Label Extension Period will 
provide addiƟonal open-label treatment with Ɵldacerfont at 200 mg QD for up to 240 weeks. 
3 OBJECTIVES AND ENDPOINTS 
ObjecƟves 
Endpoints 
Eﬃcacy 
 
Primary Eﬃcacy 
 
To evaluate the eﬀect of Ɵldacerfont in 
reducing A4 in subjects with classic CAH over 
12 weeks 
Assessment of dose response for change from baseline in log A4 
aŌer 12 weeks on double-blind, placebo-controlled treatment 
(Week 18) 
Secondary Eﬃcacy 
 
To evaluate the eﬀect of Ɵldacerfont in reducing 
A4 in subjects with classic CAH over 12 weeks 
Change from baseline in A4 as assessed on the log scale aŌer 
12 weeks on double-blind, placebo-controlled treatment 
(Week 18) 
To evaluate the eﬀect of Ɵldacerfont in reducing 
A4 in subjects with classic CAH over 12 weeks 
Absolute change from baseline in A4 as determined via 
applicaƟon of the delta theorem to the log scale analysis results 
aŌer 12 weeks on double-blind, placebo-controlled treatment 
(Week 18) 
To evaluate the eﬀect of Ɵldacerfont in reducing 
17-OHP in subjects with classic CAH over 12 
weeks 
Assessment of dose response for change from baseline in log 
17-OHP aŌer 12 weeks on double-blind, placebo-controlled 
treatment (Week 18) 
To evaluate the eﬀect of Ɵldacerfont in reducing 
17-OHP in subjects with classic CAH over 12 
weeks 
Change from baseline in 17-OHP as assessed on the log scale 
aŌer 12 weeks on double-blind, placebo-controlled treatment 
(Week 18) 
To evaluate the eﬀect of Ɵldacerfont in reducing 
17-OHP in subjects with classic CAH over 12 
weeks 
Absolute change from baseline in 17-OHP as determined via 
applicaƟon of the delta theorem to the log scale analysis results 
aŌer 12 weeks on double-blind, placebo-controlled treatment 
(Week 18) 
Exploratory Eﬃcacy 
 
To evaluate the eﬀect of Ɵldacerfont in reducing 
A4 in subjects with classic CAH over 12 weeks 
ProporƟon of subjects who achieve adequate control of A4 
(A4 ≤ 1x, 1.25x, 1.5x, 1.75x and 2x ULN) aŌer 12 weeks on 


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ObjecƟves 
Endpoints 
double-blind, placebo-controlled treatment (Week 18) for each 
treatment group 
To evaluate the eﬀect of Ɵldacerfont in reducing 
17-OHP in subjects with classic CAH over 12 weeks 
ProporƟon of subjects who achieve adequate control of 17-OHP 
(17-OHP ≤ 1200 ng/dL) aŌer 12 weeks on double-blind, 
placebo-controlled treatment (Week 18) for each treatment 
group 
To evaluate the eﬀect of Ɵldacerfont in reducing 
tesƟcular adrenal rest tumor(s) (TART[s]) in male 
classic CAH subjects with TART(s) at baseline aŌer 
12 weeks on treatment 
Change in the lesion volume of TART(s) from baseline aŌer 
12 weeks on double-blind, placebo-controlled treatment 
(Week 18) for each treatment group 
To characterize dose-exposure of Tildacerfont in 
CAH 
CorrelaƟon of Tildacerfont plasma concentraƟon vs dose   
To evaluate the eﬀect of Ɵldacerfont on 
biomarkers relaƟve to each other in subjects with 
classic CAH over 12 weeks 
EsƟmate the within subject correlaƟon of A4 and 17-OHP log 
scale values over Ɵme 
To evaluate the eﬀect of Ɵldacerfont in improving 
quality of life (QoL) in subjects with classic CAH 
aŌer 12 weeks on treatment 
Change from baseline in SF-36 total score aŌer 12 weeks on 
double-blind, placebo-controlled treatment (Week 18) for each 
treatment group 
To evaluate the eﬀect of Ɵldacerfont in improving 
QoL in subjects with classic CAH 
Change from baseline at Week 76 in SF-36 total score across all 
ITT subjects 
To evaluate the eﬀect of Ɵldacerfont in improving 
acne in classic CAH subjects with acne at baseline 
Change from baseline at Week 76 in IGA of acne severity score 
across all ITT subjects with acne at baseline 
To evaluate the eﬀect of Ɵldacerfont in improving 
hirsuƟsm in female classic CAH subjects with 
hirsuƟsm at baseline 
Change from baseline at Week 76 in modiﬁed Ferriman Gallwey 
(mFG) score for hirsuƟsm across all female ITT subjects with 
hirsuƟsm at baseline 
To evaluate the proporƟon of subjects who can 
reduce GC use in subjects with classic CAH 
ProporƟon of subjects with at least a 5 mg/day 
hydrocorƟsone   equivalent (HCe) reducƟon from baseline in GC 
dose and A4 ≤ ULN at Week 76 
To evaluate the eﬀect of Ɵldacerfont in reducing 
TART(s) in male classic CAH subjects with TART(s) 
at baseline 
Change in the total lesion volume of TART(s) from baseline at 
Week 76 across all male ITT subjects with TART(s) at baseline 
To evaluate the eﬀect of Ɵldacerfont in reducing 
A4 in subjects with classic CAH over 12 weeks 
Assessment of dose response for change from baseline in log 
ATCH aŌer 12 weeks on double-blind, placebo-controlled 
treatment (Week 18) 
To evaluate the eﬀect of Ɵldacerfont in reducing 
ATCH in subjects with classic CAH over 12 weeks 
Absolute change from baseline in ACTH as determined via 
applicaƟon of the delta theorem to the log scale analysis results 
aŌer 12 weeks on double-blind, placebo-controlled treatment 
(Week 18) 
To evaluate the eﬀect of Ɵldacerfont in reducing 
ACTH in subjects with classic CAH over 12 weeks 
Change from baseline in ACTH as assessed on the log scale aŌer 
12 weeks on double-blind, placebo-controlled treatment 
(Week 18) 
To characterize dose-exposure of Tildacerfont in 
CAH 
EsƟmate the within subject correlaƟon of A4 and 17-OHP log 
scale values with Ɵldacerfont plasma concentraƟons over Ɵme 
Exploratory Eﬃcacy (Optional Open-Label Extension Period) 
To evaluate the eﬀect of Ɵldacerfont in 
reducing GC use to near-physiologic levels in 
subjects with CAH 
ProporƟon of subjects with GC dose ≤25 mg/day in HCe 
and A4 ≤ULN at end of treatment (EOT)  


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ObjecƟves 
Endpoints 
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 Ɵldacerfont in 
reducing cardiovascular risk in subjects with 
CAH and at least one cardiovascular risk 
factor at baseline 
ProporƟon of subjects with improvement in at least one 
cardiovascular risk factor at EOT 
To evaluate the eﬀect of Ɵldacerfont in 
reducing TART(s) in male CAH subjects with 
TART(s) at baseline 
ProporƟon of male subjects with reducƟon in TART(s) at 
EOT who had TART(s) at baseline 
Safety 
 
To evaluate the safety of Ɵldacerfont in 
subjects with CAH 
AEs, SAEs 
4 STUDY DESIGN 
4.1 Overall Design 
This is a study with a 3-part treatment period that will evaluate the eﬃcacy and safety of up to 70 weeks 
of treatment with Ɵldacerfont in subjects with classic CAH who have elevated biomarkers at baseline. An 
opƟonal Open-Label Extension Period will provide addiƟonal open-label treatment with Ɵldacerfont at 
200 mg QD for up to 240 weeks. 
4.1.1 
Study Periods 
Refer to the study schemaƟc provided in SecƟon 1.2.  
This study will consist of the following periods: 
• A ≤45-day Screening Period for conﬁrmaƟon of eligibility 
o OpƟonal A4 Screening Visit 
o Screening informaƟon captured within 45 days of Day 1 in this study (parƟcularly screening 
informaƟon transferred from Spruce Biosciences Study SPR001-204 to this study) may be used 
to determine eligibility and fulﬁll screening requirements for this study.  
• A 6-week, single-blind, placebo Run-in Period, during which subjects will be assessed for adherence 
to their exisƟng GC therapy and daily ingesƟon of placebo with food 
• Subjects who conƟnue to meet all eligibility criteria at the end of the Run-in Period will then enter a 
3-part Treatment Period: 
o Part A:  The ﬁrst 12 weeks of the Treatment Period will be a randomized, double-blind, placebo-
controlled, dose-ranging study. Subjects will be randomized in a 1:1:1:1 raƟo to receive either 
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o Part B:  During the second 12 weeks of the Treatment Period, all subjects will receive acƟve 
drug (Ɵldacerfont), with possible dose escalaƟon for eligible subjects. Subjects and InvesƟgators 
will remain blinded to previous treatment in Part A and dose level of Ɵldacerfont in Part B. 
 Subjects who were randomized to placebo in Part A will receive Ɵldacerfont at 100 mg QD 
at the beginning of Part B. 
 Subjects who were randomized to Ɵldacerfont at 200 mg QD in Part A will conƟnue to 
receive Ɵldacerfont at 200 mg QD in Part B. 
 Subjects who were randomized to Ɵldacerfont at 50 mg QD or 100 mg QD in Part A will 
conƟnue to receive the same dose at the beginning of Part B if they have A4 ≤ULN at Week 
18. These subjects will be escalated to the next highest dose at the beginning of Part B if 
they have A4 >ULN at Week 18 (ie, subjects previously on 50 mg QD would be escalated to 
100 mg QD, and subjects previously on 100 mg QD would be escalated to 200 mg QD). 
Based on the results of the Week 24 visit of Part B, subjects will have another opportunity for 
Ɵldacerfont dose escalaƟon if they have A4 >ULN and are toleraƟng their current dose of 
Ɵldacerfont. Speciﬁcally: 
 Subjects currently taking 50 mg QD will be escalated to 100 mg QD. 
 Subjects currently taking 100 mg QD will be escalated to 200 mg QD. 
o Part C:  During the last 46 weeks of the Treatment Period, all subjects will be escalated to 200 
mg QD, with periodic opportuniƟes for GC adjustment for eligible subjects. Subjects and 
InvesƟgators will conƟnue to remain blinded to previous treatment in Part A and dose level of 
Ɵldacerfont in Parts B and C. 
 Subjects with A4 ≤ULN at Week 38 or Week 46 will begin to reduce their daily GC dose 
level by increments of approximately 5 mg/day HCe each Ɵme, down to a minimum of 15 
mg/day HCe (see SecƟon 6.5.1.4).  
• 
For subject’s conƟnuing into the opƟonal Open-Label Extension Period 
o The Open-Label Extension Period will provide subjects with up to 240 weeks of treatment with 
Ɵldacerfont 200 mg QD.  
o Subjects will be eligible to adjust GC dose level at each visit (see SecƟon 6.5.1.4). 
• 
A 30-day Follow-up Period at EOT 
o Subjects who do not conƟnue to the Open-Label Extension Period upon compleƟon of 
Treatment Period Part C will enter a 30-day Follow-up Period. 
o Upon compleƟon 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 mineralocorƟcoid 
regimen (as applicable) established during Part C unƟl the 30-day follow-up visit unless the 
InvesƟgator determines that the subject’s clinical status necessitates a dosing change. AŌer 
compleƟon of the study, GC therapy will be managed at the discreƟon of the subject’s treaƟng 
physician.  
Changes in GC dosing are generally not permited during this study except aŌer certain visits in Part C, 
the opƟonal Open-Label Extension Period, and in the case of stress dosing throughout the study. During 
Ɵmes of clinically signiﬁcant physical stress such as intercurrent illness with fever, surgical procedures, or 


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signiﬁcant trauma, stress dosing with extra GC (in the form of HC) for prevenƟon of adrenal crisis will be 
allowed according to “sick day guidelines” (see SecƟon 6.5.1.5). 
4.1.2 
Study Visits and Telephone Contacts 
4.1.2.1 
Study Visit Schedule 
• During the Screening Period: 
o Screening Visit at ≤45 days before Day 1   
o OpƟonal A4 Screening Visit ≤45 days before Day 1 
• During the Run-in Period: visits at Day 1 and Week 4; scheduled telephone contact at Week 2 
• During the Treatment Period: 
o Part A: visits every 4 weeks, at Week 6 (baseline) and at Weeks 10, 14, and 18; scheduled 
telephone contact at Week 8 
o Part B: visits every 6 weeks, at Weeks 24 and 30; scheduled telephone contact at Week 21 
o Part C: visits every 6 to 12 weeks, at Weeks 38, 46, and 58, 70, and 76; scheduled telephone 
contact at Week 52 
• During the opƟonal 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 aŌer the last dose of study drug for ﬁnal safety follow-up 
• PRN telephone contacts are detailed in SecƟon 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.  Since the COVID-19 pandemic is expected to 
conƟnue during the conduct of this trial, study visits can be adapted into a combinaƟon of in-clinic and 
telemedicine acƟviƟes, with opƟonal at-home visits, to miƟgate the risk of COVID-19 infecƟon associated 
with study parƟcipaƟon and to accommodate local and individual circumstances while maintaining 
parƟcipant access to healthcare resources. 
Some of the clinic acƟviƟes of the Screening Visit may be conducted remotely (at the subject’s home) if 
approved by the site’s IRB/EC. 
The EDC system will capture the mode by which data are collected for each visit/acƟvity.  
If home visits are conducted, the qualiﬁed medical professionals who will perform the study’s home 
visits are deﬁned as individuals who meet naƟonal/local licensing requirements needed to perform the 
procedures required at the home visits. Their naƟonal/local licensure will be veriﬁed, and they will 
complete training on the study protocol and GCP. If the medical professional does not meet the 
naƟonal/local licensing requirements needed to perform the opƟonal home visit acƟviƟes (physical 
examinaƟon, acne IGA score, and hirsuƟsm mFG score for females), the InvesƟgator or InvesƟgator-
delegated study personnel must complete these acƟviƟes for each visit. 
Refer to SecƟon 11 for more informaƟon on study conduct in the context of COVID-19 or other logisƟcal 
challenges. 


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4.1.2.3 
Telephone Contacts 
Sites will make scheduled telephone contacts to all subjects at Weeks 2, 8, 21, and 52 to record any AEs 
and concomitant medicaƟons. During the Week 2 telephone contact, sites will also conﬁrm subject 
adherence to study acƟviƟes. 
AŌer receiving A4 results, sites will make telephone contacts to applicable subjects concerning 
Ɵldacerfont or GC adjustment. 
• For subjects who are eligible for GC adjustment following the Week 38 and/or 46 study visits or 
during the opƟonal Open-Label Extension Period, sites will contact these subjects by telephone 
within 2 weeks aŌer the applicable study visit. The site will direct a subject to reduce his/her GC 
dose at that Ɵme 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 aŌer the dose adjustment to assess for the occurrence of AEs and the iniƟaƟon of new 
concomitant medicaƟons. 
Subjects should be instructed to telephone sites if they have any concerns about their health.  
PRN telephone contacts iniƟated by sites and telephone contacts iniƟated by subjects should be 
captured in the EDC system as “unscheduled” telephone contacts. 
4.1.3 
Study Diary/Drug Adherence Data CollecƟon 
Subjects will be asked to maintain an electronic study diary to capture daily informaƟon during the Run-
in and Treatment Periods. The InvesƟgator is responsible for ensuring that subjects record the 
appropriate informaƟon in their diaries. Subjects will document study drug and background GC 
adherence through Week 18. Female subjects will also use the study diary to record menstrual 
informaƟon (including start and stop dates of menses) across the full treatment period up to Week 76. 
4.2 ScienƟﬁc RaƟonale for Study Design 
In previous Phase 2 studies, Ɵldacerfont 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 
conƟnued clinical development of Ɵldacerfont.  
Previous Phase 2 studies of Ɵldacerfont were open-label, smaller in sample size, and shorter in duraƟon. 
The iniƟal Phase 2 Study SPR001-201 was a dose-ranging study that treated 26 CAH subjects with 
Ɵldacerfont for 2 weeks at each dose level ranging from 200 mg to 1000 mg per day. Eﬃcacy was 
observed at all dose levels/regimens of Ɵldacerfont tested without evidence of a dose trend in eﬃcacy 
response. Thus, a clear exposure-response proﬁle and an opƟmal dose were not established. The 
subsequent Phase 2 Study SPR001-202 enrolled 11 subjects with CAH (9 subjects who previously 
parƟcipated in Study SPR001-201 and 2 Ɵldacerfont-naïve subjects) and treated them with Ɵldacerfont 
400 mg QD for 12 weeks. The magnitude of the eﬃcacy response strengthened over 12 weeks of 
therapy, suggesƟng that the full treatment eﬀect of Ɵldacerfont may only be revealed aŌer longer-term 
therapy and that the 2 weeks of treatment at each dose level in Study SPR001-201 may not have been 
long enough to eﬀecƟvely dose-range. 


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Study SPR001-203 will provide a placebo-controlled, powered, longer-duraƟon, and more deﬁniƟve 
dataset than previous Phase 2 studies. Study SPR001-203 will enroll approximately 72 subjects for a 
cumulaƟve treatment duraƟon of 70 weeks. The Treatment Period will consist of a 12-week, randomized, 
double-blind, placebo-controlled, dose-ﬁnding treatment period (Part A); followed by a 12-week 
treatment period in which all subjects are treated with acƟve drug, with possible dose escalaƟon (Part 
B); followed by a 46-week treatment period in which all subjects are treated with acƟve drug, with 
possible GC adjustment (Part C). The placebo treatment group in Part A will control for any potenƟal 
placebo eﬀects in CAH paƟents and their impact on the overall Ɵldacerfont treatment eﬀect. Parts B and 
C will allow further monitoring for clinical outcomes associated with biomarker control, provide subjects 
randomized to placebo in Part A with acƟve study drug, and in Part B, dose-escalate subjects who did not 
achieve response based on A4 ≤ULN. This dose-escalaƟon strategy may help to determine whether a 
higher dose may be necessary for hormone control in subjects with higher baseline hormone levels. 
Study SPR001-203 will explore total daily doses of Ɵldacerfont tablet ≤200 mg with the objecƟve of 
establishing a clear exposure-response proﬁle and idenƟfying an opƟmal dose for the management of 
CAH (see SecƟon 4.3 for jusƟﬁcaƟon of dose). 
Eligibility for Studies SPR001-201 and SPR001-202 was based primarily on elevated 17-OHP. This 
contributed to the recruitment of a heterogeneous populaƟon of CAH paƟents that may have obscured 
the eﬃcacy signal across diﬀerent dose cohorts. Subgroup analyses of data from these studies using 
baseline A4 and ACTH levels to straƟfy subjects revealed 2 disƟnct subgroups of subjects that diﬀered by 
their mean background GC dose at study entry and Ɵldacerfont PD response proﬁles. These 2 subgroups 
had potenƟally diﬀerent treatment goals. The subgroup of subjects with elevated A4 and ACTH showed 
greater, more consistent reducƟons in key hormones in response to Ɵldacerfont treatment than the 
subgroup of subjects with lower A4 and ACTH. Subjects with elevated A4 and ACTH would require 
reducƟons in key hormones before any GC dose reducƟon and consƟtute an appropriate subpopulaƟon 
of CAH paƟents for the current study design. Parts A, B, and C will provide this subject populaƟon with 
Ɵme to achieve hormone control on Ɵldacerfont, with possible Ɵldacerfont dose escalaƟon in Part B to 
ﬁnd the best dose for each subject. AddiƟonally, Part C will provide those subjects who are able to 
achieve A4 control on Ɵldacerfont with opportuniƟes to reduce their GC dose. Study SPR001-203 has 
inclusion criteria based on elevated A4 to yield a more homogeneous study populaƟon from which to 
draw more robust conclusions. 
PaƟents on dexamethasone are excluded from this study because dexamethasone may have a moderate 
drug interacƟon with Ɵldacerfont that would confound eﬃcacy analysis. GC exposure data from Study 
SPR001-201 showed a posiƟve signal for drug-drug interacƟon (DDI) potenƟal between Ɵldacerfont and 
dexamethasone, with Ɵldacerfont increasing dexamethasone exposures approximately 1.8-fold and with 
the lower bound of the associated 95% conﬁdence intervals (CIs) generally above 1.0. See SecƟon 6.5.1.3 
for more informaƟon. 
An important goal of treatment in CAH is the reducƟon of adrenal hormone levels. To that end, this 
study will evaluate the eﬀect of Ɵldacerfont on A4 levels as its primary endpoint and the eﬀect of 
Ɵldacerfont on 17-OHP as a secondary endpoint. Exploratory eﬃcacy endpoints will assess addiƟonal 
clinical beneﬁt associated with biomarker control in terms of improvements to QoL, acne, hirsuƟsm in 
females, and TARTs in males. 


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Another important goal of treatment in CAH is the reducƟon of GC dose requirements (Speiser 2018). To 
that end, Part C of this study and the opƟonal Open-Label Extension Period will explore the potenƟal GC-
sparing eﬀects of Ɵldacerfont in subjects with elevated baseline A4 who are able to achieve A4 control 
on Ɵldacerfont. In Part C, and in the opƟonal Open-Label Extension Period, eligible subjects may begin to 
reduce their GC doses. The change from baseline in GC dose and the proporƟon of subjects with at least 
a 5 mg/day HCe reducƟon from baseline in GC dose at the end of Part C (while maintaining A4 ≤ULN) will 
be evaluated as an exploratory eﬃcacy endpoint. 
The placebo Run-in Period provides subjects Ɵme to acclimate to parƟcipaƟon in a clinical study, which 
can oŌen change subject behavior, before acƟve therapy with Ɵldacerfont is iniƟated. In the case of CAH 
paƟents parƟcipaƟng in this study, behavior changes may include improved dosing adherence to 
background GC medicaƟons and alteraƟons in daily rouƟne (such as changes to sleep schedules and 
mealƟmes) to accommodate morning laboratory assessments and daily study drug dosing with an 
evening meal. Such changes may produce eﬀects on biomarkers independent of Ɵldacerfont. The Run-in 
Period thus serves to ensure that subjects are on a stable baseline regimen of GC replacement therapy 
before the start of Ɵldacerfont dosing and provides for more accurate and stable baseline data. 
The 70-week treatment duraƟon and the opƟonal Open-Label Extension Period will provide 
longer-duraƟon informaƟon than previous Phase 2 clinical studies on the eﬀects of Ɵldacerfont on 
adrenal hormones and on whether eﬀects on other clinical outcome measures of concern can be 
achieved with Ɵldacerfont. The 30-day post-treatment washout period allows for adequate safety follow-
up and analysis of any HPA axis rebound aŌer the last dose of study drug. 
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 Ɵldacerfont in a 
fed state improves drug absorpƟon. The meal should contain approximately 25 -50% fat content because 
high fat intake with study drug may increase drug accumulaƟon. 
Individual treatment-stopping criteria and appropriate laboratory and medical assessments have been 
established to ensure subject safety. 
4.3 JusƟﬁcaƟon for Dose 
In Study SPR001-203, Ɵldacerfont tablets will be administered at doses ranging from 50 mg to 200 mg 
QD with the objecƟve of establishing a clear exposure-response proﬁle and idenƟfying an opƟmal dose 
for the management of CAH. Data from previous Phase 1 and Phase 2 studies support the safety and 
potenƟal PD eﬀects of these doses and provide the raƟonale for using these doses to achieve the 
aforemenƟoned objecƟves. 
The safety data show that Ɵldacerfont has been generally well tolerated in all clinical studies to date, 
with no related SAEs. Speciﬁcally, Ɵldacerfont 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 (reducƟons in ACTH) and reducƟons 
in key adrenal hormones (17-OHP and A4) in subjects with CAH dosed for 2 weeks with 200 mg/day 


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Ɵldacerfont, the lowest dose previously tested in subjects with CAH (see SecƟon 2.3.2). However, 
eﬃcacy was also observed at mulƟple dose levels/regimens of Ɵldacerfont tested, without evidence of a 
dose trend in eﬃcacy response. Thus, a clear exposure-response proﬁle and an opƟmal dose have not 
been established. 
A 1-compartment PK model with ﬁrst-order absorpƟon and eliminaƟon was ﬁt to PK data from Study 
SPR001-201. This model was then used to esƟmate 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 Ɵldacerfont, with no addiƟonal beneﬁt at 
the higher doses. This suggests the need for further dose-ranging at doses ≤200 mg/day. 
The long half-life of Ɵldacerfont, esƟmated to be approximately 60 hours aŌer single-dose 
administraƟon, supports QD dosing in this study. 
Guided by the safety, eﬃcacy, and exposure-response analyses from available clinical data, Spruce has 
selected Ɵldacerfont tablet doses of 50 mg, 100 mg, and 200 mg QD for tesƟng in Study SPR001-203. 
These doses lie within a clinically precedented dose range that has been well tolerated and will help to 
establish a clearer exposure-response proﬁle and an opƟmal dose. 
4.4 End of Study  
4.4.1 
End of Study DeﬁniƟon 
A subject is considered to have completed study treatment if the subject has completed all visits through 
Week 76 of the Treatment Period. A subject is considered to have completed the study if the subject has 
completed all phases of the study, including the ﬁnal 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 
OpƟonal Open-Label Extension Period 
Subjects who successfully complete all visits in the Treatment Period will be eligible to parƟcipate in an 
opƟonal Open-Label Extension Period for up to 240 weeks of addiƟonal study treatment. If addiƟonal 
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 
disconƟnued early. 
The end of the study is deﬁned as the date of the last follow-up visit of the last subject in the study. 
 


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5 STUDY POPULATION 
This study will randomize approximately 72 subjects with classic CAH currently receiving GC therapy into 
the start of the Treatment Period. The study will enroll subjects at approximately 130 invesƟgaƟve sites 
globally. 
All applicable screening evaluaƟons must be completed and reviewed to conﬁrm that potenƟal subjects 
meet all eligibility criteria. The InvesƟgator 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 informaƟon from the parallel Spruce Biosciences Study SPR001-204 may be used to determine 
eligibility and fulﬁll screening requirements for this study if the informaƟon was captured within 45 days 
before Day 1 in this study. 
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 geneƟc 
mutaƟon in CYP21A2 and/or documented (at any Ɵme) elevated 17-OHP and currently treated with 
HC, HC acetate, prednisone, prednisolone, methylprednisolone (or a combinaƟon of the 
aforemenƟoned GCs) 
3. Has been on a stable, supraphysiologic dose of GC replacement (deﬁned as ≥15 mg/day and ≤60 
mg/day in HCe) for ≥1 month before screening 
4. Has A4 >ULN at both screening and Week 4 (measured before any AM GC dose) if daily GC dose <30 
mg OR has A4 >2.5x ULN at both screening and Week 4 (measured before any AM GC dose) 
5. For subjects with the salt-wasƟng form of CAH, subject has been on a stable dose of 
mineralocorƟcoid replacement for ≥1 month before screening 
6. Agrees to follow contracepƟon guidelines (SecƟon 5.2.5). Male subjects must also agree to refrain 
from donaƟng sperm throughout the treatment period and for 90 days aŌer the last dose of study 
drug. 
7. Is able to understand all study procedures and risks involved and provides writen informed consent 
indicaƟng 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) 


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2. Has a history that includes bilateral adrenalectomy or hypopituitarism 
3. Has a history of allergy or hypersensiƟvity to Ɵldacerfont, any of its excipients, or any other CRF1 
receptor antagonist 
4. Current treatment with dexamethasone as GC therapy for CAH 
a. Prior treatment with dexamethasone is allowed as long as the transiƟon to an alternaƟve GC 
regimen (eg, HC, prednisone, or prednisolone) has resulted in a stable dose of GC replacement 
for ≥1 month before screening. 
5. Is not adherent to GC or study drug dosing regimen during the Run-in Period (deﬁned as taking <80% 
of expected doses based on drug accountability) 
6. Shows clinical signs or symptoms of adrenal insuﬃciency 
7. Has had a clinically signiﬁcant unstable medical condiƟon, 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 excepƟon 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 parƟcipaƟng in the 
study, based on the opinion of the InvesƟgator 
e. AcƟve hepaƟƟs B, hepaƟƟs C, or HIV at screening 
f. 
Subjects who plan to undergo bariatric surgery during the study are excluded. 
g. Any other condiƟon that would impact subject safety or confound interpretaƟon of study 
results  
8. Psychiatric condiƟons, including but not limited to bipolar disorder, schizophrenia, or schizoaﬀecƟve 
disorders that are not eﬀecƟvely controlled on medicaƟon and may have an adverse impact on study 
compliance. Symptoms including hallucinaƟons, delusions, and psychosis are exclusionary. 
AddiƟonally: 
a. Increased risk of suicide based on the InvesƟgator’s judgment or the results of the C-SSRS 
conducted at screening and Week 6 (eg, C-SSRS Type 3, 4, or 5 ideaƟon 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 Week 6 
9. 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 parƟcipants 
or >470 ms for female parƟcipants 
b. ALT >2x ULN 
c. Total bilirubin >1.5x ULN  
d. Total bile acids >5x ULN 


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10. RouƟnely works overnight shiŌs 
11. Subjects with travel plans/work schedules that result in signiﬁcant and frequent changes in Ɵme 
zones (>2 hours) will require Medical Monitor approval for enrollment. 
12. Females who are pregnant or nursing 
13. Use of any other invesƟgaƟonal drug from 30 days or 5 half-lives (whichever is longer) before 
screening to the end of the study 
14. Use of the following drugs from 30 days or 5 half-lives (whichever is longer) before Day 1 to the end 
of the study: 
a. Rosiglitazone, aromatase inhibitors, testosterone, growth hormones, or any other medicaƟon 
or supplement that could impact subject safety or confound interpretaƟon of study results  
b. The drugs listed in SecƟon 13.1, which are: 
i. Moderate to strong inhibitors and/or inducers of CYP3A4 
ii. SensiƟve substrates or narrow-therapeuƟc-range substrates of CYP3A4 (except hormonal 
contracepƟon containing ≤35 µg ethinyl estradiol) 
iii. SensiƟve substrates or narrow-therapeuƟc-range substrates of BCRP (except those that can 
be administered QD in the morning, separated by approximately 10 hours from evening 
administraƟon of study drug) 
15. DonaƟon or receipt of blood from 90 days before Screening to the end of the study; donaƟon or 
receipt of platelets, white blood cells, or plasma from 30 days before Screening to the end of the 
study 
5.2 Lifestyle ConsideraƟons 
5.2.1 
ShiŌ 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 rouƟnely work overnight shiŌs are 
not eligible for this study, and subjects with travel plans/work schedules that result in signiﬁcant and 
frequent changes in Ɵme zones (>2 hours) require Medical Monitor approval for enrollment. 
5.2.2 
Meals and Dietary RestricƟons 
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 aŌer compleƟng the evening meal, if necessary. If a subject has not 
consumed study drug within 30 minutes aŌer 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 consumpƟon 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 unƟl aŌer the ﬁnal 
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5.2.3 
Caﬀeine, Alcohol, and Tobacco 
Subjects will abstain from imbibing alcohol within 12 hours before the blood draw (aŌer 8 PM). 
Subjects should not use nicoƟne-containing products or drink caﬀeinated beverages within 30 minutes 
before any study-related procedure. 
5.2.4 
AcƟvity 
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 
ContracepƟon Guidelines 
5.2.5.1 
Contraception Guidelines for Male Subjects 
A male enrolling in this study must meet ONE of the following contracepƟve criteria from Screening unƟl 
90 days aŌer the last dose of study drug: 
1. Is sexually absƟnent from penile-vaginal intercourse as his usual and preferred lifestyle (absƟnent 
on a long-term and persistent basis) and agrees to remain absƟnent from Screening unƟl 90 days 
aŌer 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 
eﬀecƟve contracepƟve methods from Screening unƟl 90 days aŌer the last dose of study drug: 
a. Combined hormonal contracepƟon (containing estrogen and progestogen) associated with 
inhibiƟon of ovulaƟon: oral, intravaginal, or transdermal 
b. Progestogen-only hormonal contracepƟon associated with inhibiƟon of ovulaƟon: 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 contracepƟve criteria from Screening 
unƟl 30 days aŌer 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 alternaƟve medical 
cause. A high FSH level in the postmenopausal range may be used to conﬁrm a postmenopausal 
state in women not using hormonal contracepƟon or hormonal replacement therapy. However, a 
single FSH measurement is insuﬃcient to establish a postmenopausal state without at least 1 year 
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2. Has documentaƟon of one of the following performed before Screening: 
a. Hysterectomy 
b. Bilateral salpingectomy 
c. Bilateral oophorectomy 
3. Is sexually absƟnent from penile-vaginal intercourse as her usual and preferred lifestyle (absƟnent 
on a long-term and persistent basis) and agrees to remain absƟnent from Screening unƟl 30 days 
aŌer 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 eﬀecƟve contracepƟve methods, which must be in place 
from at least 1 month before Screening unƟl 30 days aŌer the last dose of study drug: 
a. Combined hormonal contracepƟon (containing estrogen and progestogen) associated with 
inhibiƟon of ovulaƟon: oral, intravaginal, or transdermal 
Any hormonal contracepƟon containing ethinyl estradiol must contain ≤35 µg ethinyl 
estradiol, is permited only for subjects who would not be considered at high risk for 
thromboembolic or cardiovascular complicaƟons with estrogen use, and must be used 
simultaneously with a backup method of contracepƟon. Acceptable backup methods of 
contracepƟon include diaphragm with spermicide, cervical cap with spermicide, vaginal 
sponge with spermicide, and male or female condom with or without spermicide. Dosing of 
oral formulaƟons of hormonal contracepƟon containing ethinyl estradiol should be oﬀset by 
approximately 10 hours from the evening dose of study drug. The InvesƟgator may consult 
with the Medical Monitor regarding such individuals. 
b. Progestogen-only hormonal contracepƟon associated with inhibiƟon of ovulaƟon: oral, 
injectable, or implantable 
c. IUD 
d. IUS 
e. Bilateral tubal occlusion 
5.3 Screen Failures 
Screen failures are deﬁned as parƟcipants who consent to parƟcipate but are not subsequently 
randomized in the study. A minimal set of screen failure informaƟon is required to ensure transparent 
reporƟng of screen failure parƟcipants to meet the Consolidated Standards of ReporƟng Trials 
(CONSORT) publishing requirements and to respond to queries from regulatory authoriƟes. Minimal 
informaƟon includes demography, screen failure details, and eligibility criteria. 
If a subject fails to meet eligibility criteria during or at the end of the Run-in Period, the invesƟgaƟonal 
site will schedule an abbreviated early terminaƟon visit to review AEs and concomitant medicaƟons and 
perform an abbreviated physical examinaƟon (preferably in the clinic, but also permissible via home 
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Individuals who do not meet the following criteria for parƟcipaƟon in the study may be rescreened 
according to the following guidelines: 
• Individuals who do not meet the screening A4 inclusion criteria may be rescreened if their GC 
replacement dose is reduced and stable for ≥1 month. The InvesƟgator will ﬁrst consult with the 
Medical Monitor regarding such individuals. Any morning dose of GC medicaƟon should be taken 
aŌer the screening blood draw to allow for an unimpeded assessment of hormones. 
• Individuals on incompaƟble or excluded concomitant medicaƟons may be rescreened aŌer an 
appropriate washout period (eg, 30 days or 5 half-lives, whichever is longer). The InvesƟgator 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 the start of the Treatment Period if the InvesƟgator believes that the prior 
laboratory value is not consistent with the individual’s overall clinical picture. The InvesƟgator will 
ﬁrst consult with the Medical Monitor regarding such individuals. 
If appropriate, screening informaƟon transferred from Spruce Biosciences Study SPR001-204 to this 
study may be used to determine eligibility and fulﬁll screening requirements for this study.  
6 STUDY INTERVENTION 
6.1 Study IntervenƟon AdministraƟon 
6.1.1 
Study IntervenƟon DescripƟon 
Tildacerfont is a small-molecule CRF1 receptor antagonist.  
Details about the physical, chemical, and pharmaceuƟcal properƟes of Ɵldacerfont are provided in the 
IB. 
Study drug is deﬁned as either Ɵldacerfont or placebo. 
Study treatment is deﬁned more broadly as study drug or HC for stress dosing provided by the Sponsor. 
6.1.2 
Treatment Assignment, Dosing, and AdministraƟon 
Subjects will use their own physician-prescribed supply of GCs as prescribed during the study, including 
during the Run-in Period. 
Subjects will take placebo (during the Run-in Period) or assigned study drug (during the Treatment 
Period) 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 aŌer 
compleƟng the evening meal, if necessary. 
During Part A (the ﬁrst 12 weeks of the Treatment Period), subjects will be randomized in a 1:1:1:1 raƟo 
to receive either placebo or Ɵldacerfont at a dose of 50 mg QD, 100 mg QD, or 200 mg QD. 


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During Part B (the second 12 weeks of the Treatment Period) and Part C (the last 46 weeks of the 
Treatment Period), all subjects will receive acƟve drug (Ɵldacerfont). 
• Subjects who were randomized to placebo in Part A will receive Ɵldacerfont 100 mg QD at the 
beginning of Part B. 
• Subjects who were randomized to Ɵldacerfont 200 mg QD in Part A will conƟnue to receive 
Ɵldacerfont at 200 mg QD throughout Parts B and C. 
• Based on A4 results from the Weeks 18 and 24 study visits, eligible subjects may undergo a 
Ɵldacerfont dose escalaƟon aŌer each of these study visits. Speciﬁcally: 
o Subjects taking Ɵldacerfont 50 mg QD will either conƟnue to receive the same dose (if A4 ≤ULN) 
or be escalated to Ɵldacerfont 100 mg QD (if A4 >ULN and the subject is toleraƟng his/her 
current Ɵldacerfont dose) 
o Subjects taking Ɵldacerfont 100 mg QD will either conƟnue to receive the same dose (if A4 
≤ULN) or be escalated to Ɵldacerfont 200 mg QD (if A4 >ULN and the subject is toleraƟng 
his/her current Ɵldacerfont dose). 
• At Week 30, all subjects will be escalated to 200 mg QD. 
 
Immediately following the Weeks 18 and 24 visits, subjects will conƟnue to take their previously 
assigned study drug unƟl A4 laboratory results are received, the RTSM system determines the 
appropriate Ɵldacerfont doses for the next porƟon of the study, and subjects receive their Ɵldacerfont 
doses for the next porƟon of the study. Subjects will receive enough previously assigned study drug to 
last unƟl they receive their appropriate Ɵldacerfont dose for the next porƟon of the study. Subjects will 
either return to the clinic to pick up their study drug or will be shipped their study drug. 
During the opƟonal Open-Label Extension Period, subjects will conƟnue to receive Ɵldacerfont at 200 mg 
QD. 
Only authorized study staﬀ may dispense study drug. Sites will provide subjects with dosing instrucƟons. 
The Sponsor will provide GC for periods of stress dosing. Sponsor-provided HC for stress dosing may be 
shipped directly to subjects. 
InstrucƟons for concomitant GC medicaƟon dosing are provided in SecƟon 6.5.1. Criteria for study drug 
disconƟnuaƟon are provided in SecƟon 7.1. 
6.2 PreparaƟon/Handling/Storage/Accountability 
6.2.1 
AcquisiƟon and Accountability 
The InvesƟgator is responsible for study treatment receipt and accountability, reconciliaƟon, and record 
maintenance. 
6.2.2 
FormulaƟon, Appearance, Packaging, and Labeling 
The drug product is formulated as a tablet containing 50 mg and/or 200 mg of drug substance and the 
following inacƟve ingredients: lactose monohydrate, hydroxypropyl cellulose, sodium lauryl sulfate, 


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microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, and 
Opadry® yellow.  
Placebo will be supplied as tablets that look idenƟcal to drug product but contain no drug substance. 
Study drug tablets will be supplied in blister cards. For the opƟonal Open-Label Extension Period, study 
drug will be supplied either in blister card or in botle pack. 
HC tablets for stress dosing will be supplied by the Sponsor in botles.  
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 automaƟcally) and 
accessible only to the InvesƟgator 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: RandomizaƟon and Blinding 
All subjects will receive single-blinded placebo during the Run-in Period. 
All subjects will be centrally randomized to study intervenƟon in Part A and assigned to the appropriate 
dose of Ɵldacerfont in Parts B and C using an RTSM system. Subjects will be randomized using the 
following strata: A4 ≤4x ULN and A4 >4x ULN. 
InvesƟgators, subjects, and the Sponsor’s contract research organizaƟon (CRO) will be blinded to 
assigned study intervenƟon in Part A and to dose of Ɵldacerfont in Parts B and C. To maintain the blind, 
all subjects will receive the same number of study drug tablets per dose, with the appropriate number of 
Ɵldacerfont and/or placebo tablets for the assigned study intervenƟon. The primary eﬃcacy analysis is 
planned aŌer all subjects have completed Week 18, at the end of the double-blind treatment period. 
The subject level blind will be maintained unƟl the compleƟon of the primary eﬃcacy analyses. The 
Sponsor and CRO’s will be unblinded at the Ɵme of the primary eﬃcacy analysis (Part A--- Week 18), but 
InvesƟgators, , and subjects will remain blinded to each subject’s treatment assignment during  Part B.  
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 InvesƟgator may use the code provided at the site iniƟaƟon visit to access the 
subject’s treatment assignment details via the RTSM system. 
6.4 Study IntervenƟon Compliance 
Subjects will be asked to document study drug and background GC adherence in their electronic study 
diaries through Week 18 (see SecƟon 4.1). Subjects will return study drug at each study visit to conduct 
accountability. The InvesƟgator is responsible for ensuring that dosing is administered in compliance 
with the protocol. 
Each subject’s compliance informaƟon will be reviewed during the Run-in Period to determine eligibility 
for entering the Treatment Period and then will be reviewed on an ongoing basis for subjects who enter 


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the Treatment Period. Compliance informaƟon to be reviewed will include (but not be limited to), 
adherence to the subject’s background GC regimen, 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 medicaƟon is any medicaƟon (including over-the-counter [OTC] medicaƟon, prescripƟon 
medicaƟon, vaccines, vitamins, and supplements) that the subject is receiving at screening or receives 
during the study. All concomitant medicaƟons must be recorded, along with: 
• Reason for use 
• Dates of administraƟon, including start and end dates 
• Dosage informaƟon, including dose and frequency 
All concomitant medicaƟons should be compared against the list of prohibited medicaƟons and the list 
of other medicaƟons of concern provided in SecƟon 13.1. Subjects should be instructed to contact the 
site immediately any Ɵme a new medicaƟon is required during the course of the study, including 
prescripƟon and OTC medicaƟons, even those to be used for only a short period of Ɵme (e.g., anƟbioƟcs, 
cold and ﬂu remedies, GI therapies, opioids or other pain relievers). The Medical Monitor should be 
contacted if there are any quesƟons regarding concomitant or prior therapy. 
6.5.1 
GlucocorƟcoid Replacement Therapy 
6.5.1.1 
General Procedures for Glucocorticoids 
InformaƟon to be collected at screening about a subject’s current and historical GC therapy for the past 
year include the type(s) of GC, the regimen(s), reason(s) that the subject is/was on that parƟcular GC 
regimen, and any GC stress dosing during the past year. 
To be eligible for this study, subjects must be on a stable dose of GC replacement ≥15 mg/day and ≤60 
mg/day in HCe (see SecƟon 6.5.1.2 for GC dose conversion to HCe) for ≥1 month before screening 
without any evidence of non-adherence to the GC regimen during this period (stress dosing is allowed). 
Changes in GC dosing are generally not permited during this study except during Part C and in the case 
of stress dosing throughout the study (see SecƟon 6.5.1.5). If a change in a subject’s long-term GC 
regimen is clinically indicated outside of Part C (eg, the subject experiences symptoms of chronic adrenal 
insuﬃciency), study drug will be disconƟnued. Subjects who disconƟnue study drug for this reason 
should complete the early terminaƟon follow-up visit.  
Subjects with the salt-wasƟng form of CAH must also be on a stable dose of mineralocorƟcoid 
replacement for ≥1 month before screening. A change to a subject’s GC regimen during Part C could 
necessitate an adjustment to the subject’s mineralocorƟcoid regimen. The adequacy of a subject’s 
mineralocorƟcoid dose should be monitored and adjusted as needed to adequately maintain standing 
blood pressure, plasma renin levels, and electrolytes (serum potassium in parƟcular) within acceptable 
ranges (Speiser 2018). 
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 medicaƟon unƟl aŌer the laboratory assessments have been completed. On all 


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other days during the study, subjects should take their GC medicaƟon at the usual Ɵme(s). 
MineralocorƟcoid may be taken at any Ɵme of day, but its Ɵming relaƟve to laboratory assessments 
should be consistent throughout the study. 
6.5.1.2 
Glucocorticoid Dose in Hydrocortisone Equivalents 
Table 1 deﬁnes the potencies of various GCs relaƟve to HC in treaƟng CAH. These conversion factors will 
be used to determine whether a subject’s daily GC dose saƟsﬁes study eligibility criteria and provide 
general guidelines for GC adjustment in Part C. 
Note that ﬂudrocorƟsone (a mineralocorƟcoid, not a GC) should not be converted to HCe or included in 
the calculaƟon of a subject’s total daily GC dose. 
Table 1. 
Relative Potencies of Glucocorticoids in Hydrocortisone Equivalents (HCe) 
GlucocorƟcoid 
Potency in CAH (HCe) 
HydrocorƟsone 
1 
Prednisone 
41 
Prednisolone or methylprednisolone 
51,2 
1 Zoorab 1998. 2 Clayton 2002. The protocol uses a 1:4 raƟo for HC: prednisone and 1:5 for 
HC:prednisolone. However, transiƟoning from prednisolone to prednisone will require the closest 
approximaƟon possible given the denominaƟon of tablets available. Switching from 1mg prednisolone to 
1mg prednisone is the closest approximaƟon possible and therefore is not a protocol deviaƟon. 
 
6.5.1.3 
Exclusion of Concomitant Dexamethasone 
Subjects cannot be on dexamethasone during the study. Based on nonclinical and Phase 1 clinical data, 
Ɵldacerfont is a moderate inhibitor of CYP3A4. Dexamethasone is primarily metabolized through 
CYP3A4, and Phase 2 clinical data have shown a potenƟal for DDI between Ɵldacerfont and 
dexamethasone. Thus, use of dexamethasone as GC therapy for CAH is not permited during this dose-
ﬁnding study.  
Prior treatment with dexamethasone is allowed as long as the transiƟon to an alternaƟve GC (eg, HC, 
prednisone, prednisolone) has resulted in a stable dose of GC replacement for ≥1 month before 
screening. Prednisone/prednisolone and HC are metabolized through mulƟple pathways, with CYP3A4 
comprising <18% of its metabolism (Kovacs 2019, Ohno 2008). Based on staƟc mechanisƟc modeling 
used to predict drug-drug interacƟons (FDA 2000), no clinically relevant increase in GC exposure is 
expected with prednisone/prednisolone or HC and Ɵldacerfont. Phase 2 clinical data have shown a low 
likelihood of a DDI with Ɵldacerfont.  
6.5.1.4 
Guidance for Changing Glucocorticoid Regimens in Part C and Optional Open-Label Extension 
Period 
In Treatment Period Part C, subjects with A4 ≤ULN at Week 38 or Week 46 will begin to reduce their daily 
GC dose level in increments of approximately 5 mg/day HCe each Ɵme, per Table 1.  


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In the opƟonal Open-Label Extension Period, subjects will be eligible to adjust GC dose level at each visit. 
Subjects with A4 ≤ULN at any lab assessment will begin to reduce their daily GC dose level in increments 
of approximately 5 mg/day HCe each Ɵme, per Table 1.  
Per InvesƟgator judgment, adjustments may also be made to the morning/aŌernoon/evening 
distribuƟon of a subject’s GC regimen without changing the total daily GC dose. Adjustments of GC dose 
may proceed so long as the adjustment is not precluded by an untoward clinical sign or symptom.  
Changes to dosing frequency, ie, TID to BID, should be discussed with the Medical Monitor.  
• 
Subjects with an A4 measurement of ≤ULN at Week 38, Week 46, or during the Open-Label 
Extension Period will begin to reduce their daily GC dose. Each reducƟon of the daily GC dose 
will be by approximately 5 mg/day HCe, down to a minimum of 15 mg/day in HCe 
(approximately physiologic replacement level). ReducƟon may stop at a GC level >15 mg/day in 
HCe based on InvesƟgator judgment.  
• 
If a subject has an A4 measurement of >1.25x ULN, the subject’s daily GC level should be 
increased by approximately 5 mg/day HCe each Ɵme.  
• 
The daily GC level will generally remain unchanged for subjects with A4 levels >ULN and ≤1.25x 
ULN, unless a change in the GC dose level is clinically indicated (per InvesƟgator judgment and 
discussion with the Medical Monitor). 
• 
If a subject experiences a clinically signiﬁcant episode of adrenal insuﬃciency due to 
undertreatment (as opposed to an acute stressor), the subject’s daily GC dose should be 
increased by approximately 5 mg/day HCe and should not be reduced again to the GC dose level 
associated with adrenal insuﬃciency (per InvesƟgator judgment and discussion with the Medical 
Monitor). 
Sites will contact subjects by telephone within 2 weeks aŌer each applicable study visit regarding GC 
dose adjustments. Sites will telephone subjects again 7 days aŌer each GC dose adjustment to assess for 
the occurrence of AEs and the iniƟaƟon of new concomitant medicaƟons. 
6.5.1.5 
Stress Dosing of Glucocorticoid 
During Ɵmes 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 prevenƟon of adrenal crisis shown in Table 2 (Bornstein 2016). Sites may employ 
variaƟons on these guidelines, consulƟng with the Medical Monitor, if possible, in non-urgent situaƟons. 
The Sponsor will provide all subjects with oral HC for the purposes of stress dosing (SecƟon 6.2.2). For 
subjects who are not taking HC as their background GC regimen, the stress dose of HC should be 
esƟmated based on the relaƟve potencies of GCs outlined 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 enƟre stress dose using HC tablets from the botle provided by the Sponsor. The 
subject’s physician-prescribed GCs should be temporarily held during stress dosing and reinstated as 
soon as the stress dosing period ends. 


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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 deﬁniƟve long-term, chronic alteraƟon in the usual daily GC dosing 
regimen. 
Table 2. 
Sick Day Guidelines for Stress Dosing of Hydrocortisone 
CondiƟon 
Stress Dosing of HydrocorƟsone 
Home management of fever 
>38 °C (>100.4 °F) or illness 
requiring bed rest, when 
requiring anƟbioƟcs for an 
infecƟon, or before undergoing 
a minor outpaƟent procedure 
(eg, dental work) 
• Approximately double the rouƟne oral GC dose (and give as HC) 
unƟl recovery (usually 2 to 3 days) 
• For fever >39 °C (102.2 °F) only, approximately triple the rouƟne 
oral GC dose (and give as HC) unƟl recovery (usually 2 to 3 days)1 
• Increase consumpƟon of electrolyte-containing ﬂuids and simple 
and complex carbohydrates (El-Maouche 2018), as tolerated 
Unable to tolerate oral 
medicaƟon due to 
gastroenteriƟs 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 injecƟon, followed by HC 200 mg/24 hours (via 
conƟnuous IV infusion or 50 mg bolus every 6 hours IV or IM) 
• Weight-appropriate conƟnuous 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 injecƟon, followed by HC 200 mg/24 hours (via 
conƟnuous 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 conƟnuous IV isotonic 
saline guided by individual paƟent 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 
AbbreviaƟons:  D25W, dextrose 25% in water; GC, glucocorƟcoid; HC, hydrocorƟsone; IM, intramuscular; 
IV, intravenous; SC, subcutaneous. 
1 When tripling the rouƟne 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).  


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Day-to-day physical or psychological stressors, such as a short-term strenuous acƟvity or school 
examinaƟons, do not require increased GC dosing (Clayton 2002; Crown & Lightman 2005; Merke and 
Bornstein 2005). 
Subjects will maintain stress dosing unƟl symptoms subside (or according to the clinical judgment of the 
treaƟng physician), then return to their usual GC regimen. Any scheduled lab draws should be delayed 
unƟl 5 to 7 days aŌer subjects ﬁrst return to their usual GC regimen. Any study visit delayed because of 
stress dosing will not be considered a protocol deviaƟon. Extra unscheduled study visits for safety follow-
up may be conducted in the interim. 
6.5.1.6 
Post-Treatment Glucocorticoid Dosing 
Upon compleƟon of the Treatment Period, subjects will maintain the GC regimen and mineralocorƟcoid 
regimen (as applicable) established during Part C unƟl the 30-day follow-up visit unless the InvesƟgator 
determines that the subject’s clinical status necessitates a dosing change. AŌer compleƟon of the study, 
GC therapy will be managed at the discreƟon of the subject’s treaƟng physician.  
6.5.2 
Prohibited Concomitant MedicaƟons 
Other invesƟgaƟonal 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 medicaƟons could 
aﬀect the subject’s total androgen levels. In general, subjects who require ongoing treatment with these 
medicaƟons should not be screened. 
Any other medicaƟon or supplement that could impact subject safety or confound interpretaƟon of 
study results is prohibited during the study. 
6.5.2.1 
Inducers or Inhibitors of CYP3A4 
In vitro CYP reacƟon phenotyping has indicated that Ɵldacerfont is metabolized by CYP3A4. Therefore, 
drugs that are known to be moderate to strong inducers or inhibitors of CYP3A4 are prohibited. Use of 
dexamethasone is not permited during the study (see SecƟon 6.5.1.3). Subjects will be advised to 
refrain from consumpƟon 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 unƟl aŌer the ﬁnal dose. 
6.5.2.2 
Substrates of CYP3A4 and/or BCRP 
In vitro drug interacƟon studies coupled with physiologically based pharmacokineƟc (PBPK) modeling 
have indicated that Ɵldacerfont has the potenƟal to inhibit CYP3A4 and BCRP. Tildacerfont has also 
demonstrated the potenƟal to induce CYP3A4 (mRNA), but the net eﬀect on CYP3A4 is moderate 
inhibiƟon. Phase 1 clinical data have also conﬁrmed that Ɵldacerfont is a moderate inhibitor of CYP3A4. 
Therefore, drugs that are sensiƟve substrates or narrow-therapeuƟc-range substrates of CYP3A4 and/or 
BCRP must be avoided. SensiƟve substrates or narrow-therapeuƟc-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 administraƟon of study drug) may be permited with monitoring 
for safety. 


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SensiƟve substrates are drugs whose plasma area under the concentraƟon-Ɵme 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 
therapeuƟc ranges are those for which even small increases in a subject’s exposure to these drugs 
(potenƟally induced by the concomitant use of Ɵldacerfont) could lead to serious safety concerns 
(e.g., torsades de pointes). 
Ethinyl estradiol is a CYP3A4 and BCRP substrate, and Ɵldacerfont 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 formulaƟons. Thus, any hormonal contracepƟon containing ethinyl 
estradiol used by female subjects must contain ≤35 µg ethinyl estradiol, is permited only for subjects 
who would not be considered at high risk for thromboembolic or cardiovascular complicaƟons with 
estrogen use, and must be used simultaneously with a backup method of contracepƟon according to 
SecƟon 5.2.5.2. Dosing of oral formulaƟons of hormonal contracepƟon containing ethinyl estradiol 
should be oﬀset by approximately 10 hours from the evening dose of study drug. 
SecƟon 13.1 provides a non-exhausƟve list of medicaƟons that are prohibited because of their potenƟal 
for metabolic interacƟons with Ɵldacerfont. This list shows many commonly used medicaƟons, including 
certain anƟbioƟcs, anƟfungal agents (itraconazole, ketoconazole), staƟns (lovastaƟn, simvastaƟn), 
anƟ-inﬂammatory agents (felodipine), migraine remedies (eletriptan), anxiolyƟcs (buspirone, 
midazolam), and drugs for erecƟle dysfuncƟon (avanaﬁl, sildenaﬁl, vardenaﬁl). (Many oncology drugs 
and medicaƟons used to treat the hepaƟƟs C virus and HIV are strong inhibitors of CYP3A4 but are not 
listed simply because individuals with acƟve cancer, hepaƟƟs C, and/or HIV are excluded from this study.) 
It is criƟcal that each subject’s concomitant medicaƟons are carefully compared to the list in 
SecƟon 13.1. 
In all cases, if there is a quesƟon or concern about a speciﬁc medicaƟon 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 medicaƟons. 
7 STUDY DRUG DISCONTINUATION AND PARTICIPANT WITHDRAWAL 
7.1 Study Drug DisconƟnuaƟon 
Subjects may voluntarily disconƟnue study drug at any Ɵme. The InvesƟgator and/or Sponsor may also 
disconƟnue a subject’s study drug at any Ɵme. When feasible, InvesƟgators should discuss any safety 
concerns with the Medical Monitor as soon as possible to determine whether a subject should conƟnue 
or disconƟnue study drug. Study drug will be disconƟnued in subjects who experience individual 
treatment-stopping criteria described in this secƟon. The Sponsor and InvesƟgator will make eﬀorts 
(when possible) to conƟnue to collect data (according to the Schedule of Post-Screening AcƟviƟes) on 
subjects who disconƟnue study drug. 
If study drug is disconƟnued, the InvesƟgator will report the disconƟnuaƟon to the Medical Monitor, 
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form (eCRF), schedule an early terminaƟon visit for the subject (see the Schedule of Post-Screening 
AcƟviƟes in SecƟon 1.3.3), provide or arrange for appropriate follow-up, and document the course of the 
subject’s condiƟon. 
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 eƟology. The InvesƟgator should noƟfy the Sponsor within 24 hours of awareness if any of the 
criteria deﬁned in Table 3 are met. Further suggested acƟons, follow-up assessments, and monitoring 
assessments are provided in SecƟon 13.2. A signiﬁcant change in liver chemistry that requires increased 
monitoring but does not necessarily saƟsfy stopping criteria may sƟll be considered an adverse event of 
special interest (AESI) (see SecƟon 8.3.8). 
Table 3. 
Stopping Criteria and Increased Monitoring for Liver Chemistry Elevations 
Criteria 
AcƟons 
ALT ≥5x ULN 
DisconƟnue study drug and noƟfy Sponsor. 
ALT ≥3x ULN 
AND total bilirubin ≥2x ULN  
(>35% direct bilirubin)1 
DisconƟnue study drug and noƟfy Sponsor.  
Possible Hy’s Law case—report as SAE. 
AND INR >1.5 
DisconƟnue study drug and noƟfy Sponsor.  
Possible Hy’s Law case—report as SAE. 
AND subject has symptoms (new or 
worsening) believed to be related to 
liver injury or hypersensiƟvity2 
DisconƟnue study drug and noƟfy Sponsor. 
AND total bile acids >3x ULN 
Withhold study drug and noƟfy Sponsor. 
Repeat liver chemistry tests aŌer 1 week, and 
discuss with Medical Monitor whether to 
disconƟnue study drug. 
ALT ≥3x ULN only 
Monitor weekly for 4 weeks while conƟnuing 
study drug and noƟfy Sponsor (see 
SecƟon 13.2.2) 
AND cannot be monitored weekly 
for 4 weeks 
DisconƟnue study drug and noƟfy Sponsor. 
persists for ≥4 weeks 
DisconƟnue study drug and noƟfy Sponsor. 
AbbreviaƟons:  ALT, alanine aminotransferase; INR, internaƟonal normalized raƟo; SAE, serious adverse 
event; ULN, upper limit of normal. 
1 If serum bilirubin fracƟonaƟon is not immediately available, disconƟnue study drug if ALT ≥3x ULN and 
bilirubin ≥2x ULN and record the presence/absence of detectable urinary bilirubin on dipsƟck, which is 
indicaƟve of direct bilirubin elevaƟons suggesƟng liver injury. 
2 Symptoms related to liver injury include faƟgue, nausea, vomiƟng, right upper quadrant pain or 
tenderness, and jaundice. Symptoms related to hypersensiƟvity include fever, rash, and eosinophilia. 


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7.1.2 
QT Stopping Criteria 
Study drug will be disconƟnued 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 iniƟal result that 
fulﬁlls the QT stopping criteria. 
7.1.3 
Suicidality Stopping Criteria 
Tildacerfont is considered to be a central nervous system (CNS)–acƟve drug. Some CNS-acƟve drugs may 
be associated with an increased risk of suicidal ideaƟon in certain populaƟons. Although Ɵldacerfont has 
not been shown to be associated with an increased risk of suicidal thinking or behavior in past clinical 
studies, subjects will be monitored for such events during this study using the C-SSRS (see 
SecƟon 8.2.6.1). 
Individuals who answer “yes” to QuesƟon 3, 4, or 5 in the suicidal ideaƟon secƟon of the C-SSRS at 
screening or Week 6 are not eligible for this study. Any subject who exhibits any Suicidal Behavior or 
Suicidal IdeaƟon (eg, answers “yes” to QuesƟon 3, 4, or 5 in the suicidal ideaƟon secƟon of the C-SSRS) 
will have study drug immediately disconƟnued and should be evaluated by a psychiatrist. This safety 
ﬁnding will be considered an AESI if it is not an SAE (eg, requiring hospitalizaƟon) (see SecƟon 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 SecƟon 8.2.6.2) 
at screening or Week 6 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 
InvesƟgator, will require study drug disconƟnuaƟon and appropriate follow-up. This will be considered an 
AESI if it is not an SAE (eg, requiring hospitalizaƟon) (see SecƟon 8.3.8). 
7.1.5 
Adrenal Insuﬃciency Stopping Criteria 
Symptoms of adrenal insuﬃciency include weakness, Ɵredness, anorexia, nausea, vomiƟng, 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 InvesƟgator 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 InvesƟgator is strongly encouraged to contact the Medical Monitor to review the presentaƟon and 
discuss the plan for a subject with any potenƟal AE of adrenal insuﬃciency.  
If the InvesƟgator deems the sign(s), symptom(s) and/or laboratory ﬁnding(s) to be due to adrenal 
insuﬃciency, the AE should be recorded as adrenal insuﬃciency. The sign(s), symptom(s) and laboratory 


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ﬁndings resulƟng in the diagnosis of adrenal insuﬃciency will be collected on a separate Adrenal 
Insuﬃciency Adverse Event CRF and should not be recorded on the Adverse Event CRF. 
If a subject develops an adrenal insuﬃciency AE meeƟng the seriousness criterion (SecƟon 8.3.2) or the 
deﬁniƟon of an adrenal crisis (Table 2), the  InvesƟgator should discuss with Medical Monitor. In cases 
where a clear explanaƟon for the occurrence of adrenal insuﬃciency or adrenal crisis is idenƟﬁed, 
disconƟnuaƟon of the study medicaƟon is not necessary. If there is no clear explanaƟon for serious 
event of adrenal insuﬃciency, then PI may discuss further steps with medical monitors. 
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 InvesƟgator judgment and discussion with the 
Medical Monitor). Study drug should not be disconƟnued but may be interrupted while GC dose 
adjustment is made. 
In the absence of any clear explanaƟon for the subject’s acute adrenal insuﬃciency, the InvesƟgator 
should disconƟnue study drug. This will be considered an AESI (see SecƟon 8.3.8). 
Adverse events or other condiƟons 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 
ReproducƟve Hormone Stopping Criteria 
If a subject experiences signiﬁcant changes from baseline in reproducƟve hormone(s), the InvesƟgator 
should determine whether such changes represent clinically signiﬁcant reproducƟve abnormaliƟes, 
potenƟal risks to the subject, whether to disconƟnue 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 tesƟcular dysfuncƟon in men; and signiﬁcant changes in estradiol, prolacƟn, progesterone, 
or menstrual cyclicity in women. 
InvesƟgators should keep in mind that subjects with CAH can be expected to have abnormal 
reproducƟve hormone levels because deﬁcient 21-hydroxylase enzyme acƟvity leads 1) to elevated 
levels of corƟsol precursors that are shunted into reproducƟve hormone biosyntheƟc pathways and 2) to 
low levels of the corƟsol that normally provides negaƟve feedback on the HPA axis. Standard-of-care 
therapy with GC and mineralocorƟcoid replacement does not necessarily fully normalize adrenal steroid 
producƟon pathways and signaling systems, including ACTH and CRF levels. Thus, subjects with CAH can 
be expected to have abnormal plasma concentraƟons of various androgens and progestogens at 
baseline. Therapy with an eﬀecƟve CRF receptor antagonist may in fact shiŌ the balance between 
various intermediates in the steroid biosyntheƟc pathway. InvesƟgators should inform the Medical 
Monitor before disconƟnuing study drug. 
7.1.7 
Clinically Signiﬁcant Adverse Event Stopping Criteria 
The InvesƟgator should consider study drug disconƟnuaƟon and appropriate safety follow-up for a 
subject who experiences a clinically signiﬁcant AE. When feasible, the InvesƟgator should contact the 
Medical Monitor to discuss the subject’s clinical condiƟon before disconƟnuing study drug. Clinically 
signiﬁcant AEs include but are not limited to study drug–related SAEs (SecƟon 8.3.2) and study drug–
related AESIs (SecƟon 8.3.8). 


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7.2 ParƟcipant Withdrawal from the Study 
Subjects are free to withdraw from the study at any Ɵme upon request. If the subject withdraws consent 
for disclosure of future informaƟon, the Sponsor may retain and conƟnue to use any data collected 
before the withdrawal of consent. The subject may request destrucƟon of any samples taken and not 
tested, and the InvesƟgator must document this in the site study records. 
Subjects will be withdrawn from the study by the InvesƟgator and/or Sponsor for either of the following: 
• Pregnancy 
• If any clinical AE, laboratory abnormality, or other medical condiƟon or situaƟon occurs such that 
conƟnued parƟcipaƟon in the study would not be in the best interest of the subject 
A subject may also be withdrawn from the study by the InvesƟgator and/or Sponsor at any Ɵme for other 
safety, behavioral, compliance, or administraƟve reasons such as the following: 
• Signiﬁcant protocol deviaƟon or noncompliance with study procedures/restricƟons 
• If the subject no longer meets eligibility criteria 
• Study terminaƟon by the Sponsor  
Subject withdrawal is expected to be uncommon. If possible, an early terminaƟon visit (as shown in the 
Schedule of Post-Screening AcƟviƟes in SecƟon 1.3.3) should be conducted before subject withdrawal. 
The InvesƟgator must document the date and primary reason for the withdrawal on the appropriate 
eCRF. Subjects who withdraw prematurely may be replaced at the discreƟon 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 atend scheduled visits and 
study personnel are unable to reach the subject. 
The following acƟons must be taken if a subject fails to atend a required study visit: 
• The site must atempt 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 conƟnue in the study. 
• Before a subject is deemed lost to follow-up, the InvesƟgator 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 cerƟﬁed leter to the subject’s last known mailing address (or 
local equivalent methods). Atempts to contact the subject should be documented in the subject’s 
medical record. 
• If the subject conƟnues 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 secƟon describes what study assessments and procedures will be performed and how they will be 
conducted. The Ɵming of study assessments and procedures is provided in the Schedules of AcƟviƟes in 
SecƟon 1.3. 
8.1 Eﬃcacy Assessments 
8.1.1 
Hormone Assessments 
All blood samples will be collected at 8 AM (± 1 hour) prior to administering their GC dose aŌer an 
overnight fast (nothing to eat aŌer midnight) unless otherwise speciﬁed.  
A4, 17-OHP, ACTH, and testosterone will be measured.  
Detailed instrucƟons for the collecƟon 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 PaƟent Global Impression of Change (PGIC), and the 
Clinical Global Impression – Improvement Scale (CGI-I).  
8.1.2.1 
Short Form 36 
The SF-36 (Ware and Sherbourne 1992) is a widely used, validated, paƟent-reported survey that assesses 
subjecƟve health status. The SF-36 consists of 36 items and the following 8 health domains: physical 
funcƟoning, role-physical (limitaƟons in usual role acƟviƟes because of physical health problems), bodily 
pain, general health percepƟons, vitality, social funcƟoning, role-emoƟonal (limitaƟons in usual role 
acƟviƟes because of emoƟonal problems), and mental health. Domain scores range from 0 to 100, with 
higher scores corresponding to beter subjecƟve 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-quesƟon survey that asks subjects to evaluate whether there has been an 
improvement in overall subjecƟve 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-quesƟon survey that requires the clinician to assess how much a paƟent’s 
illness has improved or worsened relaƟve to a baseline state. Clinicians select a response on a 7-point 
Likert scale. 
8.1.3 
Metabolic Assessments 
A lipid panel (total cholesterol, low-density lipoprotein [LDL], high-density lipoprotein [HDL], and 
triglycerides) and hemoglobin A1c (HbA1c), fasƟng glucose, and fasƟng insulin will be assessed as part of 
clinical laboratory (see SecƟon 13.3). HomeostaƟc model assessment of insulin resistance (HOMA-IR) will 
be calculated from fasƟng glucose and fasƟng insulin. Blood pressure (systolic and diastolic) will be 
assessed. Body weight, BMI, and waist circumference will be assessed as described in SecƟon 8.2.3.  


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8.1.4 
Hyperandrogenic Symptoms 
8.1.4.1 
Acne 
Acne severity will be evaluated using an IGA score (FDA 2018). Qualiﬁed medical professionals will assess 
the IGA score.  
InformaƟon regarding any concomitant medicaƟons for acne, including topical treatments, should be 
solicited from subjects. 
8.1.4.2 
Hirsutism 
HirsuƟsm will be evaluated in female subjects using a mFG score (Yildiz 2010; MarƟn 2018). Qualiﬁed 
medical professionals will assess the mFG score. The mFG scores each of 9 body areas on a scale of 0 (no 
hair) to 4 (hairiness typical of a man), with the sum of the separate scores providing a hormonal 
hirsuƟsm score.  
InformaƟon regarding any concomitant medicaƟons or depilatory methods for hirsuƟsm should be 
solicited from subjects. 
8.1.4.3 
Testicular Adrenal Rest Tumors 
TARTs are a common complicaƟon of CAH caused by ACTH-driven oversƟmulaƟon of aberrant adrenal 
cells within the testes (Olpin and Wit 2014) and may result in pain, discomfort, impaired 
spermatogenesis, and inferƟlity (Chihaoui 2016; Claahsen-van der Grinten 2014; Delﬁno 2012). 
Complete scrotal ultrasounds will be obtained for male subjects using a real-Ɵme scanner to detect and 
to evaluate the size and number of TARTs. Standard images should be obtained in the longitudinal and 
transverse planes. Each potenƟal TART lesion will be measured in 3 planes to allow for calculaƟon of 
TART volume. Detailed instrucƟons for performing the scrotal ultrasound will be provided separately.  
The iniƟal scrotal ultrasound may be scheduled for any Ɵme up to the Week 4 visit and will be 
considered the baseline measurement for the TART endpoint. 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 Ɵmepoints at which ultrasounds were taken. 
8.1.4.4 
Menstrual Cyclicity 
Female subjects will record menstrual informaƟon in their electronic study diaries, including the start 
and stop dates of menses. 
8.2 Safety Assessments 
Safety assessments will include monitoring and recording all AEs (including SAEs, AEs leading to 
disconƟnuaƟon/withdrawal, and AESIs), physical examinaƟon, vital signs assessment, ECGs, clinical 
laboratory, monitoring for suicide risk, and depression/anxiety. AE procedures are described in 
SecƟon 8.3. 


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8.2.1 
Physical ExaminaƟon 
A full physical examinaƟon should include assessments of the cardiovascular, respiratory, GI, 
neurological, and musculoskeletal systems; head, eyes, ears, neck, and throat (HEENT); thyroid; skin; and 
extremiƟes. The full physical examinaƟon may exclude rectal, genitourinary, and breast exams. 
An abbreviated physical examinaƟon should include the following components: cardiovascular, 
respiratory, abdomen, musculoskeletal, HEENT, and skin. 
InvesƟgators should pay special atenƟon to clinical signs related to previous serious illnesses. 
A full physical examinaƟon will be performed during the Screening Visit and at Day 1, Week 18, and 
Week 76. 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 evaluaƟon is needed 
via an unscheduled visit. 
8.2.2 
Vital Signs 
Vital signs consist of systolic and diastolic blood pressure, pulse rate, respiraƟon 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 AcƟviƟes 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 porƟon 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 siƫng in an upright posiƟon with feet ﬂat on the ﬂoor and the 
measurement arm supported at heart level. 
8.2.3 
Body Weight, Height, BMI, and Waist Circumference 
Body weight will be measured at every visit using a calibrated balance. The weight 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 plaƞorm, and be asked to look straight ahead, standing relaxed but sƟll.  
Height needs to be recorded at screening only. 
BMI will be calculated for every visit using height and weight measurements. 
Waist circumference will be measured using an appropriate tape measure placed horizontally just above 
the hip bones at the level of the belly buton, placed snugly but not compressing the skin, and aŌer the 
subject breathes out. 
8.2.4 
Electrocardiogram 
A 12-lead ECG will be obtained using an ECG machine that automaƟcally calculates the heart rate, QRS, 
QT, and QTc intervals, preferably using Fridericia’s formula. Any ECG measurement assessed by the 
InvesƟgator as a clinically signiﬁcant abnormality should be recorded in the AE secƟon of the eCRF and 
monitored unƟl resoluƟon. 


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Refer to SecƟon 7.1.2 for QT individual treatment-stopping criteria and any addiƟonal ECGs that may be 
necessary. 
8.2.5 
Clinical Laboratory and Urinalysis 
Clinical laboratory assessments include hematology, clinical chemistry, coagulaƟon, lipid panel, thyroid 
panel, LH, FSH, SHBG, renin, aldosterone, inhibin B for males only, and estradiol, prolacƟn, and 
progesterone for females only. eGFR for screening will be calculated from blood creaƟnine measured as 
part of screening clinical chemistry. 
A complete list of study-required clinical laboratory and urinalysis tests is provided in SecƟon 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 InvesƟgator must review the laboratory report, document the review, and record any clinically 
signiﬁcant laboratory ﬁndings that occur during the study in the AE secƟon 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 InvesƟgator to be more severe than 
expected for the subject’s condiƟon. 
All laboratory tests with values considered clinically signiﬁcantly during the Treatment Period or within 
30 days aŌer the last dose of study drug should be reported as AEs and repeated at least weekly unƟl the 
values return to normal or baseline or are no longer considered clinically signiﬁcant by the InvesƟgator 
or Medical Monitor. If such values do not return to normal/baseline within a period of Ɵme judged 
reasonable by the InvesƟgator, the eƟology should be idenƟﬁed and the Sponsor noƟﬁed. 
8.2.6 
Psychiatric EvaluaƟons 
8.2.6.1 
Columbia–Suicide Severity Rating Scale 
The C-SSRS will be used during the study to monitor suicidal ideaƟon and behavior. The C-SSRS is a Food 
and Drug AdministraƟon (FDA)–endorsed quesƟonnaire administered by trained study personnel to 
screen for suicidality in trials of CNS-acƟve compounds. The Baseline/Screening Version of the C-SSRS, 
which assesses both lifeƟme 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 SecƟon 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 Weeks 6, 
18, 30, 58, 70, and 76 (Zigmond and Snaith 1983). The HADS is a widely used subject-reported 
instrument that focuses on subjecƟve 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 oŌen).  
Refer to SecƟon 7.1.4 for depression and/or anxiety individual treatment-stopping criteria. 


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8.3 Adverse Events and Serious Adverse Events 
8.3.1 
DeﬁniƟon 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 relaƟonship with the study drug. Examples of Aes include but are not 
limited to: 
• Clinically signiﬁcant abnormal test results 
• Clinically signiﬁcant symptoms and signs 
• Changes in physical examinaƟon ﬁndings 
• HypersensiƟvity 
• Progression/worsening of underlying disease 
A treatment-emergent adverse event (TEAE) is an AE that is temporally associated with administraƟon of 
study drug and is deﬁned as an AE that occurs during or aŌer administraƟon of the ﬁrst dose of study 
drug of the Treatment Period unƟl 30 days aŌer the ﬁnal dose of study drug (safety follow-up visit). For 
Aes that occur on the date of the ﬁrst dose of study drug of the Treatment Period, the Ɵme of onset 
(before or aŌer 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 addiƟonal diagnosƟc tesƟng or medical/surgical intervenƟon 
• Test result leads to a change in study drug dosing or study drug disconƟnuaƟon, signiﬁcant 
addiƟonal concomitant drug treatment, or other therapy 
• Test result is considered to be an AE by the InvesƟgator or Sponsor 
Merely repeaƟng an abnormal test, in the absence of any of the above condiƟons, does not consƟtute 
an AE. Any abnormal test result that is determined to be an error does not require reporƟng as an AE. 
Examples of events that do not meet the deﬁniƟon 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 condiƟon 
• The underlying disease and its signs and symptoms, unless they are more severe than expected 
for the subject’s condiƟon 
• Medical and surgical procedures; the condiƟon that leads to the procedure is the AE if it meets the 
deﬁniƟon of an AE. For example, an acute appendiciƟs that begins during the AE reporƟng period 
should be reported as the AE, and the resulƟng appendectomy should be recorded as treatment 
for the AE. 
• AnƟcipated day-to-day ﬂuctuaƟons of pre-exisƟng disease(s) or condiƟon(s) present or detected 
at the start of the study that do not worsen 


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8.3.2 
DeﬁniƟon of Serious Adverse Event 
An SAE or serious adverse drug reacƟon 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 inpaƟent hospitalizaƟon or prolongaƟon of exisƟng hospitalizaƟon 
• Results in persistent or signiﬁcant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is an important medical event 
Medical and scienƟﬁc 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 hospitalizaƟon. However, if it is determined that the event may jeopardize the subject and may 
require intervenƟon to prevent one of the other outcomes listed in the deﬁniƟon 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 hospitalizaƟon, or the development of drug dependency or drug abuse. If either the 
Sponsor or the InvesƟgator believes that an event is serious, the event must be considered serious and 
evaluated by the Sponsor for expedited reporƟng. 
HospitalizaƟon does not include the following: 
• RehabilitaƟon faciliƟes 
• Hospice faciliƟes 
• Respite care (eg, caregiver relief) 
• Skilled nursing faciliƟes 
• Nursing homes 
• Same-day surgeries (as outpaƟent/same day/ambulatory procedures) 
HospitalizaƟon or prolongaƟon of hospitalizaƟon in the absence of a precipitaƟng clinical AE is not in 
itself an SAE. Examples include the following: 
• Admission for treatment of a pre-exisƟng condiƟon not associated with the development of a new 
AE or with a worsening of the pre-exisƟng condiƟon (eg, for workup of persistent pre-treatment 
lab abnormality) 
• Social admission (eg, subject has no place to sleep) 
• AdministraƟve admission (eg, for yearly physical exam) 
• Protocol-speciﬁed admission during a clinical trial (eg, for a procedure required by the trial 
protocol) 
• OpƟonal admission not associated with a precipitaƟng clinical AE (eg, for elecƟve cosmeƟc 
surgery) 
• Pre-planned treatments or surgical procedures should be noted in the baseline documentaƟon for 
the enƟre protocol and/or for the individual subject. 


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8.3.3 
ClassiﬁcaƟon of an Adverse Event 
As far as possible, each AE will be described by the following: 
• DuraƟon (start and end dates) 
• Severity (SecƟon 8.3.3.1) 
• RelaƟonship to study drug (SecƟon 8.3.3.2) 
• AcƟon(s) taken and, as relevant, the outcome (SecƟon 8.3.3.3) 
8.3.3.1 
Severity 
The InvesƟgator will assess the severity of each AE according to the NaƟonal Cancer InsƟtute CTCAE 
version 5.0 (CTCAE 2017), which is summarized in Table 4. 
Table 4. 
Severity of Adverse Events 
Grade 1: Mild; asymptomaƟc or mild symptoms; clinical or diagnosƟc observaƟons only; intervenƟon 
not indicated. 
Grade 2: Moderate; minimal, local, or noninvasive intervenƟon indicated; limiƟng 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; hospitalizaƟon or 
prolongaƟon of hospitalizaƟon indicated; disabling; limiƟng self-care ADL (bathing, dressing and 
undressing, feeding self, using the toilet, taking medicaƟons, and not bedridden). 
Grade 4: Life-threatening consequences; urgent intervenƟon indicated. 
Grade 5: Death related to AE. 
AbbreviaƟons: ADL, acƟviƟes of daily living; AE, adverse event. 
 
Note the disƟncƟon between the severity and the seriousness of an AE. A severe event is not necessarily 
a serious event. Severe is a category used for raƟng 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 funcƟon) but would not be classiﬁed as serious unless it met at least one of the criteria for an SAE 
listed in SecƟon 8.3.2, such as resulƟng in hospitalizaƟon. 
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 enƟre event Ɵmeframe being recorded. 
8.3.3.2 
Relationship to Study Drug 
The InvesƟgator will assess the relaƟonship of each AE to study drug (or HC stress dosing) according to 
the categories in Table 5. This assessment will serve to determine whether there exists a reasonable 
possibility that the study drug (or HC stress dosing) caused or contributed to the AE. 
 
 


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Table 5. 
Relatedness of Adverse Event to Study Drug (or HC Stress Dosing) 
UNRELATED: This category applies to those AEs that are clearly and incontroverƟbly due to extraneous 
causes (disease, environment, etc). 
UNLIKELY RELATED: This category applies to those AEs that are judged to be unrelated to the study 
drug but for which no extraneous cause may be found. An AE may be considered unlikely to be related 
to the study drug if or when it meets two of the following criteria:  
(1) it does not follow a reasonable temporal sequence in relaƟon to administraƟon of the study drug;  
(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 patern of response to the study drug; or  
(4) it does not reappear or worsen when the study drug is re-administered. 
POSSIBLY RELATED: This category applies to those AEs for which a connecƟon to study drug 
administraƟon 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 relaƟon to administraƟon of study drug; 
(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 patern of response to the study drug. 
PROBABLY RELATED: This category applies to those AEs that the InvesƟgator thinks are related to the 
study drug 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 relaƟon to administraƟon of the study drug;  
(2) it could not be reasonably explained by the known characterisƟcs of the subject’s clinical state, 
environmental or toxic factors, or other therapies administered to the subject; 
(3) it disappears or decreases on cessaƟon or reducƟon in dose of study drug. There are excepƟons 
when an AE does not disappear upon disconƟnuaƟon of the study drug yet drug-relatedness clearly 
exists (eg, as in bone marrow depression, ﬁxed drug erupƟons, or tardive dyskinesia); or  
(4) it follows a known patern of response to the study drug. 
DEFINITELY RELATED: This category applies to those AEs that the InvesƟgator thinks are 
incontroverƟbly related to the study drug. An AE may be assigned an atribuƟon of deﬁnitely related if 
or when it meets all of the following criteria:  
(1) it follows a reasonable temporal sequence in relaƟon to administraƟon of the study drug; 
(2) it could not be reasonably explained by the known characterisƟcs of the subject’s clinical state, 
environmental or toxic factors, or other therapies administered to the subject; 
(3) it disappears or decreases upon cessaƟon or reducƟon in dose of study drug and recurs with re-
exposure to the study drug (if re-challenge occurs); and 
(4) it follows a known patern of response to the study drug. 
AbbreviaƟon: AE, adverse event. 
 
The InvesƟgator will use clinical judgment and consult the IB to determine the relaƟonship. AlternaƟve 
causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well as the 
temporal relaƟonship of the event to study drug (or HC stress dosing) administraƟon will be considered 
and invesƟgated. 


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AEs classiﬁed as unrelated or unlikely related will be considered not related to treatment, and AEs 
classiﬁed as possibly, probably, or deﬁnitely related 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 condiƟons 
resulƟng 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 anƟcipated. 
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. 
AbbreviaƟon: AE, adverse event. 
 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-up 
AEs will be recorded from the Ɵme the ICF is signed unƟl 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 Ɵme period between informed consent and 
the ﬁrst dose of study drug of the Treatment Period should be recorded but will not be considered 
TEAEs. If the AE occurs on the date of the ﬁrst dose of study drug of the Treatment Period, the Ɵme of 
onset (before or aŌer intake of study drug) will be captured.  
AŌer the iniƟal AE/SAE report, the InvesƟgator is required to proacƟvely follow each subject at 
subsequent visits/contacts. All AEs/SAEs will be followed unƟl resoluƟon, stabilizaƟon, the event has 
been shown to be unrelated to study drug, or the subject is lost to follow-up (as deﬁned in SecƟon 7.3). 
8.3.5 
Adverse Event ReporƟng 
The InvesƟgator is to report all AEs, whether volunteered by the subject, discovered through 
quesƟoning, or directly detected, that occur in the Ɵme period speciﬁed in SecƟon 8.3.4 and according 
to classiﬁcaƟons described in SecƟon 8.3.3.  
Non-serious AEs that don’t require immediate reporƟng are to be reported on the AE eCRF. 
SAEs and AESIs will receive special consideraƟon in decisions about conƟnuing, modifying, or suspending 
dosing/enrollment. The InvesƟgator will noƟfy the Sponsor within 1 day of awareness for immediate 
review (see SecƟon 8.3.6). 


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8.3.6 
Serious Adverse Event ReporƟng 
Throughout the study, the InvesƟgator 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 SecƟon 8.3.8) will also be reported on the SAE Report Form in the EDC system and must be 
clearly diﬀerenƟated from SAEs. CompleƟon guidelines are provided in the InvesƟgator Site File. The 
InvesƟgator must assess and record the relaƟonship of each event to study drug. Any SAE experienced 
aŌer the follow-up period should be reported to the Sponsor only if the InvesƟgator suspects a causal 
relaƟonship to the study drug.  
Recurrent episodes, complicaƟons, or progression of the iniƟal SAE, regardless of when they occur, must 
be reported as follow-up to the original episode within 24 hours of the InvesƟgator receiving the follow-
up informaƟon. Follow-up informaƟon will also be captured in the EDC system and should describe 
whether the event resolved or conƟnues, if and how it was treated, and whether the subject conƟnued 
or withdrew from study parƟcipaƟon. An SAE occurring at a diﬀerent Ɵme 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 reacƟons (SUSARs), determined 
based on the Reference Safety InformaƟon in the most recent version of the IB at the Ɵme of the event, 
will be reported to the competent authoriƟes 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 
DirecƟve 2001/20/EC. These reports will be unblinded upon submission where required. 
8.3.7 
ReporƟng of Pregnancy 
Any subject who becomes pregnant during the study will have study drug disconƟnued 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. 
InformaƟon about pregnancies will be recorded on the Pregnancy Report Form and any follow-up 
informaƟon will be forwarded to the Sponsor. 
For any female subject who becomes pregnant while parƟcipaƟng in this study, the InvesƟgator will 
collect informaƟon 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 noƟfy 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 InvesƟgator will atempt to 
collect informaƟon about the pregnancy. The InvesƟgator must obtain informed consent from the 
pregnant partner before collecƟng such informaƟon. The InvesƟgator will also atempt 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 esƟmated delivery 
date. Any terminaƟon of the pregnancy will be reported regardless of fetal status (presence or absence 
of anomalies) or indicaƟon for the procedure. 


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Pregnancy in itself is not regarded as an AE. However, a pregnancy complicaƟon is an AE, and congenital 
abnormaliƟes/birth defects or spontaneous miscarriages should be reported as SAEs. ElecƟve 
terminaƟon of a pregnancy is not considered an AE. While the InvesƟgator is not obligated to acƟvely 
seek this informaƟon in former study subjects, he or she may learn of such an SAE through spontaneous 
reporƟng. 
8.3.8 
Adverse Events of Special Interest 
AESIs must be monitored on an ongoing basis. These events will be reported with narraƟves, allowing for 
the collecƟon of addiƟonal informaƟon, as warranted. The following may be considered AESIs for this 
study: 
• Signiﬁcant liver chemistry changes that do not saƟsfy study drug stopping rules (see SecƟon 7.1.1 
and SecƟon 13.2). Cases of Hy’s Law should be reported as SAEs.  
• Suicidality as indicated by Type 3, 4, or 5 ideaƟon on the C-SSRS (see SecƟon 7.1.3 regarding study 
drug stopping criteria for suicidality and SecƟon 8.2.6.1 regarding the C-SSRS). This safety ﬁnding 
will be reported as an AESI if it is not considered an SAE (eg, resulƟng in hospitalizaƟon).  
• Depression or anxiety that is moderate or severe (CTCAE Grade 2 or higher), as assessed by the 
InvesƟgator (see SecƟon 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 (eg, resulƟng in hospitalizaƟon). 
• Adverse events of adrenal insuﬃciency will be reported on a separate Adrenal Insuﬃciency Form. 
AddiƟonally, symptoms of adrenal insuﬃciency will be reported as SAE if they necessitate 
parental GC administraƟon by a health care professional and two of the following criteria are 
met: hypotensive (systolic blood pressure <100 mmHg); nausea or vomiƟng; severe faƟgue; 
documented hyponatremia, hyperkalemia, or hypoglycemia. If hospitalizaƟon 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 informaƟon should be obtained as source documents to 
provide the following informaƟon:  
 
Was stress dosing employed prior to the adrenal insuﬃciency event?  If yes, what 
were the GC dose and duraƟon of dosing and the cause for stress dosing prior to 
seeking medical atenƟon? 
 
What type, dose and route of parental GC was administered and the duraƟon of 
administraƟon? 
 
What concomitant medicaƟons were administered? 
 
What clinical laboratory results are available? 
 
What AEs occurred? 
 
What was the duraƟon of stay if admited to the hospital? 
 
What was deemed to be the inciƟng factor leading to adrenal crisis? 
For non-SAEs of adrenal insuﬃciency, all symptoms and ﬁndings on physical examinaƟon, vital 
sign collecƟon and/or laboratory assessments leading to the diagnosis of adrenal insuﬃciency 
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Adverse events or other condiƟons 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 infecƟon, results in GC stress dosing, the AE should be captured 
in the Adverse Event CRF. The following addiƟonal informaƟon will be collected in the paƟent 
diary during episodes of GC stress dosing: start and stop date, concomitant medicaƟons, cause 
for stress dosing (eg, infecƟon, strenuous exercise, emoƟonal stress, pain, surgery) and 
concurrent AEs. Adverse events resulƟng in the stress dosing will be reported on the Adverse 
Event CRF. 
8.4 PharmacokineƟc Assessments 
A plasma sample will be collected consistently by a qualiﬁed medical professional at 8 AM (± 1 hour) for 
measurement of Ɵldacerfont concentraƟon at each study visit indicated in the Schedule of Post-
Screening AcƟviƟes. Samples will be collected aŌer an overnight fast (nothing to eat aŌer midnight) and 
before subjects take any morning dose of GC. Tildacerfont drug concentraƟon will be determined by a 
bioanalyƟcal laboratory using validated methods. 
9 STATISTICAL CONSIDERATIONS 
StaƟsƟcal consideraƟons are summarized here. A detailed descripƟon of staƟsƟcal methods will be 
provided in the StaƟsƟcal Analysis Plan (SAP).  
9.1 StaƟsƟcal Hypotheses 
For the Primary Eﬃcacy Analysis, the null hypothesis is that there is no diﬀerence in the proﬁle of log A4 
change from baseline through 12 weeks of blinded randomized treatment between Ɵldacerfont and 
placebo. The alternaƟve hypothesis is that there is diﬀerence in the proﬁle of log A4 change from 
baseline through 12 weeks of blinded randomized treatment between Ɵldacerfont and placebo. 
9.2 Sample Size DeterminaƟon 
A sample size of n=15 subjects per group will provide at least 80% power to detect a diﬀerence of at 
least 50% in A4 mean percent change from baseline between a given dose level of Ɵldacerfont and 
placebo, assuming a common SD of 30%.  
An assumed dropout rate of 15% during the Treatment Period results in a target of 18 subjects per group 
and a total sample size of 72 subjects who enter the Treatment Period. 
9.3 PopulaƟons for Analyses  
The ITT PopulaƟon will include all randomized subjects regardless of Treatment Period eligibility or 
compleƟon. The ITT PopulaƟon will be the primary analysis set for analyzing demographics, baseline 
characterisƟcs, and eﬃcacy analyses. 


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The mITT PopulaƟon is all randomized subjects who receive at least 1 dose of study drug (Ɵldacerfont or 
placebo), have at least 1 post-baseline A4 assessment, and did not change background GC through 
Week 18 
The PP PopulaƟon for each part of the Treatment Period will include all eligible subjects who have no 
major protocol deviaƟons that would aﬀect the analysis of eﬃcacy data (deﬁned below). SThe PP 
PopulaƟon may be used for secondary analyses of the primary and secondary eﬃcacy endpoints. 
AddiƟonal criteria for the PP PopulaƟon may be speciﬁed in the SAP. The PP PopulaƟon will be idenƟﬁed 
prior to database lock. 
Major protocol deviaƟons that would aﬀect the analysis of eﬃcacy data are deﬁned as the following: 
• Subject did not meet eﬃcacy-based inclusion criteria (elevated biomarkers) 
• Subject met eﬃcacy-based exclusion criteria (use of dexamethasone, night-shiŌ worker) 
• Subject’s drug compliance was <80% over the Treatment Period 
AddiƟonal criteria may be speciﬁed in the SAP. 
The Safety PopulaƟon will include all subjects who receive at least 1 dose of study drug (Ɵldacerfont or 
placebo) during the Treatment Period, summarized by actual drug received. The Safety PopulaƟon will be 
the primary analysis set for general and safety analyses. 
The PK PopulaƟon will include all randomized subjects who receive at least 1 dose of Ɵldacerfont and 
have at least 1 evaluable PK sample.  
9.4 StaƟsƟcal Analyses 
9.4.1 
General ConsideraƟons 
All individual data will be listed as measured. All staƟsƟcal summaries and analyses will be performed 
using SAS soŌware (SAS InsƟtute Inc, Cary, North Carolina, USA). 
ConƟnuous data will be summarized using an 8-point descripƟve summary (n, mean, SD, median, IQR 
[25% quarƟle, 75% quarƟle], minimum, and maximum) or 7-point descripƟve summary (n, mean, SD, CV, 
median, minimum, and maximum) unless otherwise speciﬁed. 
Categorical data will be summarized using the frequency of events and percentage of total events. 
Baseline deﬁniƟons for each endpoint will be deﬁned in the SAP. 
Data will be presented by treatment group. Changes in primary, secondary, and exploratory endpoints 
will be analyzed over Ɵme, with change from baseline summarized for each post-baseline Ɵme point 
measured. 
All eﬃcacy analyses will be conducted on the ITT PopulaƟon using a 2-sided alpha of 0.05. The primary 
endpoint and secondary endpoints will be reported using a mulƟplicity algorithm. 
Eﬃcacy analyses at Week 18 (primary and secondary) will compare Ɵldacerfont treatment groups to 
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For missing data, a retrieved dropout approach will be used in which missing endpoint data for subjects 
who disconƟnued early will be imputed using data collected from subjects aŌer disconƟnuaƟon of study 
drug. 
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 objecƟve of the study is to evaluate the eﬀect of Ɵldacerfont in controlling A4 levels in adult 
subjects with classic CAH who have elevated biomarkers at baseline on their current, dose of GC 
replacement therapy over the 12-week, double-blind, placebo-controlled Part A of the Treatment Period. 
This objecƟve will be achieved via A4 dose response analysis. The null hypothesis is that there is no 
diﬀerence in the proﬁle of log A4 change from baseline through 12 weeks of blinded randomized 
treatment between Ɵldacerfont and placebo. The alternaƟve hypothesis is that there is diﬀerence in the 
proﬁle of log A4 change from baseline through 12 weeks of blinded randomized treatment between 
Ɵldacerfont and placebo. StaƟsƟcal tesƟng for dose response will be performed using the repeated 
measures random coeﬃcients mixed-eﬀects model. 
A sensiƟvity analysis of the primary endpoint may be conducted using a missing data–handling 
procedure. 
9.4.3 
Analysis of the Secondary Eﬃcacy Endpoints 
9.4.3.1 
Proportion Who Achieve Hormone Target Secondary Endpoints 
The secondary eﬃcacy analyses related to A4 will be achieved as an integral part of the dose response 
modelling. The secondary eﬃcacy analyses related to 17-OHP will be conducted using the same 
methodology as the primary eﬃcacy analysis  
AddiƟonal proporƟon-based analyses may be speciﬁed in the SAP. Missing values for proporƟon 
endpoints will not be imputed and will be assumed to be failures. 
AddiƟonally, changes in biomarkers will be summarized by Ɵmepoint as appropriate, mean-based or 
geometric-mean based analyses. Subjects meeƟng speciﬁc thresholds as speciﬁed in the SAP, eg, ≤ULNs, 
will also be summarized. 
9.4.3.2 
Testicular Adrenal Rest Tumor Endpoints 
The secondary endpoint, change in TART lesion volume at Week 18, will be analyzed using an ANCOVA 
model with baseline lesion size as a covariate and ﬁxed eﬀects for randomizaƟon strata and treatment. 
AddiƟonal covariates may be speciﬁed in the SAP.  
The exploratory endpoint, change in TART lesion volume at Week 76, will be analyzed using a repeated 
measure mixed eﬀects model with treatment and visit as ﬁxed eﬀects, subject as a random eﬀect, and 
the baseline score as a covariate. AddiƟonal covariates may be speciﬁed in the SAP. 


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9.4.4 
Analysis of the Exploratory Eﬃcacy Endpoints 
9.4.4.1 
Testicular Adrenal Rest Tumor Endpoints 
The exploratory endpoint, change in TART lesion volume at Week 18, will be analyzed using an ANCOVA 
model with baseline lesion size as a covariate and ﬁxed eﬀects for randomizaƟon strata and treatment. 
AddiƟonal covariates may be speciﬁed in the SAP.  
The exploratory endpoint, change in TART lesion volume at Week 76, will be analyzed using a repeated 
measure mixed eﬀects model with treatment and visit as ﬁxed eﬀects, subject as a random eﬀect, and 
the baseline score as a covariate. AddiƟonal covariates may be speciﬁed in the SAP. 
9.4.4.2 
Correlation of Tildacerfont Plasma Concentration vs Dose 
The correlaƟon of Ɵldacerfont plasma concentraƟon versus dose will be explored by presentaƟon of PK 
descripƟve staƟsƟcs by dose and scheduled Ɵme point (i.e., study Week 10 and 18).   
9.4.4.3 
Correlation of A4 Level vs 17-OHP Level 
The within subject correlaƟon OF a4 vs 17-OHP will be assessed on the log scale by randomized 
treatment arm. The esƟmated correlaƟon coeﬃcient will be extracted from a variance-covariance matrix 
and presented by randomized treatment arm. 
9.4.4.4 
Patient- and Clinician-Reported Outcomes Endpoints 
Changes in SF-36 total score, IGA acne score, and mFG hirsuƟsm score will be analyzed using a repeated 
measure mixed eﬀects model with treatment (two covariates: randomized and group at Week 76) and 
visit as ﬁxed eﬀects, subject as a random eﬀect, and the baseline score as a covariate if >2 Ɵmepoints are 
assessed. If only the baseline Ɵmepoint and a single post-baseline Ɵmepoint are assessed for the 
endpoint, an ANCOVA model with the baseline score as a covariate will be used with only a single 
treatment covariate (randomized treatment). There will be no imputaƟon of missing data. 
9.4.4.5 
Glucocorticoid Dose Reduction Endpoints 
The proporƟon of subjects with at least a 5 mg/day HCe reducƟon from baseline in GC dose and A4 
≤ULN at Week 76 will be summarized using an exact score test through logisƟc regression using the 
randomizaƟon strata and treatment group at Week 76 in the model speciﬁcaƟon. Missing values for 
proporƟon endpoints will not be imputed and will be assumed to be failures. AddiƟonal covariates may 
be speciﬁed in the SAP. 
AddiƟonal GC-related proporƟons, eg, proporƟon of subjects at speciﬁc dose levels, may be speciﬁc in 
the SAP. 
9.4.5 
Analysis of the Exploratory Eﬃcacy Endpoints in the OpƟonal Open-Label Extension Period 
The percent change from baseline in GC dose at EOT will be summarized descripƟvely. 
The proporƟon of subjects with GC dose ≤25 mg/day in HCe and A4 ≤ULN at EOT will be summarized 
descripƟvely. 


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The proporƟon of male subjects with reducƟon in TART(s) at EOT who had TART(s) at baseline will be 
summarized descripƟvely. 
The proporƟon of subjects with improvement in at least one cardiovascular risk factor at EOT will be 
summarized descripƟvely and will comprise the following cardiovascular risk factors, weight, waist 
circumference, BMI, HOMA-IR, systolic and diastolic blood pressure, cholesterol and LDL.  Thresholds for 
improvement will be speciﬁed the SAP. AddiƟonal cardiovascular risk factors may be speciﬁed in the SAP. 
9.4.6 
Safety Analyses 
The Safety PopulaƟon will be used for all safety analyses. All safety data will be presented in lisƟngs. 
Summary tables will be provided for concomitant medicaƟons, AEs, hematology and chemistry 
laboratory results, vital signs, and ECG ﬁndings. Safety data will be summarized by treatment group using 
frequency of event or descripƟve staƟsƟcs, as appropriate.  
9.4.6.1 
Extent of Exposure 
Dosing informaƟon for individual subjects will be listed. Using dosing data, esƟmates of exposure to 
Ɵldacerfont will be summarized. Dose disconƟnuaƟons and reasons for study drug disconƟnuaƟon will 
be listed and summarized. 
9.4.6.2 
Concomitant Medication Data 
Concomitant medicaƟons used before and during the Treatment Period will be summarized. 
9.4.6.3 
Adverse Event Data 
AEs will be coded using the Medical DicƟonary for Regulatory AcƟviƟes (MedDRA). AE summaries will be 
presented by System Organ Class, Preferred Term, severity, and frequency and percentage of subjects 
reporƟng each observed event.  
AEs that occur before the ﬁrst dose of study drug of the Treatment Period will be disƟnguished from 
TEAEs (deﬁned in SecƟon 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 relaƟonship to study drug and severity. 
LisƟngs will be provided for subjects who experienced an SAE or disconƟnued study drug/withdrew from 
the study because of an AE. 
9.4.6.4 
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 lisƟngs. Abnormal clinical laboratory test results will 
be listed in a separate lisƟng. 
Laboratory data will be summarized in terms of observed values, changes from baseline, values relaƟve 
to normal ranges, and changes from baseline relaƟve to normal ranges. Subjects meeƟng speciﬁc 
thresholds for laboratory data will also be summarized as speciﬁed the SAP. 


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P-values for change from baseline and change from placebo or diﬀerences in proporƟons meeƟng 
speciﬁc thresholds will be derived using t-tests as speciﬁed in the SAP. 
AddiƟonal subgroup analyses based on baseline laboratory data [elevated, normal] will be speciﬁed in 
the SAP. 
9.4.6.5 
Vital Signs Data 
Vital signs data will be summarized within appropriately deﬁned categories in terms of observed values 
(by Ɵme point), changes from baseline (by Ɵme point), and counts and percentages. Subjects meeƟng 
speciﬁc thresholds for vital signs 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. 
9.4.6.6 
Electrocardiogram Data 
The QTcF, PR interval, QT interval, QRS duraƟon, 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. 
9.4.6.7 
Psychiatric Evaluations 
C-SSRS and HADS data will be listed.  
9.4.7 
Baseline DescripƟve StaƟsƟcs 
Demographics and baseline characterisƟcs (including age, sex, race, ethnicity, height, weight, and BMI) 
will be summarized for the ITT PopulaƟon. 
Biomarkers at screening and at baseline will be summarized for the Safety PopulaƟon. 
Baseline clinical characterisƟcs and history will be summarized. 
9.4.8 
Subgroup Analyses 
The following pre-deﬁned subgroups will be analyzed: 
• Baseline A4 [≤4x ULN, >4x ULN] 
• Baseline HCe dose [≤30 mg/day, >30 mg/day] 
• Sex [male, female] 
• Age [≤30 years, >30 years]; [≤median, >median] 
Any addiƟonal subgroup analyses will be speciﬁed in the SAP. 
9.5 Primary and Final Analyses 
The primary analysis is planned aŌer all subjects have completed Week 18. The Sponsor and CRO will be 
unblinded to treatment assignment in Part A at the Ɵme of the primary analysis, but InvesƟgators, who 
conduct the study, and subjects will remain blinded. 


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The ﬁnal analysis will occur aŌer the last subject has completed the last follow-up visit or if the study is 
disconƟnued 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 the results from Week 76 up to Week 316/320.  
9.6 MulƟplicity Control 
The primary endpoint (percent change from baseline in A4 aŌer 12 weeks on treatment [Week 18]) and 
secondary endpoints (proporƟon of subjects who achieve A4 ≤ULN aŌer 12 weeks on treatment [Week 
18], proporƟon of subjects who achieve 17-OHP ≤1200 ng/dL aŌer 12 weeks on treatment [Week 18], 
and change in the lesion volume of TART(s) from baseline aŌer 12 weeks on treatment [Week 18]) will be 
reported under strict control of the Type I error using a mulƟplicity algorithm which will be detailed in 
the SAP. 
9.7 Data Monitoring Commitee 
Refer to SecƟon 10.6 (Safety Oversight) for informaƟon on the Data and Safety Monitoring Board 
(DSMB). 
10 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1 Informed Consent 
For each study subject, writen 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 regulaƟon. The ICF will also be signed and dated by the 
InvesƟgator 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. 
As part of the informed consent process, the InvesƟgator 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 Ɵme. They should be informed that their data will be stored in 
a conﬁdenƟal manner, in accordance with local data protecƟon laws. They should be informed that their 
records may be viewed by the Sponsor or its designee and by regulatory authoriƟes. The ICF and any 
other materials provided to subjects or invesƟgaƟve staﬀ must use vocabulary and language that can be 
readily understood. 
The InvesƟgator must use the most current IRB/EC-approved ICF. Any changes to the proposed ICF 
suggested by the InvesƟgator 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 aŌer IRB/EC approval. 


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10.2 Study DisconƟnuaƟon and Closure 
Premature study terminaƟon may occur because of a regulatory authority decision, change in opinion of 
the IRB/EC, drug safety problems, or Sponsor decision. In addiƟon, the Sponsor retains the right to 
disconƟnue development of Ɵldacerfont at any Ɵme. 
Premature study terminaƟon will occur if the beneﬁt/risk proﬁle becomes unfavorable because of a new 
risk or toxicity that makes the study unjusƟﬁable and/or if new scienƟﬁc 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, duraƟon, frequency, and nature of the AEs relaƟve to the exisƟng 
safety proﬁle of Ɵldacerfont to determine whether there are any substanƟal changes in risk-beneﬁt 
consideraƟons. 
If this study is prematurely terminated or disconƟnued, the Sponsor will promptly noƟfy the InvesƟgator. 
AŌer noƟﬁcaƟon, the InvesƟgator must contact all parƟcipaƟng subjects within 7 days and have them 
complete ﬁnal visit safety assessments. As directed by the Sponsor, all study materials must be collected 
and all eCRFs completed to the greatest extent possible. 
10.3 ConﬁdenƟality and Privacy 
All informaƟon obtained during the conduct of this study will be regarded as conﬁdenƟal, and writen 
permission from the Sponsor is required before disclosing any informaƟon related to this study. 
All processing of personal data at the site and by the Sponsor must be carried out in accordance with any 
legislaƟon concerning the protecƟon of personal data. The InvesƟgator must ensure that the subject’s 
privacy is maintained. The Sponsor will assign each subject a unique idenƟﬁer. Any subject records or 
datasets that are transferred from the site to the Sponsor will contain this idenƟﬁer only; subject names 
or any informaƟon that would make the subject idenƟﬁable will not be transferred. 
10.4 Future Use of Stored Specimens and Data 
Any biological samples collected for this study may be stored for up to 5 years aŌer the last study visit of 
the last subject in the study. These samples may be used in the future for the discovery, analysis, 
veriﬁcaƟon, and/or validaƟon of other biomarkers or tests related to CAH. Samples will not directly 
idenƟfy 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 Ɵme by indicaƟng so in the ICF. A record of the 
ﬁnal disposiƟon 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 invesƟgaƟve 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 
representaƟve will be available to address any issues that may arise. 


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A list of study contacts will be provided in a separate document. 
10.5.2 InvesƟgators 
Before study start, InvesƟgators are required to sign an InvesƟgator Protocol Agreement Page conﬁrming 
their agreement to conduct the study in accordance with the protocol. It is the responsibility of the 
InvesƟgator to ensure that all invesƟgaƟve 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 InsƟtuƟonal Review Board/Ethics Commitee 
The protocol and ICF must be reviewed and approved by a properly consƟtuted 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 iniƟaƟon. 
10.6 Safety Oversight 
An external, independent DSMB will review the available safety data from this study periodically and 
provide recommendaƟons 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 staƟsƟcian. 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 conƟnuaƟon, modiﬁcaƟon, or terminaƟon of the trial. The DSMB’s 
scope of responsibility, membership, conﬁdenƟality, and procedures will be established in a separate 
DSMB charter. 
10.7 Clinical Monitoring 
Before study iniƟaƟon, at a site iniƟaƟon visit or at an InvesƟgator’s meeƟng, a Sponsor representaƟve 
will review the protocol and eCRFs with the InvesƟgators 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 speciﬁcaƟons. Key study personnel must be 
available to assist the ﬁeld monitor during these visits. See SecƟon 11.4 for informaƟon on monitoring 
visits in the context of COVID-19 or other logisƟcal challenges. 
The InvesƟgator must give the monitor access to all relevant source documents to conﬁrm their 
consistency with eCRF entries. The Sponsor’s monitoring standards require full veriﬁcaƟon for the 
presence of informed consent, adherence to the inclusion/exclusion criteria, documentaƟon of SAEs, and 
recording of data that will be used for all primary and safety variables. AddiƟonal checks of the 
consistency of the source data with the CRFs are performed according to the study-speciﬁc monitoring 
plan. No informaƟon in source documents about the idenƟty of subjects will be disclosed. 
Refer to SecƟon 10.9.1 for informaƟon on eCRFs and source documents. 


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10.8 Quality Assurance and Quality Control 
In addiƟon to rouƟne 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 conﬁdenƟal. The InvesƟgator must 
noƟfy the Sponsor promptly of any inspecƟons scheduled by regulatory authoriƟes and promptly 
forward copies of inspecƟon reports to the Sponsor. 
10.9 Data Handling and Record Keeping 
10.9.1 Data CollecƟon and Management ResponsibiliƟes 
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 parƟes, except for 
authorized representaƟves of the Sponsor or appropriate regulatory authoriƟes, without writen 
permission from the Sponsor. It is the InvesƟgator's responsibility to ensure compleƟon of and to review 
and approve all eCRFs. Case report forms must be signed by the InvesƟgator. These signatures serve to 
atest that the informaƟon contained on the eCRFs is true. At all Ɵmes, the InvesƟgator has ﬁnal personal 
responsibility for the accuracy and authenƟcity of all clinical and laboratory data entered on the eCRFs. 
For each subject in the study, the InvesƟgator must maintain source documents at the trial site consisƟng 
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 informaƟon on 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 writen record, and the eCRF itself may serve as the source document. Such items will be 
prospecƟvely deﬁned between the Sponsor and InvesƟgator before study start. 
10.9.2 Study Records RetenƟon 
To enable evaluaƟons and/or audits from regulatory authoriƟes or the Sponsor or its designees, the 
InvesƟgator agrees to keep records that include the idenƟty of all subjects (suﬃcient informaƟon to link 
records [eg, eCRFs and hospital records]), all original signed ICFs, copies of all eCRFs, SAE forms, source 
documents, and treatment disposiƟon. The records should be retained by the InvesƟgator for as long as 
ICH, local regulaƟons, or the Clinical Study Agreement dictates, whichever is longer.  
If the InvesƟgator relocates, reƟres, or for any reason withdraws from the trial, the Sponsor should be 
prospecƟvely noƟﬁed, and the trial records must be transferred to an acceptable designee, such as 
another InvesƟgator, another insƟtuƟon, or the Sponsor. The InvesƟgator must obtain the Sponsor’s 
writen permission before disposing of any records, even if retenƟon requirements have been met. 
10.10 Protocol DeviaƟons 
If a protocol deviaƟon occurs that aﬀects a subject’s safety, the Sponsor must be informed as soon as 
possible. 


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If a protocol deviaƟon is implemented to eliminate an immediate hazard before a protocol amendment 
can be submited for IRB/EC review and approval/favorable opinion (see SecƟon 10.12), the deviaƟon 
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 regulaƟons. DocumentaƟon of approval 
signed by the chairperson or designee of the IRB(s)/EC(s) must be sent to the Sponsor. 
10.11 PublicaƟon and Data Sharing Policy 
Any manuscripts for publicaƟon based on data from this study must be submited to the Sponsor for 
review and comment before submission to a publisher. This requirement should not be construed as a 
means of restricƟng publicaƟon but is intended solely to ensure concurrence regarding data, evaluaƟons, 
and conclusions and to provide an opportunity for the Sponsor to share with the InvesƟgator any new or 
unpublished informaƟon of which the InvesƟgator 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 InvesƟgator should not implement any 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 deviaƟon must be documented (see SecƟon 10.10). 
If a protocol amendment is an AdministraƟve Leter, InvesƟgators must inform their IRB(s)/EC(s).  
If a protocol amendment substanƟally alters the study design or increases the potenƟal risk to the 
subject, 1) the consent form must be revised and submited 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 LogisƟcal 
Challenges 
In general, the CAH paƟent populaƟon possesses a higher-than-average risk of serious complicaƟons 
from any infecƟon or febrile illness because such condiƟons can lead to adrenal crises in CAH paƟents if 
they are not managed appropriately. The emergence of COVID-19 increases the overall infecƟon risk in 
aﬀected communiƟes, including CAH paƟents who reside in those communiƟes.  
ParƟcipaƟon in a clinical trial provides subjects with increased access to healthcare resources and 
reinforcement of appropriate pracƟces during a Ɵme of increased infecƟon risk. Study parƟcipants will 
have access to healthcare professionals on a more intensive schedule than in normal clinical pracƟce for 
the management of CAH. The standard of care for a CAH paƟent with an infecƟon or febrile illness is to 
increase the paƟent’s GC dose to accommodate the addiƟonal stress and prevent an adrenal crisis (see 


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SecƟon 6.5.1.5). The Sponsor will provide HC for stress dosing to all subjects during the study, starƟng at 
the beginning of the Run-in Period. Thus, study parƟcipants will have immediate access to supplemental 
GC in the event of COVID-19 or other infecƟon. 
The potenƟal risks of a subject receiving Ɵldacerfont and concomitantly developing COVID-19 have been 
considered. Tildacerfont is not expected to increase the risk of contracƟng 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 LogisƟcal Challenges 
All study acƟviƟes will be conducted in accordance with relevant local, regional, and naƟonal guidance 
around COVID-19. 
If in-clinic visits are no longer possible, in-clinic–only acƟviƟes (eg, scrotal ultrasound) will not be 
conducted. AŌer a site reopens or the shelter-in-place order is liŌed, atempts should be made to 
conduct any missed in-clinic acƟviƟes via an unscheduled visit. 
If a subject or a member of the subject’s household is suspected or conﬁrmed to have COVID-19, the 
InvesƟgator must consult with the Medical Monitor to determine the best course of acƟon. In this 
situaƟon, only telemedicine acƟviƟes can proceed. If the subject misses scheduled study acƟviƟes during 
this Ɵme, 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 consecuƟve scheduled visits without labs 
being drawn.  
For scenarios not delineated here or for further clariﬁcaƟon, the InvesƟgator should consult with the 
Medical Monitor to determine the best course of acƟon. 
11.3 Subject DisposiƟon in the Context of COVID-19 or Other LogisƟcal Challenges 
If a subject develops an acƟve COVID-19 infecƟon (whether conﬁrmed or suspected) during the course 
of the study, the InvesƟgator will work with the subject and the Medical Monitor to determine the best 
course of acƟon, taking into consideraƟon the AE and SAE guidelines in SecƟon 8.3 and the individual 
stopping criteria for clinically signiﬁcant AEs in SecƟon 7.1.7. If study drug is disconƟnued or a subject is 
withdrawn from the study because of COVID-19, the reason for early terminaƟon will be captured in the 
EDC system as such. 
11.4 Regulatory and Study Oversight ConsideraƟons in the Context of COVID-19 or 
Other LogisƟcal 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 unƟl they can be 
transferred to the trial site. If a protocol deviaƟon is the result of COVID-19–related circumstances, this 
informaƟon should be captured. 


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12 REFERENCES 
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Clayton PE, Miller WL, Oberﬁeld SE, Ritzén EM, Sippell WG, Speiser PW; Joint European Society for 
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Doleschall M, Szabó JA, Pázmándi J, et al. Common geneƟc variants of the human steroid 21-hydroxylase 
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Han TS, SƟmson RH, Rees DA, et al. GlucocorƟcoid treatment regimen and health outcomes in adults 
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White PC and Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deﬁciency. Endocr Rev. 
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13 APPENDICES 
13.1 Appendix of Prohibited Concomitant MedicaƟons 
Refer to SecƟon 6.5.2 for more informaƟon on prohibited concomitant medicaƟons. 
Because of their potenƟal impact on the metabolism of Ɵldacerfont, moderate to strong CYP3A4 
inducers and inhibitors are prohibited. Subjects will be advised to refrain from consumpƟon 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 unƟl aŌer the ﬁnal dose. 
In addiƟon, drugs that are sensiƟve substrates or narrow-therapeuƟc-range substrates of CYP3A4 and/or 
BCRP must be avoided. SensiƟve substrates or narrow-therapeuƟc-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 administraƟon of study drug) may be permited with monitoring 
for safety. 
Ethinyl estradiol is a CYP3A4 and BCRP substrate, and Ɵldacerfont 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 formulaƟons. Thus, any hormonal contracepƟon containing ethinyl 
estradiol used by female subjects must contain ≤35 µg ethinyl estradiol, is permited only for subjects 
who would not be considered at high risk for thromboembolic or cardiovascular complicaƟons with 
estrogen use, and must be used simultaneously with a backup method of contracepƟon according to 
SecƟon 5.2.5.2. Dosing of oral formulaƟons of hormonal contracepƟon containing ethinyl estradiol 
should be oﬀset by approximately 10 hours from the evening dose of study drug. 
The following is a non-exhausƟve list of medicaƟons that are prohibited because of their potenƟal for 
metabolic interacƟons with Ɵldacerfont. 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 
simvastaƟn 
apixaban 
dilƟazem  
ketoconazole 
phenytoin 
St John's wort 
atorvastaƟn 
elagolix  
lesinurad 
posaconazole 
teneliglipƟn 
avanaﬁl 
eletriptan 
loperamide 
queƟapine 
Ɵcagrelor 
avasimibe 
ethinyl estradiol 
(>35 µg) 
lovastaƟn 
repaglinide 
triazolam 
buspirone  
felodipine 
mibefradil  
rifampin 
vardenaﬁl  
carbamazepine  
ﬂuconazole 
midazolam 
rifapenƟne 
voriconazole 
cenobamate  
glyburide 
nefazodone 
rivaroxaban 
 
ciproﬂoxacin 
isavuconazole 
oseltamivir  
sildenaﬁl 
 


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Many oncology drugs and medicaƟons used to treat the hepaƟƟs C virus and HIV are strong inhibitors of 
CYP3A4 but are not listed above simply because individuals with acƟve cancer, hepaƟƟs C, and/or HIV 
are excluded from this study. 
13.2 Appendix of Liver Safety 
Liver chemistry stopping criteria are presented in SecƟon 7.1.1. 
13.2.1 Suggested AcƟons, Follow-up Assessments, and Monitoring When Liver Chemistry Stopping 
Criteria Are Met 
13.2.1.1 Actions 
• Immediately disconƟnue study drug. 
• Within 24 hours, report the event to the Sponsor or designated CRO and complete the AE eCRF 
(indicaƟng 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 medicaƟons taken in last 48 hours. Speciﬁcally quesƟon about medicaƟons that 
are known to increase liver enzymes, such as aspirin, acetaminophen, ibuprofen, naproxen, 
diclofenac, phenylbutazone, and any anƟbioƟcs. 
• Perform liver chemistry follow-up assessments (see SecƟon 13.2.1.2).  
• Monitor the parƟcipant unƟl liver chemistry test abnormaliƟes resolve, stabilize, or return to 
baseline (see SecƟon 13.2.1.3). 
• If restart/rechallenge is not granted, permanently disconƟnue study drug and conƟnue parƟcipant 
in the study for any protocol-speciﬁed follow-up assessments. 
13.2.1.2 Follow-up Assessments 
• Perform viral hepaƟƟs serology:  hepaƟƟs A immunoglobulin M (IgM) anƟbody, hepaƟƟs B surface 
anƟgen (HBsAg) and hepaƟƟs B core anƟbody (HBcAb), hepaƟƟs C RNA, cytomegalovirus IgM 
anƟbody, Epstein-Barr viral capsid anƟgen IgM anƟbody (or, if unavailable, heterophile anƟbody or 
monospot tesƟng), and hepaƟƟs E IgM anƟbody. 
• Obtain blood sample for PK analysis. Record on the eCRF the date/Ɵme of the PK blood sample 
draw and the date/Ɵme of the last dose of study drug before the blood sample draw. If the date or 
Ɵme of the last dose is unclear, provide the subject’s best approximaƟon. InstrucƟons for sample 
handling and shipping will be provided in the laboratory manual from the applicable central 
laboratory. 
• Measure serum creaƟne phosphokinase (CPK) and lactate dehydrogenase (LDH). 
• Obtain complete blood count with diﬀerenƟal to assess eosinophilia. 


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• Record the appearance or worsening of clinical symptoms of liver injury or hypersensiƟvity on the 
AE report form. 
• Record use of concomitant medicaƟons (including acetaminophen, herbal remedies, and other OTC 
medicaƟons) on the concomitant medicaƟons eCRF. 
• Record alcohol use in EDC according to eCRF compleƟon guidelines. 
For a possible Hy’s Law case (ALT ≥3x ULN AND total bilirubin ≥2x ULN or INR >1.5): 
• FracƟonate bilirubin if total bilirubin is ≥2x ULN. 
• Measure anƟ-nuclear anƟbody, anƟ–smooth muscle anƟbody, type 1 anƟ-liver kidney microsomal 
anƟbodies, and quanƟtaƟve total immunoglobulin G (IgG) or gamma globulins. 
• Perform serum acetaminophen adduct high-performance liquid chromatography (HPLC) assay 
(quanƟﬁes potenƟal acetaminophen contribuƟon to liver injury) in subjects with deﬁnite or likely 
acetaminophen use in the preceding week. 
• Perform liver imaging (ultrasound, magneƟc 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) unƟl abnormaliƟes resolve, stabilize, or return to baseline. 
• A specialist or hepatology consultaƟon 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) unƟl abnormaliƟes resolve, stabilize, or return to baseline. 
13.2.2 Increased Liver Chemistry Monitoring While ConƟnuing Study Drug 
If ALT ≥3x ULN and <5x ULN and total bilirubin <2x ULN, without symptoms believed to be related to 
liver injury or hypersensiƟvity, and the subject can be monitored weekly for 4 weeks, perform the 
following acƟons: 
• NoƟfy the Medical Monitor within 24 hours of learning of the abnormality to discuss subject 
safety.  
• Subject can conƟnue 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) unƟl the abnormaliƟes resolve, stabilize, or return to baseline.  
• If at any Ɵme the subject meets liver chemistry stopping criteria, proceed as described in 
SecƟon 7.1.1 and SecƟon 13.2.1. 
• If, aŌer 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 InvesƟgator may request the Sponsor to consider restarƟng 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 obstrucƟon, pancreaƟc events, 
hypotension, acute viral hepaƟƟs), 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 InvesƟgator and the study team. 
This includes the absence of markers of hypersensiƟvity (otherwise unexplained fever, rash, 
eosinophilia). Where a study medicaƟon has an idenƟﬁed geneƟc marker associated with liver 
injury (eg, lapaƟnib, abacavir, amoxicillin/clavulanate), the presence of the marker should be 
excluded. If study drug–related liver injury cannot be excluded, the guidance on appropriate acƟon 
and follow-up in the previous secƟons of this Appendix will apply. 
• There is no evidence of alcoholic hepaƟƟs. 
• Medical Monitor approval of study drug restart has been obtained. 
If restart of study drug is approved by the Sponsor in wriƟng:  
• 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 unƟl 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 aŌer study drug restart, 
study drug should be permanently disconƟnued.  
• The Medical Monitor must be informed of the outcome for the subject following study drug 
restart.  
• The Sponsor must be noƟﬁed of any AEs. 


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13.3 Appendix of Clinical Laboratory and Urinalysis Tests 
Refer to SecƟon 8.2.5 for more informaƟon on clinical laboratory and urinalysis tests. 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet count  
RBC count 
RBC indices: MCV, MCH, % reƟculocytes 
Hemoglobin 
Hematocrit 
WBC count  
DiﬀerenƟal: neutrophils, lymphocytes, monocytes, eosinophils, basophils 
Clinical Chemistry1 
Potassium 
Calcium 
Sodium 
BUN 
CreaƟnine 
Total protein 
ALP 
ALT/SGPT 
AST/SGOT  
GGT 
Total and direct bilirubin  
Total bile acids 
CoagulaƟon 
PT/INR, PTT 
Lipid Panel 
Total cholesterol, LDL, HDL, triglycerides 
Thyroid Panel 
T3 (free and total), T4 (free and total), TSH 
RouƟne Urinalysis 
Speciﬁc gravity 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, by dipsƟck 
Microscopic examinaƟon (if blood or protein is abnormal) 
Other Tests 
LH, FSH, SHBG, renin, aldosterone 
For males only: inhibin B 
For females only: estradiol, prolacƟn, progesterone 
AbbreviaƟons: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate 
aminotransferase; BUN, blood urea nitrogen; FSH, follicle-sƟmulaƟng hormone; GGT, gamma-glutamyl 
transferase; HDL, high-density lipoprotein; INR, internaƟonal normalized raƟo; LDL, low-density 
lipoprotein; LH, luteinizing hormone; MCH, mean corpuscular hemoglobin; MCV, mean corpuscular 
volume; PT, prothrombin Ɵme; PTT, parƟal thromboplasƟn Ɵme; RBC, red blood cell; SAE, serious 
adverse event; SGOT, serum glutamic-oxaloaceƟc transaminase; SGPT, serum glutamic-pyruvic 
transaminase; SHBG, sex hormone–binding globulin; TSH, thyroid-sƟmulaƟng hormone; ULN, upper limit 
of normal; WBC, white blood cell. 
1 Details of liver chemistry stopping criteria and required acƟons and follow-up assessments aŌer liver 
stopping or monitoring event are given in SecƟon 7.1.1 and SecƟon 13.2. All events of ALT ≥3x ULN plus 
total bilirubin ≥2x ULN (>35% direct bilirubin) or ALT ≥3x 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 GeneƟc Sample CollecƟon and TesƟng 
Where local regulaƟons permit and subject to discreƟonary 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 acƟon of Ɵldacerfont, and drug metabolism 
enzyme and transporter polymorphisms. Drug metabolism enzyme and transporter polymorphisms may 
be evaluated using an analyƟcal methodology that comprehensively assesses an array of drug 
metabolism enzyme and transporter genes from a single sample. AlternaƟve genotyping plaƞorms may 
be used, if appropriate, to conﬁrm iniƟal results. Certain genotyping may be omited at the discreƟon of 
the InvesƟgator and/or Sponsor (eg, if the subject was previously tested for certain genes using the same 
plaƞorm/technology). No addiƟonal tesƟng will be performed on these samples. 
Details regarding the collecƟon, 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 aŌer the last study visit of the last subject in the 
study, or as local regulaƟons allow. Any samples remaining aŌer 5 years will be destroyed. 

SAP_001.pdf: 
Page 1 of 107 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Study Title: 
A Randomized, Double-Blind, Placebo-Controlled, 
Dose-Ranging Study to Evaluate the Efficacy and Safety 
of SPR001 (Tildacerfont) in Adult Subjects with Classic 
Congenital Adrenal Hyperplasia 
 
Study Number: 
Study SPR001-203 
Investigational Drug: 
SPR001 (Tildacerfont) 
Indication: 
Treatment of Congenital Adrenal Hyperplasia 
Investigators: 
Multicenter 
IND Number: 
 
Sponsor: 
Spruce Biosciences, Inc. 
611 Gateway Drive, Suite 740 
South San Francisco, CA 94080 
 
Plan Version: 
2.0, 2 February 2024 
Plan Prepared by: 
Inka Leprince, MS 
Statistical Consultant 
PharmaStat, LLC 
 
CONFIDENTIAL 
This document is confidential and the property of Spruce Biosciences, Inc. It may not be 
copied or provided to any other party without the express written consent of  
Spruce Biosciences, Inc. 
 
2024 Spruce Biosciences, Inc. 


Spruce Biosciences, Inc. 
Study SPR001-203 SAP 
Version 2.0, 2 February 2024 
STATISTICAL ANALYSIS PLAN 
Study SPR001-203
A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study to Evaluate the 
Efficacy and Safety of SPR001 (Tildacerfont) in Adult Subjects with 
Classic Congenital Adrenal Hyperplasia 
Plan Version:  
Plan version reviewed: 
2.0, 2 February 2024
 6 February 2024 
Signature Page 
Saba Sile, MD 
VP of Clinical Development 
Spruce Biosciences Inc. 
Date 
Will Charlton, MD 
Chief Medical Officer 
Spruce Biosciences, Inc. 
Date 
Kevin Carroll, PhD. 
External Statistical Expert 
KJC Statistics Ireland Ltd. 
Date 
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Page 2 of 107 


Spruce Biosciences, Inc. 
 
Study SPR001-203 SAP 
Version 2.0, 2 February 2024 
 
Page 3 of 107 
Table of Contents 
1 
REVISION HISTORY ......................................................................................... 10 
2 
RELATED DOCUMENTS: PROTOCOL AND CASE REPORT FORMS .. 10 
3 
COMMITMENT TO GOOD STATISTICAL PRACTICE ............................. 10 
3.1 
Definition of Good Statistical Practice ................................................................... 10 
3.2 
Use of Standards ..................................................................................................... 11 
4 
PURPOSE OF THE ANALYSIS PLAN ............................................................. 11 
5 
STUDY DESIGN .................................................................................................. 12 
5.1 
Randomization and Blinding .................................................................................. 13 
5.2 
Study Treatment ...................................................................................................... 14 
5.2.1 
Study Drug Administration ..................................................................................... 14 
5.2.2 
Glucocorticoid Changes .......................................................................................... 15 
5.2.3 
Stress Dosing of Glucocorticoid ............................................................................. 16 
5.2.4 
Assessments ............................................................................................................ 16 
5.2.5 
Efficacy Assessments ............................................................................................. 16 
5.2.6 
Safety Assessments ................................................................................................. 18 
6 
STUDY OBJECTIVES AND ENDPOINTS ...................................................... 23 
7 
SAMPLE SIZE AND POWER ............................................................................ 26 
8 
ANALYSIS SETS ................................................................................................. 27 
8.1 
Intent-To-Treat Analysis Set .................................................................................. 27 
8.2 
Modified Intent-To-Treat Analysis Set .................................................................. 27 
8.3 
Per-Protocol Analysis Set ....................................................................................... 27 
8.4 
Safety Analysis Set ................................................................................................. 27 
8.5 
Randomized Safety Analysis Set ............................................................................ 28 
8.6 
Pharmacokinetic Analysis Set ................................................................................ 28 
9 
GENERAL CONSIDERATIONS ....................................................................... 28 
9.1 
Presentation of Summary Statistics ........................................................................ 28 
9.2 
Presentation of p-values .......................................................................................... 29 
9.3 
Definitions and Derived Variables ......................................................................... 29 
9.3.1 
Screened and Enrolled Subjects .............................................................................. 29 
9.3.2 
Study Day ............................................................................................................... 30 
9.3.3 
Treatment Study Day .............................................................................................. 30 
9.3.4 
End of Study Treatment Definition ........................................................................ 30 
9.3.5 
End of Study Definition .......................................................................................... 30 
9.3.6 
Age .......................................................................................................................... 30 
9.3.7 
Age at Diagnosis of CAH ....................................................................................... 30 
9.3.8 
Body Mass Index .................................................................................................... 31 


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9.3.9 
Body Surface area ................................................................................................... 31 
9.3.10 
Baseline Values ...................................................................................................... 31 
9.3.11 
Change from Baseline ............................................................................................. 32 
9.3.12 
Percent Change from Baseline ................................................................................ 32 
9.3.13 
Change from Baseline on the Log Scale ................................................................. 32 
9.3.14 
Geometric Mean Ratio and Percent Change ........................................................... 33 
9.3.15 
Upper Limit of Normal or Target by Efficacy Biomarker ..................................... 33 
9.3.16 
Responder Definitions ............................................................................................ 33 
9.3.17 
HADS Total Score .................................................................................................. 34 
9.3.18 
SF-36 Total Score ................................................................................................... 34 
9.3.19 
Modified Ferriman-Gallwey Total Score ............................................................... 35 
9.3.20 
Homeostatic Model Assessment of Insulin Resistance .......................................... 35 
9.3.21 
Testicular Adrenal Rest Tumor Volume ................................................................. 35 
9.3.22 
Cardiovascular Risk Factors ................................................................................... 35 
9.3.23 
Study Drug Exposure Variables ............................................................................. 36 
9.3.24 
Prior, Concomitant and Post treatment Medications .............................................. 39 
9.3.25 
Adverse Events ....................................................................................................... 40 
9.3.26 
Glucocorticoid Therapy .......................................................................................... 40 
9.3.27 
Variables Related to Menstrual Cycles ................................................................... 42 
9.3.28 
Geographic Regions ................................................................................................ 43 
9.4 
Analysis Windows .................................................................................................. 43 
10 
STATISTICAL AND ANALYSIS ISSUES ........................................................ 44 
10.1 
Adjustments for Covariates .................................................................................... 44 
10.2 
Handling Dropouts or Missing Data ....................................................................... 45 
10.2.1 
Handling of Efficacy Data ...................................................................................... 45 
10.2.2 
Handling of Questionnaire Data ............................................................................. 45 
10.2.3 
Handling of Laboratory Data .................................................................................. 45 
10.2.4 
Handling of Safety Data ......................................................................................... 46 
10.3 
Primary Analyses and Safety Data Monitoring ...................................................... 47 
10.4 
Multicenter Considerations ..................................................................................... 47 
10.5 
Multiple Comparisons, Multiplicity ....................................................................... 48 
10.6 
Active-Control Studies ........................................................................................... 48 
10.7 
Examination of Subgroups ..................................................................................... 48 
11 
STUDY SUBJECTS.............................................................................................. 49 
11.1 
Subject Enrollment and Disposition ....................................................................... 49 
11.1.1 
Screened and Enrolled Subjects .............................................................................. 49 
11.1.2 
Randomized Subjects .............................................................................................. 49 


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11.2 
Protocol Deviations ................................................................................................ 49 
11.3 
Demographics and Baseline Characteristics ........................................................... 50 
11.3.1 
Demographics ......................................................................................................... 50 
11.3.2 
Baseline Characteristics .......................................................................................... 50 
11.4 
Medical History ...................................................................................................... 51 
11.4.1 
General Medical History ......................................................................................... 51 
11.4.2 
Congenital Adrenal Hyperplasia History ................................................................ 51 
12 
STUDY DRUG AND OTHER MEDICATIONS ............................................... 52 
12.1 
Exposure to Study Drug and Study Treatment Compliance ................................... 52 
12.2 
Glucocorticoid Therapy .......................................................................................... 53 
12.3 
Prior and Concomitant Medications ....................................................................... 53 
13 
EFFICACY ANALYSES ..................................................................................... 54 
13.1 
Primary Efficacy Analysis ...................................................................................... 54 
13.2 
Final Efficacy Analysis ........................................................................................... 55 
13.3 
Primary Efficacy Analysis ...................................................................................... 55 
13.3.1 
Definition of A4 Dose Response Analysis ............................................................. 55 
13.3.2 
Dose Response Statistical Hypothesis .................................................................... 56 
13.3.3 
Dose Response Modeling and Testing ................................................................... 57 
13.3.4 
Summary of Descriptive Statistics for A4 .............................................................. 58 
13.3.5 
Sensitivity Analyses ................................................................................................ 58 
13.4 
Secondary Efficacy Analyses ................................................................................. 62 
13.4.1 
First Secondary Efficacy Analysis .......................................................................... 62 
13.4.2 
Second Secondary Efficacy Analysis ..................................................................... 64 
13.4.3 
Third Secondary Efficacy Analysis ........................................................................ 65 
13.4.4 
Forth Secondary Endpoint Analysis ....................................................................... 65 
13.4.5 
Fifth Secondary Endpoint Analysis ........................................................................ 65 
13.5 
Exploratory Efficacy Analyses ............................................................................... 66 
13.5.1 
A4 Responder Analysis .......................................................................................... 66 
13.5.2 
17-OHP Responder Analysis .................................................................................. 69 
13.5.3 
TART Lesion Volume CFB at Week 18 ................................................................ 69 
13.5.4 
Correlation of Tildacerfont Plasma Concentration vs Dose ................................... 70 
13.5.5 
Correlation of A4 Level versus 17-OHP Level ...................................................... 70 
13.5.6 
SF-36 Change from Baseline at Week 18 Analysis ................................................ 71 
13.5.7 
Change from Baseline Analyses through Week 76 ................................................ 72 
13.5.8 
Evaluation of ATCH ............................................................................................... 73 
13.5.9 
Within Subject Correlation of A4 and 17-OHP with tildacerfont Plasma 
Concentration .......................................................................................................... 73 


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13.5.10 
Additional Exploratory Analyses ........................................................................... 74 
14 
SAFETY ANALYSES .......................................................................................... 75 
14.1 
Adverse Events ....................................................................................................... 76 
14.1.1 
Overall Summary of TEAEs ................................................................................... 77 
14.1.2 
Summary of TEAEs by System Organ Class and Preferred Term ......................... 77 
14.2 
Clinical Laboratory Evaluation ............................................................................... 77 
14.3 
Vital Signs .............................................................................................................. 79 
14.4 
12-Lead Electrocardiogram .................................................................................... 79 
14.5 
Psychiatric Evaluations ........................................................................................... 80 
14.5.1 
The Hospital Anxiety and Depression Scale .......................................................... 80 
14.5.2 
Columbia–Suicide Severity Rating Scale ............................................................... 80 
14.6 
Quality of Life ........................................................................................................ 81 
14.6.1 
Patient Global Impression of Change ..................................................................... 81 
14.6.2 
Clinical Global Impression – Improvement Scale .................................................. 81 
15 
CHANGES RELATIVE TO THE PROTOCOL-SPECIFIED ANALYSIS ... 81 
16 
REFERENCE ........................................................................................................ 83 
17 
APPENDIX A: SCHEDULE OF ASSESSMENTS ........................................... 84 
18 
APPENDIX B: CLINICAL LABORATORY PARAMETERS ....................... 96 
19 
APPENDIX C: CALCULATING TOTAL SCORE FOR SHORT-FROM 3696 
20 
APPENDIX D:  A4 DOSE RESPONSE OVER TIME BY RANDOMIZED 
TREATMENT ARM ............................................................................................ 96 
21 
APPENDIX E: CALCULATING ABSOLUTE CFB AND ABSOLUTE 
TREATMENT EFFECTS FOR A4 AT BASED ON ANALYSES 
CONDUCTED ON THE LOG SCALE. ........................................................... 102 
 
 
 


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Page 7 of 107 
List of Tables 
Table 1 
Study 203 Objectives and Endpoints ........................................................................... 23 
Table 2 
Classification of Body Mass Index .............................................................................. 31 
Table 3 
Study SPR001-203 Baseline Specifications for Specific Variables ............................ 32 
Table 4 
Upper Limit of Normal Values by Subgroup and Key Biomarker .............................. 33 
Table 5 
Responder Definition by Endpoint............................................................................... 34 
Table 6 
Spruce 203 Cardiovascular Risk Factors by Sex ......................................................... 36 
Table 7 
First Dose of Treatment Period by Dispensation ......................................................... 37 
Table 8 
Relative Potencies of Glucocorticoids in Hydrocortisone Equivalents ....................... 41 
Table 9 
Analysis Visit Windows (Clinic Visits Only) .............................................................. 43 
Table 10 Potentially Clinically Significant Abnormalities by Laboratory Parameter ................ 78 
Table 11 Potentially Clinically Significant Abnormalities by Vital Sign Parameter .................. 79 
Table 12 Pre-Specified Threshold Levels for ECG Parameters .................................................. 80 
Table 13 Study SPR001-203 Protocol Schedule of Events at Screening (Protocol Version 7.0, 
March 14, 2022 ............................................................................................................ 84 
Table 14 Study SPR001-203 Protocol Schedule of Post-Screening Events (Protocol Version 7.0 
March 14, 2022) ........................................................................................................... 86 
Table 15 Study SPR001-203 Protocol Schedule of Post-Screening Events (Protocol Version 7.0 
March 14, 2022) ........................................................................................................... 94 
Table 16 Clinical Laboratory Parameters.................................................................................... 96 
 
List of Figures 
Figure 1 Schema of Study SPR001-203 Study Visits ................................................................ 21 
Figure 2 Schema of Study SPR001-203 Optional Open-Label Extension Period Study Visits . 22 
 
 
 


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List of Abbreviations and Definition of Terms 
Abbreviation 
Description 
17-OHP 
17-hydroxyprogesterone 
A4 
androstenedione 
ACTH 
adrenocorticotropic hormone, corticotropin 
ADAM 
analysis data model 
AE 
adverse event 
AESI 
adverse event of special interest 
AIC 
Akaike information criterion 
BID 
Twice daily 
BLQ 
Below level of quantification 
BMI 
body mass index 
BP 
blood pressure 
C-SSRS 
Columbia–Suicide Severity Rating Scale 
CAH 
congenital adrenal hyperplasia 
CGI-I 
Clinical Global Impression – Improvement Scale 
CI 
confidence interval 
CFB 
change from baseline 
CRF 
corticotropin-releasing factor 
CRO 
contract research organization 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
GC 
glucocorticoid 
GM 
geometric mean 
GMR 
geometric mean ratio 
HADS 
Hospital Anxiety and Depression Scale 
HbA1c 
hemoglobin A1c 
HC 
hydrocortisone 
HCe 
hydrocortisone equivalent(s) 
HDL 
high-density lipoprotein 
HOMA-IR 
homeostatic model assessment of insulin resistance 
HR  
heart rate 
IGA 
Investigator’s Global Assessment (of acne severity) 
ITT 
Intent to Treat (Population) 


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Page 9 of 107 
Abbreviation 
Description 
LDL 
low-density lipoprotein 
LFT 
liver function test 
log 
logarithmic function 
LS 
least squares 
MCP-Mod 
Multiple Comparison Procedure – Modelling 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDRI 
Multi Domain Response Index 
mFG 
modified Ferriman Gallwey (score for hirsutism) 
mITT 
modified Intent to Treat (Population) 
MMRM 
mixed-model for repeated measures 
PCSA 
potentially clinically significant abnormality(ies) 
PGIC 
Patient Global Impression of Change 
PK 
pharmacokinetic 
PP 
per-protocol 
PT 
preferred term 
QD 
once daily 
QoL 
quality of life 
QTcF 
Fridericia-corrected QT interval 
REML 
restricted maximum likelihood 
RTSM 
randomization and trial supply management 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SF-36 
Short Form 36 
SOC 
system organ class 
TART 
testicular adrenal rest tumor 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
WHO DD 
World Health Organization Drug dictionary 
 
 


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Version 2.0, 2 February 2024 
 
Page 10 of 107 
1 
REVISION HISTORY 
Version 
Date 
Document Owner 
Revision Summary 
1.0 
31 December 2023 
Inka Leprince 
First version 
 
2 
RELATED DOCUMENTS: PROTOCOL AND CASE REPORT FORMS 
Version 
Date 
Protocol Version 1.0 
19DEC2019 
Protocol Version 2.0 
30JAN2020 
Protocol Version 3.0 
14FEB2020 
Protocol Version 4.0 
14APR2020 
Protocol Version 5.0 
31AUG2020 
Protocol Version 6.0 
31MAR2021 
Protocol Version 7.0 
14MAR2022 
Case Report Forms 
02JAN2023 
 
 
3 
COMMITMENT TO GOOD STATISTICAL PRACTICE 
3.1 
Definition of Good Statistical Practice 
The International Council for Harmonisation Guideline on Statistical Principles for Clinical 
Trials (ICH E9) implicitly defines good statistical practice. Good statistical practice includes 
both appropriate statistical designs to minimize bias and maximize precision of analysis plus 
operational excellence to assure credibility of results. The scientific design associated with any 
clinical trial is found in the protocol. More detailed, pre-specified statistical analysis methods can 
be found in the statistical analysis plan.  
We interpret the operational side of good statistical practice as a transparent, reproducible, and 
validated approach to acquiring and analyzing clinical trial data. Reproducible research depends 
upon process transparency and also provides auditability of the statistical analysis. Analysis 
transparency requires that a navigable electronic process chain exists from defining the objective 
of the analysis to creating the results. 


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3.2 
Use of Standards 
Data standards are foundational for creating an environment where tools can be leveraged at 
different points in the analysis process. Data standards for clinical development of drugs have 
been defined and are maturing under various initiatives through the Clinical Data Interchange 
Standards Consortium (CDISC). Spruce Biosciences uses standard data tabulation model 
(SDTM) data sets and Analysis Data Model (ADaM) statistical analysis files for producing 
analysis results. Other applicable standards include regulatory guidance from the Food and Drug 
Administration (FDA) and ICH: 
• ICH Guideline on the Structure and Content of Clinical Study Reports (ICH E3) 
• ICH Guideline for Good Clinical Practice (ICH E6) 
4 
PURPOSE OF THE ANALYSIS PLAN 
This statistical analysis plan (SAP) pre-specifies the statistical analysis methods for supporting 
the completion of the clinical study report (CSR) of Study SPR001-203 for investigational 
product SPR001 (referred to as tildacerfont hereafter), an investigational drug candidate designed 
to treat classic congenital adrenal hyperplasia (CAH). This SAP will be used to analyze the 
primary efficacy, final efficacy, and safety data collected during the study. The analysis of the 
open label extension period will be covered in a separate SAP. Dose-exposure-response analyses 
combining data across multiple studies will be conducted using a separate pharmacokinetics 
SAP. The planned analyses identified in this SAP may be included in regulatory submissions 
and/or future manuscripts.  
The analysis methods described in this plan are considered a priori, in that they have been 
defined prior to clinical database lock and treatment unblinding. Exploratory analyses that are 
not defined in this SAP, may be performed to support the clinical development program. Any 
post-hoc or unplanned analyses that are performed for the CSR, but not defined in this SAP, will 
be documented in the CSR. Changes from the planned analyses stated in the study protocol are 
described in Section 15. Should the SAP and the protocol be inconsistent with respect to any 
further planned analyses, the language of the SAP is governing.  


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The analysis of pharmacokinetic (PK) concentration data and its parameters, as well as the 
analysis of the optional open-label extension period will be captured in separate SAPs. 
5 
STUDY DESIGN 
This is a multi-center, randomized, double-blind, placebo-controlled, dose-ranging clinical study 
with a 3-part Treatment Period and an optional Open-Label Extension Period. The 3-part 
Treatment Period will evaluate the efficacy and safety of up to 70 weeks of treatment with 
tildacerfont in adult subjects with classic CAH who have elevated biomarkers at baseline. At 
least 72 adult subjects will be randomized into the Treatment Period of the study. 
A 6-week, single-blind, placebo Run-in Period, will assess subjects for adherence to their 
existing GC therapy and daily ingestion of placebo with food. Upon completion of a 6-week 
single-blind, placebo Run-in Period, subjects who meet all eligibility criteria will be randomized 
into the Treatment Period. Subjects will be randomized in a 1:1:1:1 ratio to receive either 
tildacerfont at a dose of 50 mg (once daily) QD, 100 mg QD, and 200 mg QD or matching 
placebo along the randomization stratum (Week 4 A4 ≤ 4 × upper limit of normal [ULN] versus 
Week 4 A4 > 4 × ULN). The first 12 weeks of the treatment period constitute the randomized, 
double blind, placebo-controlled, dose finding treatment period (Part A). 
Following Part A, all subjects will receive tildacerfont for duration of 12 weeks (Part B) with 
opportunities to up-titrate their tildacerfont dose up to 200 mg QD based on treatment response. 
Placebo subjects will receive the 100 mg tildacerfont QD dose at the beginning of Part B. Part B 
will have possible dose escalations at Week 18 and Week 24 for eligible subjects not meeting 
androstenedione (A4) response criteria as an assessment of dose titration for non-responders 
(A4 > upper limit of normal [ULN]). 
Part C is a 46-week treatment period in which all subjects are escalated to receive 200 mg 
tildacerfont QD at Week 30, with opportunities for glucocorticoid (GC) reduction for eligible 
subjects (subjects meeting A4 ≤ ULN). 


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Subjects continuing into the optional Open-Label Extension Period will receive 200 mg 
tildacerfont QD for up to 240 weeks of treatment, with opportunities for GC adjustment for 
eligible subjects at each visit. Upon completion of the Open-Label Extension Period or 
completion of Treatment Period Part C for those subjects who do not continue into the Open-
Label Extension Period, subjects will return to the clinic within 30 days following their last dose 
for a Follow-up visit. 
Clinical visits during Parts A, B, and C in the Treatment Period, the Open-Label Extension 
Period, and Follow-up Period will include efficacy, biomarkers, safety, and pharmacokinetic 
(PK) assessments. Figure 1 depicts study visits from Screening Period to Follow-up Period and 
Figure 2 depicts study visits during the optional Open-Label Extension Period. 
The maximum duration per subject of the main Treatment Period of Study SPR001-203 is 
expected to be up to 87 weeks (i.e., a maximum of 45-day Screening Period, a 6-week Run-in 
Period, a 70-week Treatment Period, and a 30-day safety Follow-up Period). Including the 
optional Open-Label Extension Period (240 weeks), the maximum duration per subject is 
expected to be up to 327 weeks. Subjects randomized to tildacerfont in Part A will receive up to 
70 weeks of treatment with tildacerfont in the main study. For subjects randomized to placebo in 
Part A, this will include up to 58 weeks of treatment with tildacerfont in the main study. 
Assessments and procedures for evaluation of safety, efficacy, PK, and biomarkers will be 
conducted per the protocol-specified schedule (see Appendix A: Table 13, Table 14, and 
Table 15).  
5.1 
Randomization and Blinding 
All subjects will receive single-blinded placebo during the Run-in Period. Eligible subjects will 
be centrally randomized to study intervention in Part A and assigned to the appropriate dose of 
tildacerfont in Parts B and C using a randomization and trial supply management (RTSM) 
system. Subjects will be randomized to study drug treatment in a 1:1:1:1 ratio to receive placebo 
or tildacerfont at dose levels of 50 mg, 100 mg, or 200 mg, stratified by the Week 4 A4 value 
(A4 ≤ 4 × upper limit of normal [ULN] versus A4 > 4 × ULN). In Parts B and C, subjects will 


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receive tildacerfont with possible tildacerfont dose escalation at Weeks 18, 24, and 30 as 
described in Section 5.2.1. 
Investigators, subjects, and the Sponsor’s contract research organization (CRO) will be blinded 
to assigned study drug treatment assignment in Part A and to dose of tildacerfont in Part B. To 
maintain the blind, all subjects will receive the same number of study drug tablets per dose, with 
the appropriate number of tildacerfont and/or placebo tablets for the assigned study intervention. 
The subject level blind will be maintained until the completion of the final analyses. At the time 
of the primary efficacy analysis—after all subjects have completed the Week 18 visit of the 
Part A double-blind Treatment Period and the data has been hard-locked for analysis —the 
Sponsor will be unblinded to group level results, but Investigators, study personnel who conduct 
the study, and the subject-level blind will be maintained until the completion of the final 
analyses.  
5.2 
Study Treatment 
5.2.1 
Study Drug Administration 
During the Run-in Period, subjects will take placebo for 6 weeks. In Part A of the study (the first 
12 weeks of the Treatment Period), subjects will receive randomized study drug treatment (i.e., 
tildacerfont 50, 100, or 200 mg QD or matching placebo) without dose escalation. During Part B 
(the second 12 weeks of the Treatment Period) and Part C (the last 46 weeks of the Treatment 
Period), all subjects will receive tildacerfont and the dose level will be determined as follows. 
• Subjects who were randomized to placebo in Part A will receive 100 mg tildacerfont QD 
at the beginning of Part B (Week 18). 
• Subjects who were randomized to 200 mg tildacerfont QD in Part A will continue to 
receive tildacerfont at 200 mg QD throughout Parts B and C. 
• Based on A4 results from the Week 18 and Week 24 visits, eligible subjects may undergo 
a tildacerfont dose escalation after each of these study visits. The RTSM system will 
assign appropriate dose levels of tildacerfont based on subjects’ A4 results (i.e., A4 ≤ 
ULN or A4 > ULN) at Weeks 18 and 24. Specifically: 


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o 
Subjects taking tildacerfont 50 mg QD will either continue to receive the same 
dose (if A4 ≤ ULN) or be escalated to 100 mg tildacerfont QD (if A4 > ULN and 
the subject is tolerating his/her current tildacerfont dose) 
o 
Subjects taking 100 mg tildacerfont QD will either continue to receive the same 
dose (if A4 ≤ ULN) or be escalated to 200 mg tildacerfont QD (if A4 > ULN and 
the subject is tolerating his/her current tildacerfont dose). 
• At Week 30, all subjects will be escalated to 200 mg tildacerfont QD. 
During the optional Open-Label Extension Period, subjects will continue to receive tildacerfont 
at 200 mg QD. 
Tildacerfont is produced as a 50 mg tablet. The placebo is produced to look identical to the 
tildacerfont tablet. To maintain the blind, all subjects will receive the same number of study drug 
tablets, and take 4 tablets a day with the appropriate number of tildacerfont and/or placebo 
tablets for the assigned. The 200 mg tildacerfont dose will contain 4 tildacerfont tablets in each 
compartment; the 100 mg tildacerfont dose will contain 2 tildacerfont tablets and 2 placebo 
tablets; the 50 mg tildacerfont dose will contain 1 tildacerfont tablet and 3 placebo tablets; and 
the placebo dose will contain 4 placebo tablets. 
5.2.2 
Glucocorticoid Changes 
Subjects will use their own physician-prescribed supply of glucocorticoids (GCs) as prescribed 
during the study, including during the Run-in Period. During Part C of the Treatment Period, 
subjects with A4 ≤ ULN at Week 38 or Week 46 will begin to reduce their daily GC dose level 
by increments of no more than 5 mg/day in hydrocortisone equivalents (HCe), according to the 
protocol-defined conversion ratios of GC regimens summarized in Table 8, down to a minimum 
of 15 mg/day. Subjects may reduce to a dose below 15 mg HCe with medical monitor approval. 
GC reductions may stop at a higher GC level (>15 mg) based on Primary Investigator (PI) 
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5.2.3 
Stress Dosing of Glucocorticoid 
The Sponsor will provide a supply of oral hydrocortisone (HC) tablets for periods of stress 
dosing. During times of clinically significant physical stress, subjects are advised to take stress 
doses of HC, under advisement of their physician. Per the protocol, subjects who are currently 
stress dosing should reschedule efficacy and safety assessments until the event that initiated the 
stress dosing has resolved (see Protocol Section 6.5.1.5). 
5.2.4 
Assessments 
Appendix A: Table 13, Table 14, and Table 15 show the schedule of events for the study. 
5.2.5 
Efficacy Assessments 
Serum A4 collected at clinic visits for this study. 
Additional efficacy assessments collected at clinic visits in Part A of the Treatment Period and/or 
the optional Open-Label Extension Period include: 
• Serum 17-hydroxyprogesterone (17-OHP)  
• Lesion volume of testicular adrenal rest tumors (TARTs) assessed by complete scrotal 
ultrasounds in in male subjects 
• Quality of life assessments (Short Form-36 [SF-36] total score) 
• Acne assessments (Investigator’s Global Assessment [IGA] of acne severity score) 
• Hirsutism assessments (modified Ferriman Gallwey [mFG] score for hirsutism) 
• Total daily dose of GC regimen(s) 
• Cardiovascular risk factors, as collected by metabolic assessments 
5.2.5.1 Serum Biomarkers 
All blood samples for hormones and androgens will be collected at 8 AM (7 – 9 AM window) 
prior to administering the morning GC dose after an overnight fast. A4, 17 OHP, 
adrenocorticotropic hormone (ACTH), and testosterone will be measured. Hormone assessments 
will be collected at all study visits. 


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5.2.5.2 Testicular Adrenal Rest Tumors 
Scrotal ultrasounds will be obtained for adult male subjects to detect and to evaluate the size 
(volume) and number of TARTs. The initial scrotal ultrasound may be scheduled for any time up 
to the Week 4 visit and will be considered the baseline measurement for the TART endpoint. 
Only subjects with detectable TART(s) at baseline will be followed for TART changes at 
Week 18 and Week 76 of the Treatment Period, as shown in Table 14. 
5.2.5.3 Quality of Life Assessments: Short Form 36 
Quality of life will be measured using the SF-36, which will be administered on Day 1 of the 
Run-in Period; Week 6 (baseline), Week 18, and Week 76 of the Treatment Period, as shown in 
Table 14. 
5.2.5.4 Hyperandrogenic Symptoms 
5.2.5.4.1 Acne 
Acne severity will be evaluated using an IGA score by the Investigator, which will be assessed at 
Week 6 (baseline), Week 18, and Week 76 of the Treatment Period, as shown in Table 14. 
5.2.5.4.2 Hirsutism 
Hirsutism will be evaluated in female subjects using an mFG score by the Investigator, which 
will be assessed at Week 6 (baseline), Week 18, and Week 76 of the Treatment Period, as shown 
in Table 14. 
5.2.5.5 Glucocorticoid Dose Process and Documentation 
At each visit, the prior day’s type of GC, total GC dose, and distribution of daily doses, including 
timing of dosing will be recorded on a CRF called Key Glucocorticoid Dosing. If an adjustment 
in GC dose or change in distribution of the daily GC regimen is warranted, a new record will be 
entered in the Prior & Concomitant Daily Glucocorticoids/Mineralocorticoids eCRF. Changes to 
GC (for example: switch from short to intermediate) type during Part A of the study will be 
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5.2.5.6 Metabolic Assessments 
Metabolic assessments include assessments of hypertension (systolic blood pressure [SBP] and 
diastolic blood pressure [DBP]), waist circumference, fasting assessments of insulin resistance 
(hemoglobin A1c [HbA1c], fasting glucose, fasting insulin, and homeostatic model assessment 
of insulin resistance [HOMA-IR]), assessments of dyslipidemia (total cholesterol, low-density 
lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, and triglycerides). 
HbA1c, fasting glucose, fasting insulin, HOMA-IR, total cholesterol, LDL cholesterol, HDL 
cholesterol, and triglycerides will be assessed as part of clinical laboratory, described in 
Section 5.2.6.5. SBP, DBP, and waist circumference will be assessed as part of vital signs, 
described in Section 5.2.6.2.  
5.2.6 
Safety Assessments 
Safety will be assessed by repeated clinical evaluations including adverse events (AEs), 
treatment-emergent adverse events (TEAEs), serious AEs (SAEs), AEs leading to 
discontinuation/withdrawal, AEs of special interest (AESIs), vital signs, physical examination, 
electrocardiograms (ECGs), clinical laboratory tests (serum chemistry, hematology, and 
urinalysis), and psychiatric evaluations for suicide risk by Columbia–Suicide Severity Rating 
Scale (C-SSRS). 
5.2.6.1 Adverse Events 
Investigators will collect information related to AEs will be collected throughout this clinical 
trial. All AEs occurring in all subjects will be collected following signing of the first informed 
consent until approximately 30 days after the last study drug treatment. 
5.2.6.2 Vital Signs 
The following vital signs will be assessed after the subject has been sitting for approximately 
5 minutes: blood pressure (systolic and diastolic; mmHg); pulse rate (beats per minute); 
respiration rate (breaths per minute); and body temperature (°C); weight (kg); height (cm); waist 
circumference (cm). Vital signs will be obtained at Screening, and at every clinic visit during the 
Treatment Period. Height is measured at Screening. From these height and weight assessments, 


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body mass index (BMI; kg/m2) and body surface area (BSA; m2) will be calculated. Waist 
circumference is measured at Screening, Week 6 (baseline), Week 18, and Week 76 of the 
Treatment Period, as shown in Table 14. 
5.2.6.3 Physical Examinations 
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 includes the following components: cardiovascular, 
respiratory, abdomen, musculoskeletal, HEENT, and skin. 
A full physical examination will be performed during the Screening Visit and at Day 1, Week 18, 
and Week 76, as shown in Table 14. 
5.2.6.4 Electrocardiograms 
All 12-lead electrocardiogram (ECG) assessments will include heart rate, QRS, QT, and QTc 
intervals using Fridericia’s formula. ECGs will be performed at the following visits: Screening, 
Week 6, Week 18, Week 30, and Week 76, as shown in Table 14. 
5.2.6.5 Clinical Laboratory and Urinalysis 
Clinical laboratory assessments include hematology, clinical chemistry, coagulation, lipid panel, 
thyroid panel, luteinizing hormone (LH), follicle-stimulating hormone (FSH), sex hormone-
binding globulin (SHBG), renin, aldosterone, inhibin B for males only, and estradiol, prolactin, 
and progesterone for females only. Estimated glomerular filtration rate (eGFR) for screening will 
be calculated from blood creatinine measured as part of screening clinical chemistry. Clinical lab 
assessments will be performed at the following visits: Week 6, Week 10, Week 14, Week 18, 
Week 24, Week 30, Week 38, Week 46, Week 56, Week 58, Week 70, Week 76 and Week 80, 
as shown in Table 14. 


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5.2.6.6 Psychiatric Evaluations 
5.2.6.6.1 Columbia–Suicide Severity Rating Scale 
The C-SSRS will be used during the study to monitor suicidal ideation and behavior. 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: Week 6, Week 18, Week 30, 
and Week 76, as shown in Table 14. 
5.2.6.6.2 Hospital Anxiety and Depression Scale 
Subject anxiety and depression will be monitored during the study using the HADS, assessed at 
Week 6, Week 18, Week 30, Week 58, Week 70, and Week 76, as shown in Table 14.  
 


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Figure 1 Schema of Study SPR001-203 Study Visits 
 


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Figure 2 Schema of Study SPR001-203 Optional Open-Label Extension Period Study Visits 
 
 


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6 
STUDY OBJECTIVES AND ENDPOINTS 
This study will evaluate the potential of tildacerfont to reduce and control biomarkers (percent 
and absolute change in A4 and  17-OHP) in adult subjects with classic CAH who have elevated 
biomarkers at baseline on their current, supraphysiologic dose of GC replacement therapy. Part B 
and Part C will provide further monitoring for clinical outcomes with dose escalation to 
determine whether a higher dose may be necessary for hormone control in subjects with higher 
baseline hormone levels. Part C of this study and the optional Open-Label Extension Period will 
explore the potential GC-sparing effects of tildacerfont in subjects with elevated baseline A4 
who are able to achieve A4 control on tildacerfont. 
Study SPR001-203 will characterize clinical outcomes after up to 12 weeks of double-blind 
treatment and after up to 76 weeks of treatment with tildacerfont. The optional Open-Label 
Extension Period will provide additional characterization of up to 240 weeks of treatment with 
tildacerfont (see Table 1 for a summary of study objectives). 
Table 1 
Study 203 Objectives and Endpoints 
Objective 
Efficacy   Analysis 
Primary Efficacy 
To evaluate the effect of tildacerfont in 
reducing A4 in subjects with classic CAH 
over 12 weeks 
1.1. 
Assessment of dose response for change from baseline in 
log A4 after 12 weeks on double-blind, placebo-controlled 
treatment (Week 18) 
Secondary Efficacy 
To evaluate the effect of tildacerfont in 
reducing A4 in subjects with classic CAH 
over 12 weeks 
2.1. 
Change from baseline in A4 as assessed on the log scale 
after 12 weeks on double-blind, placebo-controlled 
treatment (Week 18) 
To evaluate the effect of tildacerfont in 
reducing A4 in subjects with classic CAH 
over 12 weeks 
2.2. 
Absolute change from baseline in A4 as determined via 
application of the delta theorem to the log scale analysis 
results after 12 weeks on double-blind, placebo-controlled 
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Objective 
Efficacy   Analysis 
To evaluate the effect of tildacerfont in 
reducing 17-OHP in subjects with classic 
CAH over 12 weeks 
2.3. 
Assessment of dose response for change from baseline in 
log 17-OHP after 12 weeks on double-blind, placebo-
controlled treatment (Week 18) 
To evaluate the effect of tildacerfont in 
reducing 17-OHP in subjects with classic 
CAH over 12 weeks 
2.4. 
Change from baseline in 17-OHP as assessed on the log 
scale after 12 weeks on double-blind, placebo-controlled 
treatment (Week 18) 
To evaluate the effect of tildacerfont in 
reducing 17-OHP in subjects with classic 
CAH over 12 weeks 
2.5. 
Absolute change from baseline in 17-OHP as determined 
via application of the delta theorem to the log scale 
analysis results after 12 weeks on double-blind, placebo-
controlled treatment (Week 18) 
Exploratory Efficacy 
To evaluate the effect of tildacerfont in 
reducing A4 in subjects with classic CAH 
over 12 weeks 
3.1. 
Proportion of subjects who achieve adequate control of A4 
(A4 ≤ 1x, 1.25x, 1.5x, 1.75x and 2x ULN) after 12 weeks 
on double-blind, placebo-controlled treatment (Week 18) 
for each treatment group 
To evaluate the effect of tildacerfont in 
reducing 17-OHP in subjects with classic 
CAH over 12 weeks 
3.2. 
Proportion of subjects who achieve adequate control of 17-
OHP (17-OHP ≤ 1200 ng/dL) after 12 weeks on double-
blind, placebo-controlled treatment (Week 18) for each 
treatment group 
To evaluate the effect of tildacerfont in 
reducing testicular adrenal rest tumor(s) 
(TART[s]) in male classic CAH subjects with 
TART(s) at baseline after 12 weeks on 
treatment 
3.3. 
Change in the lesion volume of TART(s) from baseline 
after 12 weeks on double-blind, placebo-controlled 
treatment (Week 18) for each treatment group 
To characterize dose-exposure of 
Tildacerfont in CAH 
3.4. 
Correlation of Tildacerfont plasma concentration vs dose 
To evaluate the effect of tildacerfont on 
biomarkers relative to each other in subjects 
with classic CAH over 12 weeks 
3.5. 
Estimate the within subject correlation of A4 and 17-OHP 
log scale values over time 
To evaluate the effect of tildacerfont in 
improving quality of life (QoL) in subjects 
with classic CAH after 12 weeks on 
treatment 
3.6. 
Change from baseline in SF-36 total score after 12 weeks 
on double-blind, placebo-controlled treatment (Week 18) 
for each treatment group 
 
 
 


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Objective 
Efficacy   Analysis 
To evaluate the effect of tildacerfont in 
improving QoL in subjects with classic CAH 
3.7. 
Change from baseline at Week 76 in SF-36 total score 
across all ITT subjects 
To evaluate the effect of tildacerfont in 
improving acne in classic CAH subjects with 
acne at baseline 
3.8. 
Change from baseline at Week 76 in IGA of acne severity 
score across all ITT subjects with acne at baseline 
To evaluate the effect of tildacerfont in 
improving hirsutism in female classic CAH 
subjects with hirsutism at baseline 
3.9. 
Change from baseline at Week 76 in modified Ferriman 
Gallwey (mFG) score for hirsutism across all female ITT 
subjects with hirsutism at baseline 
To evaluate the proportion of subjects who 
can reduce GC use in subjects with classic 
CAH 
3.10. 
Proportion of subjects with at least a 5 mg/day 
hydrocortisone   equivalent (HCe) reduction from baseline 
in GC dose and A4 ≤ ULN at Week 76 
To evaluate the effect of tildacerfont in 
reducing TART(s) in male classic CAH 
subjects with TART(s) at baseline 
3.11. 
Change in the total lesion volume of TART(s) from 
baseline at Week 76 across all male ITT subjects with 
TART(s) at baseline 
To evaluate the effect of tildacerfont in 
reducing A4 in subjects with classic CAH 
over 12 weeks 
3.12. 
Assessment of dose response for change from baseline in 
log ATCH after 12 weeks on double-blind, placebo-
controlled treatment (Week 18) 
To evaluate the effect of tildacerfont in 
reducing ATCH in subjects with classic CAH 
over 12 weeks 
3.13. 
Absolute change from baseline in ATCH as determined 
via application of the delta theorem to the log scale 
analysis results after 12 weeks on double-blind, placebo-
controlled treatment (Week 18) 
To evaluate the effect of tildacerfont in 
reducing ATCH in subjects with classic CAH 
over 12 weeks 
3.14. 
Change from baseline in ATCH as assessed on the log 
scale after 12 weeks on double-blind, placebo-controlled 
treatment (Week 18) 
 
 
 


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Objective 
Efficacy   Analysis 
To characterize dose-exposure of 
Tildacerfont in CAH 
3.15. 
Estimate the within subject correlation of A4 and 17-OHP 
log scale values with tildacerfont plasma concentrations 
over time 
Exploratory Efficacy (Optional Open-Label Extension Period) - Outside the Scope of this SAP 
To evaluate the effect of tildacerfont in 
reducing GC use to near-physiologic levels in 
subjects with classic CAH 
4.1. 
Proportion of subjects with GC dose ≤ 25 mg/day in HCe 
and A4 ≤ ULN at end of treatment (EOT) 
To evaluate the percentage change in GC use 
in subjects with classic CAH 
4.2. 
Percent change from baseline in GC dose at EOT 
To evaluate the effect of tildacerfont in 
reducing cardiovascular risk in subjects with 
classic CAH and at least one cardiovascular 
risk factor at baseline 
4.3. 
Proportion of subjects with improvement in at least one 
cardiovascular risk factor at EOT 
To evaluate the effect of tildacerfont in 
eliminating TART(s) in male classic CAH 
subjects with TART(s) at baseline 
4.4. 
Proportion of male subjects without TART(s) at EOT who 
had TART(s) at baseline 
Safety 
To evaluate the safety of tildacerfont in 
subjects with classic CAH 
5.1. 
AEs, SAEs 
 
7 
SAMPLE SIZE AND POWER 
According to the protocol, a sample size of n = 15 subjects per group will provide at least 80% 
power to detect a difference of at least 50% in A4 mean percent change from baseline between a 
given dose level of tildacerfont and placebo, assuming a common SD of 30%.  
An assumed dropout rate of 15% during the Treatment Period results in a target of 18 subjects 
per group and a total sample size of 72 subjects who enter the Treatment Period. 


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8 
ANALYSIS SETS 
8.1 
Intent-To-Treat Analysis Set 
The Intent-To-Treat (ITT) Analysis Set will include all randomized subjects regardless of 
Treatment Period eligibility or completion. The ITT Analysis Set will be the basis for 
demographics, baseline characteristics, and efficacy analyses. 
8.2 
Modified Intent-To-Treat Analysis Set 
The following modified ITT (mITT) Analysis Sets will include all randomized subjects who 
receive at least 1 dose of study drug (tildacerfont or placebo), have at least 1 post-baseline A4 
assessment, and did not change background GC through Week 18. 
8.3 
Per-Protocol Analysis Set 
The Per-Protocol (PP) Analysis Set for Part A of the Treatment Period will include all eligible 
subjects who have no major protocol deviations that would affect the analysis of efficacy data. 
The PP Analysis Set may be used for supportive secondary analyses of the primary and 
secondary efficacy endpoints.  
Major protocol deviations that would affect the analysis of efficacy data are listed as the 
following, but not limited to:  
•
Randomization error
•
Subject did not meet efficacy-based inclusion criteria (elevated biomarkers)
•
Subject met efficacy-based exclusion criteria (use of dexamethasone, night-shift worker),
without waiver
•
Subject’s aggregate drug compliance was < 80% over the Treatment Period
Additional deviations will be identified prior to database lock and updated in this section. 
8.4 
Safety Analysis Set 
The Safety (SAF) Analysis Set is defined as all subjects who received at least one dose of study 
drug (tildacerfont or placebo) during the Treatment Period, summarized by actual drug 
received.


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8.5 
Randomized Safety Analysis Set 
The Randomized Safety (RSAF) Analysis Set is defined as all subjects who received at least one 
dose of randomized study drug (tildacerfont or placebo) during the Treatment Period. The 
randomized safety analysis set, which will be based on the actual treatment received, will be 
used for evaluation of general medical history, study drug exposure, concomitant medication, 
and safety. 
8.6 
Pharmacokinetic Analysis Set 
The Pharmacokinetic (PK) analysis set will include all randomized subjects who receive at least 
one dose of tildacerfont and have at least one evaluable PK sample. 
9 
GENERAL CONSIDERATIONS 
Data summarization and presentation conventions are documented in a separate document for 
mock-shells. 
For all summaries of Part A by treatment, the columns will minimally include the randomized 
treatment groups of placebo, 50 mg tildacerfont, 100 mg tildacerfont, and 200 mg tildacerfont. 
All other summaries will use actual dose level unless otherwise specified.  
9.1 
Presentation of Summary Statistics 
For most summary statistics, data will be analyzed and displayed in tabular format.  
Unless otherwise specified, continuous serum hormones (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]).  
All other continuous variables will be summarized using an 8-point descriptive summary (n, 
mean, SD, median, Q1, Q3, minimum, and maximum) unless otherwise specified.  


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The same number of decimal places as in the observed value will be presented when reporting 
minimum and maximum; 1 additional decimal place than in the observed value will be presented 
when reporting mean, median, Q1, Q3, geometric mean, 95% CI; 2 additional decimal places 
than in the observed value will be presented when reporting SD. Geometric CV% will be 
reported to one decimal place. All percentages will be presented to 1 decimal place, unless 
otherwise specified. 
All categorical/qualitative data will be presented using the frequency of events and percentages. 
Percentages equal to 100 will be presented as 100% and percentages will not be presented for 
zero frequencies. For summaries of AEs and concomitant medications (CMs), the percentages 
will be based on the number of subjects who received the study drug dose within the period that 
is being summarized. 
All analyses and summaries will be produced using SAS® version 9.4 or higher. 
9.2 
Presentation of p-values 
Results of statistical analyses will be reported using summary tables, listings, and figures (TLFs). 
The ICH of Technical Requirements for Pharmaceuticals for Human Use numbering convention 
will be used for all CSR TLFs.  
Unless otherwise noted, all statistical testing will be two-sided and will be performed at the 0.05 
significance level. Tests will be declared statistically significant if the calculated p-value is 
< 0.05, unless otherwise specified. P-values will be reported with 4 significant digits except 
when reporting p-values less than 0.001, reported as < 0.001. 
9.3 
Definitions and Derived Variables 
9.3.1 
Screened and Enrolled Subjects 
9.3.1.1 Screened Subjects 
Subjects who signed an informed consent form are considered Screened Subjects 


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9.3.1.2 Enrolled Subjects 
Subjects who received at least one dose of placebo drug during the Run-in Period are considered 
enrolled.  
9.3.2 
Study Day 
In this study, subjects will receive placebo in a 6-week single-blind placebo Run-in Period. 
Day 1 will be the first dose date of placebo in the Run-in Period. Study Day, which follows the 
Clinical Data Interchange Standards Consortium (CDISC) Study Data Tabulation Model 
(SDTM) standard, is defined as (Assessment date - date of first study drug dosing + 1 day), 
where the assessment date is on or after the date of first study drug dosing; (Assessment 
date - date of first study drug dosing), where the assessment date is before the date of first study 
drug dosing. 
9.3.3 
Treatment Study Day 
Randomized treatment will not begin until Week 6, Treatment Study Day 1 is therefore defined 
as the first dose date in Period A following the same format as Study Day. Visits will be 
summarized using Study Day, and treatment day will be included in select listings. 
9.3.4 
End of Study Treatment Definition 
A subject is considered to have completed the main study treatment period if they completed the 
Week 76 visit. The end of study treatment is defined as the date of the last dose of study drug.  
9.3.5 
End of Study Definition 
A subject is considered to have completed the main study if the subject has completed the three 
parts of the Treatment Period, including the final follow-up visit  
9.3.6 
Age 
Age (years) is captured by the Demographics eCRF form at the Screening Visit. 
9.3.7 
Age at Diagnosis of CAH 
Age (in years) at diagnosis of CAH is captured in the Congenital Adrenal Hyperplasia History 
eCRF form at the Screening Visit. 


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9.3.8 
Body Mass Index 
Body mass index (BMI, kg/m2) is derived as weight (kg) / [height (m) × height (m)]. Height 
measured at Screening will be used to calculate BSA. Body mass index may be summarized 
using the classifications defined in Table 2. 
Table 2 
Classification of Body Mass Index 
Parameter 
BMI 
(kg/m2) 
Underweight 
< 18.8  
Normal Range 
18.5 -< 25 
Overweight 
25 -< 30 
Obese Class I 
30 -< 35 
Obese Class II 
35 - < 40 
Obese Class III 
≥ 40 
 
9.3.9 
Body Surface area  
Body surface area (BSA) is calculated per the Mosteller formula as sqrt ((height (cm) × weight 
(kg))/3600). Height measured at Screening will be used in all BSA calculations. 
9.3.10 
Baseline Values  
Baseline values of serum biomarkers (i.e., A4, 17-OHP, and ACTH) are defined as the average 
of the Day 1, Week 4 and Week 6 assessments that are on or prior to the date of the first dose of 
double-blind study drug during Part A, allowing for unscheduled assessments to be windowed 
and replace missed scheduled visits. Visit windowing conventions will be used to identify the 
assessments that are used to construct baselines (see Section 9.4). Day 1 values are defined as the 
last non-missing assessment up to Day 14 for hormone assessments. For all other parameters, 
baseline values are defined as the last non-missing assessment prior to the first dose of 
randomized, double-blind study drug in Part A of the study. The following Table 3 provides a 
guide for the baselines to use in analysis. 
 
 


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Table 3 
Study SPR001-203 Baseline Specifications for Specific Variables 
Parameter 
Screening 
Study Week 6 
(Baseline) 
Patient reported outcomes (HADS, SF-36, C-SSRS) 
 
X 
Laboratory safety test (Hematology, Chemistry [includes insulin 
profile and lipid profile], Urinalysis, Thyroid Panel, Non-
Efficacy Hormones) 
 
X 
Vital signs (includes weight profile and blood pressure profile) 
 
X 
Hirsutism (mFG score) 
 
X 
Acne (IGA score) 
 
X 
Scrotal ultrasound 
X 
 
ECG 
 
X 
GC dose level 
 
X 
 
The initial scrotal ultrasound may be scheduled for any time up to the Week 4 visit and will be 
considered the baseline measurement for the TART endpoint. 
9.3.11 
Change from Baseline 
Change from baseline is calculated as the post-baseline assessment subtracted by the baseline 
assessment. 
9.3.12 
Percent Change from Baseline 
Percent change from baseline is calculated for the individual subject as the change from baseline 
divided by the baseline assessment and multiplied by 100%.   
9.3.13 
Change from Baseline on the Log Scale 
The change from baseline on the log scale is calculated as the difference of the log (post-baseline 
assessment) subtracted by the log (baseline assessment). It is also mathematically equivalent to 
the log of the ratio of the post-baseline assessment divided by the baseline assessment. 
𝑐𝑐ℎ𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑜𝑜𝑜𝑜 𝑡𝑡ℎ𝑒𝑒log 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠= log(𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎) −log(𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏)
= log ൬𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎
𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎
൰ 


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9.3.14 
Geometric Mean Ratio and Percent Change 
For efficacy variables of A4, 17-OHP, and ACTH, the geometric mean ratio (GMR) and percent 
change from baseline will be calculated by treatment group and dose level. The GMR is derived 
from the natural logarithm of the post-baseline value divided by the baseline value [log(post-
baseline/baseline)]. The GMR is the exponential function of the mean of  
log(post baseline/baseline). The 95% CI of GMR is the exponential function of the 95% CI of 
the mean [log(post baseline/baseline)]. The percent change is derived as 100 × (GMR - 1). The 
95% CI of percent change is 100 × (95% CI of GMR - 1). 
9.3.15 
Upper Limit of Normal or Target by Efficacy Biomarker 
The ULN and Target values that are displayed in Table 4 will be used in data analysis. The age at 
screening will be used to determine those age specific ULN values. 
The following table lists the pre-specified, Sponsor-provided upper limit of normal values. 
Table 4 
Upper Limit of Normal Values by Subgroup and Key Biomarker 
Baseline Characteristic 
ACTH 
ULN 
17-OHP 
ULN 
17-OHP 
Target 
A4  ULN 
Males: 18-30 
63.3 ng/dL 
200 ng/dL 
1200 ng/dL 
 220 ng/dL 
Males: 31-50 
63.3 ng/dL 
200 ng/dL 
1200 ng/dL 
190 ng/dL 
Males: 51+ 
63.3 ng/dL 
200 ng/dL 
1200 ng/dL 
220 ng/dL 
Females: pre-menopausal 
63.3 ng/dL 
200 ng/dL 
1200 ng/dL 
285 ng/dL 
Females: post-menopausal 
63.3 ng/dL 
200 ng/dL 
1200 ng/dL 
75 ng/dL 
 
9.3.16 
Responder Definitions 
The exploratory variables are proportions of responders based on each of the serum hormone 
assessments and GC. Indicator variables will be created for each of the three responder criteria as 
depicted in Table 5. Missing assessments are counted as non-responders.  


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Table 5 
Responder Definition by Endpoint 
Endpoint 
Definition 
Proportion of subjects who achieve A4 
≤ 𝒙𝒙𝟏𝟏 × ULN after 12 weeks on 
treatment (Week 18) 
൜1
 𝐴𝐴4 ≤𝒙𝒙 × 𝑈𝑈𝑈𝑈𝑈𝑈
0
 𝐴𝐴4 > 𝒙𝒙 × 𝑈𝑈𝑈𝑈𝑈𝑈 𝑂𝑂𝑂𝑂 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 
Proportion of subjects who achieve 17-
OHP ≤ 1200 ng/dL after 12 weeks on 
treatment (Week 18) 
൜1
 17 −𝑂𝑂𝑂𝑂𝑂𝑂 ≤1200 𝑛𝑛𝑛𝑛/𝑑𝑑𝑑𝑑 
0
 17 −𝑂𝑂𝑂𝑂𝑂𝑂> 1200 𝑛𝑛𝑛𝑛/𝑑𝑑𝑑𝑑 𝑂𝑂𝑂𝑂 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 
Proportion of subjects with at least a 
5 mg/day HCe reduction from baseline 
in GC dose and A4 ≤ ULN 
൜1
∆𝐺𝐺𝐺𝐺 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑≤−5𝑚𝑚𝑚𝑚/𝑑𝑑𝑑𝑑𝑑𝑑 𝑖𝑖𝑖𝑖 𝐻𝐻𝐻𝐻𝐻𝐻 AND 𝐴𝐴4 ≤𝑈𝑈𝑈𝑈𝑈𝑈
0
∆𝐺𝐺𝐺𝐺 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑> −5 𝑚𝑚𝑚𝑚/𝑑𝑑𝑑𝑑𝑑𝑑 OR 𝐴𝐴4 > 𝑈𝑈𝑈𝑈𝑈𝑈 𝑂𝑂𝑂𝑂 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 
1 = 𝒙𝒙= 1,1.25, 1.5, 1.75 and 2. 
 
9.3.17 
HADS Total Score 
The scale consists of 14 items, 7 items each for anxiety and depression. The anxiety score is the 
sum of the odd-numbered items (questions 1, 3, 5, 7, 9, 11, 13), and the depression score is the 
sum of the even-numbered items (questions 2, 4, 6, 8, 10, 12, 14).  
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). The sub-scores are the sum of individual 
item scores within each subcategory (anxiety or depression) and ranges from 0 to 21, with higher 
scores corresponding to higher levels of anxiety or depression. The total score of the individual 
item scores and ranges from 0 to 42, with higher scores corresponding to higher levels of anxiety 
or depression. 
9.3.18 
SF-36 Total Score 
The SF-36 consists of 36 items in the following 8 domains: physical functioning, physical 
role functioning (limitations in usual role activities because of physical health problems), bodily 
pain, general health perceptions, vitality, social functioning, emotional role functioning 
(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.  


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The SF-36 total score and 8 domain scores will be computed by the CRO providing the clinical 
trial database and provided, analysis ready, in relevant output datasets. 
9.3.19 
Modified Ferriman-Gallwey Total Score 
The mFG scores each of 9 body areas on a scale of 0 (no hair) to 4 (hairiness typical of a man), 
with the sum of the separate scores providing a hormonal hirsutism score.  
The total score is the sum of the individual item scores and ranges from 0 to 36, with higher 
scores corresponding to body hair patterns more typical of a man. 
A subject with hirsutism at baseline is defined as an mFG score of 8 or more. 
9.3.20 
Homeostatic Model Assessment of Insulin Resistance 
HOMA-IR is calculated using the following equations: 
𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻- 𝐼𝐼𝐼𝐼= 𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔 (𝑚𝑚𝑚𝑚/𝐿𝐿) ∗𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖(𝑚𝑚𝑚𝑚𝑚𝑚/𝐿𝐿)
405
 𝑜𝑜𝑜𝑜 𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔 (𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚/𝐿𝐿) ∗𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖(𝑚𝑚𝑚𝑚𝑚𝑚/𝐿𝐿)
22.5
 
9.3.21 
Testicular Adrenal Rest Tumor Volume 
For each TART assessment, the total number of TARTs will be captured as well as the size 
(lesion volume) of each TART individually. The total lesion volume of all detectible TARTs per 
subject will be calculated and will be compared against baseline total lesion volume.  
9.3.22 
Cardiovascular Risk Factors 
Cardiovascular risk factors are derived from the metabolic risk factors. There are seven 
assessments spanning eight criteria that fit one of five cardiovascular risk factors. 
 
 


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Table 6 
Spruce 203 Cardiovascular Risk Factors by Sex 
Risk Factor 
Assessment 
Female Criterion 
Male Criterion 
Blood Pressure 
Systolic Blood Pressure 
≥ 120 mmHg; OR 
≥ 120 mmHg; OR 
Diastolic Blood Pressure 
≥ 70 mmHg 
≥ 70 mmHg 
Cholesterol 
LDL Cholesterol 
≥ 110 mg/dL; OR 
≥ 130 mg/dL; OR 
Total Cholesterol 
≥ 170 mg/dL 
≥ 200 mg/dL 
HOMA-IR 
Fasting HOMA-IR 
≥ 2.5 
≥ 2.5 
Waist Circumference 
Waist Circumference 
≥ 88 cm 
≥ 102 cm 
Body Mass Index 
Body Mass Index 
≥ 30 kg/m2; OR 
≥ 30 kg/m2; OR 
at least one additional risk 
factor and BMI ≥ 27 kg/m2 
at least one additional risk 
factor and BMI ≥ 27 kg/m2 
 
9.3.23 
Study Drug Exposure Variables 
9.3.23.1 Study Drug 
Study drug is defined as either tildacerfont or placebo. 
9.3.23.2 Study Treatment 
Study treatment is defined more broadly as study drug or HC for stress dosing provided by the 
Sponsor. 
9.3.23.3 Study Drug Exposure Duration (days) 
The duration (days) of study drug exposure is derived from the first dose date and the last dose 
date of a given period of time. Specifically, the duration (days) is calculated as (LASTDAY - 
FIRSTDAY+ 1 day), where LASTDAY is the date of last dose, and FIRSTDAY is the date of 
first dose. If it becomes known that a patient has multiple consecutive missed doses, an 
adjustment to the calculation of exposure duration may be made. 
The date of the first dose is captured by the CRF question, “Date first dose of study drug from 
this supply was taken by the subject?” For each treatment period, the first dose date is 
specifically collected from the following protocol-specified dispensations: 


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Table 7 
First Dose of Treatment Period by Dispensation 
Treatment Period 
Dispensation Visit 
Subsequent Visit 
Run-in 
Week 0 
Week 4 
Part A 
Week 6 
Week 10 
Part B 
Week 18 
Week 24 
Part C 
Week 30 
Week 38 
Optional Open-Label Extension Period 
Week 76 
Week 88 
 
In the absence of a scheduled dispensation, the first dose of study drug taken from an 
unscheduled dispensation that is windowed to the corresponding visit may be used. Otherwise, 
the date of the first dose of study drug from subsequent dispensation visit may be used. 
The last dose date for a treatment period can be the last dose date of study drug treatment if the 
subject did not continue to the following treatment period, or one day prior to the date of the first 
dose date of the following treatment period. 
9.3.23.4 Total Tildacerfont Dose (mg) Taken 
Total tildacerfont dosage (mg) is defined as the dosage of tildacerfont taken over a specific study 
period i (where subject is receiving a constant dose), calculated as follows: 
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝑖𝑖
= ൫(#𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷−#𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅−#𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿 𝑜𝑜𝑜𝑜 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷) × 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆ℎ൯𝑖𝑖 
and total tildacerfont dose over the entire study period is calculated as: 
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷= ෍(𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷)𝑖𝑖
𝑘𝑘
𝑖𝑖=1
 
where  
Σ represents the summation operator and the value in parentheses is summed over the sequence i = 1 to k, where  
k = number of time intervals subject is intended to receive study drug, and tablet strength 
Tablet strength is 0 mg per tablet if placebo or 50 mg tildacerfont per tablet if active drug. 


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9.3.23.5 Study Drug Compliance per Treatment Period 
Study drug compliance is defined as the percentage of study drug actually taken compared to 
what was expected based on the randomized or titrated dose for time period i (where subject is 
receiving a constant dose). Using the drug accountability data, study drug compliance is 
calculated as follows: 
%𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝑖𝑖= 100 × ൬# 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷−# 𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅−#𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿 𝑜𝑜𝑜𝑜 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷
# 𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑡𝑡𝑡𝑡 𝑏𝑏𝑏𝑏 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡
൰
𝑖𝑖
 
and total % compliance over a treatment period is calculated as: 
%𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶= 100 × ቆ∑
(#𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷−#𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅−#𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿 𝑜𝑜𝑜𝑜 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷)𝑖𝑖
𝑘𝑘
𝑖𝑖=1
∑
(#𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑡𝑡𝑡𝑡 𝑏𝑏𝑏𝑏 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡)𝑖𝑖
𝑘𝑘
𝑖𝑖=1
ቇ 
where  
Σ represents the summation operator and the value in parentheses is summed over the sequence i = 1 to k, where 
k = number of time intervals subject is receiving a constant dose. Possible constant dose levels are placebo, 50 mg 
QD tildacerfont, 100 mg QD tildacerfont, or 200 mg QD tildacerfont. At 50 mg QD tildacerfont dose level, 1 active 
tablet and 3 placebo tablets are taken per administration (i.e., 4 tablets per day); at 100 mg QD tildacerfont dose 
level, 2 active tablets and 2 placebo tablets are to be taken per administration (i.e., 4 tablets per day); at 200 mg QD 
tildacerfont, 4 active tablets are to be taken per administration (i.e., 4 tablets per day). 
The expected number of tablets to be taken is the number of expected tablets per day (4 tablets) 
multiplied by the number of days in time period i. 
9.3.23.6 Mean Daily Tildacerfont Dose (mg/day) 
Mean Daily tildacerfont Dose (mg/day) is calculated as Total Tildacerfont Dose (mg) 
(Section 9.3.23.4) divided by Treatment Duration (days) for each treatment period (Part A, Part 
B, and Part C). 
9.3.23.7 Diary Compliance 
Subjects will fill out the daily GC and study drug diary through the Run-in Period and Part A. 
For all diary compliance, missing entries are counted as non-compliance. Daily study drug diary 


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compliance is calculated as the total count of number of ‘Yes’ responses to taking study drug as 
directed divided by (LASTDAY – FIRSTDAY+ 1 day), where LASTDAY is the date of last 
dose, and FIRSTDAY is the date of first dose.  
Daily food diary compliance is calculated as the total count of number of ‘Yes’, with evening 
meal' responses to taking study drug with an evening meal, divided by (LASTDAY – 
FIRSTDAY+ 1 day).  
Daily GC diary compliance is calculated as the total count of number of ‘Yes’ or ‘Took Stress 
Dosing’ responses to taking GC as directed and number of stress dosing days, divided by 
(LASTDAY – FIRSTDAY+ 1 day).  
Weekly diary compliance is calculated as the total count of number of ‘Yes’, ‘Yes, with evening 
meal’ and/or ‘Took Stress Dosing’ responses to taking study drug as directed within the duration 
{Study Day (7n+1) to Study Day (7[n+1])}, divided by 7. Where n has values {0, 1, 2, ..., 18}. 
Missing entries are counted as non-compliance. 
Aggregate diary compliance is calculated as (study drug compliance + food compliance + GC 
diary compliance) divided by 3. 
9.3.24 
Prior, Concomitant and Post treatment Medications 
A prior medication is considered to be any medication that is taken within a year prior to the first 
randomized, double-blind study drug dosing.  
A concomitant medication (CM) is considered to be any medication with start dates or stop dates 
within the Treatment Period. Specifically, CMs are medications: that are continued from 
Screening and continued after the first double-blinded study drug dosing; with start dates within 
the first dose date through last dose date + 24 hours; with end dates within the first dose date 
through last dose date + 24 hours; having a missing CM end date, or ongoing).  
Post medications are considered to be any medication: taken after the last study drug dose date + 
24 hours, having a missing CM end date, or ongoing.  


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9.3.24.1 Prohibited Concomitant Medications 
Prohibited and cautionary concomitant medications are those medications with their potential for 
metabolic interactions with tildacerfont. Specific definitions can be found in Protocol 
Sections 6.5.2 and 13.1. Appendix 13.1 in the protocol provides a non-exhaustive list of 
medications. 
9.3.25 
Adverse Events  
AEs are those AEs with onset date from the signing of the ICF until the end of the follow up 
period.  
Treatment-emergent adverse events (TEAEs) are defined as any AEs, regardless of relationship 
to study drug, that have an onset or worsening in severity on or after the first dose of double-
blinded study drug (within Treatment Period) until 30 days after the final dose of study drug 
(safety follow-up visit).  
If a subject discontinues study drug but remains in the study, AEs with onset date after 30 days 
of last dose of study drug until the end of the follow up period will be considered post-treatment 
adverse events. 
Related TEAEs are those reported by investigators as possibly related, probably related, or 
definitely related to the study drug.  
AESIs are events that must be monitored on an ongoing basis as defined in Protocol 
Section 8.3.8 and identified in the AE eCRF page. The AESIs that are serious AEs (SAEs) will 
be handled according to guidelines from the National Cancer Institute Common Terminology 
Criteria for Adverse Events (CTCAE 2017) version 5.0, as described in Protocol Section 8.3.3.1.  
9.3.26 
Glucocorticoid Therapy 
GC therapies are concomitant medications as collected in the Prior & Concomitant Daily 
Glucocorticoids/Mineralocorticoids eCRF form. 


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9.3.26.1 Glucocorticoid Dose in Hydrocortisone Equivalents 
Table 8 defines the potencies of various GCs relative to HC in treating CAH, as pre-specified 
and provided by the Sponsor. These conversion factors will be used to standardize and determine 
whether a subject’s daily GC dose satisfies study eligibility criteria and provide general 
guidelines for GC tapering in Part C. 
Table 8 
Relative Potencies of Glucocorticoids in Hydrocortisone Equivalents 
Glucocorticoid 
Potency in CAH (HCe) 
Hydrocortisone 
1 
Prednisone 
4 
Prednisolone 
5 
Methylprednisolone 
5 
Fludrocortisone 
0 
Dexamethasone 
70 
Cortisone Acetate 
0.8 
 
9.3.26.2 Glucocorticoid Total Daily Dose in Hydrocortisone Equivalents 
Since a subject may be taking more than one dose (Morning, Midday, Midday 2, and/or Evening) 
of more than one GC medication, the total daily GC dose of a given subject at a given day is 
calculated as the sum of doses in HCe per day of concomitant GC therapies, excluding stress 
dosing. 
9.3.26.3 Stress Event 
A stress event is defined as an entry in the diary indicating a stress dose was taken. Consecutive 
days of stress dosing are counted as a single stress event. 
9.3.26.4 Baseline Glucocorticoid Dose 
Based on the GC therapies collected in the Prior & Concomitant Daily 
Glucocorticoids/Mineralocorticoids, the baseline GC dose is the GC Total Daily Dose in HCe at 
Treatment Study Day 1. 


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9.3.26.5 Glucocorticoid BSA Based Dose 
The baseline GC BSA-based dose is calculated as the GC dose (Section 9.3.26.5) divided by the 
body surface area (Section 9.3.9) at the corresponding time point, rounded to two decimal places. 
9.3.26.6 Glucocorticoid Dose at Visit 
Based on the GC therapies collected in the Prior & Concomitant Daily 
Glucocorticoids/Mineralocorticoids, GC dose at visit is calculated as the sum of the total daily 
dose in HCe of all concomitant GC therapies at the date of visit as collected in the Date of Visit 
eCRF. 
9.3.26.7 Change in Glucocorticoid Dose and A4 ≤ ULN 
A change in GC dose meeting A4 ≤ ULN criterion is defined as follows: 
GC dose change is calculated as the sum of the total daily dose in HCe of all concomitant GC 
therapies at Visit subtracted by the Baseline GC Dose. 
If at Visit X A4 ≤ ULN, the GC dose change is recorded as observed. If  at Visit X A4 > ULN, 
the GC dose change at the visit is recorded as missing.  
9.3.27 
Variables Related to Menstrual Cycles 
9.3.27.1 Length (Days) of a Menstrual Cycle 
Menstrual cycle length is calculated as (LASTDAY – FIRSTDAY+ 1 day), where FIRSTDAY is 
the date of the first day in a menstrual cycle where the subject records ‘Yes’ they menstruated 
today, and LASTDAY is the date of the last consecutive day a patient answered ‘Yes’ they 
menstruated today within the same menstrual cycle. 
9.3.27.2 Time (Days) Between Menstrual Cycles 
Time (days) between menstrual cycles is calculated as (FIRSTDATEi – LASTDATEi-1 + 1 day), 
where FIRSTDATEi is the first date of current menstrual cycle and LASTDATEi-1 is the last date 
of the previous menstrual cycle. 


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9.3.28 
Geographic Regions 
About 75 study centers will participate in this study. Three geographic regions will be classified 
by the countries where these study centers are located: North America, European Union and 
United Kingdon, and the rest of the world.  
9.4 
Analysis Windows 
Analysis visits will match the protocol-specified visits (Screening, Day 1, Week 4, etc.). 
Unscheduled clinical visits may be used to capture missed or partially completed clinical visits; 
therefore, analysis visits and their windows are defined using Study Day (See Section 9.3.2). For 
the purposes of data analysis and summary, assessments and/or measurements, the protocol-
specified visit will be preferentially flagged for analysis. In the absence of a protocol-specified 
visit, the analysis flag will be based on the collection date/time that is closest to the protocol-
scheduled time point (or target Study Day). Analysis visit windows are presented in Table 9. 
Table 9 
Analysis Visit Windows (Clinic Visits Only) 
Protocol 
Specified 
Visit Number 
eCRF Visit 
Label 
Analysis Visit 
Target Study 
Day 
Start 
(days) 
Stop 
(days) 
Visit 1a 
SCR 
Screening 
-15 
-45 
-7 
Visit 1b 
SCR 
Screening 
-15 
-45 
-7 
Visit 2 
WK0 
Day 1 
1 
-6 
14 
Visit 3 
WK4 
Week 4 
29 
15 
36 
Visit 4 
WK6 
Week 6 
43 
37 
57 
Visit 5 
WK10 
Week 10 
71 
58 
85 
Visit 6 
WK14 
Week 14 
99 
86 
113 
Visit 7 
WK18 
Week 18 
127 
114 
148 
Visit 8 
WK24 
Week 24 
169 
149 
190 
Visit 9 
WK30 
Week 30 
211 
191 
239 
Visit 10 
WK38 
Week 38 
267 
240 
295 
Visit 11 
WK46 
Week 46 
323 
296 
365 
Visit 12 
WK58 
Week 58 
407 
366 
449 
Visit 13 
WK70 
Week 70 
491 
450 
512 
Visit 14 
WK76 
Week 76 
533 
513 
575 
Visit 15 
WK80 
Follow-up 
Last dose 
Last dose +1 
Last dose +30 
Visit 1 OLE 
WK76 
Week 76 
533 
513 
575 


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Protocol 
Specified 
Visit Number 
eCRF Visit 
Label 
Analysis Visit 
Target Study 
Day 
Start 
(days) 
Stop 
(days) 
Visit 2 OLE 
WK88 
Week 88 
617 
576 
659 
Visit 3 OLE 
WK100 
Week 100 
701 
660 
785 
Visit 4 OLE 
WK124 
Week 124 
869 
786 
953 
Visit 5 OLE 
WK148 
Week 148 
1037 
954 
1121 
Visit 6 OLE 
WK172 
Week 172 
1205 
1122 
1289 
Visit 7 OLE 
WK196 
Week 196 
1373 
1290 
1457 
Visit 8 OLE 
WK220 
Week 220 
1541 
1458 
1625 
Visit 9 OLE 
WK244 
Week 244 
1709 
1626 
1793 
Visit 10 OLE 
WK268 
Week 268 
1877 
1794 
1962 
Visit 11 OLE 
WK292 
Week 292 
2046 
1963 
2130 
Visit 12 OLE 
WK316 
Week 316 
2213 
2131 
 
Visit 12 OLE 
 
Follow-up 
Last dose 
Last dose +1 
Last dose +30 
 
10 STATISTICAL AND ANALYSIS ISSUES 
10.1 Adjustments for Covariates 
The categorical, randomization stratification variable (i.e., Week 4 A4 value [0 = A4 ≤ 4 × ULN; 
1 = A4 > 4 × ULN]) will be used in all efficacy analyses. The categorical variables treatment 
group (0 = placebo, 50 = 50 mg QD tildacerfont, 100 = 100 mg QD tildacerfont, and 200 = 
200 mg QD tildacerfont) and sex (0=male, 1=female) will also be included efficacy analyses. 
The log baseline serum A4, as a continuous covariate, will be included in a model for the 
analysis of change from baseline in A4 without the randomization stratification variable. The 
baseline GC dose, as a continuous covariate, will be included in models for the analysis of serum 
A4 and the change from baseline in GCs. The baseline value of continuous efficacy endpoints 
will be included in statistical models, such analysis of covariance (ANCOVA) or mixed-model 
for repeated measures (MMRM) as a continuous covariate for exploratory endpoints. 
When fitting a logistic regression model, the treatment will be coded as 0 = placebo, 50 = 50 mg 
QD tildacerfont, 100 = 100 mg QD tildacerfont, and 200 = 200 mg QD tildacerfont. The 
treatment will be an explanatory variable in the model.  


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10.2 Handling Dropouts or Missing Data 
Every effort will be made by the Sponsor to ensure completeness of data collection. Missing data 
will be imputed as described in the following sections. 
In the subject listing, all collected and all imputed values, if any, will be presented. 
10.2.1 
Handling of Efficacy Data 
For missing A4 data, a retrieved dropout approach will be used which missing endpoint data for 
subjects who discontinued early will be imputed using data collected from subjects after 
discontinuation of study drug. If insufficient data exists (n ≤ 5 per treatment group) to perform a 
retrieved drop out approach assuming missing at random (MAR), a multiple imputation approach 
will be used assuming missing not at random (MNAR) (Section 13.4).  
10.2.2 
Handling of Questionnaire Data 
A total score for questionnaires will be calculated so long as > 50% of the items are non-missing. 
Otherwise, the total score will be set to missing.  
10.2.3 
Handling of Laboratory Data 
A retest value will be used if the first test is invalidated, e.g., specimen hemolyzed. For non-PK 
laboratory values that are continuous in nature but are presented as either above or below the 
respective quantitation limits, the following imputations will be made for the purposes of 
summarization: 
• If value is listed as < X, then the imputed value will be X/2 
• If a value is listed as ≤ X, then the imputed value will be X  
• If value is listed as > X, then the imputed value will be X+1 
• If a value is listed as ≥ X, then the imputed value will be X 
 
 


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10.2.5 
Handling of Safety Data 
10.2.5.1 Adverse Events 
If the time of onset (before or after intake of study drug) cannot be determined whether an AE is 
treatment-emergent because of a partial onset date, the event will be counted as a TEAE.  
Adverse events with incomplete onset and end dates will have their dates imputed and then will 
be evaluated for their treatment-emergent status. 
Incomplete adverse event onset date/time: 
• If day is missing: 
o If month and year are the same as the month and year of first study drug exposure, 
then impute to the date of first study drug exposure.  
o Else if day is missing and year or month is not the same as the year and month of 
first study drug exposure, then impute as Day 1 of the month. 
• If month is missing: 
o If year is the same as the year of first study drug exposure, then impute to the date 
of first study drug exposure. 
o Else if year is not the same as the year of first study drug exposure, then impute as 
January 1.  
• If year is missing then impute to the date of first study drug exposure. 
• If imputed start date is after AE end date, then impute the start date to the AE end date. 
Incomplete adverse event end date/time: 
If only have a YEAR, impute as December 31. 
Else if only have YEAR and MONTH, then impute to last day of the month. 
Otherwise missing, no imputation.If severity or relationship of an AE to study drug is not 
recorded, the severity or relationship will be imputed as “severe” or relationship as “possibly 
related,” for analysis purposes. All efforts will be made to ensue no missing severity or 
relationship of an AE to study drug prior to database lock finalization. 
10.2.5.2 Concomitant Medications 
If the start date of a medication is missing, the medication will be considered to have started 
prior to the study. Such a medication may also be considered concomitant, depending on the stop 
date or lack thereof. If the stop date of a concomitant medication is missing, then the medication 


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will be treated as ongoing. If the start date of a medication is missing, the stop date will be used 
to determine whether or not it is concomitant. Medications with other incomplete start dates or 
end dates will be imputed as follows: 
Incomplete medication start date/time: 
• If only have a YEAR, impute as January 1. 
• Else if only have YEAR and MONTH, impute as Day 1 of month. 
• Otherwise missing, no imputation. 
Incomplete medication end date/time: 
• If only have a YEAR, impute as December 31. 
• Else if only have YEAR and MONTH, then impute to last day of the month. 
• Otherwise missing, no imputation. 
 
10.3 Primary Analyses and Safety Data Monitoring 
The primary efficacy analysis will be conducted as when all subjects complete the Week 18 visit 
of the Treatment Period in Part A and the data has been hard-locked for analysis. The final 
analysis will occur after the last subject has completed the Week 76 visit or if the Sponsor 
discontinues the study. 
An external, independent data safety monitoring board (DSMB) will review the available safety 
data (both blinded and unblinded) from this study periodically. The DSMB will advise the 
Sponsor of any trends or safety issues that may impact the study or study subjects and provide 
recommendations to the Sponsor if needed per the DSMB Charter. 
10.4 Multicenter Considerations 
This trial will be conducted at approximately 110 study centers in the United States, Europe, and 
other regions. Data from all study centers will be pooled for efficacy and safety analyses. 
Because the number of subjects at each center is likely to be small, no analyses will be 
performed by center.  


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10.5 Multiple Comparisons, Multiplicity 
To control family-wise error rate, statistical hypothesis testing for the primary endpoint will be 
hierarchically dose ordered, testing first the 200mg dose versus placebo at 0.05 2-sided; then 
followed by the 100mg dose versus placebo at 0.05 2-sided if the 200mg dose reaches p≤0.05; 
and finally, the 50mg dose versus placebo at 0.05 2-sided if the 100mg dose reaches p≤0.05.  
Secondary and exploratory endpoints will not be subject to alpha control, rather these endpoints 
will be interpreted nominally at the 2-sided 5% level.   
10.6 Active-Control Studies 
The placebo group will serve as a comparator in the primary analysis of this study. 
10.7 Examination of Subgroups 
Subjects will be categorized into the following common subgroups for the purposes of evaluating 
the primary and secondary efficacy endpoints.  
• Baseline A4 (≤ 4 × ULN, > 4 × ULN) 
• Baseline GC dose in HCe (≤ 30 mg/day, > 30 mg/day) 
• Sex (Male, Female) 
• Age 
o ≤ 30 years, > 30 years 
o ≤ median age of the ITT Analysis Set, > median age of the ITT Analysis Set 
• Geographic Region ((i) North America, Not North America and (ii) NA, Latam, Europe, 
APAC)  
Forest plots will be generated to display the primary efficacy, secondary efficacy, and select 
safety evaluations from the above subgroups, along with the overall results. 


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Additional subgroups specific to only select endpoints are specified in the appropriate section in 
the SAP. 
11 STUDY SUBJECTS 
11.1 Subject Enrollment and Disposition 
11.1.1 
Screened and Enrolled Subjects 
Screening, enrollment and disposition will be summarized by country and by investigator for 
each treatment group and overall.  
The percentages will be based on total subjects who enrolled in Run-in Period of the study. A 
subject listing will be provided with the above information, as well as geographic region, 
country, and site ID for subjects who were screened and enrolled in the Run-in Period, but not 
randomized. 
11.1.2 
Randomized Subjects 
Dispositions of randomized subjects will be summarized by treatment group (including dose 
level) and overall. An additional summary will be included for subjects who were randomized 
and dose escalated. The subject disposition summary will include Parts A, B, and C of the 
Treatment Period. 
A listing of disposition will be provided for all randomized subjects. A separated listing will 
present subjects who are excluded from SAF, RSAF, ITT, mITT or PP analysis sets, along with 
reasons for the exclusions. 
11.2 Protocol Deviations 
Protocol deviations will be listed by deviation type (e.g., major) and category (e.g, 
noncompliance with study procedures or restrictions). All deviations will be identified prior to 
database lock and will be summarized and presented in listing(s); listings will include flags for 
deviation type (major or minor). Major protocol deviations are defined per Guideline for 
Industry: Structure and Content of Clinical Study from International Council for Harmonisation 


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(ICH E3) guidance. All protocol deviations and major protocol deviations will be summarized by 
deviation category and type. In addition, a listing of all deviations and major protocol deviations 
will be provided. 
11.3 Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized and listed for all randomized 
subjects (ITT).  
11.3.1 
Demographics 
Demographic characteristics will include age, age category (≤ 30 years, –> 30 years; ≤ median 
age of ITT Analysis Set, > median age of ITT Analysis Set), sex, race, ethnicity, and geographic 
region. A subject listing of demographics will be provided. 
11.3.2 
Baseline Characteristics 
The following baseline characteristics will be summarized. They will be listed in subject listings 
in the following categories: 
•
Serum hormones (baseline value [Section 9.3.10])
•
Metabolic baseline characteristics
o
Weight profile
•
Weight
•
Body mass index
•
Body mass index classification
•
Body surface area
o
Insulin Profile
•
HbA1c
•
Fasting glucose
•
Fasting insulin
•
HOMA-IR
o
Lipid Profile
•
Total cholesterol
•
LDL cholesterol
o
Blood Pressure Profile
•
Systolic blood pressure
•
diastolic blood pressure
•
Quality of life assessments (SF-36 total score)


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• Acne assessments 
• Hirsutism assessments 
• Lesion volume of TART(s)  
 
11.4 Medical History 
Medical history and CAH history will be summarized by randomized treatment group and dose 
level for ITT subjects. Individual subject listings will include subject identification number and 
randomized treatment/dose level (if a subject is randomized), along with general history and 
CAH history data collected from eCRF, for all enrolled subjects (i.e., who participated in the 
Run-in Period). 
11.4.1 
General Medical History 
General medical history, besides CAH, will be mapped to preferred terms and system organ 
classes using the Medical Dictionary for Regulatory Activities (MedDRA®) Dictionary (version 
23.0). General medical history will be summarized by system organ class (SOC) and preferred 
term (PT). A subject listing of general medical history will include start date/end date, verbatim 
medical history term, SOC, PT, and ongoing status. 
11.4.2 
Congenital Adrenal Hyperplasia History 
11.4.2.1 Signs and Symptoms 
Age at CAH diagnosis, type of CAH, and the signs and/or symptoms of CAH will be 
summarized. The most bothersome signs and/or symptoms of CAH will also be summarized. 
Signs and/or symptoms of CAH will be included in a subject listing. 
11.4.2.2 Glucocorticoid History 
The Baseline (Week 6) GC dose level in HCe, GC therapy medication(s), reasons for change to 
the current background GC therapy (if changed therapy) will be summarized. A subject listing 
will include all summarized variables, as well as any higher/lower dose of GC during adulthood, 
reason to reduce/increase to the current GC dose.  


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11.4.2.3 Hospital and Stress Dosing History 
Hospitalization and stress dosing history will be summarized separately and will include the 
frequency and percentage of subjects with at least: a) one hospitalization for adrenal 
insufficiency/crisis in the past 5 years, b) at least one hospitalization for adrenal 
insufficiency/crisis in the past 12 months, c) at least one stress dosing event in the past 12 
months. A subject listing will be included. 
12 STUDY DRUG AND OTHER MEDICATIONS 
12.1 Exposure to Study Drug and Study Treatment Compliance 
Summaries of study drug exposure and compliance will be summarized overall and separately 
for those taken during Part A, Part B, and Part C of the study. The source for study drug dosing 
and compliance is drug accountability.  
The summaries will include the total number of doses taken, mean daily dose (mg/day), duration 
(days) of exposure, and study drug compliance (see definitions in Section 9.3.23.4) by treatment 
group and dose level. A subject who received multiple dose levels of tildacerfont will be 
included in each of the dose levels for the purpose of summarization in separate rows for subjects 
with a dose escalation.  
Furthermore, number and percentage of subjects with and without dose escalation of study drug 
will be summarized by randomized treatment group and dose level received for the overall 
summary. The denominators for percentages will be the number of subjects who received the 
randomized study drug treatment.  
The drug accountability information, including number of tablets dispensed, number of tablets 
returned, number of tablets lost or destroyed, along with all summarized variables, will be listed 
in subject listings. Study drug diary compliance will be listed from the Run-in Period through the 
end of Part A, and all diary entry records will be provided in a separate listing. 


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12.2 Glucocorticoid Therapy 
Concomitant GC therapy will be summarized overall and separately for those taken during Part 
A, Part B and Part C of the study. The source of GC dosing is the Prior & Concomitant Daily 
Glucocorticoids/Mineralocorticoids eCRF. 
The following items will be summarized, overall GC diary compliance (Section 9.3.23.7), GC 
compliance by GC therapy type (i.e., hydrocortisone, prednisolone, prednisone, 
methylprednisolone, or other), proportion of subjects with a stress dosing event, number of 
unique stress dosing events (Section 9.3.26.4), duration of stress dosing events. All the above 
information will be included in a subject listing.  
12.3 Prior and Concomitant Medications 
All medication verbatim terms reported on the electronic case report form (eCRFs) will be 
mapped according to the World Health Organization (WHO) Drug Dictionary (WHO DD March 
2020 B3). The medications will be mapped to Anatomical/Therapeutic/Chemical (ATC) class 
and preferred names. 
Prior and concomitant medications (see definition in Section 9.3.24), other than glucocorticoids, 
will be summarized using WHO DD ATC class and preferred name. The summary results will be 
presented by treatment/dose level and Treatment Period (Part A, Part B, and Part C). Prior 
medications will be summarized by randomized treatment group. Concomitant medications will 
be summarized by actual dose taken concomitantly during each treatment period. For Part A, 
medications will be summarized by the actual randomized dose. For Part B, medications will be 
summarized under the treatment at the start of the medication. A subject who does-escalates in 
Part B will be counted within the denominator of each treatment group that s/he received. For 
example, a subject who started at 50 mg of tildacerfont, escalated to 100 mg of tildacerfont, and 
escalated again to 200 mg tildacerfont will be counted in all three dose levels; the medication 
that the subject starts during the treatment period will be counted once under the dose level that 


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the subject was taking at the start of the medication. For Part C, all subjects will receive 200 mg 
tildacerfont. 
These summaries will present the number and percentage of subjects using each medication. 
Subjects may have more than one medication within an ATC class and preferred name. At each 
summary level subjects are counted once if they reported one or more medications at that level. 
Each summary will be ordered by descending frequency of incidence of ATC class and preferred 
name within each ATC class.  
All medications will be provided in a subject listing with flags indicating study drug dose level. 
The variables include, but not limited to: Start date/end date/ongoing, medication name, ATC 
class and preferred name, indication, dose, unit, form, frequency, and route. 
13 EFFICACY ANALYSES 
13.1 Primary Efficacy Analysis 
The Primary Efficacy Analysis is planned after all subjects have completed the study Week 18 
visit in Part A of the study. During this first 12-week double-blind, placebo-controlled treatment 
period, there will be no dose escalation. The scheduled visits included in this treatment period 
include study Week 10, Week 14, and Week 18 corresponding respectively  to 4, 8 and 12 weeks 
of double-blind randomized treatment. Efficacy Analyses will focus on inferences between 
tildacerfont treated subjects and placebo treated subjects. As shown in Table 1, the Primary 
Efficacy Analysis (1.1), the five Secondary Efficacy Analyses (2.1, 2.2, 2.3, 2.4 and 2.5), and 
selected Exploratory Efficacy Analyses (3.1 to 3.6 and 3.15) will be analyzed at the primary 
analysis. These Efficacy Analyses will be performed using the ITT Analysis Set (Section 8.2) as 
the main analyses.  


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13.2 Final Efficacy Analysis 
The Final Efficacy Analysis will occur after the last subject has completed the study Week 76 
visit or if the study is discontinued by the Sponsor. The data from study Week 18 through 
Week 76 will be frozen prior to the final analysis. 
The scheduled visits included in this treatment period include study Week 24, Week 30, 
Week 38, Week 46, Week 58, Week 70, Week 76 visits. Exploratory Efficacy Analyses 3.7 to 
3.11 and Safety Endpoints 5.1, as shown in Table 1, will be analyzed at the final analysis. 
13.3 Primary Efficacy Analysis 
The primary objective of the study is to evaluate the effect of tildacerfont in controlling A4 
levels in adult subjects with classic CAH who have elevated biomarkers at baseline on their 
current, dose of GC replacement therapy over the 12-week, double-blind, placebo-controlled Part 
A of the Treatment Period.   This objective will be achieved via A4 dose response analysis.  
13.3.1 
Definition of A4 Dose Response Analysis  
The A4 dose response analysis is defined as follows:  
Population: The analysis will be executed on a “treatment policy” basis, i.e. in the ITT analysis 
set, including all classic CAH subjects who were randomized into the study.   
Variable: The analysis variable is the log-transformed change from baseline in serum A4 over 
the 12 week double blind period. The log-transformed change is calculated as log (A4 post 
baseline value) - log (A4 baseline value) 
Intercurrent events: For the Primary Efficacy Analysis (and all Secondary Efficacy Analyses), 
intercurrent events such as changes in GC type or lack of treatment compliance or GC 
compliance, treatment interruption or discontinuation, use of prohibited medications are 
irrelevant as primary endpoint data are collected regardless and are included in the primary 
analysis. Stress dosing is also an intercurrent event that can substantially suppress A4 values and 
confound treatment effect. To adjust for this intercurrent event, the protocol design (Protocol 


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Section 6.5.1.5) has measures to minimize the impact of stress dosing on the primary endpoint, 
such as the delay of scheduled lab draws until 5 days after the subject has returned to their 
prescribed GC regimen.  
13.3.2 
Dose Response Statistical Hypothesis  
For the Primary Efficacy Analysis, the null hypothesis is that there is no difference in the profile 
of log A4 change from baseline through 12 weeks of blinded randomized treatment between 
tildacerfont and placebo. The alternative hypothesis is that there is difference in the profile of log 
A4 change from baseline through 12 weeks of blinded randomized treatment between 
tildacerfont and placebo.    
To assess this dose response hypothesis, repeated measures random coefficients mixed-effects 
model will be used:  
𝑦𝑦𝑖𝑖𝑖𝑖𝑖𝑖= (𝛽𝛽0 + 𝜉𝜉𝑖𝑖) + (𝛽𝛽1 + 𝜂𝜂𝑖𝑖)𝑡𝑡+ (𝛽𝛽2 + 𝜃𝜃𝑖𝑖)𝑡𝑡2 + 𝛽𝛽4𝑗𝑗𝐼𝐼𝑗𝑗+ 𝛽𝛽5𝑗𝑗𝐼𝐼𝑗𝑗𝑡𝑡+ 𝛽𝛽6𝑗𝑗𝐼𝐼𝑗𝑗𝑡𝑡2 + 𝛽𝛽7κ + 𝛽𝛽8𝐺𝐺+ 𝛽𝛽9𝐷𝐷+ 𝑒𝑒𝑖𝑖𝑖𝑖𝑖𝑖 
where: 
𝑦𝑦𝑖𝑖𝑖𝑖𝑖𝑖 is the log A4 change from baseline value for subject 𝑖𝑖, 𝑖𝑖= 1, … 𝑁𝑁, at time 𝑡𝑡 in treatment group 𝑗𝑗, 𝑗𝑗=
1, 2, 3, 4 (1 = 200mg tildacerfont, 2 = 100mg tildacerfont, 3 = 50mg tildacerfont and 4 = placebo),  𝐼𝐼𝑡𝑡 
is the indicator for randomised treatment (𝐼𝐼𝑡𝑡= 1 for tilacerfont 200mg, =2 for 100mg, =3 for 50mg and =4 
for placebo), κ is log baseline A4 value, 𝐺𝐺 is the indicator for sex (𝐺𝐺= 1 male, 𝐺𝐺= 0 female) and 𝐷𝐷 
baseline GC dose (in HCe), 
𝛽𝛽0 is the fixed intercept effect. 
𝛽𝛽1 is the fixed effect of the linear component of time 
𝛽𝛽2 is the fixed effect of the quadratic component of time 
𝛽𝛽4𝑗𝑗 is the fixed effect of treatment 𝑗𝑗 parametrized such with 𝛽𝛽44 = 0 
𝛽𝛽5𝑗𝑗 is the effect of treatment 𝑗𝑗 on the linear component of time parametrized such that 𝛽𝛽54 = 0 
𝛽𝛽6𝑗𝑗 is the effect of treatment 𝑗𝑗 on the quadratic component of time parametrized such that 𝛽𝛽64 = 0 
𝛽𝛽7 is the fixed effect of baseline log A4  
𝛽𝛽8 is the fixed effect of gender 


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𝛽𝛽9 is the fixed effect of baseline GC dose 
𝜉𝜉𝑖𝑖 is the random effect of subject 𝑖𝑖 on the intercept 
𝜂𝜂𝑖𝑖 is the random effect of subject 𝑖𝑖 on the linear component of time 
𝜃𝜃𝑖𝑖 is the random effect of subject 𝑖𝑖 on the quadratic component of time 
𝑒𝑒𝑖𝑖𝑖𝑖𝑖𝑖 is the random error for subject 𝑖𝑖 on treatment 𝑗𝑗 and time 𝑡𝑡. 
 
The random effects, 𝜉𝜉𝑖𝑖, 𝜂𝜂𝑖𝑖, and 𝜃𝜃𝑖𝑖 are assumed independent and identically normally distributed 
with variance components 𝜎𝜎ξ
2, 𝜎𝜎𝜂𝜂
2, and 𝜎𝜎𝜃𝜃
2, and, independently, the random error 𝑒𝑒𝑖𝑖𝑖𝑖 is normally 
distributed with variance 𝜎𝜎2. 
 
The dose response Primary Efficacy Analysis therefore corresponds to the formal hypothesis 
statement,   
𝐻𝐻0𝐿𝐿: 𝛽𝛽51 = 𝛽𝛽52 = 𝛽𝛽53 = 0    𝑣𝑣𝑣𝑣    𝐻𝐻1𝐿𝐿:  𝛽𝛽5𝑗𝑗≠0 for at least one 𝑗𝑗 
and 
𝐻𝐻0𝑄𝑄: 𝛽𝛽61 = 𝛽𝛽62 = 𝛽𝛽63 = 0    𝑣𝑣𝑣𝑣    𝐻𝐻1𝑄𝑄:  𝛽𝛽6𝑗𝑗≠0 for at least one 𝑗𝑗 
 
The union intersection hypothesis  𝐻𝐻0𝐿𝐿 ∩  𝐻𝐻𝑄𝑄𝑄𝑄  represents the null that there is no dose response 
for tildacerfont versus placebo.  
 
13.3.3 
Dose Response Modeling and Testing 
Statistical testing for dose response will be performed using the repeated measures random 
coefficients mixed-effects model described in Section 13.3.2. A4 values will be log transformed 
prior to analysis. The model will comprise of the log A4 change from baseline through to study 
Week 18, i.e. though 12 weeks of double blind randomized treatment; note the actual time, in 
days, from baseline to each post baseline A4 value through to study week 18 will be used in this 
analysis. Randomized treatment group and sex will be included in the model as class factors and 
baseline GC dose (in HCe) as continuous covariate.  Subject specific intercept, time (in days) 


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and time x time random effects will be included. Further, randomized treatment by time and 
randomized treatment by time x time interactions will be included. The model will be fitted using 
maximum likelihood estimation.  If the variance component for time or time x time are estimated 
to be zero then the corresponding term (or terms) will be retained in the model as fixed effects 
and the analysis re-run. 
To test the union intersection hypothesis  𝐻𝐻0𝐿𝐿 ∩  𝐻𝐻𝑄𝑄𝑄𝑄, the model will be fitted with and without 
the randomized treatment by time and randomized treatment by time squared interactions terms.  
The difference in -2 log likelihood between models will be compared to the 𝜒𝜒𝑑𝑑𝑑𝑑
2  cumulative 
distribution function on the appropriate degrees of freedom (i.e. 𝑑𝑑𝑑𝑑= 6), this will provide the p-
value to determine if the union intersection hypothesis can be rejected at the 10% alpha level; if 
so then there is evidence for a treatment effect of tildercerfont over placebo. 
The fitted A4 change from baseline versus time profile will be extracted from the model for each 
randomized treatment and displayed graphically, superimposed upon the A4 time profiles for 
individual subjects.    
Note, the programming of the repeated measures random coefficients mixed-effects model is 
particularly complex, hence example SAS codes perform the analysis are presented in 
Appendix D. 
13.3.4 
Summary of Descriptive Statistics for A4 
Descriptive statistics (11-point) for the serum A4 assessments, change from baseline in serum 
A4, and % change from baseline in serum A4 will be presented by scheduled time point (i.e., 
Baseline [serum A4 only], study Week 10, Week 14, and Week 18).  Geometric means and 
geometric mean change from baseline, along with the associated log scale SDs will also be 
presented. 
13.3.5 
Sensitivity Analyses  
The Primary Efficacy Analysis will be supported by a number of sensitivity analyses. 


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13.3.5.1 
Imputation of A4 values for Missing Data 
Missing data can have an adverse effect on the estimation of endpoints. As such, multiple 
imputation of missing data via retrieved drop-out method will be used for the primary analysis. 
Retrieved drop-outs are defined as subjects who prematurely discontinue study drug treatment 
but remain in the study and still have assessments collected at the remaining scheduled visits in 
the study. These subjects can provide data that is reflective of subjects who discontinue treatment 
early without collection of assessments. Prior to performing the MI with retrieved drop-out, all 
intermittent (non-monotone) missing data will be imputed assuming missing at random (MAR). 
A total of 20 datasets will be stochastically imputed for each intermittent missing A4 value at 
Week 18 using a mixed model repeated measures (MMRM) model. In this model A4 values will 
be log transformed prior to analysis. The model will comprise of the log A4 values at visits 5, 6 
and 7 (= study weeks 10, 14 and 18) as the dependent variable with subject as random effect; 
randomized treatment group (0 = placebo, 50 = 50 mg QD tildacerfont, 100 = 100 mg QD 
tildacerfont, and 200 = 200 mg QD tildacerfont), time (=visit), sex (0=male, 1=female), and the 
interaction of treatment and time as fixed effects; and the log-transformed baseline serum A4 and 
the baseline GC dose (in HCe) as continuous covariates in the model. Within-subject correlations 
will be modeled using an unstructured covariance structure. Time ordering is a repeated measure 
within subjects. Errors for different subjects are assumed to be independent with an unstructured 
covariance structure.  
In the event the MMRM model with an unstructured covariance structure does not converge, the 
following covariance structures will be used as substitution in the order below. Each subsequent 
covariance structure will be used only if each previous covariance structure was used and the 
model did not converge. 
a) Toeplitz covariance structure (assuming measurements from samples taken closer 
together in time are more highly correlated than those from samples taken farther apart) 


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b) First order of auto-regressive [AR(1)] covariance structure (assuming measurements from 
samples taken closer together in time are more highly correlated than those from samples 
taken farther apart) 
c) Compound symmetry covariance structure (assuming equal correlation for measurements 
from a subject, regardless of how far apart in time when they were taken) 
Then a multiple imputation (MI) of the monotone missing data will be performed using 
information from retrieved dropouts, if data are available. If n ≥ 5 subjects in a treatment group 
have discontinued study drug early and have available data from which to draw values, then a 
retrieved dropout approach will be utilized for that treatment group using MI by fully conditional 
specification and predictive mean matching assuming missing not at random (MNAR).  
A total of m datasets will be stochastically imputed using multiple imputation with chained 
equations and predictive mean matching. Multiple imputation inference involves the following 
three steps: 
1. The non-monotone missing observations are filled in m times to generate m complete 
datasets using SAS® PROC MI based on the multiple imputation method. 
a. m will be set to 20. The random seed will be set to 40 
b. Using the Markov chain Monte Carlo method with a non-informative prior 
(Jeffreys) to perform a monotone-data imputation (IMPUTE=MONOTONE) by 
the randomized treatment group 
2. Each of the resulting m imputed datasets will then be imputed again. The monotone 
missing observations are filled in m times to generate m complete datasets using SAS® 
PROC MI based on the multiple imputation method. 
a. The random seed will be set to 50 
b. Using the retrieved drop out subjects with complete data, predict Week 18 A4 
change using a set of predictors resulting in a set of linear coefficients b 


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𝑙𝑙𝑙𝑙𝑙𝑙(𝐴𝐴4 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝) 
=  𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇+ 𝑆𝑆𝑆𝑆𝑆𝑆+ 𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉+ 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇∗𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉+ log(𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵 𝐴𝐴4)
+ 𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵 𝐺𝐺𝐺𝐺 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷
+ 𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎(𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤 10 𝑜𝑜𝑜𝑜 14) 𝑙𝑙𝑙𝑙𝑙𝑙(𝐴𝐴4 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝)  
c. Do a random draw from the posterior predictive distribution of b producing a new 
set of coefficients b* 
d. Use b* to generate predicted values for the Week 18 for all subjects  
e. For each missing Week 18 A4 value, identify a set of candidates with observed 
Week 18 change whose predicted values are close to the predicted value for the 
case with missing data 
f. From the candidates, randomly choose one Week 18 value and assign its observed 
value to the missing value 
g. Repeat process for every subject with missing data 
3. The analysis methods described in Section 13.3.3 will be applied to the m completed 
datasets.  
The results from the m completed datasets are combined using Rubin’s rules via SAS® 
PROC MIANALYZE The imputed treatment effect, 95% CI and 2-sided p-value will be 
presented. 
13.3.5.2 Per-Protocol Analysis and mITT Sets 
The primary analysis of A4 as described in Section 13.3.3 will be repeated in the PP and mITT 
Analysis Sets (Section 8.3) as supportive analyses.  
13.3.5.3 Subgroup Analyses 
The primary analysis of A4 as described in Section 13.3.3 repeated for each subgroup specified 
in Section 10.7 for the ITT Analysis Set.  A forest plot of the estimated treatment effects at 
Week 18 by dose level and subgroups will be provided.  


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13.3.5.4 Handling A4 Assessments Collected During GC Stress Dosing 
13.4 Secondary Efficacy Analyses 
The analysis population for Secondary Efficacy Analyses is the ITT analysis set, including all 
classic CAH subjects who were randomized into the study. 
13.4.1 
First Secondary Efficacy Analysis 
The First Secondary Efficacy Analysis (see Table 1, Analysis 2.1) relates to the change from 
baseline in A4 as assessed on the log scale after 12 weeks on double-blind, placebo-controlled 
treatment. This analysis will be achieved as an integral part of the dose response modelling as 
described in Section 13.3.3. 
The estimated mean change from baseline in log A4 values at 4, 8 and 12 weeks of double blind 
randomized treatment will be extracted from the model by treatment arm as will the difference 
and associated 95% CI and p-value between each tildacerfont dose and placebo at each of 4, 8 
and 12 weeks.  To facilitate ease of interpretation, the estimated mean change from baseline in 
log A4 for each tildacerfont dose and placebo will be back transformed resulting in the estimated 
ratio of geometric means to baseline, i.e. the back transformed log scale estimated mean change 
becomes {estimated A4 geometric mean at time 𝑥𝑥}/{estimated A4 geometric mean at baseline} 
= GMR.  Hence, GMR −1 becomes the percentage CFB in geometric means.  Further, the 
difference between each tildacerfont dose and placebo in estimated mean change from baseline 
in log A4 (along with the associated 95% CI) will also back transformed resulting in the ratio of 
{A4 GMR tilda at time 𝑥𝑥}/{A4 GMR placebo at time 𝑥𝑥} as the measure of treatment effect.  
And, again, {A4 GMR tilda at time 𝑥𝑥}/{A4 GMR placebo at time 𝑥𝑥} −1 becomes the percentage 
reduction (or increase) in  geometric mean A4 values at at time 𝑥𝑥 for tildacerfont compared to 
placebo. 
In addition orthogonal linear and quadratic contrasts between treatments at 12 weeks of double 
blind randomized treatment will also be estimated as a supportive measure of dose response at 
this time point.   


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Example SAS codes in relation to the First Secondary Efficacy Analysis are provided in  
Appendix D. 
A serial plot will be presented of the estimated mean change from baseline in log A4 over time. 
The y-axis will be the percent CFB (i.e 100{exp(estimated change from baseline in log A4) -1}) 
and the x-axis will represent the Part A visits, baseline, Week 4, Week 8, and Week 12 of double 
blind randomized treatment. All treatment groups will be presented on the graph.  
13.4.1.1 Supportive MMRM Analysis 
A supportive analysis of the log change from baseline in A4 will be achieved via conventional 
MMRM modelling as described in Section 13.3.5.1.  The log scale change from baseline (CFB) 
least squares (LS) means will be extracted from the model for each tildacerfont dose and placebo 
at study Weeks 10, 14 and 18, along with the associated SEs and 95% CIs.  Further, the 
treatment effect for each tildacerfont dose versus placebo, being the corresponding difference in 
log scale LS means, will also be extracted along with the associated SE, 95% CI and 2-sided p-
values.  
To facilitate ease of interpretation, LS means, differences in LS means and associated 95% Cis s 
will be back transformed in the same fashion described in Section 13.4.1.  
13.4.1.2 Supportive MMRM Tipping Point Analysis 
A supportive MMRM sensitivity analysis using the tipping-point approach will be conducted. 
Tipping point MI analysis is a method to explore the influence of missingness on statistical 
inference by imputing the missing data in the drug arm with an increasing degree of penalization 
(shift parameter). The analysis finds a (tipping) point in this wider range of imputed values, at 
which conclusions change from being favorable to the experimental treatment to being 
unfavorable. After such a tipping point is determined, clinical judgment can be applied as to the 
plausibility of the assumptions underlying this tipping point. Tipping point MI is performed as 
follows: 


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1. Repeat MI Step 1 as described in Section 13.3.5.1 to generate multiple imputed data sets, 
with a specified shift parameter that adjusts the imputed values for observations in the 
treatment group, not the placebo group. 
2. Repeat MI Step 2 for the imputed data sets with shift parameter applied. 
3. Repeat MI Step 3 to obtain the p-value to see if the p-value is still ≤ 0.05. 
4. Repeat steps 1-3 with a more stringent shift parameter applied until the p-value > 0.05. 
 
13.4.2 
Second Secondary Efficacy Analysis 
The preceding estimated mean change from baseline in A4 is conducted on the log scale due to 
the inherent skewness and non-Normality of untransformed A4 values.  While back 
transformation of log scale analysis results leads to interpretable quantities on the ratio scale, 
interest still resides in appreciation of the results on the absolute scale in ng/dL units.   
Given the non-Normality of A4 values, a simplistic analysis of CFB = (Week 18 A4 value – 
baseline A4 value) is inappropriate as this simple CFB will also be non-Normal, resulting in 
upwardly biased estimates of mean A4 level and inflated SDs and SEs; consequently power will 
also be eroded. 
Thus, to address the Second Secondary Efficacy Analysis (see Table 1, Analysis 2.2) and 
facilitate the presentation of results on both the ratio (i.e. % change) and absolute scales, the 
Primary Analysis repeated measures random coefficients mixed-effects model will be re-run 
exactly as described in Section 13.3.3 but with log A4 as the dependent variable as opposed to 
the change (i.e. as opposed to log A4 value minus log baseline value).   Note, this re-run of the 
model with log A4 as the dependent variable will give precisely the same results, parameter 
estimates and variance-covariance matrix estimate as the analysis with log A4 minus log baseline 
as the dependent variable. 
As described with example SAS codes in Appendix E, the delta theorem will be applied to the 
log scale results to provide consistent estimates of the CFB in A4 values on the absolute scale 


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together with as estimate for the difference in LSmeans and the associated 95% CI.  Results will 
be presented for the absolute change in A4 at 4, 8 and 12 weeks of double blind randomized 
treatment.  A serial plot will be presented of the estimated absolute mean change from baseline 
in log A4 over time. The y-axis will be the CFB in ng/dL and the x-axis will display baseline, 
week 4, week 8 and week 12 of double blind randomized treatment. All treatment groups will be 
presented on the graph.  
13.4.3 
Third Secondary Efficacy Analysis 
The Third Secondary Efficacy analysis (see Table 1, Analysis 2.3) is, in principal, identical to 
the Primary Efficacy Analysis except that now the dependent variable in 17-OHP. 
To evaluate the dose response for change from baseline in log 17-OHP through 12 weeks of 
double blind randomized treatment, the analysis and presentation of results will be conducted in 
exact concordance with the Primary Efficacy Analysis of A4 levels as described in Section 13.3 
with the only difference being the removal of log A4 as a covariate and the inclusion of the 
randomization stratification variable (study Week 4 A4 value [0 = A4 ≤ 4 × ULN; 1 = 
A4 > 4 × ULN]) as a fixed factor effect. 
13.4.4 
Forth Secondary Endpoint Analysis 
To address the Forth Secondary Efficacy Analysis regarding the change from baseline in 17-
OHP on the log scale (see Table 1, Analysis 2.4), the analysis and presentation of results will be 
conducted in exact concordance with the Second Efficacy Analysis of A4 as described in 
Section 13.4.1 with the only difference being the removal of log A4 as a covariate and the 
inclusion of the randomization stratification variable (study Week 4 A4 value [0 = 
A4 ≤ 4 × ULN; 1 = A4 > 4 × ULN]) as a fixed factor effect. 
13.4.5 
Fifth Secondary Endpoint Analysis 
To address the Fifth Secondary Efficacy Analysis regarding the change from baseline in 17-OHP 
on the absolute  scale (see Table 1, Analysis  2.5), the analysis and presentation of results will be 
conducted in exact concordance with the Third Efficacy Analysis of A4 as described in 


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Section 13.4.2 with the only difference being the removal of log A4 as a covariate and the 
inclusion of the randomization stratification variable (study Week 4 A4 value [0 = 
A4 ≤ 4 × ULN; 1 = A4 > 4 × ULN]) as a fixed factor effect. 
13.5 Exploratory Efficacy Analyses 
13.5.1 
 A4 Responder Analysis 
The Exploratory Efficacy Analysis 3.1 in Table 1 is the proportion of classic CAH subjects who 
were randomized into the study who achieve adequate control of serum A4 levels (defined 
as A4  ≤ 1x, 1.25x, 1.5x, 1.75x and 2x ULN) 12 weeks from randomization. The efficacy of 
tildacerfont is evaluated by estimating the odds of meeting a given criterion in the tildacerfont 
treatment groups to the odds of meeting the criterion in the placebo treatment group.  Subjects 
with missing A4 response data will be considered to non responders. 
The proportion of subjects with A4 response will be summarized for each randomized treatment 
group as the number of subjects at study Weeks 10, 14 and 18 who have achieved a response 
divided by the total number of subjects randomized to that specific treatment. 
13.5.1.1 Statistical Hypotheses 
The null hypothesis for a given treatment comparison is that at Week 18 (i.e after the 12 week 
double-blind, placebo-controlled treatment period), the odds of response to tildacerfont to that of 
placebo is unity versus the alternative that the relative odds is not unity,  
𝐻𝐻0𝑗𝑗: ቊ
𝜋𝜋𝑗𝑗
1 −𝜋𝜋𝑗𝑗
ቋቊ1 −𝜋𝜋𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
𝜋𝜋𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
ቋ= 1   𝑣𝑣𝑣𝑣   𝐻𝐻1𝑗𝑗: ቊ
𝜋𝜋𝑗𝑗
1 −𝜋𝜋𝑗𝑗
ቋቊ1 −𝜋𝜋𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
𝜋𝜋𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
ቋ≠1  
where 𝑗𝑗   represents tildacerfont dose, 𝑗𝑗= 50, 100 and 200, 𝜋𝜋𝑗𝑗  representes the true probability of 
response for tildacerfont dose 𝑗𝑗 and similarly for 𝜋𝜋𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝. 
13.5.1.2 Statistical Modeling and Testing 
A generalized estimating equations (GEE) model via SAS PROC GENMOD will be used to 
evaluate A4 response (defined as A4  ≤ 1x, 1.25x, 1.5x, 1.75x and 2x ULN, with a separate 


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analysis for each ULN cutoff).  The model will include response (= 0 or 1) as the dependent 
variable; treatment group (0 = placebo, 50 = 50 mg QD tildacerfont, 100 = 100 mg QD 
tildacerfont, and 200 = 200 mg QD tildacerfont), time (=study week 10, 14 and 18), sex (0=male, 
1=female), and the interaction of treatment and time as categorical covariates; log baseline A4 
and baseline GC dose (in HCe) as continuous covariates. The link function will be logit and 
distribution will be binomial. Subject IDs are used to identify the repeated measures of visits 
within subjects with an exchangeable working correlation structure.  If the model fails to 
converge, the following working correlation structures will be tried in order until convergence is 
reached: unstructured, independent and AR(1).  The model will use a binomial distribution with 
the logit link function and a significance level of 0.05 2-sided. 
The odds ratio for response at study Week 18 for each tildacerfont dose level versus placebo 
group, together with the associated 95% CI and 2-sided p-value will be extracted from the 
model.    The same will also be extracted for the odds ratio of response at study Weeks 10 
and 14.  SAS code will be of the form, 
PROC GENMOD DATA=x;  
CLASS SUBJECT TREATMENT VISIT; 
MODEL RESPONSE = TREATMENT VISIT TREATMENT*VISIT / DIST=MULTINOMIAL 
LINK=LOGIT TYPE3 AGGREGATE=TREATMENT;  
REPEATED SUBJECT=PATIENT/TYPE=IND;  
LSMESTIMATE TREATMENT 'OR 50MG V PCBO' -1 1 0 0 / EXP CL ALPHA=0.05; 
LSMESTIMATE TREATMENT 'OR 100MG V PCBO' -1 0 1 0 / EXP CL ALPHA=0.05;  
LSMESTIMATE TREATMENT 'OR 200MG V PCBO' -1 0 0 1 / EXP CL ALPHA=0.05;  
RUN; 
13.5.1.3 Graph Presentation 
The proportion of responders from the model-based analyses will be displayed graphically over 
time with the y-axis representing the proportion meeting the responder definition and the x-axis 
the study Week 10, Week 14 and Week 18. 
13.5.1.4 Supportive Analyses: Proportional Odds Analysis 
In addition to serial evaluation of A4 response defined as A4  ≤ 1x, 1.25, 1.5x, 1.75x and 2x 
ULN, a combined A4 ordinal response will be analyzed, again via a GEE approach.  Study Week 


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18 A4 response will be categorized for each subject as {A=[≤ 1x];  B=[>1x to ≤1.25x]; 
C=[>1.25x to ≤1.5x];  D = [>1.5 to ≤1.75x]; E = [>1.75 to ≤2.0x];  and F=[>2x]} ULN.   If 
there are too few subjects (n<5) in any of the categorizations A to F, the categorized will be 
collapsed to {𝐴𝐴̃=[≤ 1x];  𝐵𝐵෨=[>1x to ≤1.5x]; 𝐶𝐶̃=[>1.5x to ≤2.0x];  and 𝐷𝐷෩=[>2x]}.    
The model will include ordinal A4 response (= A, B, C, D, E, F; or 𝐴𝐴̃,  𝐵𝐵෨, 𝐶𝐶̃, 𝐷𝐷෩ if categories are 
collapsed) as the dependent variable; treatment group (0 = placebo, 50 = 50 mg QD tildacerfont, 
100 = 100 mg QD tildacerfont, and 200 = 200 mg QD tildacerfont), time (=study week 10, 14 
and 18), sex (0=male, 1=female), and the interaction of treatment and time as categorical 
covariates; log baseline A4 and baseline GC dose (in HCe) as continuous covariates. The link 
function will be cumulative logit and distribution will be multinomial. Subject IDs are used to 
identify the repeated measures of visits within subjects with an exchangeable working correlation 
structure. If the model fails to converge, the following working correlation structures will be 
tried in order until convergence is reached: unstructured, independent and AR(1). The 
significance level will be 0.05 2-sided.    
The cumulative odds ratio for response at study Week 18 to each tildacerfont dose level versus 
placebo group, together with the associated 95% CI and 2-sided p-value will be extracted from 
the model.    The same will also be extracted for the cumulative odds ratio of response at 10 and 
14 weeks.  SAS code will be of the form, 
PROC GENMOD DATA=x;  
CLASS SUBJECT TREATMENT VISIT; 
MODEL CATRESPONSE = TREATMENT VISIT TREATMENT*VISIT / DIST=MULTINOMIAL 
LINK=CLOGIT TYPE3 AGGREGATE=TREATMENT;  
REPEATED SUBJECT=PATIENT/TYPE=IND;  
LSMESTIMATE TREATMENT 'CUM OR 50MG V PCBO' -1 1 0 0 / EXP CL ALPHA=0.05; 
LSMESTIMATE TREATMENT 'CUM OR 100MG V PCBO' -1 0 1 0 / EXP CL ALPHA=0.05;  
LSMESTIMATE TREATMENT 'CUM OR 200MG V PCBO' -1 0 0 1 / EXP CL ALPHA=0.05;  
RUN; 


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13.5.2 
17-OHP Responder Analysis 
The Exploratory Efficacy Analysis 3.2 in Table 1 is the proportion of classic CAH subjects who 
were randomized into the study who achieve adequate control of serum 17-OHP levels (defined 
as 17-OHP ≤ 1200 ng/dL) after 12 weeks of randomized, double-blinded treatment.  
These data will be analyzed in the exact same manner as Exploratory Efficacy Analysis 3.1 with 
the only difference being the exclusion of log A4 as a covariate and the inclusion of the 
randomization stratification variable (study Week 4 A4 value [0 = A4 ≤ 4 × ULN; 1 = 
A4 > 4 × ULN]) as a fixed effect in the mode1. 
13.5.3 
TART Lesion Volume CFB at Week 18 
The Exploratory Efficacy Analysis 3.3 in Table 1 is the CFB in TART lesion volume after 
12 weeks of randomized, double-blinded treatment for those who had detectable TARTs at 
Baseline in the Male ITT population. The analysis will be constrained to only those subjects with 
evaluable baseline and post baseline ultrasound results. Missing data will not be imputed. 
13.5.3.1 Statistical Modeling and Testing 
Statistical analysis will be achieved via an ANCOVA model. If non-Normality is evidenced via 
Normal scores plot and plots of predicted versus residual values, the analysis will be 
accompanied by a rank-based ANCOVA model. The change from baseline to study Week 18 
(12 weeks of randomized treatment) on the log scale will be the dependent variable; randomized 
treatment group (0 = placebo, 50 = 50 mg QD tildacerfont, 100 = 100 mg QD tildacerfont, and 
200 = 200 mg QD tildacerfont) as a fixed effect; baseline TART Volume and the baseline GC 
dose (in HCe) as continuous covariates; the randomization stratum (A4 ≤ 4 × ULN versus 
A4 > 4 × ULN) as categorical explanatory variables. The estimation method for the ANCOVA 
model will REML. A significance level of 0.05 2-sided will be applied. 
The ranked value is obtained by ranking all non-missing change from baseline values at the 
specified analysis visit, if a rank-based model is used. 


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13.5.3.2 Reporting Results 
Summary of Descriptive Statistics 
Descriptive statistics (11-point) for TART lesion volume, change from baseline in TART lesion 
volume, and % change from baseline will be presented by scheduled time point (i.e., Baseline 
and study Week 18).  Geometric means and geometric mean change from baseline, along with 
the associated log scale SDs will also be presented. 
Presentation of Analysis Results 
The log scale change from baseline (CFB) least squares (LS) means will be extracted from the 
model for each tildacerfont  dose and placebo, along with the associated SEs and 95% CIs.  
Further, the treatment effect for each tildacerfont  dose versus placebo, being the corresponding 
difference in log scale LS means, will also be extracted along with the associated SE, 95% CI 
and 2-sided p-values.  
To facilitate ease of interpretation, the log scale CFB LS means for each tildacerfont dose and 
placebo and the difference between each tildacerfont dose and placebo in log scale CFB LS 
means (along with the associated 95% CI) will be back transformed as described for the Primary 
Efficacy Analysis. 
13.5.4 
Correlation of Tildacerfont Plasma Concentration vs Dose 
Exploratory Efficacy Analysis 3.4 in Table 1 is the correlation of tildacerfont plasma 
concentration versus dose. This will be explored by presentation of PK descriptive statistics by 
dose and scheduled time point (i.e., study Week 10 and 18).  Geometric means and geometric 
mean change from baseline, along with the associated log scale SDs, will be presented. 
13.5.5 
Correlation of A4 Level versus 17-OHP Level 
The Exploratory Efficacy Analysis 3.5 in Table 1 is the within subject correlation of A4 Level 
versus 17-OHP Level.  This will be assessed on the log scale by randomized treatment arm.  
Within a given treatment arm, the data will be organized within subject as follows: (i) dummy 
variable ‘vtype’= 1 for log A4 and =2 for log 17-OHP; (ii) dummy variable ‘replicate’ = 1 for 


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baseline, =2 for study Week 10, =3 for study Week 14 and =4 for study Week 18; and (iii) 
variable ‘val’ = value of log A4 or log 17-OHP.  SAS code will be for the form, 
PROC MIXED METHOD=ML DATA=X; 
CLASS SUBJECT VTYPE REPLICATE; 
MODEL VAL = VTYPE / SOLUTION DDFM=KR; 
RANDOM VTYPE /TYPE=UN SUBJECT= SUBJECT V VCORR; 
REPEATED VTYPE / TYPE=UN SUBJECT=REPLICATE(SUBJECT); 
RUN; 
 
The estimated correlation coefficient will be extracted from the VCORR matrix estimate and 
presented by randomized treatment arm. 
 
13.5.6 
SF-36 Change from Baseline at Week 18 Analysis 
Exploratory Efficacy Analysis 3.6 in Table 1 is the change from baseline in SF-36 for each 
active arm treatment group (50 mg tildacerfont QD, 100 mg tildacerfont QD, 200 mg tildacerfont 
QD) compared against the matching placebo group after 12 weeks of randomized, double-
blinded treatment. The efficacy of tildacerfont is evaluated by comparing the change from 
baseline in the tildacerfont treatment group to the placebo treatment group. 
13.5.6.1 Statistical Modeling and Testing 
If the distribution of residuals is judged non-normal, this analysis will be accompanied by a rank-
based ANCOVA model. Statistical testing will be performed using a (rank-based, if non-normal 
residuals) ANCOVA model. In general, the model will comprise the (rank of, if non-normal 
residuals) change from baseline value to study Week 18 as the dependent variable; randomized 
treatment group (0 = placebo, 50 = 50 mg QD tildacerfont, 100 = 100 mg QD tildacerfont, and 
200 = 200 mg QD tildacerfont) and sex (0=male, 1=female) as fixed effects; baseline SF-36 total 
score and baseline GC dose as continuous covariates; the randomization stratum (0 = 
A4 ≤ 4 × ULN, 1 = A4 > 4 × ULN) as categorical explanatory variables. The estimation method 
for the ANCOVA model will REML. A significance level of 0.05 2-sided will be applied. 


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The ranked value is obtained by ranking all non-missing change from baseline values at the 
specified analysis visit, if a rank-based model is used. 
13.5.6.2 Reporting Results 
Summary of Descriptive Statistics 
Descriptive statistics (11-point) for absolute and change from baseline in SF-36  will be 
presented by scheduled time point (i.e., Baseline and Week 18).   
Presentation of Analysis Results 
 The CFB least squares (LS) means will be extracted from the model for each tildacerfont  dose 
and placebo, along with the associated SEs and 95% CIs.  Further, the treatment effect for each 
tildacerfont  dose versus placebo, being the corresponding difference in  LS means, will also be 
extracted along with the associated SE, 95% CI and 2-sided p-values.  
13.5.7 
Change from Baseline Analyses through Week 76 
Exploratory Efficacy Analyses 3.7 to 3.11 in Table 1 are the change from baseline at study 
Week 76 in patient- and clinician-reported outcomes (SF-36 [3.7], IGA acne score [3.8], mFG 
hirsutism score [3.9]); Exploratory Efficacy Analysis 3.10 is the percent of subjects with at least 
a 5 mg/day (HCe) reduction from baseline to study Week 76 in GC dose; and Exploratory 
Efficacy Analysis 3.11 is the change from baseline at study Week 76 in lesion volume of 
TART(s).  For each of these study Week 76 exploratory endpoints, the efficacy of tildacerfont is 
evaluated by comparing the study Week 76 assessment against baseline. 
For Exploratory Efficacy Analyses 3.7 and 3.11, an ANCOVA model will be applied, and results 
described, in the same manner as that for Exploratory Efficacy Analysis 3.6.  
For Exploratory Efficacy Analysis 3.10, logistic regression modelling via SAS PROC GENMOD 
will be applied in a similar manner as for Exploratory Efficacy Analysis 3.1.  The logistic 
regression model will include CG response (= 0 or 1) as the dependent variable; treatment group 
(0 = placebo, 50 = 50 mg QD tildacerfont, 100 = 100 mg QD tildacerfont, and 200 = 200 mg QD 
tildacerfont) and sex (0=male, 1=female as categorical covariates; log baseline A4 and baseline 


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GC dose (in HCe) as continuous covariates. The model will use a binomial distribution with the 
logit link function and a significance level of 0.05 2-sided. 
The odds ratio for GC response at study Week 76 to each tildacerfont dose level versus placebo 
group, together with the associated 95% CI and 2-sided p-value will be extracted from the 
model.    SAS code will be of the form, 
PROC GENMOD DATA=x;  
CLASS SUBJECT TREATMENT VISIT; 
MODEL RESPONSE = TREATMENT VISIT / DIST=BINOMIAL LINK=LOGIT TYPE3 
AGGREGATE=TREATMENT;  
LSMESTIMATE TREATMENT 'OR 50MG V PCBO' -1 1 0 0 / EXP CL ALPHA=0.05; 
LSMESTIMATE TREATMENT 'OR 100MG V PCBO' -1 0 1 0 / EXP CL ALPHA=0.05;  
LSMESTIMATE TREATMENT 'OR 200MG V PCBO' -1 0 0 1 / EXP CL ALPHA=0.05;  
RUN; 
Since Exploratory Efficacy Analyses 3.8 and 3.9 relate to ordinal, logistic regression modelling 
via SAS PROC GENMOD will be applied as described in Section 13.5.1.2.  
Since the change from baseline in IGA or mFG may have sparse values may have sparse values 
(i.e., < 5 distinctive values with counts ≥ 5), the change from baseline values will be further 
classified in fewer ordered categories (i.e., improvement, no change, worsening) prior to 
analysis.    
13.5.8 
Evaluation of ATCH  
Exploratory Efficacy Analyses 3.12, 3.13 and 3.14 reflect the analysis of ATCH levels from 
baseline through 12 weeks of double blind randomized treatment.  These Exploratory Efficacy 
Analyses will be achieved in exactly the same manner as Secondary Efficacy Analyses 2.3, 2.4 
and 2.5 described in Sections 13.4.3, 13.4.4 and 13.4.5. 
13.5.9 
Within Subject Correlation of A4 and 17-OHP with tildacerfont Plasma 
Concentration 
Exploratory Efficacy Analysis 3.15 will examine scatter plots of log A4 and log 17-OHP change 
from baseline values versus corresponding log tildacerfont plasma concentrations over time by 
tildacerfont dose group and overall.    Further, a repeated measures random coefficients mixed-


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effects model will be used to estimate the relationship between the change in log A4 (and log 17-
OHP) versus the corresponding log tildacerfont plasma concentrations.  The model will be a 
simplified form of the Primary Efficacy Analysis model,   
𝑦𝑦𝑖𝑖𝑖𝑖𝑖𝑖= (𝛽𝛽0 + 𝜉𝜉𝑖𝑖) + (𝛽𝛽1 + 𝜂𝜂𝑖𝑖)𝐶𝐶𝑖𝑖𝑖𝑖𝑖𝑖+ 𝛽𝛽4𝑗𝑗𝐼𝐼𝑗𝑗+ 𝛽𝛽5𝑗𝑗𝐼𝐼𝑗𝑗𝐶𝐶𝑖𝑖𝑖𝑖𝑖𝑖+ 𝑒𝑒𝑖𝑖𝑖𝑖𝑖𝑖 
where: 
𝑦𝑦𝑖𝑖𝑖𝑖𝑖𝑖 is the log A4 change from baseline value for subject 𝑖𝑖, 𝑖𝑖= 1, … 𝑁𝑁, at time 𝑡𝑡 in treatment group 𝑗𝑗, 𝑗𝑗=
1, 2, 3 (1 = 200mg tildacerfont, 2 = 100mg tildacerfont, 3 = 50mg tildacerfont);  𝐼𝐼𝑡𝑡 is the indicator for 
randomised treatment (𝐼𝐼𝑡𝑡= 1 for tilacerfont 200mg, =2 for 100mg, =3 for 50mg); 𝐶𝐶𝑖𝑖𝑖𝑖𝑖𝑖 is the 
corresponding log tildacerfont plasma concentration, 
𝛽𝛽0 is the fixed intercept effect 
𝛽𝛽1 is the fixed effect of time 
𝛽𝛽4𝑗𝑗 is the fixed effect of treatment 𝑗𝑗 parametrized such with 𝛽𝛽43 = 0 
𝛽𝛽5𝑗𝑗 is the effect of treatment 𝑗𝑗 on time parametrized such that 𝛽𝛽53 = 0 
𝜉𝜉𝑖𝑖 is the random effect of subject I intercept 
𝜂𝜂𝑖𝑖 is the random effect of subject 𝑖𝑖  on the linear component of time 
𝑒𝑒𝑖𝑖𝑖𝑖𝑖𝑖 is the random error for subject 𝑖𝑖 on treatment 𝑗𝑗 and time 𝑡𝑡 
 
The intercept and slope values will be extracted from the model for each tildacerfont. The 
associated fitted regression line will be displayed for each tildacerfont dose, superimposed on top 
of the individual subject data over time.  The y-axis will reflect log A4 (or 17-OHP) change from 
baseline and the x-axis will reflect log  tildacerfont plasma concentration.   
13.5.10 Additional Exploratory Analyses 
13.5.10.1 
Menstrual Cycle Length 
 
Menstrual cycle length, which is defined in Section 9.3.27.1, will be summarized descriptively 
by treatment group and scheduled time point. The time between menstrual cycles, which is 
defined in Section 9.3.27.2, will also be summarized descriptively. 


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13.5.10.2 
Number of Stress Dosing Events 
A stress dosing event is derived from the daily GC diary. The number of stress dosing events 
(Section 9.3.26.4), number and proportions (expressed as percentages) of subjects who 
underwent stress dosing, along with their exact (Clopper-Pearson) 95% CIs, will be summarized 
by treatment period (Parts A, B, and C) and scheduled time point.  
13.5.10.3 
PGIC and CGI-I 
Both patients’ (PGIC) and clinician’s (CGI-I) global impression of improvement scales will be 
summarized at Weeks 18 and 76. Summaries will include the count and proportion of subjects at 
each point on the Likert scale as well as an 8-point descriptive summary. At Week 18, a t-test 
will be used to derive a p-value on the mean score of the placebo and tildacerfont groups.  
13.5.10.4 
Key Laboratory and Vital data used in Clinical Outcome Components  
Key laboratory and vitals parameters that are used to build key clinical outcomes will be 
summarized by treatment and post-baseline scheduled time point, based on randomized treatment 
received at each scheduled time point and will include p-values reporting change from baseline 
using paired-tests and difference from placebo using Wilcoxon rank sum tests. 
• Fasting glucose, HbA1c, and fasting insulin 
• Total cholesterol, LDL, HDL, triglycerides 
• Blood pressure (systolic and diastolic) 
14 SAFETY ANALYSES 
Safety will be evaluated by AEs, SAEs, AESIs, clinical laboratory, vital signs (excluding the 
efficacy variables), ECG findings, monitoring for suicide risk and depression/anxiety, as well as 
physical examination. All analyses of the safety data will be performed using the safety analysis 
set, based on the actual treatment a subject received. Subjects who received different doses of 
study drug (placebo or tildacerfont) during the study will be assigned to the treatment group from 
the time when tildacerfont was received. All descriptive statistics (described in Section 9.1) will 
be presented by treatment group (including dose level) and treatment period. 


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14.1 Adverse Events 
All AE verbatim terms reported on the eCRFs will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA® version 23.0). 
All reported AEs (including non-TEAEs) will be listed. Separate listings will be provided for 
SAEs, AESIs, and TEAEs leading to study drug discontinuation. For all TEAE tables, counting 
will be by subject and not by event. Additionally, if a subject reported the same TEAE on 
multiple occasions, the highest severity (severe > moderate > mild) or study drug relationship 
(related > probable > possible > unlikely > unrelated) recorded for the event will be summarized. 
All TEAE summary tables will present the number and percentages of subjects reporting TEAEs, 
unless otherwise specified. A summary of TEAEs by severity, seriousness, and relation to study 
drug will be tabulated.  
AEs experienced during the Run-in Period will be reported separately. For Part A, AEs will be 
summarized by the actual randomized dose. For Part B, AEs will be summarized under the 
treatment at the onset of the AE. A subject who does-escalates in Part B will be counted within 
the denominator of each treatment group that s/he received. For example, a subject who started at 
50 mg of tildacerfont, escalated to 100 mg of tildacerfont, and escalated again to 200 mg 
tildacerfont will be counted in all three dose levels; the AE that the subject experiences will be 
counted once under the dose level that the subject was taking at the onset of the AE. For Part C, 
all subjects will receive 200 mg tildacerfont. 
An overall summary of AEs will be presented by study period (i.e., Part A, Part B, and Part C). 
The overall summary will include the number and percentage of subjects experiencing any AEs, 
study drug related AEs, AEs by maximum severity (highest toxicity grade), SAEs, study drug 
related SAEs, discontinued due to AE, and deaths.  
The number and percentage of subjects experiencing each AE, study drug related AE, and SAEs 
will be summarized by treatment group according to system organ class and preferred term. 


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Additional table including only preferred term summarized by treatment for the number and 
percentage of subjects experiencing each AE will be presented as well 
14.1.1 
Overall Summary of TEAEs 
Overall summary of TEAEs will be presented by study period (i.e., Part A, Part B, and Part C) as 
well as by treatment (including dose level) group. Subjects will be counted only once at the 
highest severity when summarizing TEAE by severity.  
14.1.2 
Summary of TEAEs by System Organ Class and Preferred Term 
In addition, TEAEs will be summarized by MedDRA SOC and PT. Each summary table will be 
presented by study period (i.e., Part A, Part B, and Part C) and treatment (including dose level) 
group. A subject experiencing multiple occurrences of an adverse event will be counted only 
once for each PT. Subjects with multiple PTs within a SOC will be counted only once for that 
SOC. The summaries will be presented for: 
• TEAEs by SOC and PT 
• TEAEs by Baseline GC dose in HCe (≤ 30 mg/day, > 30 mg/day), SOC, and PT 
• Moderate or Severe TEAEs by SOC and PT 
• Study drug-related TEAEs by SOC and PT  
• Study drug-related TEAEs by GC therapy, SOC, and PT 
• AESIs by SOC and PT 
• Serious TEAEs by SOC and PT 
• Serious study drug-related TEAEs by SOC and PT 
• TEAEs leading to study drug discontinuation by SOC and PT 
• TEAEs leading to death by SOC and PT 
14.2 Clinical Laboratory Evaluation 
Laboratory parameters hematology, chemistry, lipid panel, thyroid panel, urinalysis, and other 
tests) will be summarized by treatment (including dose level) and scheduled time point from 
randomization, based on actual treatment received at each scheduled time point and will include 
both observed values and change from baseline values.  
In addition, the number and percentage of subjects with potentially clinically significant 
abnormalities (PCSA, see Table 10) in selected chemistry, hematology, and hormone parameters 


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(i.e., above the specified upper limit or below the specified limit) will be summarized in shift 
from baseline tables by scheduled time point. 
Table 10 Potentially Clinically Significant Abnormalities by Laboratory Parameter 
Parameter 
PCSA Low 
PCSA High 
Chemistry 
 
 
ALT 
 
>3 x ULN  
AST 
 
>3 x ULN  
ALP 
 
>1.5 x ULN 
Total Bilirubin 
 
>1.5 x ULN 
Creatinine 
 
> 1.8 mg/dL or > 0.4 mg/dL increase 
from baseline (> 159.16 μmol/L or > 
35.37 μmol/L increase from baseline) 
Sodium 
< 130 mEq/L (< 130 mmol/L) 
>150 mEq/L (> 150 mmol/L) 
Glucose 
< 3 mmol/L (< 54 mg/dL)  
 
Potassium 
< 3 mEq/L (< 3 mmol/L) 
≥5.5 mEq/L (≥ 5.5 mmol/L) 
Calcium 
 
>11.4 mg/dL (> 2.84 mmol/L) 
BUN 
 
> 30 mg/dL and > 10 mg/dL increase 
from baseline (> 10.71 mmol/L and > 
3.57 mmol/L increase from baseline) 
INR 
 
>1.5 x ULN 
Total Bile Acids 
 
>5 x ULN or >3 x ULN if ALT is >3 x 
ULN 
FSH 
 
>15 IU/L if baseline was <5 IU/L 
 
 
 
Hematology 
 
 
Hemoglobin 
≤10 g/dL and >2 g/dL reduction 
from baseline (≤ 100 g/L and > 20 
g/L) 
 
Leukocytes 
<500/µL (< 0.5 x 109/L) 
 
Neutrophils 
<1800/µL and >500/µL reduction 
from baseline 
 
Platelets 
<50,000/µL (< 50 x 109/L) 
 
 
 
 
 


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All laboratory results will be listed with reference ranges and range indicator (Low, High). In 
addition, laboratory results that meet or exceed the pre-specified PCSA levels (Table 10) will be 
flagged.  
14.3 Vital Signs 
Descriptive statistics for pulse rate, respiratory rate, temperature, including baseline values and 
change from baseline values, will be summarized by treatment group and scheduled time point. 
In addition, the number and percentage of subjects with potentially clinically significant 
abnormalities (PCSA, see Table 11) in selected vital sign parameters (i.e., above the specified 
upper limit or below the specified limit) will be summarized in shift from baseline tables by 
scheduled time point. All vital signs parameters will be listed.  
Table 11 Potentially Clinically Significant Abnormalities by Vital Sign Parameter 
14.4 12-Lead Electrocardiogram 
Electrocardiogram (ECG) data, such as clinical interpretation of ECGs, heart rate (HR) values, 
and interval assessments of QRS duration, QT interval, and the Fridericia's corrected value of the 
interval between the Q and T waves on the ECG tracing (QTcF) will be listed. Descriptive 
statistics for observed values and change from baseline at each scheduled time point will be 
presented for these 12-lead ECG interval and HR assessments.  
In addition, the number and percentage of subjects with any abnormal values (i.e. outside a pre-
specified threshold) will be summarized by treatment and scheduled time point. The pre-
specified levels of ECG QTc thresholds are provided by Spruce (See Table 12 below). 
 
 
Vital Sign Parameters 
PCSA Low 
PCSA High 
Pulse Rate (bpm) 
< 40 
> 110 
Systolic Blood Pressure (mmHg) 
< 85 
> 160 
Diastolic Blood Pressure (mmHg) 
< 45 
> 100 


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Table 12 Pre-Specified Threshold Levels for ECG Parameters 
All ECG parameters will be listed with flags for the above pre-specified level. A separate listing 
of subjects with values of QTcF > 500 msec or an increase > 60 msec will be provided, as 
necessary. 
14.5 Psychiatric Evaluations 
14.5.1 
The Hospital Anxiety and Depression Scale 
The HADS is a self-assessment questionnaire that has been found to be a reliable instrument for 
detecting states of anxiety and depression in subjects in clinical trials. The total score of HADS, 
change from baseline in total score will be summarized by time point, treatment group (dose 
level), and Study Period (A, B/C).  
14.5.2 
Columbia–Suicide Severity Rating Scale 
All responses from the Baseline/Screening Version of the C-SSRS assesses both lifetime history 
and history from the last 6 months will be listed by subject and by visit. Tables will include 
results from the Suicidal Ideation and Suicidal Behavior sections of the C-SSRS. Number and 
percentage of subjects with a response of “Yes” at any point on the Suicidal Ideation and 
Suicidal Behavior items will be summarized by treatment group and scheduled time point, if 
sufficient number (i.e., > 5 in any dose level) of subjects responded “Yes”.  
ECG Parameter 
Pre-Specified Level 
Heart Rate (bpm) 
< 40, > 120, > 130 
Heart Rate Change from Baseline (bpm) 
> 20, > 30 
QRS Interval (msec) 
> 120 
QTcF (msec) 
Normal 
Borderline 
Prolonged 
Males: ≤ 430, Females: ≤ 450 
Male: > 430 to 450, Female > 450 to 470 
Males: > 450, Females: > 470 
Male and Female: > 500 
QTcF change from Baseline (msec) 
≤ 30, > 30 to 60, > 60 


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14.6 Quality of Life 
14.6.1 
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 on a 7-point Likert scale at Week 18 and 
Week 76. Responses will be listed by subject and visit. 
14.6.2 
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 on a 7-point Likert scale at 
Week 18 and Week 76. Responses will be listed by subject and visit. 
15 CHANGES RELATIVE TO THE PROTOCOL-SPECIFIED ANALYSIS 
Protocol Section 4.4.1 defines the completion of study treatment as completing “all visits 
through Week 76 of the Treatment Period.” In the SAP Section 9.3.4, the end of study treatment 
is redefined to the completion of the Week 76 visit to remove the ambiguity surrounding the 
classification of subjects with missed or out-of-window visits. 
Protocol Section 4.4.2 defines the end of the study as completing “all phases of the study, 
including the final follow-up visit.” In the SAP Section 9.3.5, the end of study treatment is 
clarified as the completion of the three Treatment Period parts as well as the final Follow-up visit 
Protocol Section 8.1.2.2 identifies the Patient Global Impression of Change and Protocol Section 
8.1.2.2 identifies the Clinical Global Impression – Improvement Scale as efficacy assessments 
that evaluate the quality of life. Given that the protocol synopsis and Protocol Section 3 
Objectives and Endpoints do not mention PGIC and CGI-I as efficacy assessments, these 
assessments will be listed as described in SAP Section 14.6. 
The mITT Population was defined in Protocol Section 9.3 as all randomized subjects who 
receive at least 1 dose of study drug (tildacerfont or placebo), have at least 1 A4 assessment, and 
did not change background GC through Week 18. This definition has been updated to specify 


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that subjects must have at least one post-baseline A4 assessment in order to make this population 
relevant to the efficacy analyses. 
The Per-Protocol Analysis Set for each part of the Treatment Period was defined in Protocol 
Section 9.3 as all eligible subjects who have no major protocol deviations that would affect the 
analysis of efficacy data. This definition has been updated to only pertain to Part A of the 
Treatment Period in order to align with the analyses of the primary and secondary endpoints. 
Since Protocol Section 6.1 defines study drug as either tildacerfont or placebo, the Safety 
Analysis Set should include all subjects treated with study drug, which includes the single-
blinded placebo Run-in Period. The SAP Section 8.4 therefore defines the Safety Analysis Set as 
subjects who receive at least one dose of study drug during the Run-in or Treatment Period, and 
the SAP Section 8.5 defines the Randomized Safety Analysis Set to serve the intention of the 
protocol-defined Safety population defined in Protocol Section 9.3. 
Protocol Section 9.4.4.1 specified the analysis of changes IGA acne score, and mFG hirsutism 
score using a repeated measure mixed effects model if >2 time points are assessed or an 
ANCOVA for a single post-baseline time point. Given that these scores are ordinal and not 
continuous variables, the cumulative logit model was deemed more appropriate for the analyses 
of these two exploratory endpoints. 
 
 
 
 


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16 REFERENCE 
Benjamini, Y. a. (1995). Controlling the False Discovery Rate: A Practical and Powerful 
Approach to Multiple Testing. Journal of the Royal Statistical Society. Series B 
(Methodological), 57(1), 289-300. 
FDA. (2007). Guidance for Industry Developing Products for Weight Management. FDA. 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use. (1996). Guideline for Industry: Structure and Content of Clinical Study 
Reports (ICH E3). Rockville, MD: Federal Register. 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use. (1998). Guideline for Industry: Statistical Principles for Clinical Trials 
(ICH E9). Rockville, MD: Federal Register. 
Ouyang, J., Carroll, K., Koch, G., & Li, J. (2017, March 7). Coping with missing data in phase 
III pivotal registration trials: Tolvaptan in subjects with kidney disease, a case study. 
Pharmaceutical Statistics. Retrieved from https://doi.org/10.1002/pst.1808 
Tandon, P. a. (2021, April 19). The multi-domain responder index: a novel analysis tool to 
capture a broader assessment of clinical benefit in heterogeneous complex rare diseases. 
Orphanet Journal of Rare Diseases, 16(183). 
Use, I. C. (1996). Guideline for Industry: Structure and Content of Clniical Stduy Reports (ICH 
E3). Rockville, MD: Federal Register. 
Use, I. C. (1998). Guideline for Industry: Statistical Principles for Clnical Trials. Rockville, 
MD: Federal Register. 
WHO. (2008). Waist circumference and waist-hip ratio: report of a WHO expert consultation. 
WHO. 
 


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17 Appendix A: Schedule of Assessments 
Table 13 Study SPR001-203 Protocol Schedule of Events at Screening 
(Protocol Version 7.0, March 14, 2022 
 
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 1 
≤45 days before Day 1 1 
Informed consent 
X 
X 
Inclusion/exclusion criteria 
 
X 
Demography 
 
X 
Medical history 
 
X 
Prior medications from past year 
 
X 
Concomitant medications 
 
X 
Prior and current GC regimens 2 
 
X 
Vital signs 3, body weight 
 
X 
Height 
 
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 
 
1 Screening information captured within 45 days of the start of Day 1 in this study (particularly screening 
information transferred from Spruce Biosciences Study SPR001-204) will be used to determine eligibility 
and fulfill screening requirements for this study.  
2 Subjects must be on a stable, supraphysiologic dose of GC replacement (defined as ≥ 15 and ≤ 60 mg 
HCe per day) 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. 


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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 1 
≤45 days before Day 1 1 
Hormones from blood  
X5 
X4, 6 
Clinical laboratory 7 
 
X4 
Urinalysis 
 
X 4 
HbA1c 
 
X 4 
12-lead ECG 
 
X 4 
Report subject’s status to site 
 
X 4 
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 
 
5 A4 and 17-OHP will be measured. The blood draw for the A4 and 17-OHP 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, 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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Table 14 Study SPR001-203 Protocol Schedule of Post-Screening Events (Protocol Version 7.0 March 14, 2022) 
 
Placebo  
Run-in Period 
Treatment Period 
Follow-
up8 
ET 
Part A 
Part B 
Part C 
STUDY VISIT NUMBER 
2 
 
3 
4 
Base 
line 
 
5 
6 
7 
 
8 
9 
10 
11 
 
12 
13 
14 
15 
 
STUDY WEEK 
0 
2 
4 
6 
8 
10 
14 
18 
21 
24 
30 
38 
46 
52 
58 
70 
76 
80 
 
STUDY DAY 9 
1 
15 
29 
43 
57 
71 
99 
127 148 
169 211 267 323 365 407 491 533 
Last dose 
 +30 days 
 
Study Visit (V)/ 
Telephone Contact (T) 10 
V 
T 
V 
V 
T 
V 
V 
V 
T 
V 
V 
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 
X 
X 
X 
Hormones from blood 11,12 
X 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
8 Subjects who do not continue to the optional Open-Label Extension Period upon completion of Treatment Period Part C will enter a 30-day 
Follow-up Period. 
9 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 after the Week 0 visit must be completed within a +6-day window after the 
indicated study days. 
10 During scheduled telephone contacts, sites will record any AEs and concomitant medications. After receiving A4 results, sites will make 
telephone contacts to applicable subjects concerning study drug dose escalation and GC reduction (detailed later in this Schedule of Post-
Screening Activities). 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. 
11 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. 
12 A4, 17-OHP, ACTH, and testosterone will be measured. 


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Placebo  
Run-in Period 
Treatment Period 
Follow-
up8 
ET 
Part A 
Part B 
Part C 
STUDY VISIT NUMBER 
2 
 
3 
4 
Base 
line 
 
5 
6 
7 
 
8 
9 
10 
11 
 
12 
13 
14 
15 
 
STUDY WEEK 
0 
2 
4 
6 
8 
10 
14 
18 
21 
24 
30 
38 
46 
52 
58 
70 
76 
80 
 
STUDY DAY 9 
1 
15 
29 
43 
57 
71 
99 
127 148 
169 211 267 323 365 407 491 533 
Last dose 
 +30 days 
 
Study Visit (V)/ 
Telephone Contact (T) 10 
V 
T 
V 
V 
T 
V 
V 
V 
T 
V 
V 
V 
V 
T 
V 
V 
V 
V 
V 
Clinical laboratory 11,13 
 
 
 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Urinalysis 11 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
HbA1c, fasting glucose and insulin, 
HOMA-IR 11 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
PK 11,14 
 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
Genetic sample 15 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 16, body weight 
X 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Waist circumference 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
13 Clinical laboratory assessments include hematology, clinical chemistry (including liver function tests such as ALT, AST, ALP, GGT, 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. 
14 A single blood sample will be drawn for PK measurement at each specified study visit. 
15 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 Protocol Section 13.4 for specifics on genetic testing that may be performed. 
16 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. 


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Placebo  
Run-in Period 
Treatment Period 
Follow-
up8 
ET 
Part A 
Part B 
Part C 
STUDY VISIT NUMBER 
2 
 
3 
4 
Base 
line 
 
5 
6 
7 
 
8 
9 
10 
11 
 
12 
13 
14 
15 
 
STUDY WEEK 
0 
2 
4 
6 
8 
10 
14 
18 
21 
24 
30 
38 
46 
52 
58 
70 
76 
80 
 
STUDY DAY 9 
1 
15 
29 
43 
57 
71 
99 
127 148 
169 211 267 323 365 407 491 533 
Last dose 
 +30 days 
 
Study Visit (V)/ 
Telephone Contact (T) 10 
V 
T 
V 
V 
T 
V 
V 
V 
T 
V 
V 
V 
V 
T 
V 
V 
V 
V 
V 
12-lead ECG 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
X 
X 
HADS 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
 
X  
SF-36 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X  
PGIC 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X  
Scrotal ultrasound for males 
 
 
X 17 
 
 
 
 
X 
18 
 
 
 
 
 
 
 
 
X 18 
 
X 
18 
Inclusion/exclusion criteria 19 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
17 The initial scrotal ultrasound can be performed anytime during screening up to Week 4 of run-in and will be considered the baseline 
measurement for TART. 
18 Scrotal ultrasounds will only be conducted in subjects who had TART(s) at baseline. 
19 If a subject fails to meet eligibility criteria during or at the end of the Run-in Period, the investigational site will schedule an abbreviated early 
termination visit to review AEs and concomitant medications and perform an abbreviated physical examination (preferably in the clinic, but also 
permissible via home visit). 


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Placebo  
Run-in Period 
Treatment Period 
Follow-
up8 
ET 
Part A 
Part B 
Part C 
STUDY VISIT NUMBER 
2 
 
3 
4 
Base 
line 
 
5 
6 
7 
 
8 
9 
10 
11 
 
12 
13 
14 
15 
 
STUDY WEEK 
0 
2 
4 
6 
8 
10 
14 
18 
21 
24 
30 
38 
46 
52 
58 
70 
76 
80 
 
STUDY DAY 9 
1 
15 
29 
43 
57 
71 
99 
127 148 
169 211 267 323 365 407 491 533 
Last dose 
 +30 days 
 
Study Visit (V)/ 
Telephone Contact (T) 10 
V 
T 
V 
V 
T 
V 
V 
V 
T 
V 
V 
V 
V 
T 
V 
V 
V 
V 
V 
GC monitoring 20 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
CGI-I 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Randomization to treatment in Part 
A21/Determination of tildacerfont 
dose in Parts B and C 22 
 
 
 
X 
 
 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
20 Subjects must be on a stable regimen of GC replacement ≥15 and ≤60 mg HCe per day throughout the Run-in Period, Part A, and Part B. 
Subjects will confirm whether their GC regimen was followed each day in a study diary. 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 laboratory assessments have been completed.  
21 In Part A, subjects will be randomized to tildacerfont 50 mg QD, tildacerfont 100 mg QD, tildacerfont 200 mg QD, or placebo.  
22 In Parts B and C, all subjects will receive tildacerfont. Subjects who were randomized to placebo in Part A will receive tildacerfont 100 mg QD 
at the beginning of Part B. Subjects who were randomized to tildacerfont 200 mg QD in Part A will continue to receive tildacerfont 200 mg QD 
throughout Parts B and C. Based on A4 results from the Weeks 18 and 24 study visits, eligible subjects may undergo a tildacerfont dose escalation 
after each of these study visits. Specifically, subjects taking tildacerfont 50 mg QD will either continue to receive the same dose (if A4 ≤ULN) or 
 


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Placebo  
Run-in Period 
Treatment Period 
Follow-
up8 
ET 
Part A 
Part B 
Part C 
STUDY VISIT NUMBER 
2 
 
3 
4 
Base 
line 
 
5 
6 
7 
 
8 
9 
10 
11 
 
12 
13 
14 
15 
 
STUDY WEEK 
0 
2 
4 
6 
8 
10 
14 
18 
21 
24 
30 
38 
46 
52 
58 
70 
76 
80 
 
STUDY DAY 9 
1 
15 
29 
43 
57 
71 
99 
127 148 
169 211 267 323 365 407 491 533 
Last dose 
 +30 days 
 
Study Visit (V)/ 
Telephone Contact (T) 10 
V 
T 
V 
V 
T 
V 
V 
V 
T 
V 
V 
V 
V 
T 
V 
V 
V 
V 
V 
Dispense study drug 23 
X 
 
 
X 
 
X 
X 
X 
24 
 
X 24 X 24 X 24 X 24 
 
X 
X 
 
 
 
Study drug accountability 
 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
 
be escalated to tildacerfont 100 mg QD (if A4 >ULN and the subject is tolerating his/her current tildacerfont dose); subjects taking tildacerfont 
100 mg QD will either continue to receive the same dose (if A4 ≤ULN) or be escalated to tildacerfont 200 mg QD (if A4 >ULN and the subject is 
tolerating his/her current tildacerfont dose). At Week 30, all subjects will be escalated to 200 mg QD. 
23 Either the subject will pick up study drug in the clinic or the 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 <50% fat content. Study drug may be consumed up to 30 
minutes after completing the evening meal, if necessary. 
24 Immediately following each indicated study visit, subjects will continue to take their previously assigned study drug until A4 laboratory results 
are received, the RTSM system determines the appropriate tildacerfont doses for the next portion of the study, and subjects receive their 
tildacerfont doses for the next portion of the study. Subjects will receive enough previously assigned study drug to last until they receive their 
appropriate tildacerfont dose for the next portion of the study. Subjects will either return to the clinic to pick up their study drug or will be shipped 
their study drug. 


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Placebo  
Run-in Period 
Treatment Period 
Follow-
up8 
ET 
Part A 
Part B 
Part C 
STUDY VISIT NUMBER 
2 
 
3 
4 
Base 
line 
 
5 
6 
7 
 
8 
9 
10 
11 
 
12 
13 
14 
15 
 
STUDY WEEK 
0 
2 
4 
6 
8 
10 
14 
18 
21 
24 
30 
38 
46 
52 
58 
70 
76 
80 
 
STUDY DAY 9 
1 
15 
29 
43 
57 
71 
99 
127 148 
169 211 267 323 365 407 491 533 
Last dose 
 +30 days 
 
Study Visit (V)/ 
Telephone Contact (T) 10 
V 
T 
V 
V 
T 
V 
V 
V 
T 
V 
V 
V 
V 
T 
V 
V 
V 
V 
V 
Dispense HC for stress dosing and 
perform accountability 25 
X 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
PRN telephone contact to follow up 
after possible tildacerfont dose 
escalation 26 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
PRN telephone contacts regarding 
GC reduction 27 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
25 Bottles of HC for stress dosing (see Protocol Section 6.5.1.5) will be dispensed starting at Day 1 and thereafter as needed to replace opened 
bottles. Accountability for HC will be performed at every study visit. 
26 For subjects who are eligible for blinded tildacerfont dose escalation following the indicated study visits (ie, subjects with A4 >ULN who have 
not reduced GC), the site will telephone the subject again 7 days after the dose adjustment to assess for the occurrence of AEs and the initiation of 
new concomitant medications. Subjects who were not eligible for study drug dose escalation will not be telephoned. 
27 In Part C, subjects with A4 ≤ULN at Week 38 or Week 46 will begin to reduce their daily GC dose level by increments of no more than 5 
mg/day HCe each time, down to a minimum of 15 mg/day HCe. Sites will contact subjects who are eligible for a GC reduction by telephone 
within 2 weeks after each applicable study visit. Subjects who are not eligible for a GC reduction will not be telephoned. The site will direct the 
subject to reduce 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 
 


Spruce Biosciences, Inc. 
 
Study SPR001-203 SAP 
Version 2.0, 2 February 2024 
 
Page 92 of 107 
 
 
Placebo  
Run-in Period 
Treatment Period 
Follow-
up8 
ET 
Part A 
Part B 
Part C 
STUDY VISIT NUMBER 
2 
 
3 
4 
Base 
line 
 
5 
6 
7 
 
8 
9 
10 
11 
 
12 
13 
14 
15 
 
STUDY WEEK 
0 
2 
4 
6 
8 
10 
14 
18 
21 
24 
30 
38 
46 
52 
58 
70 
76 
80 
 
STUDY DAY 9 
1 
15 
29 
43 
57 
71 
99 
127 148 
169 211 267 323 365 407 491 533 
Last dose 
 +30 days 
 
Study Visit (V)/ 
Telephone Contact (T) 10 
V 
T 
V 
V 
T 
V 
V 
V 
T 
V 
V 
V 
V 
T 
V 
V 
V 
V 
V 
Review study diary/drug adherence 
28 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 29 
X 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Acne IGA score 30 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Hirsutism mFG score for females 30 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
subject’s GC dose is adjusted, the site will telephone the subject again 7 days after the dose adjustment to assess for the occurrence of AEs and the 
initiation of new concomitant medications.  
28 Subjects will use an electronic study diary to document study drug and background GC adherence through Week 18. Female subjects will also 
use the study diary to record menstrual information (including start and stop dates of menses) across the full treatment period up to Week 76. 
29 A full physical examination will be conducted at Day 1, Week 18, 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. 
30 At Week 6, acne will be evaluated in all subjects and hirsutism in all female subjects. After Week 6, acne/hirsutism will only be evaluated in 
subjects who had acne/hirsutism at Week 6. 


Spruce Biosciences, Inc. 
 
Study SPR001-203 SAP 
Version 2.0, 2 February 2024 
 
Page 93 of 107 
 
17-OHP = 17-hydroxyprogesterone; A4 = androstenedione; ACTH = adrenocorticotropic hormone; AE = adverse event; ALP = alkaline phosphatase; 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CGI-I = Clinical Global Impression – Improvement Scale; C-SSRS = Columbia–Suicide 
Severity Rating Scale; 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-glutamyl transferase; HADS = Hospital Anxiety and Depression Scale; 
HbA1c = hemoglobin A1c; HC(e) = hydrocortisone (equivalents); HIV = human immunodeficiency virus; HOMA-IR = homeostatic model assessment of insulin 
resistance; IGA = Investigator’s Global Assessment (score for acne); INR = international normalized ratio; IRB = Institutional Review Board; LH = luteinizing 
hormone; mFG = modified Ferriman-Gallwey (score for hirsutism); PGIC = Patient Global Impression of Change; PK = pharmacokinetics; PRN = as needed; 
PROs = patient-reported outcome measures; PT = prothrombin time; PTT = partial thromboplastin time; RTSM = randomization and trial supply management 
(system); SF-36 = Short Form 36; SHBG = sex hormone–binding globulin; T = telephone contact; TART = testicular adrenal rest tumor; V = study visit.


Spruce Biosciences, Inc. 
 
Study SPR001-203 SAP 
Version 2.0, 2 February 2024 
 
Page 94 of 107 
Table 15 Study SPR001-203 Protocol Schedule of Post-Screening Events (Protocol Version 7.0 March 14, 2022) 
 
Extension Treatment Period 
Follow-
up 
ET 
 
STUDY VISIT NUMBER 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
 
STUDY WEEK 
76 88 100 124 148 
172 
196 
220 
244 
268 
292 
316 
320 
 
STUDY DAY37F31 
533 617 701 869 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 
V 
Urine pregnancy test for FCP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hormones from blood38F32,
39F33 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Clinical laboratory32 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Vital signs40F34, body weight, waist circumference 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
SF-36 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
C-SSRS 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Scrotal ultrasound for males 41F35 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 35 
Concomitant medications  
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 
Abbreviated physical examination 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Dispense study drug42F36 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
31 All study visits should be performed within a +30-day window after the indicated study days.  
32 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. 
33 A4 and 17-OHP and testosterone will be measured. 
34 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. 
35 Scrotal ultrasounds will only be conducted in subjects who had TART(s) at baseline. 
36 Subject will pick up study drug in the clinic. Study drug will be taken daily between 6 PM and midnight, with an evening meal. The evening meal should 
contain <50% fat content. Study drug may be consumed up to 30 minutes after completing the evening meal, if necessary. 


Spruce Biosciences, Inc. 
 
Study SPR001-203 SAP 
Version 2.0, 2 February 2024 
 
Page 95 of 107 
 
 
Extension Treatment Period 
Follow-
up 
ET 
 
STUDY VISIT NUMBER 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
 
STUDY WEEK 
76 88 100 124 148 
172 
196 
220 
244 
268 
292 
316 
320 
 
STUDY DAY37F31 
533 617 701 869 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 
V 
Study drug accountability 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
GC dose adjustment telephone contacts43F37 
X  X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Dispense HC for stress dosing and perform accountability44F38 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
17-OHP = 17 hydroxyprogesterone; A4 = androstenedione; C-SSRS = Columbia–Suicide Severity Rating Scale; ET = early termination; FCP = female of 
childbearing potential; GC = glucocorticoid; HC(e) = hydrocortisone (equivalents); SF-36 = Short Form 36; V = study visit 
 
 
 
37 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). 
38 Bottles of HC for stress dosing (see Section Protocol 6.5.1.5) will be dispensed as needed. Accountability for bottles of HC will be performed at every study 
visit. 


Spruce Biosciences, Inc. 
 
Study SPR001-203 SAP 
Version 2.0, 2 February 2024 
 
Page 96 of 107 
18 Appendix B: Clinical Laboratory Parameters 
Table 16 Clinical Laboratory Parameters 
19 Appendix C: Calculating Total Score for Short-From 36 
20 Appendix D:  A4 Dose Response Over Time by Randomized Treatment arm  
Example SAS codes to execute the dose response random coefficients analysis model.   
DATA STUDY2;                                                                                                                     
  INPUT ID EXERTYPE DIET PULSE TIME;                                                                                             
CARDS;                                                                                                                           
1 1 1 90 0                                                                                                                       
1 1 1 92 228                                                                                                                     
1 1 1 93 296                                                                                                                     
1 1 1 93 639                                                                                                                     
2 1 1 90 0                                                                                                                       
2 1 1 92 56                                                                                                                      
2 1 1 93 434                                                                                                                     
2 1 1 93 538                                                                                                                     
3 1 1 97 0                                                                                                                       
3 1 1 97 150                                                                                                                     
3 1 1 94 295                                                                                                                     
3 1 1 94 541                                                                                                                     
4 1 1 80 0                                                                                                                       
4 1 1 82 121                                                                                                                     
4 1 1 83 256                                                                                                                     
4 1 1 83 575                                                                                                                     
5 1 1 91 0                                                                                                                       
Chemistry 
Hematology 
Urinalysis 
Thyroid 
Glucose, fasting 
Platelet count 
Specific gravity 
T3 
Potassium 
RBC count 
pH 
T4 
Calcium 
MCV 
Glucose 
TSH 
Sodium 
MCH 
Protein 
 
BUN 
% reticulocytes 
Blood 
Other 
Creatinine 
Hemoglobin 
Ketones 
LH 
Total protein 
Hematocrit 
Bilirubin 
FSH 
ALP 
WBC count 
Urobilinogen 
SHBG 
ALT/SGPT 
Neutrophils 
Nitrite 
Renin 
AST/SGOT 
Lymphocytes 
Microscopic examination 
Aldosterone 
GGT 
Monocytes 
 
Male: Inhibin B  
Total bilirubin 
Eosinophils 
Lipid 
Female: Estradiol 
Direct bilirubin 
Basophils 
Total cholesterol 
Female: Prolactin 
Total bile acids 
 
LDL 
Female: Progesterone 
PT/INR 
 
HDL 
 
PTT 
 
Triglycerides 
 


Spruce Biosciences, Inc. 
 
Study SPR001-203 SAP 
Version 2.0, 2 February 2024 
 
Page 97 of 107 
 
5 1 1 92 161                                                                                                                     
5 1 1 91 252                                                                                                                     
5 1 1 91 526                                                                                                                     
6 1 2 83 0                                                                                                                       
6 1 2 83 73                                                                                                                      
6 1 2 84 320                                                                                                                     
6 1 2 84 570                                                                                                                     
7 1 2 87 0                                                                                                                       
7 1 2 88 40                                                                                                                      
7 1 2 90 325                                                                                                                     
7 1 2 90 730                                                                                                                     
8 1 2 92 0                                                                                                                       
8 1 2 94 205                                                                                                                     
8 1 2 95 276                                                                                                                     
8 1 2 95 761                                                                                                                     
9 1 2 97 0                                                                                                                       
9 1 2 99 57                                                                                                                      
9 1 2 96 244                                                                                                                     
9 1 2 96 695                                                                                                                     
10 1 2 100 0                                                                                                                     
10 1 2 97 143                                                                                                                    
10 1 2 100 296                                                                                                                   
10 1 2 100 722                                                                                                                   
11 2 1 86 0                                                                                                                      
11 2 1 86 83                                                                                                                     
11 2 1 84 262                                                                                                                    
11 2 1 84 566                                                                                                                    
12 2 1 93 0                                                                                                                      
12 2 1 103 116                                                                                                                   
12 2 1 104 357                                                                                                                   
12 2 1 104 479                                                                                                                   
13 2 1 90 0                                                                                                                      
13 2 1 92 191                                                                                                                    
13 2 1 93 280                                                                                                                    
13 2 1 93 709                                                                                                                    
14 2 1 95 0                                                                                                                      
14 2 1 96 112                                                                                                                    
14 2 1 100 219                                                                                                                   
14 2 1 100 367                                                                                                                   
15 2 1 89 0                                                                                                                      
15 2 1 96 96                                                                                                                     
15 2 1 95 339                                                                                                                    
15 2 1 95 639                                                                                                                    
16 2 2 84 0                                                                                                                      
16 2 2 86 92                                                                                                                     
16 2 2 89 351                                                                                                                    
16 2 2 89 508                                                                                                                    
17 2 2 103 0                                                                                                                     
17 2 2 109 196                                                                                                                   
17 2 2 114 213                                                                                                                   
17 2 2 120 634                                                                                                                   
18 2 2 92 0                                                                                                                      
18 2 2 96 117                                                                                                                    
18 2 2 101 227                                                                                                                   
18 2 2 101 614                                                                                                                   
19 2 2 97 0                                                                                                                      
19 2 2 98 70                                                                                                                     
19 2 2 100 295                                                                                                                   
19 2 2 100 515                                                                                                                   
20 2 2 102 0                                                                                                                     
20 2 2 104 165                                                                                                                   
20 2 2 103 302                                                                                                                   
20 2 2 103 792                                                                                                                   
21 3 1 93 0                                                                                                                      
21 3 1 98 100                                                                                                                    
21 3 1 110 396                                                                                                                   
21 3 1 115 498                                                                                                                   
22 3 1 98 0                                                                                                                      
22 3 1 104 104                                                                                                                   
22 3 1 112 310                                                                                                                   


Spruce Biosciences, Inc. 
 
Study SPR001-203 SAP 
Version 2.0, 2 February 2024 
 
Page 98 of 107 
 
22 3 1 117 518                                                                                                                   
23 3 1 98 0                                                                                                                      
23 3 1 105 148                                                                                                                   
23 3 1 118 208                                                                                                                   
23 3 1 121 677                                                                                                                   
24 3 1 87 0                                                                                                                      
24 3 1 122 171                                                                                                                   
24 3 1 127 320                                                                                                                   
24 3 1 133 633                                                                                                                   
25 3 1 94 0                                                                                                                      
25 3 1 110 57                                                                                                                    
25 3 1 116 268                                                                                                                   
25 3 1 119 657                                                                                                                   
26 3 2 95 0                                                                                                                      
26 3 2 126 163                                                                                                                   
26 3 2 143 382                                                                                                                   
26 3 2 147 501                                                                                                                   
27 3 2 100 0                                                                                                                     
27 3 2 126 70                                                                                                                    
27 3 2 140 347                                                                                                                   
27 3 2 148 737                                                                                                                   
28 3 2 103 0                                                                                                                     
28 3 2 124 61                                                                                                                    
28 3 2 140 263                                                                                                                   
28 3 2 143 588                                                                                                                   
29 3 2 94 0                                                                                                                      
29 3 2 135 164                                                                                                                   
29 3 2 130 353                                                                                                                   
29 3 2 137 560                                                                                                                   
30 3 2 99 0                                                                                                                      
30 3 2 111 114                                                                                                                   
30 3 2 140 362                                                                                                                   
30 3 2 148 501                                                                                                                   
;                                                                                                                                
RUN;                                                                                                                             
                                                                                                                                 
DATA STUDY2;                                                                                                                     
 SET STUDY2;                                                                                                                     
 G=EXERTYPE;                                                                                                                     
RUN;                                                                                                                             
                                                                                                                                 
PROC SORT DATA=STUDY2; BY ID TIME; RUN;  
                                                                                                                                 
DATA BASE;                                                                                                                       
 SET STUDY2(RENAME=(PULSE=BASE));                                                                                                
 IF TIME=0;                                                                                                                      
KEEP ID BASE;                                                                                                                    
RUN;                                                                                                                             
                                                                                                                                 
PROC SORT DATA = BASE; BY ID; RUN;  
  
DATA STUDY2;                                                                                                                     
 MERGE STUDY2 BASE;                                                                                                              
 BY ID;                                                                                                                          
 IF TIME >0;                                                                                                                     
 DUM=1;                                                                                                                          
RUN;                                                                                                                             
                                                                                                                                 
PROC SORT DATA = STUDY2; BY ID G TIME; RUN;                                                                                      
                                                                                                                                 
DATA STUDY2;                                                                                                                     
 SET STUDY2;                                                                                                                     
 BY ID G TIME;                                                                                                                   
  IF FIRST.ID THEN DO;                                                                                                           
    T=0;                                                                                                                         
  END;                                                                                                                           
  T+DUM;                                                                                                                         
RUN;                                                                                                                             
                                                                                                                                 
DATA STUDY2;                                                                                                                     


Spruce Biosciences, Inc. 
 
Study SPR001-203 SAP 
Version 2.0, 2 February 2024 
 
Page 99 of 107 
 
 SET STUDY2;                                                                                                                     
 CFB=PULSE-BASE;                                                                                                                 
 LPULSE=LOG(PULSE);                                                                                                              
 LBASE=LOG(BASE);                                                                                                                
 LCFB=LPULSE-LBASE;                                                                                                              
RUN;                                                                                                                             
DATA STUDY2;                                                                                                                     
 SET STUDY2;                                                                                                                     
 G=EXERTYPE;                                                                                                                     
RUN;                                                                                                                             
                                                                                                                                 
PROC SORT DATA=STUDY2;                                                                                                           
  BY ID TIME;                                                                                                                    
RUN;                                                                                                                             
                                                                                                                                 
** FULL MODEL WITH TIME*G AND TIME*TIME*G = DOSE RESPONSE PARAMETERS **;                                                         
                                                                                                                                 
PROC MIXED DATA=STUDY2 COVTEST NOCLPRINT METHOD=ML  ;                                                                            
  CLASS ID G ;                                                                                                                   
  MODEL  PULSE =  BASE TIME G TIME*G TIME*TIME TIME*TIME*G /                                                                     
  SOLUTION OUTP=PRED1RX OUTPM = PRED1FX;                                                                                         
  RANDOM INTERCEPT TIME TIME*TIME  / SUBJECT = ID SOLUTION;                                                                      
                                                                                                                                 
 ** ESTIMATES WHEN BASELINE = 90 BPM, I.E. LOG BASE = 4.5 **;                                                                    
 ESTIMATE "INTERCEPT: 1 " INTERCEPT 1 BASE 90 G   1 0 0 ;                                                                        
 ESTIMATE "INTERCEPT: 2 " INTERCEPT 1 BASE 90 G   0 1 0 ;                                                                        
 ESTIMATE "INTERCEPT: 3 " INTERCEPT 1 BASE 90 G   0 0 1 ;                                                                        
                                                                                                                                 
 ** TRT EFFECTS AND CONTRASTSAT 600 DAYS **;                                                                                     
                                                                                                                                 
ESTIMATE "VALUE AT 600 1"  INTERCEPT 1 BASE 90   G   1 0 0  TIME    600 G*TIME 600 0 0                                           
                           TIME*TIME  360000  G*TIME*TIME  360000 0 0 ;                                                          
                                                                                                                                 
ESTIMATE "VALUE AT 600 2"  INTERCEPT 1  BASE 90  G   0 1 0  TIME    600 G*TIME 0 600 0                                           
                           TIME*TIME  360000  G*TIME*TIME  0 360000 0 ;                                                          
                                                                                                                                 
ESTIMATE "VALUE AT 600 3"  INTERCEPT 1 BASE 90   G   0 0 1  TIME    600 G*TIME 0 0 600                                           
                           TIME*TIME  360000  G*TIME*TIME  0 0 0      ;                                                          
                                                                                                                                 
ESTIMATE "VALUE AT 600 1-3"  G 1 0 -1 TIME    0   G*TIME 600 0 -600 TIME*TIME  0 G*TIME*TIME  360000 0 0;                        
                                                                                                                                 
ESTIMATE "VALUE AT 600 2-3"  G 0 1 -1 TIME    0   G*TIME 0 600 -600 TIME*TIME  0 G*TIME*TIME  0 360000 0 ;                       
                                                                                                                                 
ESTIMATE "LINEAR CONTRAST @ 600"    G   -1 0 1 TIME    0   G*TIME -600 0 600                                                     
                                    TIME*TIME  0  G*TIME*TIME  -360000 0 0;                                                      
                                                                                                                                 
ESTIMATE "QUADRATIC CONTRAST @ 600" G   1 -2 1 TIME    0   G*TIME 600 -1200 600                                                  
                                    TIME*TIME  0  G*TIME*TIME  360000 -720000 0;                                                 
ODS OUTPUT FITSTATISTICS=FIT1;                                                                                                   
ODS OUTPUT SOLUTIONF=F1;                                                                                                         
ODS OUTPUT COVPARMS =C1;                                                                                                         
                                                                                                                                 
TITLE 'RC MODEL TIME G TIME*G TIME*TIME TIME*TIME*G';                                                                            
RUN;                                                                                                                             
TITLE;                                                                                                                           
                                                                                                                                 
** REDUCUED MODEL WITH TIME*G AND TIME*TIME*G = DOSE RESPONSE PARAMETERS **;                                                     
PROC MIXED DATA=STUDY2 COVTEST NOCLPRINT METHOD=ML  ;                                                                            
  CLASS ID G ;                                                                                                                   
  MODEL  PULSE =  BASE TIME G TIME*TIME /                                                                                        
                 SOLUTION;                                                                                                       
  RANDOM INTERCEPT TIME TIME*TIME / SUBJECT = ID SOLUTION;                                                                       
                                                                                                                                 
 ** ESTIMATES WHEN BASELINE = 90 BPM, I.E. LOG BASE = 4.5 **;                                                                    
 ESTIMATE "INTERCEPT: 1 " INTERCEPT 1 BASE 90 G   1 0 0 ;                                                                        
 ESTIMATE "INTERCEPT: 2 " INTERCEPT 1 BASE 90 G   0 1 0 ;                                                                        
 ESTIMATE "INTERCEPT: 3 " INTERCEPT 1 BASE 90 G   0 0 1 ;                                                                        
                                                                                                                                 
 ** TRT EFFECTS AND CONTRASTSAT 600 DAYS **;                                                                                     
                                                                                                                                 


Spruce Biosciences, Inc. 
 
Study SPR001-203 SAP 
Version 2.0, 2 February 2024 
 
Page 100 of 107 
 
ESTIMATE "VALUE AT 600 1" INTERCEPT 1 BASE 90   G   1 0 0  TIME  600 TIME*TIME  360000  ;                                        
                                                                                                                                 
ESTIMATE "VALUE AT 600 2" INTERCEPT 1  BASE 90  G   0 1 0  TIME  600 TIME*TIME  360000  ;                                        
                                                                                                                                 
ESTIMATE "VALUE AT 600 3" INTERCEPT 1 BASE 90   G   0 0 1  TIME  600 TIME*TIME  360000     ;                                     
                                                                                                                                 
ESTIMATE "VALUE AT 600 1-3" G   1 0 -1 TIME    0    TIME*TIME  0     ;                                                           
                                                                                                                                 
ESTIMATE "VALUE AT 600 2-3" G   0 1 -1 TIME    0    TIME*TIME  0      ;                                                          
                                                                                                                                 
ESTIMATE "LINEAR CONTRAST @ 600"      G   -1 0 1 TIME  0  TIME*TIME  0 ;                                                         
                                                                                                                                 
ESTIMATE "QUADRATIC CONTRAST @ 600"   G   1 -2 1 TIME  0  TIME*TIME  0   ;                                                       
                                                                                                                                 
ODS OUTPUT FITSTATISTICS=FIT2;                                                                                                   
ODS OUTPUT SOLUTIONF=F2;                                                                                                         
ODS OUTPUT COVPARMS =C2;                                                                                                         
                                                                                                                                 
TITLE 'RC MODEL TIME G TIME*TIME';                                                                                               
RUN;                                                                                                                             
TITLE;                                                                                                                           
                                                                                                                                 
DATA C1;                                                                                                                         
 SET C1;                                                                                                                         
 TP='COVPARM';                                                                                                                   
RUN;                                                                                                                             
DATA F1;                                                                                                                         
 SET F1;                                                                                                                         
 TP='FIXED  ';                                                                                                                   
RUN;                                                                                                                             
                                                                                                                                 
DATA DF1;                                                                                                                        
 LENGTH P $24;                                                                                                                   
 LENGTH MODEL $12;                                                                                                               
 SET F1(RENAME=(EFFECT=P) ) C1(RENAME=(COVPARM=P));                                                                              
 IF ESTIMATE NE 0;                                                                                                               
 DUM=1;                                                                                                                          
 MODEL='FULL';                                                                                                                   
KEEP MODEL TP ESTIMATE STDERR P DUM;                                                                                             
RUN;                                                                                                                             
                                                                                                                                 
/*                                                                                                                               
PROC PRINT DATA = DF1;                                                                                                           
RUN;                                                                                                                             
*/                                                                                                                               
                                                                                                                                 
DATA C2;                                                                                                                         
 SET C2;                                                                                                                         
 TP='COVPARM';                                                                                                                   
RUN;                                                                                                                             
DATA F2;                                                                                                                         
 SET F2;                                                                                                                         
 TP='FIXED  ';                                                                                                                   
RUN;                                                                                                                             
                                                                                                                                 
DATA DF2;                                                                                                                        
 LENGTH P $24;                                                                                                                   
 LENGTH MODEL $12;                                                                                                               
 SET F2(RENAME=(EFFECT=P) ) C2(RENAME=(COVPARM=P));                                                                              
 IF ESTIMATE NE 0;                                                                                                               
 DUM=1;                                                                                                                          
 MODEL='REDUCED';                                                                                                                
KEEP MODEL TP ESTIMATE STDERR P DUM;                                                                                             
RUN;                                                                                                                             
                                                                                                                                 
/*                                                                                                                               
PROC PRINT DATA = DF2;                                                                                                           
RUN;                                                                                                                             
*/                                                                                                                               
                                                                                                                                 


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DATA DF;                                                                                                                         
 SET DF1 DF2;                                                                                                                    
RUN;                                                                                                                             
                                                                                                                                 
/*                                                                                                                               
PROC PRINT DATA = DF;                                                                                                            
RUN;                                                                                                                             
*/                                                                                                                               
                                                                                                                                 
PROC SORT DATA = DF;BY MODEL;RUN;                                                                                                
PROC UNIVARIATE DATA = DF NOPRINT;                                                                                               
BY MODEL;                                                                                                                        
VAR DUM;                                                                                                                         
OUTPUT OUT=DF_ SUM=DF;                                                                                                           
RUN;                                                                                                                             
                                                                                                                                 
/*                                                                                                                               
PROC PRINT DATA = DF_;                                                                                                           
RUN;                                                                                                                             
*/                                                                                                                               
                                                                                                                                 
PROC TRANSPOSE DATA = DF_ OUT=DFT(DROP=_NAME_ _LABEL_);                                                                          
VAR DF;                                                                                                                          
ID MODEL;                                                                                                                        
RUN;                                                                                                                             
                                                                                                                                 
DATA DFT;                                                                                                                        
 SET DFT;                                                                                                                        
 DUM=1;                                                                                                                          
RUN;                                                                                                                             
                                                                                                                                 
/*                                                                                                                               
PROC PRINT DATA = DFT;                                                                                                           
RUN;                                                                                                                             
*/                                                                                                                               
                                                                                                                                 
DATA LOGL1;                                                                                                                      
 SET FIT1(RENAME=(VALUE=NEG2LOGLFULL));                                                                                          
 IF SUBSTR(DESCR,1,2)='-2';                                                                                                      
 DUM=1;                                                                                                                          
KEEP DUM NEG2LOGLFULL;                                                                                                           
RUN;                                                                                                                             
                                                                                                                                 
DATA LOGL2;                                                                                                                      
 SET FIT2(RENAME=(VALUE=NEG2LOGLREDUCED));                                                                                       
 IF SUBSTR(DESCR,1,2)='-2';                                                                                                      
 DUM=1;                                                                                                                          
KEEP DUM NEG2LOGLREDUCED;                                                                                                        
RUN;                                                                                                                             
                                                                                                                                 
PROC SORT DATA = DFT;BY DUM;RUN;                                                                                                 
PROC SORT DATA = LOGL1;BY DUM;RUN;                                                                                               
PROC SORT DATA = LOGL2;BY DUM;RUN;                                                                                               
                                                                                                                                 
DATA LOGL;                                                                                                                       
 MERGE LOGL1 LOGL2 DFT;                                                                                                          
 BY DUM;                                                                                                                         
 CHI=NEG2LOGLREDUCED - NEG2LOGLFULL;                                                                                             
 DF=FULL-REDUCED;                                                                                                                
 PDOSEREPONSE=PUT(1-CDF('CHISQUARE',CHI,DF),PVALUE6.4);                                                                          
RUN;                                                                                                                             
                                                                                                                                 
PROC PRINT DATA = LOGL;                                                                                                          
TITLE 'PRIMARY ANALYSIS DOSE RESPONSE UNION INTERSECTION P-VALUE';                                                               
RUN;                                                                                                                             
TITLE;                                                        
QUIT;                                                                                                                            
                                                                                                                 
                                                                                                                 


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21 Appendix E: Calculating Absolute CFB and Absolute Treatment Effects for A4 at 
Based on Analyses Conducted on the Log Scale.  
The A4 Primary Efficacy Analysis is conducted on the log scale due to the inherent skewness 
and non-Normality of untransformed A4 values.  While back transformation of log scale analysis 
results leads to interpretable quantities on the ratio scale, interest still resides in appreciation of 
the results on the absolute scale in ng/dL units.  Given the non-Normality of A4 values, a 
simplistic analysis of CFB = (Week 18 A4 value – baseline A4 value) is inappropriate as this 
simple CFB will also be non-Normal, resulting in upwardly biased estimates of mean A4 level 
and inflated SDs and SEs. 
Thus, to address the Second Secondary Efficacy Analysis (Table 1, Analysis 2.2), the Primary 
Analysis repeated measures random coefficients mixed-effects model will be re-run exactly as 
described in Section 13.3.3 but with log A4 as the dependent variable as opposed to the change 
(i.e. as opposed to log A4 value minus log baseline value).  Note, this re-run of the model with 
log A4 as the dependent variable will give precisely the same results, parameter estimates and 
variance-covariance matrix estimate as the analysis with log A4 minus log baseline as the 
dependent variable.  The resulting estimates of mean log A4 and mean change from baseline in 
log A4 will be used via the Delta Theorem to provide consistent estimate of A4 treatment effects 
on the absolute scale.  
Delta Theorem 
Suppose 𝑥𝑥𝑖𝑖𝑖𝑖 are independent, identically distributed Normal random variables with 𝑖𝑖= 𝐸𝐸 and 𝐶𝐶 
representing experimental and control treatments, and 𝑗𝑗= 1 … 𝑛𝑛𝑖𝑖 representing subject number.  
Then 𝑥𝑥𝑖𝑖𝑖𝑖~𝑁𝑁(𝜇𝜇𝑖𝑖, 𝜎𝜎2)  and 𝑥𝑥𝑖𝑖~𝑁𝑁(𝜇𝜇𝑖𝑖𝜎𝜎2 𝑛𝑛𝑖𝑖
⁄
). 


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Suppose there is interest in the function of  𝑥𝑥𝑖𝑖, i.e., 𝑢𝑢𝑖𝑖= 𝑓𝑓(𝑥𝑥𝑖𝑖). Then, the delta theorem (= first 
order Taylors expansion of 𝑢𝑢𝑖𝑖) as described by Armitage et al (Armitage 2010) states that the 
variance of 𝑢𝑢𝑖𝑖 is given by 
𝑉𝑉𝑉𝑉𝑉𝑉(𝑢𝑢𝑖𝑖) = ൤𝜕𝜕𝜕𝜕
𝜕𝜕𝑥𝑥𝑖𝑖
൨
2
𝑉𝑉𝑉𝑉𝑉𝑉(𝑥𝑥𝑖𝑖) 
And, further, 
𝑉𝑉𝑉𝑉𝑉𝑉(𝑢𝑢𝐸𝐸−𝑢𝑢𝐶𝐶) = ൤𝜕𝜕𝜕𝜕
𝜕𝜕𝑥𝑥𝐸𝐸
൨
2
𝑉𝑉𝑉𝑉𝑉𝑉(𝑥𝑥𝐸𝐸) + ൤𝜕𝜕𝜕𝜕
𝜕𝜕𝑥𝑥𝐶𝐶
൨
2
𝑉𝑉𝑉𝑉𝑉𝑉(𝑥𝑥𝐶𝐶) + 2 ൤𝜕𝜕𝜕𝜕
𝜕𝜕𝑥𝑥𝐸𝐸
൨൤𝜕𝜕𝜕𝜕
𝜕𝜕𝑥𝑥𝐶𝐶
൨𝐶𝐶𝐶𝐶𝐶𝐶(𝑥𝑥𝐸𝐸, 𝑥𝑥𝑐𝑐) 
In the case of the Primary Efficacy Analysis, let 𝑥𝑥𝑖𝑖 represent the estimated A4 CFB o the log 
scale, 𝐿𝐿𝑖𝑖,  with 𝑉𝑉𝑉𝑉𝑉𝑉(𝐿𝐿𝑖𝑖) = [𝑆𝑆𝑆𝑆(𝑥𝑥𝑖𝑖)]2 and 𝐶𝐶𝐶𝐶𝐶𝐶(𝐿𝐿𝐸𝐸, 𝐿𝐿𝐶𝐶) = 𝐶𝐶𝐶𝐶𝐶𝐶(𝑥𝑥𝐸𝐸, 𝑥𝑥𝐶𝐶) where 𝐶𝐶𝐶𝐶𝐶𝐶(. , . ) denotes 
covariance. 
Interest lies in A4 on the absolute scale, i.e. in the function 𝑓𝑓(𝑦𝑦) = 𝑒𝑒−𝑦𝑦, and thus in the function  
𝑢𝑢𝑖𝑖= 𝑒𝑒−𝐿𝐿𝑖𝑖.  Hence,  
𝑉𝑉𝑉𝑉𝑉𝑉(𝑢𝑢𝑖𝑖) = [−𝑒𝑒−𝐿𝐿𝑖𝑖]2𝑉𝑉𝑉𝑉𝑉𝑉(𝐿𝐿𝑖𝑖) = 𝑒𝑒−2𝐿𝐿𝑖𝑖∙𝑉𝑉𝑉𝑉𝑉𝑉(𝐿𝐿𝑖𝑖) 
and 
𝑉𝑉𝑉𝑉𝑉𝑉(𝑢𝑢𝐸𝐸−𝑢𝑢𝐶𝐶) = 𝑒𝑒−2𝐿𝐿𝐸𝐸∙𝑉𝑉𝑉𝑉𝑉𝑉(𝐿𝐿𝐸𝐸) + 𝑒𝑒−2𝐿𝐿𝐶𝐶∙𝑉𝑉𝑉𝑉𝑉𝑉(𝐿𝐿𝐶𝐶) + 2 𝐶𝐶𝐶𝐶𝐶𝐶(𝐿𝐿𝐸𝐸, 𝐿𝐿𝐶𝐶) ∙𝑒𝑒−𝐿𝐿𝐸𝐸∙𝑒𝑒−𝐿𝐿𝐶𝐶 
Hence, the estimate of the absolute difference in mean A4 values, 𝐸𝐸−𝐶𝐶, is given by 
𝑢𝑢𝐸𝐸−𝑢𝑢𝐶𝐶= 𝑒𝑒−𝐿𝐿𝐸𝐸−𝑒𝑒−𝐿𝐿𝐶𝐶 with 𝑆𝑆𝑆𝑆(𝑢𝑢𝐸𝐸−𝑢𝑢𝐶𝐶) = ඥ𝑉𝑉𝑉𝑉𝑉𝑉(𝑢𝑢𝐸𝐸−𝑢𝑢𝐶𝐶) such that the 100(1 −𝛼𝛼)% CI is 
given by  
(𝑢𝑢𝐸𝐸−𝑢𝑢𝐶𝐶) ± 𝑡𝑡𝑑𝑑𝑑𝑑,𝛼𝛼2
⁄ ∙ඥ𝑉𝑉𝑉𝑉𝑉𝑉(𝑢𝑢𝐸𝐸−𝑢𝑢𝐶𝐶) 
where 𝑡𝑡𝑑𝑑𝑑𝑑,𝛼𝛼2
⁄  represents the (1 −𝛼𝛼2
⁄ ) precentile of the studentized 𝑡𝑡 cumulative distribution 
function on 𝑑𝑑𝑑𝑑, where 𝑑𝑑𝑑𝑑 is the error degrees of freedom associated with the corresponding log 
scale A4 treatment effect estimate at 18 Weeks from the Primary Efficacy Analysis model. 


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Example SAS Code 
The following SAS codes provides an illustrative application of the Delta Theorem. 
OPTIONS PAGESIZE=58 LINESIZE=180 NONUMBER NODATE;                                                                
                                                                                                                 
                                                                                                                 
** DEPENDENT VARIABLE IS LOG PULSE ** ;                                                                          
PROC MIXED DATA=STUDY2  COVTEST NOCLPRINT METHOD=ML;                                                             
  CLASS ID G T;                                                                                                  
  MODEL LPULSE = LBASE T G T*G / SOLUTION OUTP=PRED1R OUTPM = PRED1F;                                            
  REPEATED T / TYPE=UN SUBJECT = ID;                                                                             
  LSMEANS T*G / PDIFF DIFF ALPHA=0.05 CL COV;                                                                    
  ODS OUTPUT LSMEANS=LSM;                                                                                        
  ODS OUTPUT DIFFS=LSMDIFF;                                                                                      
TITLE 'LOG ABS MMRM';                                                                                            
RUN;                                                                                                             
TITLE;                                                                                                           
  
*** TRT EFFECT BASE ON ABSOLUTE SCALE  **;                                                                       
%MACRO ABSTRTEFF(DRUG,PCBO,T,CVPOS,DAT);                                                                         
DATA DRUG;                                                                                                       
 SET LSM;                                                                                                        
 LENGTH LABEL $12.;                                                                                              
 LABEL=LEFT(TRIM(PUT(&DRUG,1.0)))||' V '||LEFT(TRIM(PUT(&PCBO,1.0)));                                            
 IF T=&T AND G=&DRUG;                                                                                            
 CV=COV&CVPOS;                                                                                                   
 TIME=&T;                                                                                                        
 DRUG=ESTIMATE;                                                                                                  
 SEDRUG=STDERR;                                                                                                  
 DF=DF;                                                                                                          
KEEP LABEL TIME DF DRUG SEDRUG CV;                                                                               
RUN;                                                                                                             
DATA PCBO;                                                                                                       
 SET LSM;                                                                                                        
 LENGTH LABEL $12.;                                                                                              
 LABEL=LEFT(TRIM(PUT(&DRUG,1.0)))||' V '||LEFT(TRIM(PUT(&PCBO,1.0)));                                            
 IF T=&T AND G=&PCBO;                                                                                            
 TIME=&T;                                                                                                        
 PCBO=ESTIMATE;                                                                                                  
 SEPCBO=STDERR;                                                                                                  
KEEP LABEL TIME PCBO SEPCBO;                                                                                     
RUN;                                                                                                             
PROC SORT DATA = DRUG;BY LABEL TIME;RUN;                                                                         
PROC SORT DATA = PCBO;BY LABEL TIME;RUN;                                                                         
DATA COMB&DAT;                                                                                                   
 MERGE DRUG PCBO;                                                                                                
 BY LABEL TIME;                                                                                                  
 ABSDRUG=EXP(DRUG);                                                                                              
 ABSPCBO=EXP(PCBO);                                                                                              
 ABSEFF= ABSDRUG-ABSPCBO;                                                                                        
 ABSDRUGV= SEDRUG**2*ABSDRUG**2;                                                                                 
 ABSPCBOV= SEPCBO**2*ABSPCBO**2;                                                                                 
 V = SEDRUG**2*ABSDRUG**2 + SEPCBO**2*ABSPCBO**2 - 2*CV*ABSDRUG*ABSPCBO;                                         
 ABSLOWER = ABSDRUG-ABSPCBO - SQRT(V)*QUANTILE('T',0.975,DF);                                                    
 ABSUPPER = ABSDRUG-ABSPCBO + SQRT(V)*QUANTILE('T',0.975,DF);                                                    
 ABSP = 2*(1-CDF('T',ABS(ABSDRUG-ABSPCBO)/SQRT(V),DF));                                                          
RUN;                                                                                                             
                                                                                                                 


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%MEND ABSTRTEFF;                                                                                                 
                                                                                                                 
%ABSTRTEFF(1,3,1,7,1);                                                                                           
%ABSTRTEFF(1,3,2,7,2);                                                                                           
%ABSTRTEFF(1,3,3,7,3);                                                                                           
%ABSTRTEFF(2,3,1,7,4);                                                                                           
%ABSTRTEFF(2,3,2,7,5);                                                                                           
%ABSTRTEFF(2,3,3,7,6);                                                                                           
                                                                                                                 
DATA COMB;                                                                                                       
 SET COMB1 COMB2 COMB3 COMB4 COMB5 COMB6;                                                                        
RUN;                                                                                                             
                                                                                                                 
PROC PRINT DATA = COMB;                                                                                          
TITLE 'TREATMENT EFFECT ON ABSOLUTE SCALE';                                                                      
RUN;                                                                                                             
TITLE;                                                                                                           
                                                                                                                 
** DEPENDENT VARIABLE IS NOW LOG CHANGE =  LOG PULSE – LOG BASE ** ;                                             
PROC MIXED DATA=STUDY2  COVTEST NOCLPRINT METHOD=ML;                                                             
  CLASS ID G T;                                                                                                  
  MODEL LCFB = LBASE T G T*G / SOLUTION OUTP=PRED1R OUTPM = PRED1F;                                              
  REPEATED T / TYPE=UN SUBJECT = ID;                                                                             
  LSMEANS T*G / PDIFF DIFF ALPHA=0.05 CL COV;                                                                    
  ODS OUTPUT LSMEANS=LSM_;                                                                                       
  ODS OUTPUT DIFFS=LSMDIFF_;                                                                                     
TITLE 'LOG CFB MMRM';                                                                                            
RUN;                                                                                                             
TITLE;                                                                                                           
  
DATA LSMDIFF_;                                                                                                   
 SET LSMDIFF_;                                                                                                   
IF T = _T AND G NE _G ;                                                                                          
IF _G=3;                                                                                                         
TIME=T;                                                                                                          
LABEL=LEFT(TRIM(PUT(G,1.0)))||' V '||LEFT(TRIM(PUT(_G,1.0)));                                                    
KEEP ESTIMATE STDERR LOWER UPPER PROBT TIME LABEL;                                                               
RUN;                                                                                                             
                                                                                                                 
*** TRT EFFECT ON LOG SCALE **;                                                                                  
%MACRO ABSTRTEFF2(DRUG,PCBO,T,DAT);                                                                              
DATA DRUG;                                                                                                       
 SET LSM_;                                                                                                       
 LENGTH LABEL $12.;                                                                                              
 LABEL=LEFT(TRIM(PUT(&DRUG,1.0)))||' V '||LEFT(TRIM(PUT(&PCBO,1.0)));                                            
 IF T=&T AND G=&DRUG;                                                                                            
 TIME=&T;                                                                                                        
 DRUG_=ESTIMATE;                                                                                                 
KEEP LABEL TIME DRUG_;                                                                                           
RUN;                                                                                                             
DATA PCBO;                                                                                                       
 SET LSM_;                                                                                                       
 LENGTH LABEL $12.;                                                                                              
 LABEL=LEFT(TRIM(PUT(&DRUG,1.0)))||' V '||LEFT(TRIM(PUT(&PCBO,1.0)));                                            
 IF T=&T AND G=&PCBO;                                                                                            
 TIME=&T;                                                                                                        
 PCBO_=ESTIMATE;                                                                                                 
KEEP LABEL TIME PCBO_;                                                                                           
RUN;                                                                                                             
PROC SORT DATA = DRUG;BY LABEL TIME;RUN;                                                                         
PROC SORT DATA = PCBO;BY LABEL TIME;RUN;                                                                         


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DATA COMB_&DAT;                                                                                                  
 MERGE DRUG PCBO;                                                                                                
 BY LABEL TIME;                                                                                                  
RUN;                                                                                                             
                                                                                                                 
%MEND ABSTRTEFF2;                                                                                                
                                                                                                                 
%ABSTRTEFF2(1,3,1,1);                                                                                            
%ABSTRTEFF2(1,3,2,2);                                                                                            
%ABSTRTEFF2(1,3,3,3);                                                                                            
%ABSTRTEFF2(2,3,1,4);                                                                                            
%ABSTRTEFF2(2,3,2,5);                                                                                            
%ABSTRTEFF2(2,3,3,6);                                                                                            
                                                                                                                 
DATA COMB_;                                                                                                      
 SET COMB_1 COMB_2 COMB_3 COMB_4 COMB_5 COMB_6;                                                                  
RUN;                                                                                                             
                                                                                                                 
PROC PRINT DATA = COMB_;                                                                                         
TITLE 'TREATMENT EFFECT ON LOG SCALE';                                                                           
RUN;                                                                                                             
TITLE;                                                                                                           
                                                                                                                 
PROC SORT DATA = COMB;BY LABEL TIME;RUN;                                                                         
PROC SORT DATA = COMB_;BY LABEL TIME;RUN;                                                                        
PROC SORT DATA = LSMDIFF_;BY LABEL TIME;RUN;                                                                     
                                                                                                                 
DATA ALL;                                                                                                        
 MERGE COMB COMB_ LSMDIFF_;                                                                                      
 BY LABEL TIME;                                                                                                  
 BASED = DRUG - DRUG_;                                                                                           
 BASEP = PCBO - PCBO_;                                                                                           
 BASEC = LEFT(TRIM(PUT(ROUND(EXP(BASED),0.1),5.1)));                                                             
 DRUGC = LEFT(TRIM(PUT(ROUND(EXP(DRUG ),0.1),5.1)))||' 
['||LEFT(TRIM(PUT(ROUND(SQRT(ABSDRUGV),0.01),6.2)))||']';                         
 PCBOC = LEFT(TRIM(PUT(ROUND(EXP(PCBO ),0.1),5.1)))||' 
['||LEFT(TRIM(PUT(ROUND(SQRT(ABSPCBOV),0.01),6.2)))||']';        ;                
 PCTCHGDRUG = LEFT(TRIM(PUT(ROUND(100*(EXP(DRUG_)-1),0.1),6.1)))||'% 
['||LEFT(TRIM(PUT(ROUND(SEDRUG,0.0001),6.4)))||']';                 
 PCTCHGPCBO = LEFT(TRIM(PUT(ROUND(100*(EXP(PCBO_)-1),0.1),6.1)))||'% 
['||LEFT(TRIM(PUT(ROUND(SEPCBO,0.0001),6.4)))||']';                 
 EFFECTPCTCHG = LEFT(TRIM(PUT(ROUND(100*(EXP(ESTIMATE)-1),0.1),6.1)))||'% 
('||LEFT(TRIM(PUT(ROUND(100*(EXP(LOWER)-1),0.1),6.1)))         
                ||'%, '||LEFT(TRIM(PUT(ROUND(100*(EXP(UPPER)-1),0.1),6.1)))||'%)';                               
 EFFECTABSCHG = LEFT(TRIM(PUT(ROUND(ABSEFF,0.1),6.1)))||' 
('||LEFT(TRIM(PUT(ROUND(ABSLOWER,0.1),6.1)))                                   
                ||', '||LEFT(TRIM(PUT(ROUND(ABSUPPER,0.1),6.1)))||')';                                           
 P_LOGEFFECT = PUT(PROBT,PVALUE7.4);                                                                             
 P_ABSEFFECT = PUT(ABSP,PVALUE7.4);                                                                              
RUN;                                                                                                             
                                                                                                                 
PROC SORT DATA = ALL;BY LABEL TIME;RUN;                                                                          
PROC PRINT DATA = ALL SPLIT='*' ;                                                                                
BY LABEL;                                                                                                        
ID LABEL;                                                                                                        
LABEL TIME= 'TIME*POINT'                                                                                         
    LABEL= 'TRT*COMP'                                                                                            
    BASEC= 'BASELINE*(BPM)'                                                                                      
    DRUGC= 'DRUG ABS*MEAN [SE]*(BPM)'                                                                            
    PCBOC= 'PCBO ABS*MEAN [SE]*(BPM)'                                                                            
    PCTCHGDRUG = 'DRUG PCT CFB*MEAN [SE]'                                                                        


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    PCTCHGPCBO = 'PCBO PCT CFB*MEAN [SE]'                                                                        
    EFFECTPCTCHG= 'DRUG-PCBO PCT EFFECT*(95 %CI)'                                                                
    EFFECTABSCHG= 'DRUG-PCBO ABS EFFECT*(95 %CI) (BPM)'                                                          
    P_LOGEFFECT='DRUG-PCBO P-VALUE' ;                                                                            
VAR TIME BASEC DRUGC PCBOC PCTCHGDRUG PCTCHGPCBO EFFECTPCTCHG EFFECTABSCHG P_LOGEFFECT ; 
RUN;