A Phase 2 Study to Evaluate the Safety, Efficacy and Pharmacokinetics of SPR001 (Tildacerfont) in Children Aged 2 to 17 Years With Congenital Adrenal Hyperplasia (CAH)
Phase: PHASE2
Conditions: Congenital Adrenal Hyperplasia, 21-OHD
Sponsor: Spruce Biosciences

SPR001-205 
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A Phase 2 Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of SPR001 (Tildacerfont) in 
Children Aged 2 to 17 Years with Congenital Adrenal Hyperplasia 
 
US IND Number: 
131761 
Study Number: 
SPR001-205 
Document Type: 
Clinical study protocol  
Protocol Version: 
5.0 (supersedes Protocol dated 14 October 2022) 
Protocol Date: 
30 November 2023 
Investigational Medicinal Product: 
SPR001 (tildacerfont) 
Indication: 
Congenital adrenal hyperplasia (CAH)  
Sponsor: 
Spruce Biosciences, Inc. 
611 Gateway Boulevard  
Suite 740 
South San Francisco, CA 94080 
Registries: 
ClinicalTrials.gov: NCT05128942 
 
EU Clinical Trials Registry: NA 
 
 
 
 
Statement of Confidentiality 
This document contains proprietary and confidential information of Spruce Biosciences, Inc. Acceptance 
of this document constitutes agreement by the recipient that no previously unpublished information 
contained herein will be published or disclosed without the prior written approval of Spruce Biosciences, 
Inc., with the exception that this document may be disclosed to study personnel under your supervision 
who need to know the contents for conducting the study and to appropriate Institutional Review Boards 
(IRBs) or Ethics Committees (ECs) under the condition that the personnel have agreed to keep this 
information confidential. The foregoing shall not apply to disclosure required by governmental 
regulations or laws; however, Spruce Biosciences, Inc. shall be promptly notified of any such disclosure.  
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SPONSOR APPROVAL PAGE 
 
 
A Phase 2 Study to Evaluate the Safety, Efficacy, and Pharmacokinetics, of SPR001 (Tildacerfont) in 
Children Aged 2 to 17 Years with Congenital Adrenal Hyperplasia  
Study Number: SPR001-205 
Protocol Version: 5.0 
Protocol Date: 30 November 2023 
 
 
This protocol has been reviewed and approved by Spruce Biosciences, Inc.: 
 
 
 
__________________________________________________ 
 
_________________ 
Will Charlton, MD  
 
 
 
 
 
 
 
Date 
Chief Medical Officer  
 
 
 
__________________________________________________ 
 
_________________ 
Vaeling Miller   
 
 
 
 
 
 
 
Date 
Vice President, Development Operations 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE 
A Phase 2 Study to Evaluate the Safety, Efficacy, and Pharmacokinetics, of SPR001 (Tildacerfont) in 
Children Aged 2 to 17 Years with Congenital Adrenal Hyperplasia  
Study Number: SPR001-205 
Protocol Version: 5.0 
Protocol Date: 30 November 2023 
 
x 
I confirm agreement to conduct the study in compliance with the protocol. 
x 
I confirm that I have read the Investigator’s Brochure. 
x 
I acknowledge that I am responsible for overall study conduct. I agree to personally conduct or 
supervise the described study. 
x 
I agree to ensure that all associates, colleagues, and employees assisting in the conduct of the study 
understand their obligations and will comply with the study protocol. 
 
Mechanisms are in place to ensure that site staff receives the appropriate training and information 
throughout the study. 
 
 
Site Name: __________________________________________________________________ 
Principal Investigator Name: ____________________________________________________ 
 
___________________________________________________    _______________________ 
Principal Investigator’s Signature  
 
 
 
 
Date 
 
 
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PROTOCOL SYNOPSIS 
 
Sponsor: Spruce Biosciences, Inc. 
Study Title: A Phase 2 Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of SPR001 (Tildacerfont) in 
Children Aged 2 to 17 Years with Congenital Adrenal Hyperplasia  
Protocol Number: SPR001-205  
Phase: 2 
COHORTS 1- 3 (12-week Treatment) 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the safety of tildacerfont in participants with CAH 
Adverse events (AEs) and serious 
adverse events (SAEs) 
Secondary 
 
To determine the efficacy of tildacerfont on disease control or 
reduction of glucocorticoid (GC) use in participants with classic 
CAH during 12 weeks of treatment 
Proportion of participants who achieve 
a reduction in androstenedione (A4) or 
reduction in glucocorticoid (GC) dosing 
during treatment period 
To determine the efficacy of tildacerfont on disease control in 
participants with classic CAH after 4 or 12 weeks of treatment 
 
Proportion of participants with 
elevated baseline A4 who achieve a 
reduction in A4 at Week 4 
Proportion of participants with 
elevated baseline A4 who achieve A4 
normalization at Week 4 or Week 12 
To determine the consistency of preliminary tildacerfont 
pharmacokinetics (PK) in participants with those simulated in a 
physiologically based PK (PBPK) model 
Tildacerfont plasma concentrations will 
be compared with the current PBPK 
simulation for consistency 
Exploratory 
 
To explore changes in pharmacodynamic (PD) biomarkers in 
participants with CAH 
Change from baseline in 
adrenocorticotropic hormone (ACTH), 
17hydroxyprogesterone (17-OHP), A4, 
testosterone, and 11-ketotestoterone 
(11KT) 
COHORTS 4, 5, 6, 7, 8, and 9 (4-week Treatment) 
Objectives 
Endpoints 
Primary 
To evaluate the safety of tildacerfont in participants with CAH 
Adverse events (AEs) and serious 
adverse events (SAEs) 
Secondary 
To determine the efficacy of tildacerfont on disease control in 
participants with classic CAH after 4 weeks of treatment 
Proportion of participants who achieve 
reduction in androstenedione (A4) at 
Week 4 
Proportion of participants who achieve 
A4 normalization at Week 4 
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To determine the consistency of preliminary tildacerfont 
pharmacokinetics (PK) in participants with those simulated in a 
physiologically based PK (PBPK) model 
Tildacerfont plasma concentrations will 
be compared with the current PBPK 
simulation for consistency 
Exploratory 
To explore changes in pharmacodynamic (PD) biomarkers in 
participants with CAH 
Change from baseline in 
adrenocorticotropic hormone (ACTH), 
17hydroxyprogesterone (17-OHP), A4, 
testosterone, and 11-ketotestoterone 
(11KT)  
EXTENSION (Cohorts 1-9)  
 
Objectives 
Endpoints 
Primary 
To evaluate the safety of tildacerfont in participants with CAH 
Adverse events (AEs) and serious 
adverse events (SAEs) 
Secondary 
To determine the efficacy of tildacerfont on reduction of 
glucocorticoid (GC) use in participants with classic CAH  
Proportion of participants who achieve 
reduction in glucocorticoid (GC) dosing 
(beyond 12 weeks for Cohorts 1-3 and 
beyond 4 weeks for Cohorts 4-9) 
Proportion of participants who achieve 
approximately physiologic GC dosing (ч 
11 g/m2/d) 
To determine the efficacy of tildacerfont on disease control in 
participants with classic CAH 
Proportion of participants with 
elevated A4 at completion of treatment 
period (Week 12 for Cohorts 1-3 and 
Week 4 for Cohorts 4-9) who achieve a 
reduction in A4  
Proportion of participants with 
elevated A4 at completion of treatment 
period who achieve A4 normalization  
Exploratory 
To explore changes in pharmacodynamic (PD) biomarkers in 
participants with CAH 
Change from baseline in 
adrenocorticotropic hormone (ACTH), 
17hydroxyprogesterone (17-OHP), A4, 
testosterone, and 11-ketotestoterone 
(11KT) (at Week 4 for all cohorts and 
Week 12 for Cohorts1-3) 
To explore the impact of tildacerfont on skeletal maturation 
Change from baseline in predicted 
adult height 
 
Study Rationale: Congenital adrenal hyperplasia is a serious, chronically debilitating, and life-threatening 
genetic disorder characterized by impaired adrenal synthesis of cortisol and consequent overproduction of 
adrenal androgens. Cortisol deficiency disrupts the balance of the hypothalamic-pituitary-adrenal axis by 
removing the negative feedback to the hypothalamus and pituitary provided by physiologic cortisol levels. 
This leads to the compensatory hypersecretion of corticotropin-releasing factor (CRF) by the hypothalamus, 
overproduction of ACTH by the pituitary gland, and consequent adrenal hyperplasia and overproduction of 
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downstream adrenal pre-cursors and hormones such as 17-OHP and A4, leading to androgen excess (Merke 
2005, Speiser 2018). Androgen excess may result in atypical genitalia in 46,XX newborns, risk for life 
threatening adrenal crises, ongoing virilization throughout childhood, menstrual dysfunction, early puberty, 
testicular adrenal rest tumors (TARTs) in males, skeletal maturation leading to compromised adult height, and 
impaired fertility (Merke and Auchus 2020). 
The current standard of care for CAH includes multiple daily doses of oral GCs to replace deficient cortisol. 
However, as opposed to patients with other forms of adrenal insufficiency, CAH patients generally require 
supraphysiologic doses of GCs to normalize ACTH and therefore control androgen levels (Claahsen-van der 
Grinten 2022). This therapy is problematic as it has significant side effects (e.g., loss of bone mineral density, 
iatrogenic Cushing’s syndrome, poor quality of life, metabolic disorders, and increased cardiovascular risk), a 
narrow therapeutic window, and overall poor treatment effectiveness with higher GC doses conferring 
increased risk (Stewart 2019). Treatment of children with CAH involves a challenging balance between GC and 
androgen levels. Elevated androgen levels can cause premature adrenarche and central precocious puberty 
as well as skeletal maturation leading to compromised adult height. GCs increase metabolic and infection 
risks and suppress growth by blunting the response to growth hormone (Allen 1998).  
Tildacerfont, a potent and highly selective small-molecule antagonist of CRF1 receptors, is being studied for 
the treatment of CAH on the basis of its ability to block the CRF1 receptors in the pituitary gland. This 
blockage may decrease the CRF signal produced by the hypothalamus, thereby decreasing ACTH 
overproduction by the pituitary and reducing excess accumulation of downstream adrenal hormones. This 
mechanism of action has been validated in CAH in earlier-phase clinical studies of tildacerfont. Given its 
mechanism of action, tildacerfont may enable a CAH patient to have normal androgen levels while taking GC 
at approximately physiologic replacement levels. 
dŝůĚĂĐĞƌĨŽŶƚŚĂƐďĞĞŶƚĞƐƚĞĚŝŶϲĐŽŵƉůĞƚĞĚWŚĂƐĞϭƐƚƵĚŝĞƐƵƐŝŶŐƐŝŶŐůĞĚŽƐĞƐƌĂŶŐŝŶŐĨƌŽŵϮƚŽϴϬϬථŵŐŽƌ
multiple doses ranging from 50 to 200 mg QD. Once daily dosing has been studied in 2 completed Phase 2 
studies using multiple doses ranging from 200 to 1000 mg QD for 2 weeks, and up to 400 mg QD 
for ϭϮථǁĞĞŬƐ͘Twice daily (BID) dosing of tildacerfont has been well tolerated in adults with CAH in previous 
clinical studies at doses up to 200 mg BID for 2 weeks. Safety data show that tildacerfont has been generally 
well tolerated in all clinical studies to date, with no related serious adverse events (SAEs) in current on-going 
studies.  
Data from the 2 completed Phase 2 studies in adults demonstrated proof of concept for tildacerfont as a 
treatment for CAH, with meaningful reductions in ACTH (demonstrating target engagement) and 17-OHP and 
A4 (demonstrating efficacy in decreasing downstream adrenal hormones) and continued improvement in 
biomarker levels over a period of 12 weeks.  
SPR001-205 will be the first study of tildacerfont in children and will be used to assess safety and to 
determine the consistency of preliminary tildacerfont PK in pediatrics with those simulated in a PBPK model. 
It will also characterize changes in androgen levels over the first 4 weeks of treatment (all cohorts), and the 
ability to reduce GC doses (based on A4 normalization) over 12 weeks of treatment (Cohorts 1-3).  
Based on the fact that CYP enzyme activity peaks in early childhood and decreases into adulthood, and 
CYP3A4 is the primary pathway of tildacerfont elimination, children may have more rapid drug clearance than 
adults. As a result, BID dosing is being studied to optimize consistency of exposure. All BID dosing regimens 
have been or will be evaluated in adults prior to being administered to pediatric participants. Thus, two adult 
cohorts have been added (Cohorts 4 and 5). BID dosing in pediatric participants will be evaluated in Cohorts 
6-9.   
An optional extension period will provide additional open-label treatment with tildacerfont to provide long-
term safety data for up to two years. 
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Please see Section 1.2 for Study Rationale.  
Study Design: This is a Phase 2 open-label study with up to 10 cohorts that will evaluate the safety, efficacy, 
and PK of different tildacerfont dosing regimens potentially up to 200mg QD for 12 weeks in children with 
classic CAH, and up to 400mg BID for 4 weeks in children and adults with classic CAH.  
Cohorts 1 and 1a (if indicated) and Cohort 2 in children aged 11-17 years and Cohort 3 in children aged 2-10 
years will study weight-based dose equivalents of up to 200mg QD, the dose currently being studied in adults 
with CAH in studies SPR001-203 (12 weeks treatment at 200mg QD) and SPR001-204 (24 weeks treatment at 
200mg QD). Treatment in Cohorts 1-3 will be for 12 weeks. 
Cohorts 4 and 5 in adults, Cohorts 6 and 8 in children aged 11-17 years, and Cohorts 7 and 9 in children aged 
2-10 years will evaluate doses higher than 200mg QD that will be administered BID for 4 weeks. 
Cohort 4 (adults) and Cohort 6 (11-17 years) will initiate concurrently at 200mg BID (200 mg BID has been 
previously evaluated in adults in study SPR001-201). Upon completion of the 4-week dosing on 4 sentinel 
participants from Cohorts 4 and 6 combined, the DMC will assess safety data and provide recommendations 
on continued dosing. If the DMC assesses it to be safe to proceed to a higher dose, Cohort 5 (adults) may be 
initiated at 300mg or 400mg BID and Cohort 7 (2-10 years) may be initiated at 200mg BID. Following the 
completion of the 4-week dosing periods for Cohorts 5 and 7, the DMC will review safety data from 4 sentinel 
participants and offer recommendations on whether to proceed to Cohort 8 (11-17 years) and at what dose 
(300mg or 400mg BID). Following completion of Cohort 8, the DMC will review the safety data from 4 sentinel 
participants and provide a recommendation on whether to proceed with Cohort 9 and at what dose (300mg 
or 400mg BID) (Table 1). 
All cohorts including doses above 200 mg BID will be adaptive, so that the determination to initiate a cohort, 
and at what dose, may be determined by the Sponsor, within the guidelines of the protocol, based on 
recommendations by an independent Data Monitoring Committee (DMC) and emerging safety and exposure 
data. Individual and study stopping criteria will further ensure safety of the participants.  
Please see Section 3 for details on Study Design and Section 6 for details on stopping criteria. 
Study Conduct: There are 7 scheduled visits over approximately 18 weeks for Cohorts 1 to 3; and 5 scheduled 
visits over approximately 10 weeks for Cohorts 4 to 9. Visits are detailed in the Schedule of Activities. All visits 
should be performed on site, but alternative arrangements may be used if an on-site visit is not feasible. 
Adverse events and concomitant medications will be collected at each visit. 
Any participant enrolled under protocol amendment 3 may be re-consented to protocol amendment 4 and 
receive the 12-week treatment course; however, because they will have already contributed PK data, they 
will not be required to have blood draws for tildacerfont concentration on Days 1 and 14 between 0.5 to- 1.5 
hours and between 3 to 5 hours post dosing. Additionally, any participant enrolled under amendment 4 (or 
any other tildacerfont study) may be re-consented and enrolled under protocol amendment 5. 
Please see Section 3 and Section 10.2 for details on Study Conduct.  
Duration of Participant Participation: Approximately 18 weeks inclusive of Screening, Treatment, and Follow-
up for Cohorts 1 to 3; and 10 weeks for Cohorts 4 to 9. The extension period allows for treatment up to 2 
years. Please see Section 3.1.2 and Section 3.1.3 for Details on Duration. 
 
 
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Planned Sample Size and Number of Sites: The study is expected to enroll approximately 20 children across 
the first 3 cohorts (i.e., Cohorts 1, 2, and 3), 10 in the 11-to 17- year age group and 10 in the 2-to 10- year age 
group. If the optional Cohort 1a is initiated (up to 5 participants), however, Cohorts 1 to 3 may enroll up to 25 
children total, 15 in the 11-to 17-year-old age group and 10 in the 2-to 10-year-old age group.  
Up to an additional six cohorts (Cohorts 4-9) are planned to investigate BID dosing over 4 weeks of treatment. 
The study will also ĞŶƌŽůůƵƉƚŽĂƉƉƌŽǆŝŵĂƚĞůǇϭϱĂĚƵůƚƐĂŐĞĚшϭϴǇĞĂƌƐĂĐƌŽƐƐŽŚŽƌƚƐϰĂŶĚϱ͖ĂŶĚƵƉƚŽ
approximately 30 children across 4 additional cohorts [up to 15 in the 11- to 17-year age group (Cohorts 6 
and 8) and up to 15 in the 2- to 10-year age group (Cohorts 7 and 9)].  
If all possible doses are studied, total sample size of this study may be up to approximately 55 children and 15 
adults Please see Table S-1 for subject numbers by dosing cohort: 
Table S-1 
Cohorts: 
Ages (years): 
Corresponding 
Adult Dose 
Subject Numbers: 
1 
11-17 
50 mg QD 
5 
1a 
11-17 
To be determined 
based on DMC 
recommendation 
(50 or 100 mg 
QD) 
5 
2 
11-17 
200 mg QD  
5 
3 
2-10 
50 mg QD, 100 mg 
QD, OR 200 mg 
QD 
10 
4  
>18 
200 mg BID 
5 
5 
>18 
300 mg BID 
and/or 400 mg 
BID 
5+51 
6 
11-17 
200 mg BID 
5 
7 
2-10 
200 mg BID 
5 
8  
11-17 
300 mg BID 
and/or 400 mg 
BID 
5+51 
9  
2-10 
300 mg BID 
and/or 400 mg 
BID 
5+51 
 
 
 
Up to 70 subjects total 
1+5 allows for the option of dosing 300mg before or after 400 mg Cohort is initiated if indicated by the DMC 
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The study will be conducted at approximately 15 investigative sites within North America. Please see Section 
8.1 for details on Planned Sample size. 
Study Drug and Route of Administration: Tildacerfont, an oral small-molecule corticotropin-releasing factor 
type-1 (CRF1) receptor antagonist will be supplied as tablets that can be consumed whole or crushed and 
sprinkled on food. For administration at home, study drug should be taken with food. Study drug may be 
consumed up to 30 minutes after food, if necessary. If a participant has not consumed study drug within 
30 minutes after food, the participant should consume study drug with a snack.  
Participants will be advised to refrain from consumption of grapefruit, grapefruit juice, or any fruits that are 
known to be strong CYP3A4 inhibitors (e.g., pomegranate) from 1 day before the first dose of study drug until 
after the final dose." Please see Section 5 for details on Study Drug. 
Participant Population: Patients aged 2 years and older with classic CAH (21-OHD), inclusive of salt-wasting 
and simple virilizing forms. (Please see Section 1.2.2 for details on Study Population) 
Criteria for Inclusion: 
1. Male and female participants aged 2 to 10 years (Cohorts 3, 7, and 9), 11 to 17 years (Cohorts 1, 1a, 
2, 6, and 8Ϳ͕ĂŶĚшϭϴǇĞĂƌƐ;ŽŚŽƌƚƐϰĂŶĚϱͿ at Screening. 
2. For participants aged 2 to 5 years, a minimum weight at Screening of 11 kg. 
3. Has a known childhood diagnosis of classic CAH due to 21-hydroxylase deficiency (21-OHD) based on 
genetic mutation in CYP21A2 and/or documented (at any time) elevated 17-OHP and currently 
treated with hydrocortisone (HC), HC acetate, prednisone, prednisolone, methylprednisolone (or a 
combination of these). Other types of CAH may be allowed with Sponsor approval. 
4. For participants in Cohorts 4-9, 1.2X ULN < A4 < 4X ULN. A4 values outside of this range may be 
allowed with Medical Monitor (MM) approval. 
5. A stable dose of GC ƌĞƉůĂĐĞŵĞŶƚĨŽƌшϭŵŽŶƚŚďĞĨŽƌĞScreening without evidence of non-adherence 
(as assessed by Investigator). Weight-based dose adjustments or stress dosing in the month prior to 
Screening are not exclusionary but should be discussed with the Medical Monitor (MM). 
6. For participantƐŽŶŵŝŶĞƌĂůŽĐŽƌƚŝĐŽŝĚƌĞƉůĂĐĞŵĞŶƚ͕ĂƐƚĂďůĞĚŽƐĞĨŽƌшϭŵŽŶƚŚƉƌŝŽƌƚŽScreening. 
7. For participants on gonadotropin hormone-releasing hormone (GnRH) analogues, a stable dose 
initiated ш 3 months prior to screening.   
8. For participants on aromatase inhibitors, a stable dose for ш 3 months prior to screening.   
9. If sexually active and capable of reproduction, agrees to follow protocol contraception guidelines. 
10. Have provided written informed consent and/or assent, and/or parent/legal guardian permission, as 
applicable, prior to undergoing any study procedure, including Screening procedures. The participant 
and/or parent/legal guardian must be able to read and understand all the study procedures.  
Criteria for Exclusion: 
1. CAH not due to 21-OHD. 
2. History of allergy or hypersensitivity to tildacerfont or other CRF1 receptor antagonists.  
3. History of bilateral adrenalectomy or hypopituitarism. 
4. Current treatment with dexamethasone. Participants may be transitioned off dexamethasone prior to 
Screening at the Investigator’s discretion. 
5. A clinically significant unstable medical condition, medically significant illness, or chronic disease 
(other than CAH) within 30 days, including but not limited to: 
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a. Malignancy or <3 years since remission, except successfully treated localized skin cancer 
b. Estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2 (per the creatinine-based 
Schwartz equation) 
c. Current or history of liver disease (with the exception of Gilbert’s syndrome). Resolved/cured 
viral hepatitis may be allowed with MM approval 
d. History of alcohol or substance abuse within the last year, or otherwise that would likely prevent 
the participant from reliably or safely participating in the study, per Investigator judgement 
e. Human immunodeficiency virus (HIV) at Screening 
f. Any other condition that would impact participant safety or confound interpretation of study 
results, in the opinion of the Investigator or MM. 
6. Psychiatric conditions, including but not limited to major depression, bipolar disorder, schizophrenia, 
or schizoaffective disorders that are not effectively controlled on medication and may have an 
adverse impact on study compliance. Exclusionary symptoms include hallucinations, delusions, and 
psychosis. Baseline values for depression and anxiety questionnaires are not exclusionary but may 
inform exclusion of a participant based on Exclusion Criterion 5. 
7. Clinically significant abnormal laboratory or electrocardiogram (ECG) results during Screening. 
Abnormal results requiring review and discussion with the MM to discern eligibility include, but are 
not limited to: 
a. Any clinically meaningful abnormal ECG results, including Fridericia-corrected QT interval (QTcF) 
>450 ms (males) or >460 ms (females) 
b. Alanine aminotransferase (ALT) >2x ULN 
c. Total bilirubin >1.5x ULN (except if due to Gilbert’s syndrome). 
8. Females who are pregnant or nursing. 
9. Use of any other investigational drug (other than tildacerfont) or device within 30 days or 5 half-lives 
(whichever is longer) prior to Screening through the end of the study (EOS). Prior exposure to 
tildacerfont is allowed, but tildacerfont should be discontinued for at least 2 weeks prior to 
randomization. The screening window may serve as the washout period. 
10. Use of the following drugs from 30 days or 5 half-lives (whichever is longer) before Screening through 
the EOS: 
a. Rosiglitazone, testosterone, growth hormone, or any other medication or supplement that could 
impact participant safety or confound interpretation of study results 
b. Moderate to strong inhibitors and/or inducers of cytochrome P450 3A4 (CYP3A4) 
c. Sensitive substrates or narrow-therapeutic-range substrates of CYP3A4 (except hormonal 
contraception containing <20 mcg ethinyl estradiol) 
d. Sensitive substrates or narrow-therapeutic-range substrates of breast cancer resistance protein 
(BCRP) (except those that can be administered QD in the morning, separated by approximately 10 
hours from evening administration of study drug). 
11. Donation or receipt of blood from 90 days before Screening through the EOS; donation or receipt of 
platelets, white blood cells, or plasma from 30 days before Screening through the EOS. 
12. Any known or anticipated swallowing difficulty or dysphagia during Screening or the duration of the 
study. 
Safety Assessments: Safety assessments will include monitoring and recording all AEs (including SAEs, AEs 
leading to discontinuation/withdrawal, dose-liming toxicities, and AEs of special interest), physical 
examination, vital signs assessment, ECGs, clinical laboratories, and psychiatric evaluation. 
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Pharmacodynamic and Tildacerfont Concentration Comparisons:   
PD measurements include concentrations of ACTH, 17-OHP, A4, testosterone, and 11KT in the blood. PK 
measurements will include the plasma concentration of tildacerfont.   
For Cohorts 1, 2, 4, 5, 6,7, 8, and 9 (and 1a if indicated), serial blood samples for PK and PD will be drawn 
during Visits 2 and 3 (Day 1 and Week 2) during the following time windows relative to study drug dosing: 
pre-dose (pre-GC and pre-tildacerfont dose, approximately 8 AM ± 1 hour), 0.5 to 1.5 hours post-dose, and 3 
to 5 hours post-dose. Serial samples should be attempted in all cases but may be declined in the 2–10-year 
age group at Investigator’s discretion (e.g., unable to establish IV, behavioral challenges impede collection 
and risk other assessments). A blood sample for plasma concentration and PD markers of tildacerfont will be 
drawn at approximately 8 AM ± 1 hour at all other visits.  
For Cohort 3, a blood sample for determining the plasma concentration of tildacerfont and PD markers will be 
drawn at approximately 8 AM ± 1 hour at all visits. Morning GC and tildacerfont doses must be held until after 
the blood draw.  
Statistical Methods: A sample size of up to 70 participants (i.e., 15 adults, 30 participants 11- to 17-years of 
age, and 25 participants 2- to 10-years), will provide adequate data to assess the initial safety of tildacerfont 
in a pediatric and adult population and provide data to support the continued use of the PBPK model to 
determine pediatric dosing requirements in future studies. 
The Safety Population will include all participants who receive at least 1 dose of study drug and will be the 
primary analysis set for general and safety analyses. 
The PK Population will include all participants in the Safety Population with at least 1 post-dose sample above 
the limit of quantification.  
The PD Population will include all participants in the Safety Population with at least 1 evaluable post-baseline 
PD assessment. 
All individual data will be listed as measured. All statistical summaries and analyses will be performed using 
SAS software (SAS Institute Inc, Cary, North Carolina, USA). 
All continuous variables will be presented using an 8-point descriptive summary (n, mean, standard deviation, 
median, interquartile range [25th percentile, 75th percentile], minimum, and maximum) by dose, as available. 
Categorical variables will be summarized by frequency and by percentage of participants in corresponding 
categories. 
Any changes to the protocol-specified analyses will be pre-specified in the SAP before database lock. 
Please see Section 8 for details on Statistical Methods. 
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TABLE OF CONTENTS 
SPONSOR APPROVAL PAGE............................................................................................................. 2 
INVESTIGATOR PROTOCOL AGREEMENT PAGE .............................................................................. 3 
PROTOCOL SYNOPSIS ...................................................................................................................... 4 
TABLE OF CONTENTS..................................................................................................................... 12 
LIST OF TABLES .............................................................................................................................. 16 
LIST OF FIGURES ............................................................................................................................ 16 
LIST OF ABBREVIATIONS ............................................................................................................... 17 
1. 
INTRODUCTION .......................................................................................................... 19 
1.1. 
Background ................................................................................................................ 19 
1.1.1. 
Congenital Adrenal Hyperplasia ................................................................................ 19 
1.1.2. 
Current Treatment for CAH ....................................................................................... 20 
1.1.3. 
Overview of Tildacerfont ........................................................................................... 20 
1.2. 
Study Rationale .......................................................................................................... 21 
1.2.1. 
Rationale for the Study Design .................................................................................. 21 
1.2.2. 
Study Population ........................................................................................................ 22 
1.2.3. 
Rationale for the Study Drug Dosing ......................................................................... 22 
1.3. 
Risk/Benefit Assessment ........................................................................................... 24 
2. 
OBJECTIVES AND ENDPOINTS .................................................................................... 25 
3. 
STUDY DESIGN ........................................................................................................... 28 
3.1. 
Overall Design ............................................................................................................ 28 
3.1.1. 
Data Monitoring Committee ..................................................................................... 32 
3.1.2. 
Study Visits ................................................................................................................. 33 
3.1.2.1. 
Visit 1 (Screening) ...................................................................................................... 33 
3.1.2.2. 
Visit 2 (Day 1) ............................................................................................................. 33 
3.1.2.3. 
Visit 3 (Week 2; Day 14 ±3 days) ............................................................................... 34 
3.1.2.4. 
Visit 4 (Week 4 ±3 days) (EOT for Cohorts 4-9) ......................................................... 35 
3.1.2.5. 
Visit 5 (Week 8 ±3 days) (Cohorts 1-3 only) .............................................................. 36 
3.1.2.6. 
Visit 6 (EOT for Cohorts 1-3) (Week 12 ±3 days) ....................................................... 36 
3.1.2.7. 
Safety Follow-up Visit Telephone Call (30 days after last dose ±7 days) .................. 37 
3.1.2.8. 
Early Termination Visit ............................................................................................... 37 
3.1.2.9. 
End of Study ............................................................................................................... 38 
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3.1.3. 
Extension Period ........................................................................................................ 38 
4. 
STUDY POPULATION .................................................................................................. 40 
4.1. 
Eligibility Criteria ........................................................................................................ 40 
4.1.1. 
Inclusion Criteria ........................................................................................................ 40 
4.1.2. 
Exclusion Criteria ....................................................................................................... 40 
4.2. 
Lifestyle Considerations ............................................................................................. 42 
4.2.1. 
Meals and Dietary Restrictions .................................................................................. 42 
4.2.2. 
Activity ....................................................................................................................... 42 
4.2.3. 
Contraception Guidelines .......................................................................................... 42 
4.2.3.1. 
Contraception Guidelines for Male Participants ....................................................... 42 
4.2.3.2. 
Contraception Guidelines for Female Participants ................................................... 42 
4.3. 
Screen Failures ........................................................................................................... 43 
5. 
STUDY TREATMENT ................................................................................................... 44 
5.1. 
Treatment Administration ......................................................................................... 44 
5.2. 
Preparation/Handling/Storage/Accountability ......................................................... 45 
5.2.1. 
Acquisition and Accountability .................................................................................. 45 
5.2.2. 
Formulation, Appearance, Packaging, and Labeling ................................................. 45 
5.2.3. 
Product Storage ......................................................................................................... 46 
5.2.4. 
Preparation and Administration ................................................................................ 46 
5.3. 
Concomitant Therapy ................................................................................................ 46 
5.3.1. 
Glucocorticoid Replacement Therapy ....................................................................... 46 
5.3.1.1. 
General Procedures for Glucocorticoids ................................................................... 46 
5.3.1.2. 
A4-Based Glucocorticoid Dose Adjustment Algorithm ............................................. 47 
5.3.1.3. 
Stress Dosing of Glucocorticoids ............................................................................... 47 
5.3.2. 
Prohibited Concomitant Medications ....................................................................... 48 
6. 
STUDY DRUG DISCONTINUATION AND PARTICIPANT WITHDRAWAL ....................... 50 
6.1. 
Study Drug Discontinuation ....................................................................................... 50 
6.1.1. 
Dose-Limiting Toxicity Stopping Criteria ................................................................... 50 
6.1.2. 
Safety Monitoring and Stopping Rules for Abnormal Liver Chemistry 
Measurements ........................................................................................................... 50 
6.1.3. 
Laboratory Monitoring of Liver Function .................................................................. 51 
6.1.4. 
QT Stopping Criteria .................................................................................................. 52 
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6.1.5. 
Suicidality Stopping Criteria ....................................................................................... 52 
6.1.6. 
Depression or Anxiety Stopping Criteria ................................................................... 52 
6.1.7. 
Clinically Significant Adverse Events .......................................................................... 52 
6.1.8. 
Dose Limiting Toxicity ................................................................................................ 52 
6.2. 
Participant Withdrawal from the Study .................................................................... 52 
6.3. 
Lost to Follow-up ....................................................................................................... 53 
7. 
STUDY ASSESSMENTS AND PROCEDURES ................................................................. 54 
7.1. 
Safety Assessments .................................................................................................... 54 
7.1.1. 
Physical Examination ................................................................................................. 54 
7.1.2. 
Vital Signs ................................................................................................................... 54 
7.1.3. 
Body Weight and Height ............................................................................................ 54 
7.1.4. 
Electrocardiogram ..................................................................................................... 54 
7.1.5. 
Clinical Laboratories .................................................................................................. 54 
7.1.6. 
Psychiatric Evaluations .............................................................................................. 55 
7.1.6.1. 
Columbia – Suicide Severity Rating Scale .................................................................. 55 
7.1.6.2. 
Depression Assessment ............................................................................................. 55 
7.1.6.3. 
Anxiety Assessment ................................................................................................... 55 
7.1.6.4. 
Survey of Well-Being of Young Children .................................................................... 56 
7.2. 
Adverse Events and Serious Adverse Events ............................................................. 56 
7.2.1. 
Definition of Adverse Event ....................................................................................... 56 
7.2.2. 
Definition of Serious Adverse Event .......................................................................... 57 
7.2.3. 
Classification of an Adverse Event ............................................................................. 57 
7.2.3.1. 
Severity ...................................................................................................................... 58 
7.2.3.2. 
Relationship to Study Drug ........................................................................................ 58 
7.2.3.3. 
Action Taken .............................................................................................................. 60 
7.2.3.4. 
Outcome .................................................................................................................... 60 
7.2.4. 
Time Period and Frequency for Event Assessment and Follow-up ........................... 60 
7.2.5. 
Adverse Event Reporting ........................................................................................... 60 
7.2.6. 
Serious Adverse Event Reporting .............................................................................. 61 
7.2.7. 
Reporting of Pregnancy ............................................................................................. 61 
7.2.8. 
Adverse Events of Special Interest ............................................................................ 62 
7.3. 
Pharmacokinetic and Pharmacodynamic Assessments ............................................ 63 
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8. 
STATISTICAL CONSIDERATIONS ................................................................................. 65 
8.1. 
Sample Size Determination ....................................................................................... 65 
8.2. 
Populations for Analyses ........................................................................................... 65 
8.3. 
Statistical Analyses..................................................................................................... 65 
8.3.1. 
General Considerations ............................................................................................. 65 
8.3.2. 
Demographics and Baseline Characteristics .............................................................. 65 
8.3.3. 
Concomitant Medications ......................................................................................... 65 
8.3.4. 
Safety Analyses .......................................................................................................... 65 
8.3.4.1. 
Extent of Exposure ..................................................................................................... 66 
8.3.4.2. 
Adverse Event Data.................................................................................................... 66 
8.3.4.3. 
Clinical Laboratory Data ............................................................................................. 66 
8.3.4.4. 
Vital Signs Data .......................................................................................................... 66 
8.3.4.5. 
Electrocardiogram Data ............................................................................................. 66 
8.3.5. 
Pharmacokinetic Analyses ......................................................................................... 66 
8.3.6. 
Pharmacodynamic Analyses ...................................................................................... 66 
8.3.7. 
Psychiatric Evaluation Analyses ................................................................................. 67 
9. 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....................... 68 
9.1. 
Informed Consent ...................................................................................................... 68 
9.2. 
Study Discontinuation and Closure ........................................................................... 68 
9.3. 
Confidentiality and Privacy ........................................................................................ 68 
9.4. 
Key Roles and Study Governance .............................................................................. 69 
9.4.1. 
Sponsor ...................................................................................................................... 69 
9.4.2. 
Investigators .............................................................................................................. 69 
9.4.3. 
Institutional Review Board ........................................................................................ 69 
9.4.4. 
Data Monitoring Committee ..................................................................................... 69 
9.5. 
Clinical Monitoring ..................................................................................................... 69 
9.6. 
Quality Assurance and Quality Control ..................................................................... 70 
9.7. 
Data Handling and Record Keeping ........................................................................... 70 
9.7.1. 
Data Collection and Management Responsibilities ................................................... 70 
9.7.2. 
Study Records Retention ........................................................................................... 70 
9.8. 
Protocol Deviations .................................................................................................... 70 
9.9. 
Publication and Data Sharing Policy .......................................................................... 71 
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9.10. 
Amendments ............................................................................................................. 71 
10. 
RISK MITIGATION DURING THE CLINICAL TRIAL ........................................................ 72 
10.1. 
Risk/Benefit Assessment in the Context of COVID-19 or Other Obstacles ............... 72 
10.2. 
Study Conduct in the Context of COVID-19 or Other Obstacles ............................... 72 
10.3. 
Participant Disposition in the Context of COVID-19 or Other Obstacles .................. 72 
10.4. 
Regulatory and Study Oversight Considerations in the Context of COVID-19 
or Other Obstacles ..................................................................................................... 72 
11. 
REFERENCES ............................................................................................................... 73 
12. 
APPENDICES ............................................................................................................... 75 
APPENDIX 1. SCHEDULE OF ACTIVITIES FOR COHORTS 1, 1A, 2, AND 3 .................................... 76 
APPENDIX 2. SCHEDULE OF ACTIVITIES FOR OPEN-LABEL EXTENSION FOR COHORTS 1, 
1A, 2, AND 3 ............................................................................................................... 79 
APPENDIX 3. SCHEDULE OF ACTIVITIES FOR COHORTS 4, 5, 6, 8, 7, AND 9 .............................. 81 
APPENDIX 4. SCHEDULE OF ACTIVITIES FOR EXTENSION PERIOD FOR COHORTS 4, 5, 6, 
8, 7, AND 9 ................................................................................................................. 84 
APPENDIX 5. PROHIBITED CONCOMITANT MEDICATIONS ........................................................ 86 
APPENDIX 6. CLINICAL LABORATORY TESTS............................................................................... 87 
 
LIST OF TABLES 
Table 1. Study Cohorts .................................................................................................................. 30 
Table 2. Tildacerfont Dose Levels and Pediatric Weight-Based Dosing ....................................... 45 
Table 3. Sick Day Guidelines for Stress Dosing of Glucocorticoids ............................................... 48 
Table 4. Stopping Criteria and Increased Monitoring for Liver Chemistry Elevations ................. 51 
Table 5. Severity of Adverse Events .............................................................................................. 58 
Table 6. Relatedness of Adverse Event to Study Drug.................................................................. 59 
Table 7. Outcome of Adverse Events ............................................................................................ 60 
Table 8. Tildacerfont Concentration and PD Sampling Time Points ............................................. 64 
 
LIST OF FIGURES 
Figure 1. 
Overall Study Design for Cohorts 1, 1a, 2, and 3 ....................................................... 31 
Figure 2. 
Overall Study Design for Cohorts 4, 5, 6, 8, 7, and 9 ................................................. 32 
 
 
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LIST OF ABBREVIATIONS 
11KT 
11-ketotestosterone 
17-OHP 
17-hydroxyprogesterone 
21-OHD 
21-hydroxylase deficiency 
A4 
androstenedione 
ACTH 
adrenocorticotropic hormone, corticotropin 
ADL 
activities of daily living 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase  
BCRP 
breast cancer resistance protein 
BID 
twice daily 
BMI 
body mass index 
BSA 
body surface area 
CAH 
congenital adrenal hyperplasia 
CBC 
complete blood count 
CNS 
central nervous system 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
coronavirus disease 2019 
CRF 
corticotropin-releasing factor 
CRF1, CRF2 
corticotropin-releasing factor type-1 or type-2 
CRO 
contract research organization 
C-SSRS 
Columbia–Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events  
CYP 
cytochrome P450 
DLT 
dose-limiting toxicity 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
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EOT  
end of treatment 
ET 
early termination 
FDA 
Food and Drug Administration 
FOCP 
female of childbearing potential 
GC 
glucocorticoid 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GI 
gastrointestinal 
GnRH 
gonadotropin hormone-releasing hormone 
HC 
hydrocortisone 
HIV 
human immunodeficiency virus 
HPA 
hypothalamic-pituitary-adrenal 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IUS 
intrauterine system 
MedDRA 
Medical Dictionary for Regulatory Activities 
MM 
Medical Monitor 
OTC 
over-the-counter 
PBPK 
physiologically-based pharmacokinetic 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PROMIS 
Patient Reported Outcomes Measurement Information System 
QD 
once daily 
QTcF 
Fridericia-corrected QT interval 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SUSAR 
suspected unexpected serious adverse reaction 
SWYC 
Survey of Well-being of Young Children 
TART 
testicular adrenal rest tumor 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
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1. 
INTRODUCTION 
1.1. 
Background 
1.1.1. 
Congenital Adrenal Hyperplasia 
Congenital adrenal hyperplasia (CAH) is a serious, chronically debilitating, and life-threatening genetic 
disorder characterized by impaired adrenal synthesis of cortisol and consequent overproduction of 
adrenal androgens (Merke and Bornstein 2005).  
Approximately 95% of patients with CAH have a mutation in the cytochrome P450 21A2 (CYP21A2) 
gene, which encodes the cytochrome P450c21 enzyme, commonly known as 21-hydroxylase (Anderson 
2010, Speiser 2018). 
Mutations in other genes that encode enzymes critical in adrenal steroidogenesis (CYP191, HSD3B2, 
CYP11B1, and POR) contribute to the remaining approximately 5% of CAH cases (Turcu and Auchus 
2015). 21-Hydroxylase catalyzes the conversion of progesterone to 11-deoxycorticosterone (a precursor 
to aldosterone) and the conversion of 17-hydroxyprogesterone (17-OHP) to 11-deoxycortisol (the 
precursor to cortisol) (White and Speiser 2000, Bachelot 2008, Doleschall 2014, Auchus 2015). A 21-
hydroxylase deficiency (21-OHD) thus results in a critical blockade in the adrenal steroid synthesis 
pathways that produce cortisol (and aldosterone in some individuals) and an accumulation of the 
precursors to these steroids. These steroid precursors are then diverted into the synthetic pathway for 
adrenal androgens, resulting in overproduction of androstenedione (A4) and downstream adrenal 
androgens. 
Cortisol deficiency disrupts the balance of the hypothalamic-pituitary-adrenal (HPA) axis by removing 
the negative feedback to the hypothalamus and pituitary provided by physiologic cortisol levels. This 
leads to the compensatory hypersecretion of corticotropin-releasing factor (CRF) by the hypothalamus, 
overproduction of adrenocorticotropic hormone (ACTH) by the pituitary gland, and consequent adrenal 
hyperplasia and overproduction of downstream adrenal pre-cursors and hormones such as 17-OHP and 
A4, leading to androgen excess (Merke and Bornstein 2005, Speiser 2018).  
The clinical manifestations of CAH are the direct result of cortisol and aldosterone deficiencies and of 
androgen overproduction (Merke and Bornstein 2005, Anderson 2010, Reisch 2019). 
Cortisol deficiency can result in adrenal insufficiency and life-threatening adrenal crises. Androgen 
excess may result in atypical genitalia in 46,XX newborns, risk for life threatening adrenal crisis, ongoing 
virilization throughout childhood, menstrual dysfunction, early puberty, testicular adrenal rest tumors 
(TARTs) in males, skeletal maturation leading to compromised adult height, and impaired fertility 
(Merke and Auchus 2020).  
CAH is typically classified as either classic (the more severe form that usually presents with adrenal crisis 
in infancy or virilization during early childhood) or nonclassic (the milder form that may not become 
evident until later childhood or early adulthood). Classic CAH can be further sub-classified as salt-
wasting or simple virilizing. Approximately 75% of patients with classic CAH have the salt-wasting form 
of CAH characterized by the loss of large amounts of sodium via urine, hyponatremia, hyperkalemia, and 
elevated plasma renin activity indicating hypovolemia, leading to dehydration and hypotension that can 
be life threatening in early infancy (Speiser 2018). Salt-wasting CAH is caused by severe aldosterone 
deficiency resulting from mutations that completely ablate 21-hydroxylase activity. Milder mutations 
that result in even 1% to 2% residual 21-hydroxylase activity enable sufficient aldosterone production to 
avoid neonatal adrenal crisis and produce the simple virilizing form of CAH (caused by impaired cortisol 
production) in the remaining 25% of classic CAH. 
Refer to the Investigator’s Brochure (IB) for additional information on CAH. 
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1.1.2. 
Current Treatment for CAH 
There are no approved therapies for CAH. The current standard of care for CAH includes multiple daily 
doses of oral glucocorticoids (GCs) to replace deficient cortisol. However, as opposed to patients with 
other forms of adrenal insufficiency, CAH patients require supraphysiologic doses of GCs to normalize 
ACTH and therefore control androgen levels (Claahsen-van der Grinten 2022). This therapy is 
problematic as it has significant side effects (e.g., loss of bone mineral density, iatrogenic Cushing’s 
syndrome, poor quality of life, metabolic disorders, and increased cardiovascular risk), a narrow 
therapeutic window, and overall poor treatment effectiveness, with higher GC doses conferring 
increased risk (Steward 2019). Evidence-based treatment guidelines for CAH are only beginning to be 
developed (Reisch 2015, Speiser 2018), and current overall treatment effectiveness for patients with 
CAH is poor (Mnif 2012, Bachelot 2015). 
Treatment of children with CAH involves a challenging balance between GC and androgen levels. 
Elevated androgen levels can cause premature adrenarche and central precocious puberty as well as 
skeletal maturation leading to compromised adult height. GCs increase metabolic and infection risks and 
suppress growth by blunting the response to growth hormone (Allen 1998).  
Despite the availability of GCs as a treatment for CAH, approximately two-thirds of patients with CAH 
are considered outside the acceptable bounds of biochemical control based on 17-OHP and A4 levels 
(Han 2014). Among patients with 21-OHD treated with GCs, normal serum A4 has been shown to be 
achieved in only 36% of patients (Anderson 2010).  
Over a lifetime, the treatment of patients with CAH shifts from an emphasis on normal childhood 
growth to pubertal development to adult fertility and long-term health concerns, including metabolic 
abnormalities, cardiovascular disease, osteoporosis, and overall diminished quality of life (Anderson 
2010, Auchus 2015). 
Given the serious nature of CAH and the limitations and risks of chronic GC therapy, new treatments are 
urgently needed for patients with CAH. Corticotropin-releasing factor type-1 (CRF1) receptor antagonism 
may provide a means of decoupling the treatment goals of CAH – physiologic cortisol replacement and 
androgen control. The ability to control androgen levels through ACTH modulation could reduce 
patients’ dependence on high-dose GCs and alleviate the challenges associated with 
hyperandrogenemia and supraphysiologic GC exposure.  
1.1.3. 
Overview of Tildacerfont  
Tildacerfont, a potent and highly selective small-molecule antagonist of CRF1 receptors, is being studied 
for the treatment of CAH on the basis of its ability to block the CRF1 receptors in the pituitary gland. This 
blockage may decrease the CRF signal produced by the hypothalamus, thereby decreasing ACTH 
overproduction by the pituitary and reducing excess accumulation of downstream adrenal hormones. 
This mechanism of action has been validated in CAH in earlier-phase clinical studies of tildacerfont. 
Given its mechanism of action, tildacerfont may enable a CAH patient to have normal androgen levels 
while taking GC at approximately physiologic replacement levels. 
dŝůĚĂĐĞƌĨŽŶƚŚĂƐďĞĞŶƚĞƐƚĞĚŝŶϲĐŽŵƉůĞƚĞĚWŚĂƐĞϭƐƚƵĚŝĞƐƵƐŝŶŐƐŝŶŐůĞĚŽƐĞƐƌĂŶŐŝŶŐĨƌŽŵϮƚŽϴϬϬථŵŐ
or multiple doses ranging from 50 to 200 mg QD. Once daily dosing has been studied in 2 completed 
Phase 2 studies using multiple doses ranging from 200 to 1000 mg QD for 2 weeks, and up to 400 mg QD 
for ϭϮථǁĞĞŬƐ͘Twice daily (BID) dosing of tildacerfont has been well tolerated in adults with CAH in 
previous clinical studies at doses up to 200 mg BID for 2 weeks. Safety data show that tildacerfont has 
been generally well tolerated in all clinical studies to date, with no related serious adverse events (SAEs) 
in current on-going studies. 
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Data from the 2 completed Phase 2 studies in adults demonstrated proof of concept for tildacerfont as a 
treatment for CAH, with meaningful reductions in ACTH (demonstrating target engagement) and 17-OHP 
and A4 (demonstrating efficacy in decreasing downstream adrenal hormones in CAH) and showed 
continued improvement in biomarker levels over a period of 12 weeks.  
Tildacerfont’s mechanism of action is well-suited to potentially address the underlying pathophysiology 
driving excess adrenal androgen production in CAH as it blocks CRF1 receptor engagement at the level of 
the anterior pituitary, and as demonstrated in completed clinical studies in adults, reduces the levels of 
not only ACTH, but also downstream resultant adrenal androgens and androgen precursors (17-OHP and 
A4) in patients with CAH. Thus, tildacerfont has the potential to effect normalization of androgen levels 
while allowing for GC replacement at approximately physiologic dose levels. 
Nonclinical studies and clinical studies of tildacerfont are summarized in Section 1.3 and full details are 
available in the IB. 
1.2. 
Study Rationale 
1.2.1. 
Rationale for the Study Design 
SPR001-205 is an open-label dose ranging phase 2 study to evaluate the potential of tildacerfont to 
reduce androgen levels and GC burden in participants ages 2-years and older with classic CAH. SPR001-
205 will be the first study of tildacerfont in children and will be used to assess safety and to determine 
the consistency of preliminary tildacerfont pharmacokinetics (PK) in pediatrics with those simulated in a 
physiologically based pharmacokinetic (PBPK) model. In Cohorts 1-3, the study will also characterize 
changes in androgen levels over 12 weeks of treatment, and the ability to reduce GC doses based on A4 
normalization. In Cohorts 4-9, it will characterize changes in androgen levels over the first 4 weeks of 
treatment with BID dosing. An optional extension period will provide additional treatment with 
tildacerfont to provide long-term safety data for up to two years. 
In completed Phase 2 studies in adult participants with classic CAH, tildacerfont exhibited an acceptable 
safety profile and proof-of-concept efficacy in reducing ACTH, 17-OHP, and A4 levels at effective doses, 
which support the continued clinical development of tildacerfont for the treatment of CAH. 
As the first study of tildacerfont in a pediatric CAH population, the primary objective is to gain 
knowledge of the safety profile of tildacerfont. Secondary objectives of the study are to characterize the 
efficacy of tildacerfont in reducing A4 levels after 4 weeks of treatment (all cohorts) and reducing GC 
doses based on A4 normalization over 12 weeks of treatment (Cohorts 1-3), as well as comparing plasma 
concentrations of tildacerfont in pediatric participants with those of a simulated PBPK model. 
Exploratory objectives include assessing changes from baseline in levels of ACTH, 17-OHP, A4, 
testosterone, and 11-ketotestosterone (11KT).  
In the interest of progressing cautiously, the study’s cohorts are defined by decreasing age in addition to 
ascending tildacerfont dose. Dosing will begin in Cohort 1 with participants in the older age group of 11 
to 17 years and with the lowest dose level. Subsequent cohorts will be initiated only after a 
recommendation from the Data Monitoring Committee (DMC) is reviewed by the Sponsor. The final 
decision to progress cohorts will be made by the Sponsor. Cohort 2 will continue with participants in the 
older pediatric age group but dosing at a higher level (no greater than the weight-adjusted adult 
equivalent of 200 mg once daily [QD]). Cohort 3 will dose no higher than Cohort 2 but enroll participants 
in the younger age group of 2 to 10 years. An optional interim dose cohort (Cohort 1a) may be enrolled 
only if needed per DMC recommendation and Sponsor decision, in the event of a safety concern in 
participants in Cohort 1 (Figure 1). 
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Due to changing HPA axis dynamics across developmental stages (associated with changing GC 
requirements) and the fact that younger children have increased liver CYP enzyme activity (which may 
lead to increased tildacerfont clearance), alternative dosing regimens will also be explored, including BID 
dosing in Cohorts 4-9. Cohorts 4 and 5 will include adult patients (to further establish safety), Cohorts 6, 
8 will include children 11-17 years of age, and Cohort 7 and 9 will include children 2-10 years of age. All 
cohorts including doses above 200 mg QD will be adaptive, so that the determination to initiate a 
cohort, and at what dose, may be determined by the Sponsor, within the guidelines of the protocol, 
based on recommendations by the DMC and emerging safety and exposure data (Figure 2). 
Cohort 4 (adults) and Cohort 6 (11-17 years) will initiate concurrently at doses of 200mg BID. Initiation of 
200mg adult equivalent BID in adolescents is supported by the prior study of 200mg QD in Cohort 2 and 
the prior study of doses up to 200mg BID and 1000mg QD in adults (SPR001-201). 
Following DMC recommendation, Cohorts 5 and 7 may be initiated concurrently. Cohort 5 will include 
adults receiving either 300 or 400mg BID, and Cohort 7 will consist of children 2-10 years old receiving 
200mg adult equivalent BID. If 300m BID is pursued in Cohort 5, a DMC meeting may be called to review 
safety data of 5 participants and make a recommendation regarding the potential enrollment of another 
5 participants at a dose of 400mg. 
Cohorts 8 and 9 may be initiated to investigate either a 300 or 400 mg adult equivalent BID dose 
(depending on DMC recommendation and Sponsor decision) in children (2-10 and 11-17 years 
respectively). If Cohort 8 is initiated, the DMC will convene once safety data is available for 4 
participants and make a recommendation regarding initiation of Cohort 9. If 300mg equivalent BID is 
pursued in either cohort and escalation to 400mg is considered, a DMC meeting will be called to review 
safety data of 5 participants and make a recommendation regarding the potential enrollment of another 
5 participants at a dose of 400mg equivalent BID. Thus Cohorts 8 and 9 may enroll up to 10 participants 
for each cohort (Table 1). 
1.2.2. 
Study Population 
The study is expected to enroll approximately 20 children across Cohorts 1, 2, and 3, specifically 10 
participants in the 11- to 17-year-old age group (i.e., 5 participants in Cohort 1 and 2) and 10 in the 2- to 
10-year-old age group (i.e., 10 participants in Cohort 3). If the optional Cohort 1a is initiated, Cohorts 1-3 
may, however, enroll up to approximately 25 children. 
This study will also enroll approximately 5 adults ĂŐĞĚшϭϴǇĞĂƌƐin Cohort 4 and 5-10 adults in Cohort 5. 
Therefore, up to approximately 15 adults may be enrolled. Cohorts 6 and 7 will enroll approximately 5 
children each in the 11-17- and 2-10-year age groups, respectively. If Cohorts 8 and 9 are initiated, each 
will also enroll approximately 5-10 children. Therefore, up to 30 children may be enrolled in the BID 
dosing cohorts (Table 1). 
1.2.3. 
Rationale for the Study Drug Dosing 
dŝůĚĂĐĞƌĨŽŶƚŚĂƐďĞĞŶƚĞƐƚĞĚŝŶϲĐŽŵƉůĞƚĞĚWŚĂƐĞϭƐƚƵĚŝĞƐƵƐŝŶŐƐŝŶŐůĞĚŽƐĞƐƌĂŶŐŝŶŐĨƌŽŵϮƚŽϴϬϬථŵŐ
or multiple doses ranging from 50 to 200 mg QD. Once daily dosing has been studied in 2 completed 
Phase 2 studies using multiple doses ranging from 200 to 1000 mg QD for 2 weeks, and up to 400 mg QD 
for ϭϮථǁĞĞŬƐ͘/ĚŽƐŝŶŐŽĨƚŝůĚĂĐĞƌĨŽŶƚŚĂƐďĞĞŶǁĞůůƚŽůĞƌĂƚĞĚŝŶĂĚƵůƚƐǁŝƚŚ,ŝŶƉƌĞǀŝŽƵƐĐůŝŶŝĐĂů
studies at doses up to 200 mg BID for 2 weeks. Safety data show that tildacerfont has been well 
tolerated in all clinical studies to date, with no related serious adverse events (SAEs) in any of the 
completed or the on-going SPR001-205 study. One SUSAR that included worsening diarrhea and 
enteritis in the context of acute adrenal insufficiency and a history of colitis was reported in SPR001-203, 
one of two ongoing placebo-controlled trials in adults with CAH. 
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As there is a food effect with tildacerfont, clinical development has been and continues to be conducted 
in the fed state. The clinical efficacy/pharmacodynamic (PD) data show CRF1 receptor target 
engagement (reductions in ACTH) and reductions in key adrenal pre-cursors and hormones (17-OHP and 
A4) in participants with CAH dosed for 2 weeks with tildacerfont at 200 mg/day or higher. A 1-
compartment PK model with first-order absorption and elimination was fit to PK data from Study 
SPR001-201 and used to estimate the steady-state exposure for each participant at each dose.  
The adult exposure levels observed after 2 weeks of treatment were extrapolated to pediatric 
participants based on body weight and age for this study using a PBPK approach based on healthy 
adults. The PBPK model was based on in vitro and in vivo information on the metabolism and PK of 
tildacerfont and was validated using the plasma concentration-time profiles in healthy adults in the fed 
state. To account for differing CYP3A4 expression by age, the Upreti ontogeny profile was used in the 
pediatric dose predictions in three age groups, 2 to 5, 6 to 10, and 11 to 17 (Upreti and Walhstrom 
2016). Pediatric doses on a mg/kg basis were predicted by age group to correspond to the adult 
exposures at the same dose levels. Within the lower dose cohorts (50 mg and 100 mg), dose bands were 
constructed such that participants would not receive a dose greater than 20% over the predicted mg/kg 
conversion. Weight bands were constructed such that participants in higher dose cohorts would not 
receive a dose greater than 10% over the predicted mg/kg conversion of the corresponding adult dose.  
Preliminary PK data from Cohorts 1-3 show that the PBPK model overestimates drug exposure in 
children, such that the weight-based adult equivalent doses utilized in the children do not provide the 
exposures observed in adults. Additionally, an inverse relationship between age and exposure is 
apparent. This may be due to differences in drug metabolism across developmental stages, specifically 
CYP enzyme activity which is the primary driver of tildacerfont elimination. CYP enzyme activity peaks in 
early childhood and declines into adulthood. Consequently, children sometimes require relatively higher 
doses than adults to achieve optimal exposures of drugs that are eliminated by CYP-dependent 
metabolism (i.e., the Upreti ontogeny profile may not have adequately adjusted for physiologic 
differences that impact tildacerfont exposure). 
Higher doses and more frequent administration of tildacerfont may support increased and more 
consistent exposure in spite of the more rapid elimination in children. Further dose exploration is 
supported by the fact that no safety signal has been observed in Cohorts 1-3 at the time of this 
amendment, which includes 30 pediatric participants on doses up to 200mg adult equivalent QD for up 
to 24 weeks (1Nov23). Additionally, the 200mg QD dose which is the dose being used in the on-going 
adult CAH studies have a safety margin of 13.7 relative to the NOAEL from pre-clinical studies. This 
margin is expected to be greater in children because the exposures observed in SPR001-205 have been 
substantially lower than those observed in the adult studies. 
The maximum planned dose is 400 mg BID, subject to adjustment based on safety and PK data obtained 
during this study. The design of this amendment allows for the evaluation of exposure in adults starting 
at 200mg BID and continuing (per DMC recommendation) with dosing up to 400mg BID, such that all new 
dosing regimens have been or will be tested in adults prior to children. Additionally, pediatric exposure at 
200mg BID can be evaluated prior to increasing to up to 400mg BID in children. Given that pediatric 
exposures are observed to be less in children than adults, this stepwise approach optimizes the ability to 
ensure that no pediatric exposures exceed those previously studied in adults. 
Pediatric weight-based tildacerfont dose levels equivalent to doses of 50 mg, 100 mg, 200 mg QD, as 
well as 200mg, 300 mg, and 400 mg BID in adults are defined in Table 2 by age group.  
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1.3. 
Risk/Benefit Assessment 
Tildacerfont has been generally well tolerated at effective doses and has demonstrated the ability to 
reduce ACTH and downstream adrenal androgen production in adult patients with CAH and elevated 
adrenal androgen levels in Phase 2a studies. The most frequently reported non-procedural associated 
adverse events (AEs) were headache and diarrhea. No drug-related SAEs have been reported in 
completed clinical studies to date. 
Potential clinically significant risks identified in the pre-clinical program include histopathological 
changes in the thyroid gland and male reproductive tract, developmental toxicity and mild, possibly 
treatment-related trends in increased Fridericia-corrected QT interval (QTcF) duration. However, no 
corresponding functional decline in thyroid or male reproductive biochemical assessments has been 
observed in human studies completed to date, nor have any cardiovascular safety concerns been noted 
with either vital signs or electrocardiogram (ECG) monitoring. Developmental toxicity has not been 
evaluated in human clinical trials.  
Hepatic effects were also noted in the pre-clinical program, and reversible liver enzyme elevations have 
been observed in clinical studies.  
Additional details of known and potential risks of tildacerfont are provided in the IB. Study SPR001-205 
has incorporated multiple design elements to mitigate these potential risks including extensive 
laboratory assessments (Section 7.1.5), an independent Hepatic Adjudication Committee to assess 
potential liver issues, ECG monitoring (Section 7.1.4), contraception requirements (Section 4.2.3), and 
stopping criteria (Section 6.1). 
As tildacerfont is metabolized by CYP3A4, drug-drug interaction risk necessitates the prohibition of 
concomitant use of known moderate to strong inducers or inhibitors of CYP3A4. Moreover, as 
tildacerfont is a moderate inhibitor of CYP3A4, drugs that are sensitive substrates or narrow-
therapeutic-range substrates of CYP3A4 and/or breast cancer resistance protein (BCRP) must be 
avoided; for sensitive substrates or narrow-therapeutic-range substrates of BCRP in the absence of 
CYP3A4, cautionary use is advised with separation of at least 10 hours from tildacerfont and ongoing 
assessment for loss of efficacy.  
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2. 
OBJECTIVES AND ENDPOINTS 
COHORTS 1-3 (12-week Treatment) 
Objectives 
Endpoints 
Primary 
 
To evaluate the safety of tildacerfont in 
participants with CAH  
AEs and SAEs 
Secondary 
 
To determine the efficacy of tildacerfont on 
disease control or reduction of GC use in 
participants with classic CAH during 12 weeks 
of treatment  
Proportion of participants who achieve a reduction 
in A4 or reduction in GC dosing during treatment 
period  
To determine the efficacy of tildacerfont on 
disease control in participants with classic CAH 
after 4 or 12 weeks of treatment 
Proportion of participants with elevated baseline A4 
who achieve a reduction in A4 at Week 4 
Proportion of participants with elevated baseline A4 
who achieve A4 normalization at Week 4 or Week 12 
To determine the consistency of preliminary 
tildacerfont PK in participants with those 
simulated in a PBPK model 
Tildacerfont plasma concentrations will be compared 
with the current PBPK simulation for consistency 
Exploratory  
 
To explore changes in pharmacodynamic (PD) 
biomarkers in participants with CAH 
Change from baseline in adrenocorticotropic 
hormone (ACTH), 17hydroxyprogesterone (17-OHP), 
A4, testosterone, and 11-ketotestoterone (11KT) 
COHORTS 4, 5, 6, 8, 7, and 9 (4-week Treatment) 
Objectives 
Endpoints 
Primary 
To evaluate the safety of tildacerfont in 
participants with CAH 
Adverse events (AEs) and serious adverse events 
(SAEs)  
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Secondary 
To determine the efficacy of tildacerfont on 
disease control in participants with classic CAH 
after 4 weeks of treatment 
Proportion of participants who achieve reduction in 
androstenedione (A4) at Week 4 
Proportion of patients who achieve A4 normalization 
at Week 4. 
To determine the consistency of preliminary 
tildacerfont pharmacokinetics (PK) in 
participants with those simulated in a 
physiologically based PK (PBPK) model 
Tildacerfont plasma concentrations will be compared 
with the current PBPK simulation for consistency  
Exploratory 
To explore changes in pharmacodynamic (PD) 
biomarkers in participants with CAH 
Change from baseline in adrenocorticotropic 
hormone (ACTH), 17hydroxyprogesterone (17-OHP), 
A4, testosterone, and 11-ketotestoterone (11KT) 
EXTENSION (Cohorts 1-9) 
Objectives 
Endpoints 
Primary 
To evaluate the safety of tildacerfont in 
participants with CAH 
AEs and SAEs 
Secondary 
To determine the efficacy of tildacerfont on 
reduction of glucocorticoid (GC) use in 
participants with classic CAH after 4 weeks or 
12 weeks of treatment 
Proportion of participants who achieve reduction in 
glucocorticoid (GC) dosing (beyond 12 weeks for 
Cohorts 1-3 and beyond 4 weeks for Cohorts 4-9) 
Proportion of participants who achieve 
ĂƉƉƌŽǆŝŵĂƚĞůǇƉŚǇƐŝŽůŽŐŝĐ'ĚŽƐŝŶŐ;чϭϭŐͬŵ2/d) 
To determine the efficacy of tildacerfont on 
disease control in participants with classic CAH 
Proportion of participants with elevated A4 at 
completion of treatment period (Week 12 for 
Cohorts 1-3 and Week 4 for Cohorts 4-9) who 
achieve a reduction in A4 
Proportion of participants with elevated A4 at 
completion of treatment period who achieve A4 
normalization 
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Exploratory 
To explore changes in pharmacodynamic (PD) 
biomarkers in pediatric participants with CAH 
Change from baseline in adrenocorticotropic 
hormone (ACTH), 17-hydroxyprogesterone (17-OHP), 
A4, testosterone, and 11-ketotestoterone (11KT), (at 
Week 4 for all cohorts and Week 12 for Cohorts 1-3) 
To explore the impact of tildacerfont on 
skeletal maturation 
Change from baseline in predicted adult height 
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3. 
STUDY DESIGN 
3.1. 
Overall Design 
This is a Phase 2, open-label, dose-ranging study designed to provide safety, efficacy, and PK of 
tildacerfont, as well as the impact of tildacerfont on adrenal androgens and GC requirements in 
participants with classic CAH.  
Three staggered cohorts (Cohorts 1-3) are planned to investigate QD dosing over 12 weeks of treatment, 
with an additional optional Cohort 1a, dependent on accumulating safety data. The study is expected to 
enroll approximately 20 children across the first 3 cohorts (i.e., Cohorts 1, 2, and 3), 10 in the 11-to 17- 
year age group and 10 in the 2-to 10- year age group. If the optional Cohort 1a is initiated (up to 5 
participants), however, Cohorts 1 to 3 may enroll up to 25 children total, 15 in the 11-to 17-year-old age 
group and 10 in the 2-to 10-year-old age group. 
Up to an additional six cohorts (Cohorts 4-9) are planned to investigate BID dosing over 4 weeks of 
treatment. The study will also ĞŶƌŽůůƵƉƚŽĂƉƉƌŽǆŝŵĂƚĞůǇϭϱĂĚƵůƚƐĂŐĞĚшϭϴǇĞĂƌƐĂĐƌŽƐƐCohorts 4 and 
5; and up to approximately 30 children across 4 additional cohorts [up to 15 in the 11- to 17-year age 
group (Cohorts 6 and 8) and up to 15 in the 2- to 10-year age group (Cohorts 7 and 9)].  
If all possible doses are studied, total sample size of this study may be up to approximately 55 children 
and 15 adults (Table 1).  
Participants enter the study on their current GC regimen (note: dexamethasone is excluded). In Cohorts 
1-3, GC dose may be adjusted based on A4 levels at specified weeks and at any visit during the 
extension. In Cohorts 4-9, there will be no GC adjustment during the 4-week study period, but GC doses 
can be adjusted for those who participate in the optional extension at Week 4 and any subsequent visit. 
For further details refer to Section 5.3.1.2. 
Cohorts 1 to 3: 
Cohorts 1, 1a (if indicated), and 2 will include children ages 11- to 17-years old (up to approximately 5 
participants in each cohort), and Cohort 3 (up to approximately 10 participants) will include children 
ages 2- to 10-years old.  
For these cohorts, the study will last approximately 18 weeks including a 2-week Screening Period, a 12-
week Treatment Period and a Safety Follow-up visit 30 days after the last dose of study drug (during the 
Treatment Period). Participants may continue in an extension period upon completion of the 12-week 
Treatment Period. If participants enroll in the extension study after the 12-week Treatment Period, the 
Safety Follow-up Visit will occur 30 days after the last dose in the extension.  
Dosing will begin in Cohort 1 with participants 11- to 17- years of age dosing at the adult equivalent of 
50 mg QD. Cohort 2 will continue in the same 11– to 17-year-old age group but dosing at 200 mg QD. 
Cohort 3 will enroll participants 2-to 10-years of age but dose no higher than Cohort 2. If safety concerns 
are identified in the Cohort 1 participants, an interim dose Cohort 1a may be initiated prior to 
proceeding to Cohort 2 dosing.  
Cohort 1 will include up to approximately 5 participants who will receive a tildacerfont dose that is 
equivalent to the adult dose of 50 mg. Data from the first 2 participants will be considered sentinel and 
will inform a safety review by an independent DMC. After reviewing the first 2 weeks of data from the 
sentinel participants, the DMC will make one of three recommendations regarding continuing 
enrollment:  
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1) If data suggest the dose was well-tolerated by the sentinel participants, Cohort 2 (200 mg 
equivalent) will be initiated.   
2) If a safety concern is identified, for example, a sentinel participant experiences an individual 
stopping criterion or a suspected unexpected serious adverse reaction (SUSAR), the DMC may 
withhold their recommendation until additional safety data are available from the additional 3 
participants in Cohort 1. 
3) The DMC may also recommend initiating an interim cohort (Cohort 1a) of up to 5 participants to 
evaluate the same or a different dose (e.g., 50 or 100 mg adult equivalent) before proceeding to 
Cohort 2 (200 mg equivalent). After reviewing 2 weeks of safety data from Cohort 1a sentinel 
participants (i.e., first 2 participants), the DMC may recommend initiating Cohort 2. However, if 
safety concerns are identified, the DMC may recommend reviewing safety data from an 
additional 3 patients prior to recommending/not recommending initiation of Cohort 2. The DMC 
will review safety data from Cohort 1a participants and recommend a dose increase to Cohort 2, 
or initiation of Cohort 3 at the dose used in Cohort 1a. 
Cohort 2 will receive the equivalent of the adult dose of 200 mg. Cohort 2 may enroll up to 
approximately 5 participants. This allows for up to approximately 10 planned participants in the 11- to 
17-year-old age group across Cohorts 1, and 2, and up to approximately 15 participants if Cohort 1a is 
initiated.    
Following DMC review of safety data from the first 2 weeks for sentinel participants in Cohort 2 (or 
Cohort 1a, if utilized), Cohort 3 may be initiated. Cohort 3 will dose no higher than the highest dose 
found to be safe in 11-to 17-year-olds but enroll up to approximately 10 participants in the younger age 
group of 2 to 10 years. There will be a DMC) review of data from Cohort 3 regarding the initiation of 
further cohorts with BID dosing (Table 1, Figure 1).  
Cohorts 4 to 9: 
All participants in Cohorts 4 to 9 will be enrolled for a 4-week study period. Before escalating to the next 
highest dose cohort, the DMC will evaluate a total of 4 sentinel participants from the combined cohorts 
(to initiate a new dosing regimen in a pediatric cohort, data from at least 2 pediatric sentinels must be 
included in the review).  
The study will last approximately 10 weeks including a 2-week Screening Period, a 4-week Treatment 
Period and a Safety Follow-up visit 30 days after the last dose of study drug). Participants may continue 
in an extension period upon completion of the 4-week Treatment Period. If participants enroll in the 
extension after the 4-week Treatment Period, the Safety Follow-up Visit will occur 30 days after the last 
dose in the extension. Cohorts 4 and 5 will include aĚƵůƚƐĂŐĞĚшϭϴǇĞĂƌƐ (up to approximately 5 
participants in Cohort 4 and 10 participants in Cohort 5). The 10 participants that may be evaluated in 
Cohort 5 is to allow for the possibility of more than one dose tested (i.e., 300mg or 400mg BID – per 
DMC recommendation). Cohorts 6 and 8 will include children ages 11 to 17 years old (up to 
approximately 5 participants in each cohort) and Cohorts 7 and 9 will include children ages 2 to 10 years 
old (up to approximately 5 participants in each cohort). Cohorts 8 and 9 may include approximately 5 
additional participants each if more than one dose is tested (i.e., 300mg and 400mg equivalent BID). For 
example, if 5 children are treated with 300mg BID in Cohort 8, the DMC may review safety data from all 
5 after 4 weeks of treatment and make a recommendation regarding enrolling another approximately 5 
children at 400mg BID (Table 1, Figure 2).  
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Cohorts 4 and 6 will begin simultaneously with a dose of 200 mg BID in participants aged шϭϴ years and 
200 mg adult equivalent BID in participants aged 11-17 years (200 mg BID has been previously evaluated 
in adults in study SPR001-202). 
The DMC will convene once 4 weeks of safety data is available for 4 sentinels from Cohorts 4 and 6 
combined. After reviewing data from these 4 participants (in addition to all other available safety data), 
the DMC will make a recommendation regarding initiation of Cohorts 5 and 7. 
Cohort 5 will enroll adult participants at 300 or 400mg BID (per DMC recommendation) and will provide 
safety data in adults to support the administration of higher BID doses (i.e., up to 400mg BID) in children 
and adolescents. Cohort 7 may begin simultaneously with Cohort 5 and will enroll children aged 2-10 
years at a dose of 200mg adult equivalent BID. 
Once safety data are available for Cohort 5 and 7 sentinels, the DMC will convene and make a 
recommendation regarding initiation of pediatric cohorts at doses >200mg BID. The Sponsor will then 
decide whether to initiate Cohort 8 at a dose up to 400mg BID. Subsequently, the DMC may review data 
from 4 sentinels from Cohort 8 and make a recommendation regarding further dose increase in the 
younger age group. Sponsor may then decide whether to initiate Cohort 9 at a dose up to 400mg BID.  
A sparse serial blood sampling approach for PK will also be used in Cohorts 4 to 9 on Day 1 (Visit 2) and 
Week 2/Day 14 (Visit 3). Blood samples for tildacerfont concentration should be obtained pre-dose and 
between 0.5 - 1.5 hours and 3 - 5 hours post dosing. At these visits, participants will dose in clinic with a 
meal at 8 am (± 1 hour). 
All participants in Cohorts 4-9 will receive open-label tildacerfont for the 4-week treatment period, after 
which they may be offered optional continued treatment if the clinical Investigator believes it is in the 
participant’s best interest. Once enrolled in the extension period, participants may adjust tildacerfont 
dose up to the highest dose recommended by the DMC per age group at the Investigator’s discretion. 
Table 1. Study Cohorts 
Cohort Age 
Corresponding Adult Dose 
Subject 
Numbers 
Treatment 
Duration 
1 
11- to 17-years 
50 mg QD 
5 
12 Weeks 
1aa 
11- to 17-years 
To be determined based on DMC 
recommendation 
(50 or 100 mg QD) 
 
5 
2 
11- to 17-years 
200 mg QD  
5 
3 
2- to 10-years 
50 mg QD, 100 mg QD, OR 200 mg QD 
10 
4 
>18-years 
200 mg BID 
5 
4 weeks 
5 
>18-years 
300 and/or 400 mg BID 
5+5c 
6 
11- to 17-years 
200 mg BID 
5 
8b 
11- to 17-years 
300 and/or 400 mg BID 
5+5c 
7 
2- to 10-years 
200 mg BID 
5 
9b 
2- to 10-years 
300 and/or 400 mg BID 
5+5c 
 
 
 
Up to 70 
subjects total 
 
Abbreviations: BID=twice daily; DMC=Data Monitoring Committee; QD=once daily. 
a Cohort 1a is an optional interim dose cohort that may be enrolled only if needed per DMC recommendation and Sponsor 
decision, in the event of a safety concern in participants in Cohort 1. 
b Cohort 8 and 9 are adaptive cohorts that may be enrolled based on emerging safety data and per DMC and Sponsor 
recommendation/approval.  
c+5 allows for the option of dosing 300mg before or after 400 mg Cohort is initiated if indicated by the DMC 
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A schema of the study design is presented in Figure 1 for Cohorts 1, 1a, 2, and 3; and in Figure 2 for 
Cohorts 4, 5, 6, 7, 8 , and 9. 
Figure 1. 
Overall Study Design for Cohorts 1, 1a, 2, and 3
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Figure 2. 
Overall Study Design for Cohorts 4, 5, 6, 8, 7, and 9 
Note: Any participant enrolled under protocol amendment 3 may be re-consented to protocol amendment 4 and receive the 
12-week treatment course; however, because they will have already contributed PK data, they will not be required to have 
blood draws for tildacerfont concentration on Days 1 and 14 between 0.5 to- 1.5 hours and between 3 to 5 hours post dosing.
Additionally, any participant enrolled under amendment 4 (or any other tildacerfont study) may be re-consented and enrolled 
under protocol amendment 5.
3.1.1.
Data Monitoring Committee
An independent DMC will review the available data on an ongoing basis throughout the study and 
before initiating a new cohort. The DMC will be composed of independent reviewers who are not 
involved in the conduct of the study. The DMC will advise the Sponsor of any trends or safety issues that 
may impact the study or study participants. In particular, the occurrence of any clinically significant AE 
(including but not limited to SAEs, AEs leading to study drug discontinuation/study withdrawal, dose-
limiting toxicities [DLTs], and adverse events of special interest [AESIs], all considered at least possibly 
related to study drug) will receive special consideration (see Section 7.2.5). The Sponsor will make final 
decisions concerning the continuation, modification, or termination of the trial. The DMC’s scope of 
responsibility, membership, confidentiality, and procedures will be established in a separate DMC 
charter. Three DMC reviews are planned during and upon completion of Cohorts 1-3. Three additional 
DMC reviews are planned during Cohorts 4-9. Ad hoc DMC meetings may be called by the Sponsor or 
the DMC Chair (Figure 2). 
For Cohorts 1-3, the DMC will review safety data from a minimum of 2 sentinel participants for 2 weeks 
at each meeting. For Cohorts 4-9, the DMC will review safety data from a minimum of 4 sentinel 
participants at each meeting, but it is not required that 2 come from each cohort. However, to initiate a 
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new dosing regimen in a pediatric cohort, data from at least 2 pediatric sentinels must be included in the 
review.  
3.1.2. 
Study Visits 
Each participant will undergo a Screening Period of up to approximately 14 days, a 12-week (Cohorts 1 
to 3) or 4-week Treatment Period (Cohorts 4 to 9), and a 30-day Safety Follow-up Period. The Screening 
Period may be extended as approved by the Sponsor and/or contract research organization (CRO) 
designee. The Schedule of Activities for the study is provided in Appendix 1 and Appendix 3 for Cohorts 
1 to 3 and Cohorts 4 to 9, respectively. The Schedule of Activities for the extension is in Appendix 2 and 
Appendix 4, respectively. 
3.1.2.1. 
Visit 1 (Screening) 
Initial Screening will be conducted as an outpatient visit at approximately Day -14; the screening window 
may be extended with Sponsor/Medical Monitor (MM) approval. The following activities will be 
performed: 
x 
Informed consent/assent and/or parent/legal guardian permission, as applicable (prior to 
undergoing any study procedures) 
x 
Assessment of participant eligibility (Inclusion/Exclusion Criteria) 
x 
Review of demographics, medical history, and medications (both current and from the past 
year) 
x 
Hepatitis B, C, and human immunodeficiency virus (HIV) screening 
x 
Pregnancy test for females of childbearing potential (FOCP) (serum) 
x 
Screening/safety labs (see Appendix 1 and Appendix 3) 
x 
Urinalysis 
x 
Vital signs: blood pressure, pulse rate, body temperature, respiration rate, weight, and height 
(height is only measured during the Screening Visit).  
x 
Physical exam (abbreviated/directed) 
x 
12-lead ECG 
x 
Baseline Suicidality Questionnaire- Columbia–Suicide Severity Rating Scale (C-SSRS) (for 
participants aged ш6 years only)  
x 
Baseline Depression and Anxiety Questionnaires (Patient Reported Outcomes Measurement 
Information System [PROMIS] ;ĨŽƌƉĂƌƚŝĐŝƉĂŶƚƐĂŐĞĚшϱǇĞĂƌƐŽŶůǇͿ or Survey of Well-being of 
Young Children [SWYC] depending on age of participant) 
x 
Bone age and predicted adult height calculated from x-ray image of left hand and wrist (if 
deemed appropriate by the principal investigator). Alternatively, a calculation using historical 
data is acceptable if image is within 6 months prior to screening. An x-ray may be repeated at 
the discretion of the Investigator. This will not be performed in adults (Cohorts 4 & 5). 
3.1.2.2. 
Visit 2 (Day 1) 
Visit 2 will be conducted as an outpatient visit during which a supervised first dose of tildacerfont will be 
administered after completion of a morning meal. The following activities will also be performed during 
the visit: 
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x 
Re-confirm participant meets inclusion/exclusion criteria 
x 
Review concomitant medications for any changes 
x 
Pregnancy test for FOCP (urine) 
x 
For Cohorts 1, 2, 4, 5, 6, 7, 8, and 9 (and 1aif indicated), serial blood samples will be collected at 
3 timepoints: pre-dose (prior to GC dosing and tildacerfont dosing), 0.5 to 1.5 hours post-GC and 
tildacerfont dose, and 3 to 5 hours post-GC and tildacerfont dose. After the pre-dose sample, 
participants will receive a meal and take their morning GC dose and study drug. Fasting is not 
required. Blood samples will be used to assess tildacerfont concentrations and to compare to 
the PBPK model, as well as PD markers including ACTH, 17-OHP, A4, testosterone, and 11KT. 
o Note: Cohorts 1 and 2 (and 1a if indicated) will receive study drug in the mornings for the 
first 14 days, so they will continue to take study drug at home with a morning meal until Day 
14/Visit 3. 
x 
For Cohorts 3 only one pre-dose sample will be drawn, after which participants will receive a 
meal and their morning GC dose and study drug. They should be observed for approximately 1 
hour after receiving study drug.  
o Note: Cohort 3 will only receive the first dose of study drug in the morning to allow clinical 
observation. They will switch to home dosing with an evening meal on Day 2. 
x 
Vital signs: blood pressure, pulse rate, body temperature, respiration rate, and weight (pre-
dose)  
x 
Physical exam (full) 
x 
Safety labs (pre-dose, see Appendix 1 and Appendix 3)  
x 
Dispense study drug (12-week or 4-week supply, depending on cohort) 
x 
Assess for AEs 
3.1.2.3. 
Visit 3 (Week 2; Day 14 ±3 days) 
Visit 3 will be conducted as an outpatient visit. Cohorts 1, 2, 4, 5, 6, 7, 8, and 9 (and 1a if indicated) will 
receive study drug and morning GC dose after completion of a morning meal. Cohort 3 will have 
received study drug the evening prior and will not require supervised dosing or a meal. Note: Cohort 1, 
2, 4, 5, 6, 7,8 and 9 (and 1a, if indicated) participants will need to bring study drug to the visit for in-clinic 
dosing to collect tildacerfont concentrations. The following activities will also be performed during the 
visit: 
x 
Review concomitant medications for any changes 
x 
Pregnancy test for FOCP (urine) 
x 
Safety labs (predose; see Appendix 1 and Appendix 3) 
x 
For Cohorts 1, 2, 4, 5, 6, 7, 8, and 9 (and 1a, if indicated), serial blood samples will be collected 
at 3 timepoints: pre-dose (prior to GC dosing and tildacerfont dosing), 0.5 to 1.5 hours post-GC 
and tildacerfont dose, and 3 to 5 hours post-GC and tildacerfont dose. After the pre-dose 
sample, participants will receive a meal and take their morning GC dose and study drug. Fasting 
is not required. Blood samples will be used to assess tildacerfont concentrations and to compare 
to the PBPK model, as well as PD markers, including ACTH, 17-OHP, A4, testosterone, and 11KT. 
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o Note: Cohorts 1 and 2 (and 1a if indicated) will switch to evening dosing with a meal at 
home on Day 15. 
x 
For Cohorts 3, only one pre-dose sample will be drawn, after which participants will receive their 
morning GC dose and tildacerfont dose. Fasting is not required. Blood samples will be used to 
assess tildacerfont concentrations as well as PD markers including ACTH, 17-OHP, A4, 
testosterone, and 11KT. 
x 
Cortisol 
x 
Urinalysis (pre-dose) 
x 
Vital signs: blood pressure, pulse rate, body temperature, respiration rate, and weight (pre-
dose) 
x 
Physical exam (abbreviated/directed) 
x 
12-lead ECG (pre-dose) 
x 
Suicidality Questionnaire- C-SSRS since last visit (participants aged ш6 years only)  
x 
Depression and Anxiety Questionnaires (PROMIS or SWYC depending on age of participant) 
x 
Study drug accountability 
x 
Assess for AEs 
3.1.2.4. 
Visit 4 (Week 4 ±3 days) (EOT for Cohorts 4-9) 
Visit 4 will be conducted as an outpatient visit. The following activities will be conducted: 
x 
Review concomitant medications for any changes 
x 
Pregnancy test for FOCP (urine) 
x 
Safety labs (see Appendix 1 and Appendix 3) 
x 
Pharmacodynamics (ACTH, 17-OHP, A4, testosterone, and 11KT) drawn prior to GC dosing at 
approximately 8 AM (±1 hour). Fasting is not required. 
x 
Cortisol 
x 
Tildacerfont concentration (single sample) drawn prior to GC dosing at approximately 8 AM (±1 
hour). Fasting is not required. 
x 
GC dosing adjustments to be determined after A4 value is measured. Pre-GC A4 is drawn at visit, 
and once results are received Investigator or designee will call participant and advise regarding 
any GC dose change. This process applies to all Cohort 1-3 participants and any Cohort 4-9 
participants who continue treatment in the extension period.   
x 
Vital signs: blood pressure, pulse rate, body temperature, respiration rate, and weight 
x 
Physical exam (abbreviated/directed) 
x 
Suicidality Questionnaire- C-SSRS since last visit (participants aged ш6 years only)  
x 
Depression and Anxiety Questionnaires (PROMIS or SWYC depending on age of participant) 
x 
Study drug accountability 
x 
Assess for AEs 
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x 
Weight-based tildacerfont dose adjustment, if indicated 
x 
For Cohort 4-9 participants, offer continued treatment in extension at Investigator’s discretion, 
re-consent if applicable. 
3.1.2.5. 
Visit 5 (Week 8 ±3 days) (Cohorts 1-3 only) 
Visit 5 will be conducted as an outpatient visit. The following activities will be performed: 
x 
Review concomitant medications for any changes 
x 
Pregnancy test for FOCP (urine) 
x 
Safety labs (see Appendix 1) 
x 
Pharmacodynamics (ACTH, 17-OHP, A4, testosterone, and 11KT) drawn prior to GC dosing at 
approximately 8 AM (±1 hour). Fasting is not required. 
x 
Cortisol 
x 
Tildacerfont concentration (single sample) drawn prior to GC dosing at approximately 8 AM (±1 
hour). Fasting is not required. 
x 
GC dosing adjustments to be determined after A4 value is resulted 
x 
Vital Signs: blood pressure, pulse rate, body temperature, respiration rate, and weight 
x 
Physical exam (abbreviated/directed) 
x 
Suicidality Questionnaire- C-SSRS since last visit (participants aged 6- to 17-years only)  
x 
Depression and Anxiety Questionnaires (PROMIS or SWYC depending on age of participant) 
x 
Study drug accountability 
x 
Assess for AEs 
3.1.2.6. 
Visit 6 (EOT for Cohorts 1-3) (Week 12 ±3 days) 
Visit 6 will be conducted as an outpatient visit. The following activities will be performed: 
x 
Review concomitant medications for any changes 
x 
Pregnancy test for FOCP (urine) 
x 
Safety labs (see Appendix 1) 
x 
Pharmacodynamics (ACTH, 17-OHP, A4, testosterone, and 11KT) drawn prior to GC dosing at 
approximately 8 AM (±1 hour). Fasting is not required. 
x 
Cortisol 
x 
Tildacerfont concentration (single sample) drawn prior to GC dosing at approximately 8 AM (±1 
hour). Fasting is not required. 
x 
GC dosing adjustments (for Cohort 1-3 patients who are continuing in the EP) to be determined 
after A4 value is resulted 
x 
Urinalysis 
x 
Vital signs: blood pressure, pulse rate, body temperature, respiration rate, and weight 
x 
Physical exam (full) 
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x 
12-lead ECG 
x 
Suicidality Questionnaire- C-SSRS since last visit (participants aged 6- to 17-years only)  
x 
Depression and Anxiety Questionnaires (PROMIS or SWYC depending on age of participant) 
x 
Study drug accountability 
x 
Assess for AEs 
3.1.2.7. 
Safety Follow-up Visit Telephone Call (30 days after last dose ±7 days) 
Approximately 30 days after the last dose of study drug (post the 12- or 4-week treatment period, 
depending on cohort, or post the extension), participants will have a final follow-up visit conducted by 
telephone. Concomitant medications and AEs will be reviewed. If any ongoing safety issues are 
identified, the participant may be asked to visit the clinic for additional tests, labs, or assessments.   
3.1.2.8. 
Early Termination Visit 
Some study participants may need to end their study participation before completing all of the visits. 
Participants who end their participation before completing the study will be scheduled for an Early 
Termination Visit. The following activities will be performed at the clinic: 
x 
Review concomitant medications for any changes 
x 
Pregnancy test for FOCP (urine) 
x 
Safety labs (see Appendix 1 and Appendix 3) 
x 
Pharmacodynamics (ACTH, 17-OHP, A4, testosterone, and 11KT) drawn prior to GC dosing at 
approximately 8 AM (±1 hour). Fasting is not required. 
x 
Tildacerfont concentration (single sample) drawn prior to GC dosing at approximately 8 AM (±1 
hour). Fasting is not required. 
x 
Urinalysis 
x 
Vital signs: blood pressure, pulse rate, body temperature, respiration rate, and weight 
x 
Physical exam (full) 
x 
12-lead ECG 
x 
Suicidality Questionnaire- C-SSRS since last visit (participants aged ш6 years only)  
x 
Depression and Anxiety Questionnaires (PROMIS or SWYC depending on age of participant) 
x 
Study drug accountability 
x 
Assess for AEs 
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3.1.2.9. 
End of Study 
A participant is considered to have completed the main study treatment period if they completed Visit 6 
(Week 12) or Visit 4 (Week 4), depending on cohort. A participant is considered to have completed the 
study if the participant has completed the Follow-up Visit. The end of the study is defined as the date of 
the last Follow-up Visit of the last participant in the study.  
3.1.3. 
Extension Period 
Participants who complete the 12- or 4-week treatment period, depending on cohort, may be eligible to 
continue dosing to complete 2 years on treatment in an extension study. Participants will sign a separate 
informed consent form at Week 12 or Week 4. Pending DMC review, participants in Cohorts 1 and 1a (if 
indicated) will receive the adult equivalent dose of 200 mg QD during the extension (i.e., Cohort 1 
participants will immediately switch to 200 mg equivalent if the DMC has already recommended this 
dose for Cohort 2, or participants may enter the extension period on 50 mg equivalent and increase to 
200 mg equivalent after such a recommendation is made). If a Cohort 1-3 participant is to dose escalate 
to the 200 mg equivalent, they may do so at the next scheduled visit or come to the clinic for an 
unscheduled visit and pick up their new supply of study drug. Participants will receive a follow-up phone 
call 2 weeks after dose escalation to check for AEs.  
Further tildacerfont dose adjustments may occur during the extension on a case-by-case basis at the 
discretion of the Investigator with Sponsor approval. Any extension participant may receive the highest 
dose recommended by the DMC for their age group. Dose changes (increase or decrease) may occur at a 
scheduled visit, an unscheduled visit, or via a phone visit, but any dose escalation > 200mg QD will be 
followed by safety labs (link to list) within 2-4 weeks of the change. Once all participants are in the 
extension period, safety- data will be reviewed every 6 months by the DMC. Weight-based dose 
adjustments may be made at any extension visit, with no follow-up labs required. 
For Cohorts 1-3, the first visit of the extension will be Week 12. For Cohorts 4-9, Week 4 will be the first 
extension visit, followed by extension clinic visits at Weeks 8 and 12 (±2 weeks). Starting at Week 12, all 
participants will attend clinic visits every 12 weeks (±2 weeks).  
Approximately a 12-week supply of study drug, as appropriate, will be dispensed at each visit. 
Approximately 30 days after the last dose of study drug, participants will have a final follow-up visit 
conducted by telephone. Concomitant medications and AEs will be reviewed. If any ongoing safety 
issues are identified, the participant may be asked to visit the clinic for additional tests, labs, or 
assessments.   
The extension study visits will include the following: 
x 
Review concomitant medications for any changes 
x 
Physical exam (abbreviated/directed) 
x 
Vital signs: blood pressure, pulse rate, body temperature, respiration rate, and weight 
x 
Safety labs (see Appendix 2 and Appendix 4) 
x 
Pregnancy test for FOCP (urine) 
x 
Urinalysis (Weeks 48 and 96 only) 
x 
Pharmacodynamics (ACTH, 17-OHP, A4, testosterone, and 11KT) drawn prior to GC dosing at 
approximately 8 AM (±1 hour). Fasting is not required. 
x 
Tildacerfont concentration (single sample) 
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x 
Study drug accountability 
x 
Suicidality Questionnaire- C-SSRS since last visit (participants aged ш6 years only)  
x 
Depression and Anxiety Questionnaires (PROMIS or SWYC depending on age of participant) 
x 
GC dosing adjustments 
x 
Assess for AEs 
x 
Bone age and predicted adult height calculated from X-ray image of left hand and wrist (every 6 
months if deemed appropriate by Investigator, see Appendix 2 and Appendix 4). 
x 
Tildacerfont dose adjustment as needed (based on recommendation of investigator or due to 
weight-based dosing changes) 
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4. 
STUDY POPULATION 
4.1. 
Eligibility Criteria  
4.1.1. 
Inclusion Criteria  
A participant must meet all of the following criteria to be eligible for this study: 
1. Male and female participants aged 2- to 10-years (Cohorts 3, 7, and 9), 11- to -17 years (Cohorts 
1, 1a, 2, 6, and 8Ϳ͕ĂŶĚшϭϴǇĞĂƌƐ;ŽŚŽƌƚƐϰĂŶĚϱͿ at Screening. 
2. For participants aged 2 to 5 years, a minimum weight at Screening of 11 kg.  
3. Has a known childhood diagnosis of classic CAH due to 21-hydroxylase deficiency (21-OHD) 
based on genetic mutation in CYP21A2 and/or documented (at any time) elevated 17-OHP and 
currently treated with hydrocortisone (HC), HC acetate, prednisone, prednisolone, 
methylprednisolone (or a combination of these). Other types of CAH may be allowed with 
Sponsor approval. 
4. For participants in Cohorts 4-9, 1.2X ULN < A4 < 4X ULN. A4 values outside of this range may be 
allowed with Medical Monitor (MM) approval. 
5. A ƐƚĂďůĞĚŽƐĞŽĨ'ƌĞƉůĂĐĞŵĞŶƚĨŽƌшϭŵŽŶƚŚďĞĨŽƌĞScreening without evidence of 
non-adherence (as assessed by Investigator). Weight-based dose adjustments or stress dosing in 
the month prior to Screening are not exclusionary but should be discussed with the MM. 
6. For participantƐŽŶŵŝŶĞƌĂůŽĐŽƌƚŝĐŽŝĚƌĞƉůĂĐĞŵĞŶƚ͕ĂƐƚĂďůĞĚŽƐĞĨŽƌшϭŵŽŶƚŚƉƌŝŽƌƚŽ
Screening. 
7. For participants on gonadotropin hormone-releasing hormone (GnRH) analogues, a stable dose 
initiated ш 3 months prior to screening.   
8. For participants on aromatase inhibitors, a stable dose for ш 3 months prior to screening.   
9. If sexually active and capable of reproduction, agrees to follow contraception guidelines (Section 
4.2.3). 
10. Have provided written informed consent or assent, and/or parent/legal guardian permission, as 
applicable, prior to undergoing any study procedure, including Screening procedures. The 
participant and/or parent/legal guardian must be able to read and understand all the study 
procedures.  
4.1.2. 
Exclusion Criteria  
A participant will not be eligible for this study if he/she meets any of the following criteria: 
1. CAH not due to 21-OHD. 
2. History of allergy or hypersensitivity to tildacerfont or other CRF1 receptor antagonist. 
3. History of bilateral adrenalectomy or hypopituitarism. 
4. Current treatment with dexamethasone. Participants may be transitioned off dexamethasone 
prior to Screening at the Investigator’s discretion.  
5. A clinically significant unstable medical condition, medically significant illness, or chronic disease 
(other than CAH) within 30 days, including but not limited to: 
a. Malignancy or <3 years of remission, except successfully treated localized skin cancer 
b. Estimated glomerular filtration rate (eGFR) of <45 mL/min/1.73 m2 (per the creatinine-based 
Schwartz equation) 
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c. Current or history of liver disease (with the exception of Gilbert’s syndrome). 
Resolved/cured viral hepatitis may be allowed with MM approval 
d. History of alcohol or substance abuse within the last year, or otherwise that would likely 
prevent the participant from reliably or safely participating in the study, per Investigator 
judgement 
e. HIV at Screening 
f. Any other condition that would impact participant safety or confound interpretation of 
study results, in the opinion of the Investigator or MM. 
6. Psychiatric conditions, including but not limited to major depression, bipolar disorder, 
schizophrenia, or schizoaffective disorders that are not effectively controlled on medication and 
may have an adverse impact on study compliance. Exclusionary symptoms include 
hallucinations, delusions, and psychosis. Baseline values for depression and anxiety 
questionnaires are not exclusionary but may inform exclusion of a participant based on 
Exclusion Criterion 5. 
7. Clinically significant abnormal clinical laboratory or ECG results during Screening. Abnormal 
results requiring review and discussion with the MM to discern eligibility include, but are not 
limited to: 
a. Any clinically meaningful abnormal ECG results, including QTcF >450 ms (males) or >460 ms 
(females) 
b. Alanine aminotransferase (ALT) >2x upper limit of normal (ULN) 
c. Total bilirubin >1.5x ULN (except if due to Gilbert’s syndrome). 
8. Females who are pregnant or nursing. 
9. Use of any other investigational drug (other than tildacerfont) or device within 30 days or 5 half-
lives (whichever is longer) prior to Screening through the end of the study (EOS). Prior exposure 
to tildacerfont is allowed, but tildacerfont should be discontinued for at least 2 weeks prior to 
randomization. The screening window may serve as the washout period. 
10. Use of the following drugs from 30 days or 5 half-lives (whichever is longer) before Screening 
through the EOS (see Appendix 3): 
a. Rosiglitazone, testosterone, growth hormone, or any other medication or supplement that 
could impact participant safety or confound interpretation of study results 
b. Moderate to strong inhibitors and/or inducers of CYP3A4 
c. Sensitive substrates or narrow-therapeutic-range substrates of CYP3A4 (except hormonal 
contraception containing <20 mcg ethinyl estradiol) 
d. Sensitive substrates or narrow-therapeutic-range substrates of BCRP (except those that can 
be administered QD in the morning, separated by approximately 10 hours from evening 
administration of study drug). 
11. Donation or receipt of blood from 90 days before Screening through the EOS; donation or 
receipt of platelets, white blood cells, or plasma from 30 days before Screening through the 
EOS. 
12. Any known or anticipated swallowing difficulty or dysphagia during Screening or the duration of 
the study. 
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4.2. 
Lifestyle Considerations 
4.2.1. 
Meals and Dietary Restrictions 
Study drug can be consumed whole or crushed and sprinkled on food. For administration at home, study 
drug should be taken with food. Study drug may be consumed up to 30 minutes after food, if necessary. 
If a participant has not consumed study drug within 30 minutes after food, the participant should 
consume study drug with a snack. 
Participants will be advised to refrain from consumption of grapefruit, grapefruit juice, or any fruits that 
are known to be strong CYP3A4 inhibitors (e.g., pomegranate) from 1 day before the first dose of study 
drug until after the final dose. 
4.2.2. 
Activity 
Participants must 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. 
4.2.3. 
Contraception Guidelines 
4.2.3.1. 
Contraception Guidelines for Male Participants 
Males capable of reproduction enrolling in this study must meet ONE of the following contraceptive 
criteria from Screening until 90 days after the last dose of study drug: 
1. Is sexually abstinent from penile-vaginal intercourse as his usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agrees to remain abstinent from Screening 
until 90 days after the last dose of study drug. 
2. Agrees to use a male condom AND female partner uses/has in place one of the following highly 
effective contraceptive methods from Screening until 90 days after the last dose of study drug: 
a. Combined hormonal contraception (containing estrogen and progesterone) associated with 
inhibition of ovulation: oral, intravaginal, or transdermal 
b. Progesterone-only hormonal contraception associated with inhibition of ovulation: oral, 
injectable, or implantable 
c. Intrauterine device (IUD) 
d. Intrauterine system (IUS) 
e. Bilateral tubal occlusion. 
4.2.3.2. 
Contraception Guidelines for Female Participants 
Females of childbearing potential enrolling in this study must meet ONE of the following contraceptive 
criteria from Screening until 30 days after the last dose of study drug: 
1. Is sexually abstinent from penile-vaginal intercourse as her usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agrees to remain abstinent from Screening 
until 30 days after the last dose of study drug. 
2. Must have a negative serum pregnancy test at Screening and negative urine pregnancy tests at 
all protocol-specified timepoints. Agrees to use one of the following highly effective 
contraceptive methods, which must be in place from at least 1 month before Screening until 30 
days after the last dose of study drug: 
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a. Combined hormonal contraception (containing estrogen and progesterone) associated with 
inhibition of ovulation: oral, intravaginal, or transdermal. Any hormonal contraception 
containing ethinyl estradiol must contain <20 mcg ethinyl estradiol. 
b. Progesterone-only hormonal contraception associated with inhibition of ovulation: oral, 
injectable, or implantable 
c. IUD 
d. IUS. 
4.3. 
Screen Failures 
Screen failures are defined as participants who consent to participate but are not subsequently enrolled 
in a study cohort. Minimal information, including demography, screen failure details, and eligibility 
criteria is required to ensure transparent reporting of screen failures to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries from 
regulatory authorities.  
Individuals who do not meet the following criteria for participation in the study may be rescreened 
according to the following guideline (Note: The Investigator will first consult with the MM regarding 
such individuals): 
1. Individuals on incompatible or excluded concomitant medications may be rescreened after an 
appropriate washout period (e.g., 30 days or 5 half-lives, whichever is longer).  
2. Individuals who have an exclusionary laboratory value during the Screening Period may be 
retested before the start of the Treatment Period if the Investigator believes that the prior 
laboratory value is not consistent with the individual’s overall clinical picture.  
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5. 
STUDY TREATMENT 
Details about the physical, chemical, and pharmaceutical properties of tildacerfont are provided in the 
IB. 
5.1. 
Treatment Administration 
Participants will be treated with oral tildacerfont QD for 12 weeks (Cohorts 1 to 3) or BID for 4 weeks 
(Cohorts 4 to 9). 
Pediatric age and weight-based tildacerfont dose levels are defined in Table 2. For each dose level, the 
amount of study drug that a participant will receive will depend on the participant’s age and body 
weight at Screening according to Table 2.  
Cohort 1 will be dosed at the equivalent of the adult 50 mg dose. Cohort 2 will receive the equivalent of 
the adult dose of 200 mg. If needed based on a safety concern in participants in Cohort 1, an interim 
dose Cohort 1a may be included. Cohort 3 will dose no higher than Cohort 2 (or Cohort 1a) but enroll up 
to approximately 10 participants in the younger age group of 2- to 10- years.  
Cohorts 4, 6, and 7 will dose at the 200 mg adult dose equivalent BID; and Cohort 5, 8 and 9 will dose at 
up to 400 mg adult dose equivalent twice per day. Based on DMC recommendation and Sponsor 
decision, taking into account all available safety and exposure data, Cohorts 5, 8 and 9 may be initiated 
at 300mg adult equivalent BID for approximately 5 participants each, and then another approximately 5 
may be enrolled in each at 400mg adult equivalent BID after DMC review. 
 
 
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Table 2. Tildacerfont Dose Levels and Pediatric Weight-Based Dosing 
Weight at Screening 
(kg) 
50 mg QD 
adult 
equivalent 
dose 
100 mg QD 
adult 
equivalent 
dose 
200 mg QD or 
BID adult 
equivalent dose 
300mg BID 
adult 
equivalent 
dose 
400 mg BID 
adult 
equivalent 
dose 
Age group: 2- to 5-years 
13 to 14.1 
25 
50 
75 
100 
150 
14.1 to <21.2 
25 
50 
75 
100 
150 
21.2 to <26.1 
25 
50 
100 
150 
200 
26.1 to <31.8 
25 
75 
100 
150 
200 
31.8 to <33.9 
25 
75 
150 
150 
300 
шϯϯ͘ϵ 
50 
100 
150 
150 
300 
Age group: 6- to 10-years 
20 to <23.7 
25 
50 
75 
100 
150 
23.7 to <29.9 
25 
50 
100 
150 
200 
29.9 to <35.5 
25 
75 
100 
150 
200 
35.5 to <39.2 
25 
75 
150 
200 
300 
39.2 to <47.5 
50 
100 
150 
200 
300 
шϰϳ͘ϱ 
50 
100 
200 
300 
400 
Age group: 11- to 17-years 
26 to <30.5 
25 
50 
75 
100 
150 
30.5 to <39.2 
25 
50 
100 
150 
200 
39.2 to <45.7 
25 
75 
100 
150 
200 
45.7 to <53.4 
25 
75 
150 
200 
300 
53.4 to <61 
50 
100 
150 
200 
300 
>61 
50 
100 
200 
300 
400 
Abbreviations: QD=once daily. 
5.2. 
Preparation/Handling/Storage/Accountability 
5.2.1. 
Acquisition and Accountability 
The Investigator is responsible for study drug receipt and accountability, reconciliation, and record 
maintenance. 
5.2.2. 
Formulation, Appearance, Packaging, and Labeling 
Tildacerfont will be provided in bottles of 25 mg, 50 mg and 200 mg tablets. Each bottle will be labeled 
with the product name, strength, lot number, recommended storage conditions, name of the Sponsor, 
and an Investigational Use Statement (e.g., “Caution: New Drug – Limited by Federal [USA] Law to 
Investigational Use”). Labeling will comply with all legal requirements and supply no information about 
individual participants.  
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5.2.3. 
Product Storage  
Study drug should be stored at room temperature. Study drug must be stored in a secure, 
environmentally controlled area that is monitored (manually or automatically) and accessible only to the 
Investigator and authorized study staff prior to dispensation to the participant. For additional 
information on product storage, please refer to the Pharmacy Manual. 
5.2.4. 
Preparation and Administration 
Participants will be taking between 1 and 6 tablets daily, depending on the dose and Cohort assignment. 
Participants can either swallow the tablet[s] whole or crush the tablet[s] and sprinkle on soft foods.  
Cohorts 1 to 3 will receive doses QD. The dose will be taken with the evening meal. The first 2 weeks in 
Cohorts 1, 1a, and 2 will require dosing with a morning meal. 
Cohorts 4-9 will receive BID dosing. Each dose should be taken with the morning and evening meal. 
If necessary, the study drug may be taken up to 30 minutes after completing the meal(s) at home. If a 
participant has not consumed study drug within 30 minutes following the meal(s), the participant should 
consume study drug with a snack. Study drug will be dispensed at Day 1 for the duration of the study. 
The Day 1 and Day 14 morning doses of tildacerfont will be administered in the clinic for Cohorts 1, 2, 4, 
5, 6, 7, 8, and 9 (and 1a, if indicated) and Day 1 only for Cohort 3. Any remaining study drug will be 
returned for accountability at Visit 6 (Week 12) for Cohorts 1 to 3 and Visit 4 (Week 4) for Cohorts 4 to 9, 
any early termination (ET) Visits, and during extension visits. The Investigator is responsible for ensuring 
that dosing is administered in compliance with the protocol. 
Preparation and administration instructions are included in the Pharmacy Manual. 
5.3. 
Concomitant Therapy 
Concomitant medication is any medication (including over-the-counter [OTC] medication, prescription 
medication, vaccines, vitamins, and supplements) that the participant is receiving at Screening or 
receives during the study. All concomitant medications must be recorded, along with: 
x 
Reason for use 
x 
Dates of administration, including start and end dates 
x 
Dosage information, including dose and frequency. 
All concomitant medications should be compared against the list of prohibited medications and the list 
of other medications of concern provided in Appendix 3. Participants/guardians should be instructed to 
contact the site immediately any time a new medication is required during the course of the study, 
including prescription and OTC medications, even those to be used for only a short period of time (e.g., 
antibiotics, cold and flu remedies, GI therapies, opioids or other pain relievers). The MM should be 
contacted if there are any questions regarding concomitant or prior therapy. 
5.3.1. 
Glucocorticoid Replacement Therapy 
5.3.1.1. 
General Procedures for Glucocorticoids 
Concomitant medications include GCs. Information to be collected at Screening about a participant’s 
current and prior GC therapy for the past month include the type(s) of GC, the regimen(s), and any GC 
stress dosing during the past month. 
To be eligible for this study, participants must be on a stable dose of GC replacement ĨŽƌш1 month 
before Screening without evidence of non-adherence (standard of care weight-based dose adjustments 
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and stress dosing are allowed). Participants with the salt-wasting form of CAH who take 
mineralocorticoids ŵƵƐƚĂůƐŽďĞŽŶĂƐƚĂďůĞĚŽƐĞŽĨŵŝŶĞƌĂůŽĐŽƌƚŝĐŽŝĚƌĞƉůĂĐĞŵĞŶƚĨŽƌшϭ month before 
Screening.  
On the mornings of all study visits, including the Screening Visit, participants should delay taking any 
morning dose of GC medication. On Day 1 all participants will receive a supervised tildacerfont dose in 
clinic and can take their morning GC dose at that time (after the pre-dose assessments). The same 
applies to Cohorts 1, 2, 4, 5, 6,7, 8, and 9 (and 1aif indicated) for Day 14. On all other visits, participants 
can take their morning GC dose after completion of the 8 AM (± 1 hour) assessments (PK, PD, and 
safety). On all other non-clinic visit days during the study, participants should take their GC medication 
at the usual time(s). Mineralocorticoid may be taken at any time of day, but its timing relative to 
laboratory assessments should be consistent throughout the study. 
5.3.1.2. 
A4-Based Glucocorticoid Dose Adjustment Algorithm 
In all cohorts, GC dose (frequency, distribution of doses, or total daily dose) may be adjusted based on 
A4 levels at Weeks 4 (all participants Cohorts 1 to 3; and participants in Cohorts 4 to 9 if continuing in 
the extension) and 8 (all participants in Cohorts 1 to 3), and Week 12 (participants in Cohorts 1 to 3 if 
continuing in the extension period). In the extension, GC dose may be adjusted based on A4 levels at 
each visit. See the Pharmacy Manual for further guidance on GC dose adjustments.  
The below A4-based algorithm will be used to guide changes to GC replacement therapy. Reductions 
below physiologic levels should be discussed with the MM.  
ϰ>ĞǀĞůч1x ULN  
x 
Reduce GC dose  
A4 Level 1.0 to ч1.5x ULN  
x 
Maintain GC dose  
A4 Level >1.5x ULN  
x 
Increase GC dose 
The Sponsor or designee may contact the site after Weeks 4, 8, and 12 (or any extension visit) to confirm 
GC dose adjustments (note: only Week 4 for Cohorts 4 to 9). The Investigator should contact the MM if 
the Investigator does not intend to follow A4-based GC dose adjustment algorithm at a visit. 
If a change in GC is warranted by the A4 algorithm, sites will contact participants by telephone after 
receipt of results (within approximately 2 weeks) after each applicable study visit. If no GC dose 
adjustment is warranted based on the A4 level, the site does not need to contact the participant.  
5.3.1.3. 
Stress Dosing of Glucocorticoids 
During times of clinically significant physical stress such as intercurrent illness with fever, surgical 
procedures, or significant trauma, participants may take extra GC consistent with the “sick day 
guidelines” for prevention of adrenal crisis shown in Table 3 (Bornstein 2016). The stress doses 
suggested in Table 3 are based on published, clinical best practice. However, management of stress 
dosing of GCs is ultimately at the discretion of the Investigator and/or inpatient managing physician (if 
hospitalized). The GCs received during a stress dosing period during the study will be captured as 
concomitant medications while the stress itself should be captured as an AE. 
If stress dosing occurs, the MM should be consulted on how this will affect the study visit schedule and 
continued participation in the study.  
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Table 3. Sick Day Guidelines for Stress Dosing of Glucocorticoids 
Condition 
Stress Dosing 
Home management of fever >38 °C 
(>100.4 °F) or illness requiring bed 
rest, when requiring antibiotics for an 
infection, or before undergoing a 
minor outpatient procedure (e.g., 
dental work) 
x Approximately double the routine oral GC dose (and give as HC) 
until recovery (usually 2 to 3 days) 
x For fever >39 °C (102.2°F) only, approximately triple the routine 
oral GC dose (and give as HC) until recovery (usually 2 to 3 days). 
Increase consumption of electrolyte-containing fluids and simple 
and complex carbohydrates (El-Maouche 2018), as tolerated. 
Unable to tolerate oral medication 
due to gastroenteritis or trauma 
x HC 50 mg/m2 IM (approximately 50 mg HC for school-age children, 
100 mg HC for adolescents) 
Minor to moderate surgical stress 
x HC 50 mg/m2 IM or double or triple the routine oral GC dose 
(usually 1 to 2 days) 
Major surgery with general 
anesthesia, trauma, or disease that 
requires intensive care 
x HC 50 mg/m2 IV, followed by HC 50 to 100 mg/m2 per day divided 
every 6 hours 
x Weight-appropriate continuous IV fluids with 5% dextrose and 
0.2% or 0.45% NaCl 
x Rapid tapering and switch to oral regimen depending on clinical 
state 
Acute adrenal crisis 
x Rapid bolus of normal saline (0.9%) 20 mL/kg. Can repeat up to a 
total of 60 mL/kg within 1 hour for shock 
x HC 50 to 100 mg/m2 bolus, followed by HC 50 to 100 mg/m2 per 
day divided every 6 hours 
x 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. Alternatively, 5 to 10 mL/kg of D10W for children <12 
years of age 
x Cardiac monitoring: rapid tapering and switch to oral regimen 
depending on clinical state 
Abbreviations: D10W=dextrose 10%; D25W=dextrose 25%; GC=glucocorticoid; HC=hydrocortisone; IM=intramuscular; 
IV=intravenous. 
To prevent hypoglycemia, the participant should drink small amounts of clear sugar-containing liquids 
frequently and/or consume carbohydrates if the participant is able, glucose monitoring should be 
considered, and IV sodium and glucose replacement may be required (Clayton 2002, Merke and 
Bornstein 2005, Han 2014).  
Day-to-day physical or psychological stressors, such as a short-term strenuous activity or school 
examinations, do not require increased GC dosing (Clayton 2002, Crown and Lightman 2005, Merke and 
Bornstein 2005). 
Participants will maintain stress dosing until symptoms subside (or according to the clinical judgment of 
the treating physician), then return to his/her usual GC regimen.   
5.3.2. 
Prohibited Concomitant Medications 
x 
Use of other investigational drugs and devices are prohibited during the study. 
x 
Rosiglitazone, testosterone, growth hormone, or any other medication or supplement that could 
impact participant safety or confound interpretation of study results are prohibited. 
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x 
Moderate to strong inhibitors and/or inducers of cytochrome P450 3A4 (CYP3A4); this includes 
consumption of grapefruit, grapefruit juice, or any foods that are known to be strong CYP3A4 
inhibitors from 1 day before the first dose of study drug until after the final dose. 
x 
Sensitive substrates or narrow-therapeutic-range substrates of CYP3A4 (e.g., dexamethasone and 
oxycodone)  
Note: This does NOT apply to ŚŽƌŵŽŶĂůĐŽŶƚƌĂĐĞƉƚŝŽŶĐŽŶƚĂŝŶŝŶŐч20 mcg ethinyl estradiol.  
x 
Sensitive substrates or narrow-therapeutic-range substrates of BCRP (except those that can be 
administered QD in the morning, separated by approximately 10 hours from evening administration 
of study drug) 
Appendix 5 provides a non-exhaustive list of medications, including many commonly used medications, 
which are prohibited because of their potential for metabolic interactions with tildacerfont. It is critical 
that each participant’s concomitant medications are carefully compared to the list in Appendix 5. 
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6. 
STUDY DRUG DISCONTINUATION AND PARTICIPANT WITHDRAWAL 
6.1. 
Study Drug Discontinuation 
Participants and/or their parent/guardian may voluntarily discontinue study drug at any time. The 
Investigator and/or Sponsor may also discontinue a participant’s study drug at any time. When feasible, 
Investigators should discuss any safety concerns with the MM as soon as possible to determine whether 
a participant should continue or discontinue study drug. Study drug will be discontinued in participants 
who experience individual treatment-stopping criteria described within this section. The Sponsor and 
Investigator will make efforts (when possible) to continue to collect data on participants who 
discontinue study drug. 
If study drug is discontinued, the Investigator will report the discontinuation to the MM, document the 
date and reason for study drug discontinuation on the appropriate electronic case report form (eCRF), 
schedule an ET visit for the participant (see the Schedule of Activities in Appendix 1, Appendix 2, 
Appendix 3, and Appendix 4) provide or arrange for appropriate follow-up, and document the course of 
the participant’s condition. 
Participants who prematurely discontinue study drug may be replaced at the discretion of the Sponsor 
to ensure adequate numbers of evaluable participants. 
6.1.1. 
Dose-Limiting Toxicity Stopping Criteria 
A DLT is defined as a Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or higher 
treatment-emergent adverse event (TEAE) considered at least possibly related to study drug. If a 
participant experiences a DLT, study drug will be discontinued. DLTs are clinically significant AEs (see 
Section 6.1.7). 
6.1.2. 
Safety Monitoring and Stopping Rules for Abnormal Liver Chemistry Measurements 
The following was adapted in accordance with the non-binding recommendations contained within the 
FDA Guidance for Industry Drug-Induced Liver Injury: Pre-marketing Clinical Evaluation, from the U.S. 
Department of Health and Human Services in July 2009. 
Special attention is paid to potential liver toxicity because tildacerfont was identified as a bile salt export 
pump (BSEP) inhibitor based on pre-clinical studies. Although in vitro BSEP inhibition does not reliably 
predict in vivo BSEP inhibition, Spruce believes that the pre-clinical findings warrant ongoing clinical 
monitoring (Jonathan 2018). Consequently, abnormal transaminase results will be assessed as follows. 
If stopping criteria are met at any time during the Treatment Period, study drug should be held until 
confirmatory testing of the transaminase, with additional measurements of total bilirubin, alkaline 
phosphatase (ALP), complete blood count (CBC) with differential and international normalized ratio 
(INR), is performed. Ideally, confirmatory testing would be performed within 48 hours of the initial 
receipt of the abnormal result. Confirmation testing through the central lab is preferred, but local 
laboratory testing may be necessary in certain circumstances. Confirmed cases meeting stopping criteria 
will be reported as an AESI and in cases where a possible Hy’s Law case is present, the event should also 
be reported as an SAE. Table 4 outlines specific stopping criteria for this study. 
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Table 4. Stopping Criteria and Increased Monitoring for Liver Chemistry Elevations 
Criteria 
Actions 
Participant has symptoms (new or worsening) 
believed to be related to liver injury or 
hypersensitivity1 
Hold study drug, measure liver chemistry 
(AST/ALT/ALP), CBC with differential, total 
bilirubin, total bile acids and INR as soon as 
possible and notify Sponsor. 
ALT 3x ULN 
Discontinue study drug and notify Sponsor. 
ALT 3x ULN 
AND total bilirubin 2x ULN  
(>35% direct bilirubin)2 
Discontinue study drug and notify Sponsor.  
Possible Hy’s Law case—report as an AESI and 
SAE. 
AND INR >1.5 
Discontinue study drug and notify Sponsor.  
Possible Hy’s Law case—report as an AESI and 
SAE. 
Total Bile Acids >5xULN 
Discontinue study drug and notify Sponsor. 
Abbreviations: AESI=adverse event of special interest; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate 
aminotransferase; CBC=Complete Blood Count, INR=international normalized ratio; SAE=serious adverse event; ULN=upper 
limit of normal. 
1 Symptoms related to liver injury include fatigue, nausea, vomiting, right upper quadrant pain or tenderness, and jaundice. 
Symptoms related to hypersensitivity include fever, rash, and eosinophilia. Due to similarities in symptoms with adrenal 
insufficiency, clinical judgement will be required to assess likelihood that symptoms may be hepatic in origin. 
2 If serum bilirubin fractionation is not immediately available, discontinue study drug if ALT 3x ULN and bilirubin 2x ULN and 
record the presence/absence of detectable urinary bilirubin on dipstick, which is indicative of direct bilirubin elevations 
suggesting liver injury. 
Investigation of the underlying cause of these transaminase elevations should include, but is not limited 
to: 
x 
A detailed history of symptoms as well as current and prior medical diseases, especially biliary 
tract disease, co-morbid conditions associated with development of nonalcoholic 
steatohepatitis, and cardiovascular disease that would compromise adequate blood supply to 
the liver 
x 
Examination of concomitant drug use (inclusive of OTC, herbal/dietary supplements, alcohol and 
recreational drug use) 
x 
Environmental and chemical exposures 
x 
Serology testing, as appropriate, based on laboratory findings, clinical exam and exposure 
history (i.e., viral hepatitis, Epstein Barr virus) 
x 
Additional investigations as appropriate such as gastrointestinal (GI)/hepatology consultation, 
imaging studies or other laboratory testing may be performed at the discretion of the 
Investigator, in consultation with the Sponsor MM. 
6.1.3. 
Laboratory Monitoring of Liver Function 
x 
Monitor liver enzymes, total bilirubin, total bile acids, and INR at least two times a week until 
transaminase levels are <3x ULN, total bile acids are <5x ULN, total bilirubin <2xULN, and INR 
чϭ͘ϱǆh>EŽƌůĞǀĞůƐƐƚĂďŝůŝǌĞ͕ĂŶĚƚŚĞparticipant is asymptomatic. 
x 
Obtain additional tests to evaluate liver function, such as fractionated bilirubin, as deemed 
appropriate. 
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x 
Thereafter, repeat testing will be performed as appropriate for the clinical circumstance until 
resolution or stability of transaminase values, total bilirubin, total bile acids and INR is achieved 
and any symptoms, if present, have abated. 
In the event that study drug is discontinued, the decision to rechallenge will be made on a case-by-case 
basis and will require written approval by the Sponsor. 
6.1.4. 
QT Stopping Criteria 
Study drug will be discontinued for a participant if either of the following criteria is met: 
x 
QTcF >500 msec OR uncorrected QT >600 msec 
x 
Change from Screening in QTcF of >60 msec 
One repeat ECG should be performed to confirm the accuracy and persistence of an initial result that 
fulfills the QT stopping criteria. 
6.1.5. 
Suicidality Stopping Criteria 
Tildacerfont is a central nervous system (CNS)-active drug. Some CNS-active drugs may be associated 
with an increased risk of suicidal ideation in certain populations. Although tildacerfont has not been 
shown to be associated with an increased risk of suicidal thinking or behavior in past clinical studies, 
participants will be monitored for such events during this study using the C-SSRS. Any participant who 
exhibits Suicidal Behavior or Suicidal Ideation in their responses on the C-SSRS, will have study drug 
immediately discontinued and should be evaluated by a psychiatrist. This safety finding will be 
considered an AESI if it is not an SAE (e.g., requiring hospitalization) (see Section 7.2.8). 
6.1.6. 
Depression or Anxiety Stopping Criteria 
Participants will be monitored for depression and anxiety during the study using the Patient Reported 
Outcomes Measurement Information System (PROMIS) Pediatric SF (Short Form) v2.0, the PROMIS 
Parent-Proxy SF (Short Form) v2.0, or the Survey of Well-Being of Young Children (SWYC). The 
questionnaire used will depend upon the participant’s age. Any participant who develops severe 
depression or anxiety (CTCAE Grade 3 or higher), as assessed by the Investigator, will require study drug 
discontinuation and appropriate follow-up. This will be considered an AESI and if seriousness criteria are 
met, also reported as an SAE (e.g., requiring hospitalization) (see Section 7.2.8). 
6.1.7. 
Clinically Significant Adverse Events 
Clinically significant AEs include but are not limited to SAEs, AEs leading to study drug 
discontinuation/study withdrawal (e.g., based on stopping criteria in Section 6.1), DLTs (Section 6.1.1), 
and AESIs (Section 7.2.8). The occurrence of any clinically significant AE will be reported to the DMC on 
an ongoing basis. 
The Investigator should consider study drug discontinuation and appropriate safety follow-up for a 
participant who experiences a potentially clinically significant AE. When feasible, the Investigator should 
contact the MM to discuss the participant’s clinical condition before discontinuing study drug.  
6.1.8. 
Dose Limiting Toxicity  
If 2 participants in a cohort meet individual stopping criteria, the entire cohort will be stopped or dose-
reduced. 
6.2. 
Participant Withdrawal from the Study 
Participants and/or their parent or guardian are free to withdraw from the study at any time upon 
request. If the participant/parent/guardian withdraws consent for disclosure of future information, the 
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Sponsor may retain and continue to use any data collected before the withdrawal of consent. The 
participant’s parent or guardian may request destruction of any samples taken and not tested, and the 
Investigator must document this in the site study records. 
Participants will be withdrawn from the study by the Investigator and/or Sponsor for either of the 
following: 
x 
Pregnancy 
x 
If any clinical AE, laboratory abnormality, or other medical condition or situation occurs such 
that continued participation in the study would not be in the best interest of the participant 
A participant may also be withdrawn from the study by the Investigator and/or Sponsor at any time for 
other safety, behavioral, compliance, or administrative reasons such as the following: 
x 
Significant protocol deviation or noncompliance with study procedures/restrictions 
x 
If the participant no longer meets eligibility criteria 
x 
Study termination by the Sponsor  
If possible, an ET visit (see Schedule of Activities in Appendix 1 and Appendix 2) should be conducted for 
any participant that received at least one dose of study drug before participant withdrawal. The 
Investigator must document the date and primary reason for the withdrawal on the appropriate eCRF. 
Participants who withdraw prematurely may be replaced at the discretion of the Sponsor to ensure 
adequate numbers of evaluable participants.  
6.3. 
Lost to Follow-up 
A participant will be considered lost to follow-up if the participant fails to attend scheduled visits and 
study personnel are unable to reach the participant. 
The following actions must be taken if a participant fails to attend a required study visit: 
x 
The site must attempt to contact the participant and/or their parents/guardians and reschedule 
the missed visit as soon as possible, counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether the participant wishes to and/or should 
continue in the study. 
x 
Before a participant is deemed lost to follow-up, the Investigator or designee must make every 
effort to regain contact with the participant and/or their parents/guardians, including, where 
possible, making 3 telephone calls to the participant and, if necessary, sending a certified letter 
to the participant’s last known mailing address (or local equivalent methods). Attempts to 
contact the participant should be documented in the participant’s medical record. 
x 
If the participant continues to be unreachable, the participant will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
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7. 
STUDY ASSESSMENTS AND PROCEDURES 
The timing of study assessments and procedures is provided in the Schedule of Activities in Appendix 1 
(Cohorts 1-3) and Appendix 3 (Cohorts 4-9). The Schedule of Activities for the extension period is 
provided in Appendix 2 (Cohorts 1-3) and Appendix 4 (Cohorts 4-9). 
7.1. 
Safety Assessments 
Safety assessments will include monitoring and recording all AEs (including SAEs, AEs leading to 
discontinuation/withdrawal, DLTs, and AESIs), physical examination, vital signs assessment, ECGs, and 
clinical laboratories. AE procedures are described in Section 7.2. 
7.1.1. 
Physical Examination 
A full physical examination should include assessments of the cardiovascular, respiratory, abdomen, 
neurological, and musculoskeletal systems; head, eyes, ears, neck, and throat; thyroid; skin; and 
extremities. The full physical examination may exclude rectal, genitourinary, and breast exams. 
An abbreviated/directed physical examination should include the following components: cardiovascular, 
respiratory, abdomen, and any other systems indicated by history or clinical judgment. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
7.1.2. 
Vital Signs 
Vital signs consist of systolic and diastolic blood pressure, pulse rate, respiration rate, and body 
temperature. The participant should ideally have an empty bladder. Vital signs will be measured as 
specified in the Schedule of Activities (Appendix 1 and Appendix 2) and as clinically indicated. 
7.1.3. 
Body Weight and Height 
Total body weight (actual body weight) will be measured at every visit using a calibrated balance. Height 
needs to be recorded at Screening only. Body mass index (BMI) and body surface area (BSA) will be 
calculated using these measurements. 
7.1.4. 
Electrocardiogram 
A 12-lead ECG will be obtained using an ECG machine that automatically calculates the heart rate, QRS, 
QT, and QTc intervals, preferably using QTcF. Tracings may be repeated as needed until the Investigator 
feels the results are reliable. Any ECG measurement assessed by the Investigator as a clinically 
significant abnormality should be recorded in the AE section of the eCRF and monitored until resolution. 
Refer to Section 6.1.4 for QT individual treatment-stopping criteria and any additional ECGs that may be 
necessary. 
7.1.5. 
Clinical Laboratories 
All visits will take place in the morning so that labs can be drawn prior to the first GC dose. Participants 
may arrive in time to have labs drawn at 7am (8am ± 1 hour). Fasting is not required for laboratory 
assessments. Clinical laboratory assessments include coagulation panel (Screening only), hematology, 
chemistry (including liver function tests AST, ALT, ALT, gamma-glutamyl transferase [GGT], total and 
direct bilirubin, and total bile acids), and thyroid panel. eGFR for Screening and throughout the trial will 
be calculated from blood creatinine measured as part of Screening clinical chemistry utilizing the 
creatinine-based Schwartz equation.  
A complete list of study-required clinical laboratory tests is provided in Appendix 6. 
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All study-required clinical laboratory tests should be conducted in accordance with the laboratory 
manual and will be performed by a central laboratory. If it is not feasible to draw labs in clinic, local labs 
may be used to monitor safety. Local A4 levels may be used for GC dose adjustment during the 
extension period with Sponsor’s approval. 
The Investigator must review the laboratory report, document the review, and record any clinically 
significant laboratory findings that occur during the study in the AE section of the eCRF. Laboratory 
reports must be filed with the source documents. Clinically significant laboratory findings are those that 
are not associated with the underlying disease, unless judged by the Investigator to be more severe than 
expected for the participant’s condition. 
All laboratory tests with values considered clinically significantly during the Treatment Period or within 
30 days after the last dose of study drug should be reported as AEs and repeated at least weekly until 
the values return to normal or baseline or are no longer considered clinically significant by the 
Investigator or MM. If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified, and the Sponsor notified. 
7.1.6. 
Psychiatric Evaluations 
Psychiatric evaluations may be conducted at any time during the study with changes in psychiatric status 
or if a concern arises; questionnaires may be administered on an as-needed basis. 
7.1.6.1. 
Columbia – Suicide Severity Rating Scale  
The C-SSRS will be used during the study to monitor suicidal ideation and behavior. The C-SSRS is a Food 
and Drug Administration (FDA)–endorsed questionnaire administered by trained study personnel to 
screen for suicidality risk and ideation in patients participating in trials of CNS-active compounds. The 
Baseline/Screening Version of the C-SSRS, which assesses both lifetime history and history from the last 
12 months, will be used at screening to determine participant eligibility. The Since Last Visit Version of 
the C-SSRS will be used at all subsequent visits specified. 
Refer to Section 6.1.5 for suicidality individual treatment-stopping criteria. 
7.1.6.2. 
Depression Assessment 
The PROMIS Pediatric SF v2.0 and the PROMIS Parent Proxy SF v2.0 will be used during the study to 
monitor participants for depression (Yount 2019). The PROMIS Pediatric SF v2.0 is self-administered and 
the PROMIS Parent Proxy SF v2.0 is completed by the parent of a child in the study, to assess for 
symptoms of depression. The assessment consists of 8 items using multiple choice response format and 
will be used at screening and all subsequent visits specified. 
Refer to Section 6.1.6 for depression and/or anxiety individual treatment-stopping criteria. 
7.1.6.3. 
Anxiety Assessment  
The PROMIS Pediatric Anxiety SF v2.0 and the PROMIS Parent Proxy Anxiety SF v2.0 will be used during 
the study to monitor participants for anxiety. The Pediatric version is self-administered and the PROMIS 
Parent Proxy SF v2.0 is completed by the parent of a child in the study to assess for symptoms of 
anxiety. The assessment consists of 8 items using a multiple-choice response format and will be used at 
screening and all subsequent visits specified. 
Refer to Section 6.1.6 for depression and/or anxiety individual treatment-stopping criteria. 
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7.1.6.4. 
Survey of Well-Being of Young Children 
The SWYC is a brief questionnaire (completed by parents) that assesses the following 3 categories of 
well-being in children 2 to 4 years of age: developmental, emotional/behavioral, and family. 
Refer to Section 6.1.6 for depression and/or anxiety individual treatment-stopping criteria. 
7.2. 
Adverse Events and Serious Adverse Events 
7.2.1. 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a participant participating in a clinical trial. Examples of 
AEs include but are not limited to: 
x 
Clinically significant abnormal test results 
x 
Clinically significant symptoms and signs 
x 
Changes in physical examination findings 
x 
Hypersensitivity 
x 
Progression/worsening of underlying disease 
A TEAE is defined as an AE that occurs during or after administration of the first dose of study drug until 
30 days after the final dose of study drug (Safety Follow-up Visit). For AEs that occur on the date of the 
first dose of study drug, the time of onset (before or after intake of study drug) must be specified. 
An abnormal test result should be reported as an AE if any of the following criteria are met: 
x 
It is associated with accompanying symptoms   
x 
It requires additional diagnostic testing or medical/surgical intervention 
x 
It leads to a change in study drug dosing or study drug discontinuation, significant additional 
concomitant drug treatment, or other therapy 
x 
It is considered to be an AE by the Investigator or Sponsor 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not constitute 
an AE. Any abnormal test result that is determined to be an error does not require reporting as an AE. 
Examples of events that do not meet the definition of an AE include but are not limited to: 
x 
Clinically significant abnormal test result or other abnormal safety assessment associated with 
the underlying disease, unless it is more severe than expected for the participant’s condition 
x 
The underlying disease and its signs and symptoms, unless they are more severe than expected 
for the participant’s condition 
x 
Medical and surgical procedures; the condition that leads to the procedure is the AE if it meets 
the definition of an AE. For example, an acute appendicitis that begins during the AE reporting 
period should be reported as the AE, and the resulting appendectomy should be recorded as 
treatment for the AE 
x 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected 
at the start of the study that do not worsen. 
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7.2.2. 
Definition of Serious Adverse Event 
An SAE or serious adverse drug reaction is any untoward medical occurrence at any dose that meets any 
of the following criteria: 
x 
Results in death 
x 
Is life threatening (immediate risk of death) 
x 
Requires inpatient hospitalization or prolongation of existing hospitalization 
x 
Results in persistent or significant disability/incapacity 
x 
Is a congenital anomaly/birth defect 
x 
Is an important medical event 
Medical and scientific judgment should be exercised in determining whether an event is an important 
medical event. An important medical event may not be immediately life threatening and/or result in 
death or hospitalization. However, if it is determined that the event may jeopardize the participant and 
may require intervention to prevent one of the other outcomes listed in the definition above, the 
important medical event should be reported as serious. Examples of such events include allergic 
bronchospasm that requires intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in hospitalization, or the development of drug dependency or drug abuse. 
If either the Sponsor or the Investigator believes that an event is serious, the event must be considered 
serious and evaluated by the Sponsor for expedited reporting. 
Hospitalization does not include rehabilitation, hospice, or skilled nursing facilities; respite care; nursing 
homes; observation in an Emergency Department of Acute Care center, or same-day surgeries (as 
outpatient/same day/ambulatory procedures). 
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical AE is not in 
itself an SAE. Examples include the following: 
x 
Admission for treatment of a pre-existing condition not associated with the development of a 
new AE or with a worsening of the pre-existing condition (e.g., for workup of persistent pre-
treatment lab abnormality) 
x 
Social admission (e.g., participant has no place to sleep) 
x 
Administrative admission (e.g., for yearly physical exam) 
x 
Protocol-specified admission during a clinical trial (e.g., for a procedure required by the trial 
protocol) 
x 
Optional admission not associated with a precipitating clinical AE (e.g., for elective cosmetic 
surgery) 
x 
Pre-planned treatments or surgical procedures should be noted in the baseline documentation 
for the entire protocol and/or for the individual participant. 
7.2.3. 
Classification of an Adverse Event 
The Investigator must record all AEs in the eCRF with information about: 
x 
Duration (start and end dates) 
x 
Severity (Section 7.2.3.1) 
x 
Relationship to study drug (Section 7.2.3.2) 
x 
Action(s) taken and, as relevant, the outcome (Section 7.2.3.3 and Section 7.2.3.4) 
x 
Seriousness (Section 7.2.2) 
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7.2.3.1. 
Severity 
The Investigator will assess the severity of each AE according to the National Cancer Institute CTCAE 
version 5.0 (CTCAE 2017), which is summarized in Table 5. 
Table 5. Severity of Adverse Events 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated. 
Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL (preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc.). 
Grade 3: Severe or medically significant but not immediately life threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL (bathing, dressing and 
undressing, feeding self, using the toilet, taking medications, and not bedridden). 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
Grade 5: Death related to AE. 
Abbreviations: ADL=activities of daily living; AE=adverse event. 
Note the distinction between the severity and the seriousness of an AE. A severe event is not necessarily 
a serious event. Severe is a category used for rating the intensity of an event, and both AEs and SAEs can 
be assessed as severe. For example, a headache may be severe (interferes significantly with participant’s 
usual function) but would not be classified as serious unless it met at least one of the criteria for an SAE 
listed in Section 7.2.2, such as resulting in hospitalization. 
If there is a change in the severity of an ongoing AE, it will be recorded as part of the same event, with 
the worst grade of severity for the entire event timeframe being recorded. 
7.2.3.2. 
Relationship to Study Drug 
The Investigator will assess the relationship of each AE to study drug according to the categories in 
Table 6. This assessment will serve to determine whether there exists a reasonable possibility that the 
study drug caused or contributed to the AE. 
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Table 6. Relatedness of Adverse Event to Study Drug 
UNRELATED: This category applies to those AEs that are clearly and incontrovertibly due to 
extraneous causes (disease, environment, etc.). 
UNLIKELY RELATED: This category applies to those AEs that are judged to be unrelated to 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 relation to administration of the study drug;  
(2) it could readily have been produced by the participant’s clinical state, environmental or toxic 
factors, or other therapies administered to the participant;  
(3) it does not follow a known pattern 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 connection to study drug 
administration cannot be ruled out with certainty. An AE may be considered possibly related if or 
when it meets two of the following criteria: 
(1) it follows a reasonable temporal sequence in relation to administration of study drug; 
(2) it could not readily have been produced by the participant’s clinical state, environmental or toxic 
factors, or other therapies administered to the participant; or  
(3) it follows a known pattern of response to the study drug. 
PROBABLY RELATED: This category applies to those AEs that the Investigator 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 relation to administration of the study drug;  
(2) it could not be reasonably explained by the known characteristics of the participant’s clinical state, 
environmental or toxic factors, or other therapies administered to the participant; 
(3) it disappears or decreases on cessation or reduction in dose of study drug. There are exceptions 
when an AE does not disappear upon discontinuation of the study drug yet drug-relatedness clearly 
exists (e.g., as in bone marrow depression, fixed drug eruptions, or tardive dyskinesia); or  
(4) it follows a known pattern of response to the study drug. 
DEFINITELY RELATED: This category applies to those AEs that the Investigator thinks are 
incontrovertibly related to the study drug. An AE may be assigned an attribution of definitely related if 
or when it meets all of the following criteria:  
(1) it follows a reasonable temporal sequence in relation to administration of the study drug; 
(2) it could not be reasonably explained by the known characteristics of the participant’s clinical state, 
environmental or toxic factors, or other therapies administered to the participant; 
(3) it disappears or decreases upon cessation or reduction in dose of study drug and recurs with re-
exposure to the study drug (if rechallenge occurs); and 
(4) it follows a known pattern of response to the study drug. 
Abbreviation: AE=adverse event. 
The Investigator will use clinical judgment and consult the IB to determine the relationship. Alternative 
causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well as the 
temporal relationship of the event to study drug administration will be considered and investigated. 
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. 
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7.2.3.3. 
Action Taken 
The action taken with the study drug in response to an AE must be classified as one of the following: 
x 
No change (study medication schedule maintained or no action taken) 
x 
Study medication interrupted 
x 
Study medication discontinued. 
AEs requiring therapy must be treated with recognized standards of medical care to protect the health 
and well-being of the participant. If medication is administered to treat the AE, this medication should 
be recorded. 
7.2.3.4. 
Outcome 
The outcome of each AE will be recorded as one of the categories in Table 7. 
Table 7. Outcome of Adverse Events 
Not recovered/not resolved: The event has not improved or recuperated. 
Recovered/resolved: The event has improved or recuperated. The participant 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 participant recuperated but retained pathological conditions 
resulting from the prior disease or injury. Record the AE stop date. The AE stop date will represent the 
date the AE stabilized with no change in event outcome anticipated. 
Unknown: There is an inability to access the participant/guardian or the participant’s records to 
determine the outcome (i.e., participant/guardian withdraws consent or is lost to follow-up). No AE 
stop date should be recorded. 
Fatal: The AE directly caused death. Record the date of death as the AE stop date. 
Abbreviation: AE=adverse event. 
7.2.4. 
Time Period and Frequency for Event Assessment and Follow-up 
AEs will be recorded from the time the informed consent form (ICF) is signed until the end of the follow-
up period. AEs will be assessed at each study visit, and participants should be encouraged to contact the 
study site to report AEs that occur between scheduled visits. AEs that occur in the time period between 
informed consent and the first dose of study drug of the Treatment Period should be recorded but will 
not be considered TEAEs.  
After the initial AE/SAE report, the Investigator is required to proactively follow each participant at 
subsequent visits/contacts. All AEs/SAEs will be followed until resolution, stabilization, the event has 
been shown to be unrelated to study drug, or the participant is lost to follow-up (as defined in 
Section 6.3). 
7.2.5. 
Adverse Event Reporting 
The Investigator is to report all AEs, whether volunteered by the participant, discovered through 
questioning, or directly detected, that occur in the time period specified in Section 7.2.4 and according 
to classifications described in Section 7.2.3.  
Non-serious AEs that do not require immediate reporting are to be reported on the AE eCRF. SAEs and 
AESIs will be reported on the SAE Report Form (see Section 7.2.6). 
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Clinically significant AEs such as SAEs, AEs leading to study drug discontinuation/study withdrawal (e.g., 
based on stopping criteria in Section 6.1), DLTs (Section 6.1.1), and AESIs (Section 7.2.8) that are 
considered at least possibly related to study drug will be reported to the DMC on an ongoing basis. 
7.2.6. 
Serious Adverse Event Reporting 
Throughout the study, the Investigator is to report all SAEs, regardless of suspected causality, to the 
Sponsor within 24 hours of learning of its occurrence using the SAE Report Form. AESIs (see 
Section 7.2.8) will also be reported in the electronic data capture (EDC) system and on the SAE Report 
Form and must be clearly differentiated from SAEs. Completion guidelines are provided in the 
Investigator Site File. The Investigator must assess and record the relationship of each event to study 
drug. Any SAE experienced after the follow-up period should be reported to the Sponsor only if the 
Investigator suspects a causal relationship to the study drug.  
Recurrent episodes, complications, or progression of the initial SAE, regardless of when they occur, must 
be reported as follow-up to the original episode within 24 hours of the Investigator receiving the follow-
up information. Follow-up information will also be captured in the EDC system and should describe 
whether the event resolved or continues, if and how it was treated, and whether the participant 
continued or withdrew from study participation. An SAE occurring at a different time interval or 
otherwise considered completely unrelated to a previously reported SAE should be reported separately 
as a new event. 
The Sponsor will ensure that all SUSARs, determined based on the Reference Safety Information in the 
most recent version of the IB at the time of the event, will be reported to the FDA) and to all 
Institutional Review Boards (IRBs)/Ethics Committees (ECs) overseeing the conduct of the study, in 
accordance with FDA 21 CFR 312.32.  
7.2.7. 
Reporting of Pregnancy 
Any participant who becomes pregnant during the study will have study drug discontinued immediately 
and be withdrawn from the study. All pregnancies in female participants or in the female partners of 
male participants must be reported to the Sponsor within 24 hours of the site learning of the pregnancy. 
Information about pregnancies will be recorded on the Pregnancy Report Form and any follow-up 
information will be forwarded to the Sponsor. 
For any female participant who becomes pregnant while participating in this study, the Investigator will 
collect information about the pregnancy and follow up with the participant to determine the outcome of 
the pregnancy and the status of mother and child. 
Male participants will be instructed to notify the site in the event that any female partner becomes 
pregnant. If any female partner of a male participant who received at least 1 dose of study drug 
becomes pregnant within 90 days of the male participant’s last dose of study drug, the Investigator will 
attempt to collect information about the pregnancy. The Investigator must obtain informed consent 
from the pregnant partner before collecting such information. The Investigator will also attempt to 
follow up with the female partner to determine the outcome of the pregnancy and the status of mother 
and child.  
Generally, follow-up will not be required for longer than 6 to 8 weeks beyond the estimated delivery 
date. Any termination of the pregnancy will be reported regardless of fetal status (presence or absence 
of anomalies) or indication for the procedure. 
Pregnancy itself is not regarded as an AE. However, a pregnancy complication is an AE, and congenital 
abnormalities/birth defects or spontaneous miscarriages should be reported as SAEs. Elective 
termination of a pregnancy is not considered an AE. While the Investigator is not obligated to actively 
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seek this information in former study participants, he or she may learn of such an SAE through 
spontaneous reporting. 
7.2.8. 
Adverse Events of Special Interest 
AESIs are those AEs (independent of seriousness criteria) that are of specific concern to this study and 
for which ongoing monitoring and communication with the Investigator and Sponsor may be 
appropriate. These events will be reported on the SAE Report Form, allowing for the collection of 
additional information, as warranted. The following may be considered AESIs for this study: 
x 
Significant liver chemistry changes that do not satisfy study drug stopping rules (see 
Section 6.1.2). Cases of Hy’s Law should be reported as an AESI and SAE. 
x 
Suicidality as indicated by responses on the C-SSRS (see Section 6.1.5 regarding study stopping 
criteria). 
x 
Depression or anxiety that is moderate or severe (CTCAE Grade 2 or higher), as assessed by the 
Investigator (see Section 6.1.6 regarding study drug stopping criteria for depression or anxiety). 
This will be reported as an AESI and if seriousness criteria are met, reported as an SAE.  
x 
Adverse events of adrenal insufficiency are considered AESIs and will be reported on a separate 
Adrenal Insufficiency Form. Additionally, symptoms of adrenal insufficiency will be reported as 
SAE if they necessitate parenteral GC administration by a health care professional and two of 
the following criteria occur or are met: hypotension (systolic blood pressure <90 mmHg); nausea 
or vomiting; severe fatigue; documented hyponatremia, hyperkalemia, or hypoglycemia. If 
hospitalization was required or the event of adrenal insufficiency is deemed to be an important 
medical event, life-threatening, or 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 the health care provider, 
emergency facility or hospital should be obtained as source documents to provide the 
following information:  
 
Was stress dosing employed prior to the adrenal insufficiency event? If yes, what were 
the GC dose and duration of dosing and the cause for stress dosing prior to seeking 
medical attention? 
 
What type, dose and route of parenteral GC was administered and the duration of 
administration? 
 
What concomitant medications were administered? 
 
What clinical laboratory results are available? 
 
What AEs occurred? 
 
What was the duration of stay if admitted to the hospital? 
 
What was deemed to be the inciting factor leading to adrenal crisis?  
For non-SAEs of adrenal insufficiency, all symptoms and findings on physical examination, vital sign 
collection and/or laboratory assessments leading to the diagnosis of adrenal insufficiency will be 
collected. 
Adverse events or other conditions that lead to GC stress dosing should not be reported as AEs of 
adrenal insufficiency since the stress dosing is done to prevent, not treat, adrenal insufficiency. If an AE, 
such as an infection, results in GC stress dosing, the AE should be captured in the Adverse Event CRF. 
The following additional information will be collected in the patient diary during episodes of GC stress 
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dosing: start and stop date, concomitant medications, cause for stress dosing (e.g., infection, strenuous 
exercise, emotional stress, pain, surgery) and concurrent AEs. Adverse events resulting in stress dosing 
will be reported on the Adverse Event CRF. 
7.3. 
Pharmacokinetic and Pharmacodynamic Assessments 
A summary of blood draws for assessment of tildacerfont concentration and PD is presented in Table 8.
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Table 8. Tildacerfont Concentration and PD Sampling Time Points 
Sample 
Day 1 
Week 2 
Week 4 
Week 8 
Week 12 
ET 
F/U 
EP  
(all visits) 
PD markers 
(ACTH, 17-
OHP, A4, 
testosterone, 
and 11KT) 
Cohorts 1, 
2, 4, 5, 6, & 
7 (8 & 9 if 
indicated) 
 
Pre-dose1 
0.5-1.5 hr 
post-dose 
3-5 hr post 
dose 
Cohort 3 
Single 
sample1 
Cohorts 1, 2, 
4, 5, 6, & 7 
(8 & 9 if 
indicated) 
 
Pre-dose1 
0.5-1.5 hr 
post-dose 
3-5 hr post 
dose 
Cohort 3 
Single 
sample1 
Cohorts 1, 2, 
4, 5, 6, & 7 
(8 & 9 if 
indicated) 
 
Single 
sample1 
 
Cohorts 1, 2, 
& 3 (1a if 
indicated) 
 
 
Single 
sample1 
 
Cohorts 1, 
2, & 3 (1a if 
indicated) 
 
 
Single 
sample1 
 
All 
Cohorts 
 
 
 
Single 
sample1 
 
X2 
All 
Participants 
 
 
 
Single 
sample1 
Tildacerfont 
concentrations 
Cohorts 1, 
2, 4, 5, 6, & 
7 (8 & 9 if 
indicated) 
Pre-dose1 
0.5-1.5 hr 
post-dose 
3-5 hr post 
dose 
Cohort 3 
Single 
sample1 
Cohorts 1, 2, 
4, 5, 6, & 7 
(8 & 9 if 
indicated) 
Pre-dose1 
0.5-1.5 hr 
post-dose 
3-5 hr post 
dose 
Cohort 3 
Single 
sample1 
Cohorts 1, 2, 
4, 5, 6, & 7 
(8 & 9 if 
indicated) 
Single 
sample1 
Cohorts 1, 2, 
& 3 (1a if 
indicated) 
 
Single 
sample1 
Cohorts 1, 
2, & 3 (1a if 
indicated) 
 
Single 
sample1 
All 
Cohorts 
 
 
Single 
sample1 
X2 
All 
Participants 
 
 
Single 
sample1 
Abbreviations: 11KT = 11-ketotestosterone, 17-OHP= 17-hydroxyprogesterone; A4 = androstenedione; 
ACTH=adrenocorticotropic hormone, corticotropin; F/U = follow-up; GC = glucocorticoid; EP= extension period; 
PD=pharmacodynamics. 
1 These samples will be collected at approximately 8 AM (± 1 hour) before participants take any morning dose of GC (except for 
Cohorts 4 to 9, where sample will be collected prior to the tildacerfont morning dose and GC dose) and do not require fasting. 
2 As needed based upon abnormalities in prior visits.  
Concentration of tildacerfont will be measured by a bioanalytical laboratory using validated methods. 
Detailed instructions for the collection and handling of biological samples will be provided separately in 
the Laboratory Manual. 
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8. 
STATISTICAL CONSIDERATIONS 
Statistical considerations are summarized here. A detailed description of statistical methods will be 
provided in the Statistical Analysis Plan (SAP).  
8.1. 
Sample Size Determination 
A sample size of up to approximately 70 participants (i.e., 15 adults, 30 children 11- to 17-years of age, 
and 25 children 2- to 10-years), will provide adequate data to assess the initial safety of tildacerfont in a 
pediatric and adult population and provide data to support the continued use of the PBPK model to 
determine pediatric dosing requirements in future studies. 
8.2. 
Populations for Analyses  
The Safety Population will include all participants who receive at least 1 dose of study drug and will be 
the primary analysis set for general and safety analyses. 
The PK Population will include all participants in the Safety Population with at least 1 post-dose sample 
above the limit of quantification.  
The PD Population will include all participants in the Safety Population with at least 1 evaluable post-
baseline PD assessment. 
8.3. 
Statistical Analyses 
8.3.1. 
General Considerations 
All individual data will be listed as measured. All statistical summaries and analyses will be performed 
using SAS software (SAS Institute Inc, Cary, North Carolina, USA). 
All continuous variables will be presented using an 8-point descriptive summary (n, mean, standard 
deviation, median, interquartile range [25th percentile, 75th percentile], minimum, and maximum) by 
dose, as available. Categorical variables will be summarized by frequency and by percentage of 
participants in corresponding categories. 
Any changes to the protocol-specified analyses will be pre-specified in the SAP before database lock. 
8.3.2. 
Demographics and Baseline Characteristics 
Listings and summaries will be provided for demographics (age, sex, ethnicity, and race) and baseline 
characteristics (weight, height, BMI, and BSA) for the Safety Population. 
Baseline biomarkers and GC regimen will be summarized for the Safety Population. 
8.3.3. 
Concomitant Medications 
Prescription, OTC, and alternative medication use will be listed.  
8.3.4. 
Safety Analyses 
The Safety Population will be used for all safety analyses. Safety data will be listed by participant and 
summarized by adult equivalent dose levels (50, 100, 200 mg QD; and 200 mg, possibly 300 and/or 
400 mg BID) using the frequency of event or descriptive statistical summaries, as appropriate. Listings 
and summary tables will be provided for AEs, clinical laboratory tests, vital signs, and ECG data. 
Urinalysis, psychiatric evaluations, concomitant medications, and physical examinations will be 
presented in listings only. 
A DMC will review accumulating safety information by cohort. Refer to Section 9.4.4 for information on 
the DMC. 
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8.3.4.1. 
Extent of Exposure 
Dosing information for individual participants will be listed and include nominal dose (mg) and dose 
adjusted for body weight (mg/kg). Using dosing data, estimates of exposure to tildacerfont will be 
summarized. Dose discontinuations and reasons for study drug discontinuation will be listed and 
summarized. 
8.3.4.2. 
Adverse Event Data 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). AE summaries will be 
presented by System Organ Class, Preferred Term, severity, and frequency and percentage of 
participants reporting each observed event.  
AEs that occur before the first dose of study drug of the Treatment Period will be distinguished from 
TEAEs (defined in Section 7.2.1). All AEs, AESIs and TEAEs will be listed by participant. The frequency of 
participants who experience TEAEs will be summarized overall and by cohort. TEAEs will also be 
summarized by relationship to study drug and severity. 
Listings will be provided for participants who experienced an SAE or discontinued study drug/withdrew 
from the study because of an AE. 
8.3.4.3. 
Clinical Laboratory Data 
Clinical laboratory test results will be listed by participant. Reference ranges provided by the laboratory 
for each parameter will be used to evaluate the clinical significance of laboratory test results. Values 
outside the relevant reference range will be flagged in the listings. Abnormal clinical laboratory test 
results will be listed in a separate listing. 
Laboratory data will be summarized in terms of observed values, changes from baseline, values relative 
to normal ranges, and changes from baseline relative to normal ranges. 
8.3.4.4. 
Vital Signs Data 
Vital signs data will be summarized within appropriately defined categories in terms of observed values 
(by time point), changes from baseline (by time point), and counts and percentages. 
8.3.4.5. 
Electrocardiogram Data 
The QTcF, PR interval, QT interval, QRS duration, and heart rate from standard digital ECGs will be 
summarized within appropriately defined categories in terms of observed values, changes from baseline, 
and counts and percentages. 
8.3.5. 
Pharmacokinetic Analyses 
Tildacerfont concentration data will be listed by participant. Validation and refinement of the PBPK 
model using concentration data will be described in a separate pharmacometrics analysis plan.   
8.3.6. 
Pharmacodynamic Analyses 
The PD Population will be used for all PD analyses.  
Change from baseline in PD biomarkers, ACTH, 17-OHP, A4, testosterone, and 11KT will be summarized 
descriptively using the 8-point summary as well as geometric mean ratios comparing baseline to post 
baseline, as appropriate. T will be summarized separately for males and females. 
Change from baseline in select PD ratios will also be summarized, A4/T (males only) and 11KT/T (males 
and females, separately). Other ratios may be identified in the statistical analysis plan.  
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The proportion of participants with a reduction in biomarkers at Weeks 4 (all cohorts) and 12 (Cohorts 1 
to 3 only) will be summarized descriptively, including by subgroup, baseline A4 чh>E͕ĂƐĞůŝŶĞϰ >ULN: 
x 
Any reduction 
x 
шϱϬйƌĞĚƵĐƚŝŽŶ 
x 
A4 чh>E  
Change from baseline in GC total daily dose at Week 12 and during the extension period will be 
summarized descriptively: 
x 
Absolute change (mg) 
x 
Absolute change adjusted for body surface area (mg/m2) 
x 
Percent change (%) 
x 
Proportion of participants with GC reduction 
x 
Proportion of participants with baseline dosing >3x daily who decrease frequency of 
administration чϯǆĚĂŝůǇ 
The proportion of participant ǁŝƚŚĂшϭŵŐͬŵ2 GC reduction or any reduction from baseline in A4 at 
Week 12 will be summarized descriptively.  
Changes in adrenal biomarkers and GC will be summarized in a similar manner for the extension period. 
8.3.7. 
Psychiatric Evaluation Analyses 
The psychiatric evaluation analysis will be conducted on the Safety Population. Assessments of 
suicidality, depression, and anxiety will be listed. 
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9. 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
9.1. 
Informed Consent 
For each study participant, written informed consent/assent must be obtained before the participant 
may be enrolled into the study and before any protocol-specified procedures may be conducted. In the 
case of pediatric participants (<18 years old) in this study, the participant’s legal guardian will sign and 
date the ICF (which will be witnessed, where required by law or regulation), and a pediatric participant 
who is capable will sign and date a separate assent document. Emancipated or mature minors may give 
autonomous consent, as permitted by institutional requirements and local laws. The ICF will also be 
signed and dated by the Investigator and/or designee. The process of obtaining informed 
consent/assent should be documented in the participant source documents. Each participant/guardian 
will be provided a copy of the signed and dated ICF/assent form. For participants who continue in the 
extension period, a separate ICF/assent form is required. 
As part of the informed consent/assent process, the Investigator or designee must explain to each 
participant/guardian the purpose and procedures of the study and the possible risks involved. 
Participants/guardians should be informed that they may withdraw from the study at any time. They 
should be informed that their data will be stored in a confidential manner, in accordance with local data 
protection laws. They should be informed that their records may be viewed by the Sponsor or its 
designee and by regulatory authorities. The ICF/assent form and any other materials provided to 
participants/guardians or investigative staff must use vocabulary and language that can be readily 
understood. 
The Investigator must use the most current IRB-approved ICF/assent form. Any changes to the proposed 
ICF/assent form suggested by the Investigator must be agreed to by the Sponsor before submission to 
the IRB, and a copy of the approved version must be provided to the Sponsor after IRB approval. 
9.2. 
Study Discontinuation and Closure 
Premature study termination may occur because of a regulatory authority decision, change in opinion of 
the IRB, drug safety problems, or Sponsor decision. In addition, the Sponsor retains the right to 
discontinue development of tildacerfont at any time. 
Premature study termination will occur if the benefit/risk profile becomes unfavorable because of a new 
risk or toxicity that makes the study unjustifiable and/or if new scientific evidence that could affect 
participant safety becomes available during the study (e.g., from other clinical trials). When AEs occur, 
the Sponsor will evaluate the severity, duration, frequency, and nature of the AEs relative to the existing 
safety profile of tildacerfont to determine whether there are any substantial changes in risk-benefit 
considerations. 
If this study is prematurely terminated or discontinued, the Sponsor will promptly notify the 
Investigator. After notification, the Investigator must contact all participating participants 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. 
9.3. 
Confidentiality and Privacy 
All information obtained during the conduct of this study will be regarded as confidential, and written 
permission from the Sponsor is required before disclosing any information related to this study. 
All processing of personal data at the site and by the Sponsor must be carried out in accordance with 
any legislation concerning the protection of personal data. The Investigator must ensure that the 
participant’s privacy is maintained. The Sponsor will assign each participant a unique identifier. Any 
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participant records or datasets that are transferred from the site to the Sponsor will contain this 
identifier only; participant names or any information that would make the participant identifiable will 
not be transferred. 
9.4. 
Key Roles and Study Governance 
9.4.1. 
Sponsor 
The Sponsor or its designee will provide protocol training to investigative staff as appropriate. Clinical 
monitors will conduct site visits as needed to ensure study procedures are conducted in accordance with 
the protocol, Good Clinical Practice (GCP), and all applicable regulatory requirements. Throughout the 
study, a Sponsor representative will be available to address any issues that may arise. 
A list of study contacts will be provided in a separate document. 
9.4.2. 
Investigators 
Before study start, Investigators are required to sign an Investigator Protocol Agreement Page 
confirming their agreement to conduct the study in accordance with the protocol. It is the responsibility 
of the Investigator to ensure that all investigative personnel are fully informed of all relevant aspects of 
the study, including detailed knowledge of and training in all procedures to be followed. 
9.4.3. 
Institutional Review Board 
The protocol and ICF/assent form must be reviewed and approved by a properly constituted IRB before 
study start. A signed and dated statement that the protocol and ICF/assent form have been approved by 
the IRB must be given to the Sponsor before study initiation. 
9.4.4. 
Data Monitoring Committee 
An independent DMC consisting of external experts not associated with this study will be established to 
monitor data on an ongoing basis to ensure the continuing safety of the participants enrolled in this 
study and to approve cohort progression.  
DMC responsibilities are further described in the DMC charter. 
9.5. 
Clinical Monitoring 
Before study initiation, at a site initiation visit or at an Investigator’s meeting, a Sponsor representative 
or designee will review the protocol and eCRFs with the Investigators and their staff. During the study, 
the field monitor will regularly check the completeness of participant records, the accuracy of entries on 
the eCRFs, adherence to the protocol and to GCP, the progress of enrollment, and that study drug is 
being stored, dispensed, and accounted for according to specifications. Key study personnel must be 
available to assist the field monitor during these visits. See Section 10.4 for information on monitoring 
visits in the context of coronavirus disease 2019 (COVID-19). 
The Investigator must give the monitor access to all relevant source documents to confirm their 
consistency with eCRF entries. The Sponsor’s monitoring standards require full verification for the 
presence of informed consent/assent, adherence to the inclusion/exclusion criteria, documentation of 
SAEs, and recording of data that will be used for all primary and safety variables. Additional checks of 
the consistency of the source data with the eCRFs are performed according to the study-specific 
monitoring plan. No information in source documents about the identity of participants will be 
disclosed. 
Refer to Section 9.7.1 for information on eCRFs and source documents. 
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9.6. 
Quality Assurance and Quality Control 
In addition to routine clinical monitoring by the Sponsor, the study may be evaluated by Sponsor 
internal auditors and government inspectors, who must be allowed access to case report forms, source 
documents, and other study files. Sponsor audit reports will be kept confidential. The Investigator must 
notify the Sponsor promptly of any inspections scheduled by regulatory authorities and promptly 
forward copies of inspection reports to the Sponsor. 
9.7. 
Data Handling and Record Keeping 
9.7.1. 
Data Collection and Management Responsibilities 
An eCRF must be completed for each enrolled participant. Completed original eCRFs are the sole 
property of the Sponsor and should not be made available in any form to third parties, except for 
authorized representatives of the Sponsor or appropriate regulatory authorities, without written 
permission from the Sponsor. It is the Investigator’s responsibility to ensure completion of and to review 
and approve all eCRFs. Electronic CRFs must be signed by the Investigator. These signatures serve to 
attest that the information contained on the eCRFs is true. At all times, the Investigator has final 
personal responsibility for the accuracy and authenticity of all clinical and laboratory data entered on 
the eCRFs. 
For each participant in the study, the Investigator must maintain source documents at the trial site 
consisting of the original assent form/ICF signed by the participant/guardian (a copy of which is given to 
the participant/guardian), the hospital/clinic or physician medical records/chart for the participant, case 
and visit notes, laboratory data, ECGs, and the results of any other tests or assessments. All information 
on eCRFs must be traceable to these source documents in the participant’s file. In some cases, certain 
items entered on the eCRF may not require a separate written record, and the eCRF itself may serve as 
the source document. Such items will be prospectively defined between the Sponsor and Investigator 
before study start. 
9.7.2. 
Study Records Retention 
To enable evaluations and/or audits from regulatory authorities or the Sponsor or its designees, the 
Investigator agrees to keep records that include the identity of all participants (sufficient information to 
link records [e.g., eCRFs and hospital records]), all original signed ICFs/assent forms, copies of all eCRFs, 
SAE forms, source documents, and treatment disposition. The records should be retained by the 
Investigator for as long as ICH, local regulations, or the Clinical Study Agreement dictates, whichever is 
longer. 
If the Investigator relocates, retires, or for any reason withdraws from the trial, the Sponsor should be 
prospectively notified, and the trial records must be transferred to an acceptable designee, such as 
another Investigator, another institution, or the Sponsor. The Investigator must obtain the Sponsor’s 
written permission before disposing of any records, even if retention requirements have been met. 
9.8. 
Protocol Deviations 
If a protocol deviation occurs that affects a participant’s safety, the Sponsor must be informed as soon 
as possible. 
If a protocol deviation is implemented to eliminate an immediate hazard before a protocol amendment 
can be submitted for IRB review and approval/favorable opinion (see Section 9.10), the deviation will be 
reported as soon as possible to 1) the IRB for review and approval/favorable opinion, 2) the Sponsor, 
and 3) regulatory authority(ies), if required by local regulations. Documentation of approval signed by 
the chairperson or designee of the IRB(s) must be sent to the Sponsor. 
Protocol deviations will be included in the Clinical Study Report. 
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9.9. 
Publication and Data Sharing Policy 
Any manuscripts for publication based on data from this study must be submitted to the Sponsor for 
review and comment before submission to a publisher. This requirement should not be construed as a 
means of restricting publication but is intended solely to ensure concurrence regarding data, 
evaluations, and conclusions and to provide an opportunity for the Sponsor to share with the 
Investigator any new or unpublished information of which the Investigator may be unaware. 
9.10. 
Amendments 
The study shall be conducted as described in this protocol. All revisions to the protocol must be 
discussed with and prepared by the Sponsor. The Investigator should not implement any change to the 
protocol without a prior protocol amendment that has been reviewed by and received documented 
approval/favorable opinion from the IRB, except where necessary to eliminate an immediate hazard(s) 
to study participants. Any significant protocol deviation must be documented (see Section 9.8). 
If a protocol amendment is an Administrative Letter, Investigators must inform their IRB(s). 
If a protocol amendment substantially alters the study design or increases the potential risk to the 
participant, 1) the consent/assent form must be revised and submitted to the IRB(s) for review and 
approval/favorable opinion, 2) the revised assent/consent form must be used to obtain 
re-assent/consent from participants currently enrolled in the study and their guardians if they are 
affected by the amendment, and 3) the revised assent/consent form must be used to obtain 
assent/consent from any new participants/guardians before enrollment. 
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10. 
RISK MITIGATION DURING THE CLINICAL TRIAL  
10.1. 
Risk/Benefit Assessment in the Context of COVID-19 or Other Obstacles 
In general, the CAH patient population possesses a higher-than-average risk of serious complications 
from any infection or febrile illness because such conditions can lead to adrenal crises in patients with 
CAH if they are not managed appropriately. The emergence of diseases such as COVID-19 increases the 
overall infection risk in affected communities, including patients with CAH who reside in those 
communities.  
Participation in a clinical trial provides participants with increased access to healthcare resources and 
reinforcement of appropriate practices during a time of increased infection risk. Study participants will 
have access to healthcare professionals on a more intensive schedule than in normal clinical practice for 
the management of CAH. The standard of care for a CAH patient with an infection or febrile illness is to 
increase the patient’s GC dose to accommodate the additional stress and prevent an adrenal crisis (see 
Section 5.3.1.3).  
10.2. 
Study Conduct in the Context of COVID-19 or Other Obstacles 
If a clinic visit is not possible because of COVID-19 restrictions, or other unforeseen obstacles, they will 
not be conducted. A telemedicine visit may be conducted as an alternative to an on-site clinic visit. Local 
labs may be used. A GC dose reduction based on the local A4 may be allowed with Sponsor approval.  
10.3. 
Participant Disposition in the Context of COVID-19 or Other Obstacles 
If a participant develops an active COVID-19 infection (whether confirmed or suspected), or another 
such disease during the course of the study, the Investigator will work with the participant/guardian and 
the MM to determine the best course of action, taking into consideration the AE and SAE guidelines in 
Section 7.2 and the individual stopping criteria for clinically significant AEs in Section 6.1.7. If study drug 
is discontinued or a participant is withdrawn from the study because of COVID-19 or another such 
disease, the reason for ET will be captured in the EDC system as such. 
10.4. 
Regulatory and Study Oversight Considerations in the Context of COVID-19 or Other 
Obstacles 
If planned onsite monitoring visits are not possible because of COVID-19, other unforeseen obstacles, 
remote monitoring may occur, if allowed by local and federal legal and regulatory requirements. If a 
protocol deviation is the result of COVID-19–related or other such circumstances, this information 
should be captured. 
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11. 
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Auchus RJ. Management considerations for the adult with congenital adrenal hyperplasia. Mol Cell 
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Claahsen-van der Grinten HL, Speiser PW, Ahmed SF, et al. Congenital Adrenal Hyperplasia-Current 
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Clayton PE, Miller WL, Oberfield SE, Ritzén EM, Sippell WG, Speiser PW; Joint European Society for 
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Crown A, Lightman S. Why is the management of glucocorticoid deficiency still controversial: a review of 
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Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. US Dept of Health and Human 
Services, National Institutes of Health, National Cancer Institute; 2017. 
Doleschall M, Szabó JA, Pázmándi J, et al. Common genetic variants of the human steroid 21-hydroxylase 
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El-Maouche D, Hargreaves CJ, Sinaii N, Mallappa A, Veeraraghavan P, Merke DP. Longitudinal 
assessment of illnesses, stress dosing, and illness sequelae in patients with congenital adrenal 
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Han TS, Walker BR, Arlt W, et al. Treatment and health outcomes in adults with congenital adrenal 
hyperplasia. Nat Rev Endocrinol. 2014;10:115-124. 
Jonathan P. Jackson, Kimberly M. Freeman, Robert L. St. ClaireIII, Chris B. Black, and Kenneth R. 
Brouwer. Cholestatic Drug Induced Liver Injury: A Function of Bile Salt Export Pump Inhibition and 
Farnesoid X Receptor Antagonism. Applied In Vitro Toxicology. Sep 2018.265-27.  
Merke DP, Bornstein SR. Congenital Adrenal Hyperplasia. Lancet. 2005;365:2125-2136. 
Merke DP, Auchus RJ. Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency. N Engl J Med. 
2020 Sep 24;383(13):1248-1261. 
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Mnif MF, Kamoun M, Mnif F, et al. Long-term outcome of patients with congenital adrenal hyperplasia 
due to 21-hydroxylase deficiency. Am J Med Sci. 2012;344:363-73. 
Reisch N. Substitution therapy in adult patients with congenital adrenal hyperplasia. Best Pract Res Clin 
Endocrinol Metab. 2015;29:33-45. 
Reisch N. Review of health problems in adult patients with classic congenital adrenal hyperplasia due to 
21-hydroxylase deficiency. Exp Clin Endocrinol Diabetes. 2019;127(2-03):171-177. 
Speiser PW, Arlt W, Auchus RJ, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase 
deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018;103(11):4043-
4088. 
Stewart PM. Modified-release hydrocortisone: Is it time to change clinical practice? J Endocr Soc. 2019 
Apr 11;3(6):1150-1153. 
Turcu AF, Auchus RJ. Adrenal steroidogenesis and congenital adrenal hyperplasia. Endocrinol Metab Clin 
North Am. 2015;44(2):275-296. 
Upreti VV, Walhstrom JL. Meta-analysis of hepatic cytochrome P450 ontogeny to underwrite the 
prediction of pediatric pharmacokinetics using physiologically based pharmacokinetic modeling. J Clin 
Pharmacol. 2016;56(3):266-283. 
White PC and Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev. 
2000;21:245-291. 
Yount SE, Cella D, & Blozis S. PROMIS®: Standardizing the patient voice in health psychology research 
and practice. Health Psychology. 2019;38(5):343-346. 
 
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12. 
APPENDICES 
APPENDIX 1. SCHEDULE OF ACTIVITIES FOR COHORTS 1, 1A, 2, AND 3 .................................... 76 
APPENDIX 2. SCHEDULE OF ACTIVITIES FOR OPEN-LABEL EXTENSION FOR COHORTS 1, 
1A, 2, AND 3 ............................................................................................................... 79 
APPENDIX 3. SCHEDULE OF ACTIVITIES FOR COHORTS 4, 5, 6, 8, 7, AND 9 .............................. 81 
APPENDIX 4. SCHEDULE OF ACTIVITIES FOR EXTENSION PERIOD FOR COHORTS 4, 5, 6, 
8, 7, AND 9 ................................................................................................................. 84 
APPENDIX 5. PROHIBITED CONCOMITANT MEDICATIONS ........................................................ 86 
APPENDIX 6. CLINICAL LABORATORY TESTS............................................................................... 87 
 
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APPENDIX 1. 
SCHEDULE OF ACTIVITIES FOR COHORTS 1, 1A, 2, AND 3 
 
Screening1 
Treatment Period 
Early  
Termination 
Safety  
Follow-
up2 
Day 1 
Week 2 
Week 4 
Week 8 
Week 12 
(EOT) 
VISIT NUMBER 
1 
2 
3 
4 
5 
6 
 
7 
STUDY DAY 
ч14 days 
before V2 
1 
14 
28 
56 
84 
 
Last 
dose  
+30 
days 
Visit windows 
 
 
±3 days 
±3 days 
±3 days 
±3 days 
 
± 7 days 
Informed consent/assent 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
Demography & medical history 
X 
 
 
 
 
 
 
 
Review of prior medications from past year 
X 
 
 
 
 
 
 
 
Review of concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Hepatitis B & C and HIV Screening 
X 
 
 
 
 
 
 
 
Pregnancy test for FOCP 3 
X 
X 
X 
X 
X 
X 
X 
X6 
Laboratory assessments 4, 5  
X 
X 
X 
X 
X 
X 
X 
X6 
Pharmacodynamics and Tildacerfont Concentration Samples (by Cohort) 
 
 
 
 
 
 
 
 
Cohorts 1 & 2 PD markers and tildacerfont concentration 
(serial, drawn together) 7  (also 1a if indicated) 
 
X 
X 
 
 
 
 
 
Cohorts 1 & 2 PD markers (single sample)8  (also 1a if indicated) 
 
 
 
X 
X 
X 
X 
X6 
Cohorts 1 & 2 tildacerfont concentration (single sample)9 (also 1a if 
indicated) 
 
 
 
X 
X 
X 
X 
X6 
Cohort 3 PD markers (single sample)8 
 
X 
X 
X 
X 
X 
X 
X6 
Cohort 3 tildacerfont concentration (single sample)9 
 
X 
X 
X 
X 
X 
X 
X6 
A4-based GC dose adjustment10 
 
 
 
X 
X 
X 
 
 
Weight-based tildacerfont dose adjustment 
X 
 
 
 
 
X 
 
 
Urinalysis 11 
X 
 
X 
 
 
X 
X 
X6 
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Screening1 
Treatment Period 
Early  
Termination 
Safety  
Follow-
up2 
Day 1 
Week 2 
Week 4 
Week 8 
Week 12 
(EOT) 
VISIT NUMBER 
1 
2 
3 
4 
5 
6 
 
7 
STUDY DAY 
ч14 days 
before V2 
1 
14 
28 
56 
84 
 
Last 
dose  
+30 
days 
Visit windows 
 
 
±3 days 
±3 days 
±3 days 
±3 days 
 
± 7 days 
Vital signs 12, body weight 
X 
X 
X 
X 
X 
X 
X 
X6 
Physical exam 13 
X 
X 
X 
X 
X 
X 
X 
X6 
12-lead ECG  
X 
 
X14 
 
 
X 
X 
X6 
Bone age and predicted adult height15 
X 
 
 
 
 
 
 
 
C-SSRS 16 
X 
 
X 
X 
X 
X 
X 
X6 
PROMIS 17  
X 
 
X 
X 
X 
X 
X 
X6 
SWYC18 
X 
 
X 
X 
X 
X 
X 
X6 
Dispense study drug19 
 
X 
 
 
 
 
 
 
Study drug accountability 
 
 
X 
X 
X 
X 
X 
 
Clinic drug administration 20 
 
X 
X 
 
 
 
 
 
Review any AEs 
 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: 11KT=11-ketotestosterone; A4=androstenedione; ACTH=adrenocorticotropin hormone; AEs=adverse events; ALT=alanine aminotransferase; ALP=alkaline 
phosphatase; AST=aspartate aminotransferase; CRO=contract research organization; C-SSRS= Columbia–Suicide Severity Rating Scale; ECG=electrocardiogram; 
eGFR=estimated glomerular filtration rate; EOT=end of treatment; ET=early termination; FOCP=female of childbearing potential; GC=glucocorticoid; GGT=gamma-glutamyl 
transferase; HIV=human immunodeficiency virus; EP=open-label extension; PD=pharmacodynamics; PK=pharmacokinetics; PROMIS=Patient Reported Outcomes Measurement 
Information System; 17-OHP=17-hydroxyprogesterone; SWYC=Survey of Well-being of Young Children; T=testosterone. 
1 The Screening Period may be extended as approved by the Sponsor or CRO designee. 
2 For participants continuing in the EP period, the Safety Follow-up Visit will be 30 days after their last dose in the EP Period. 
3 A pregnancy test will be performed at every visit for FOCP. The Screening Visit will include a serum pregnancy test. All subsequent visits will include urine pregnancy tests. Any 
positive urine pregnancy test must be followed up by a serum pregnancy test for confirmation. 
4 Labs will be drawn at approximately 8 AM (±1 h) before any morning dose of GC medication.  
5 Laboratory assessments include: coagulation panel (Screening only), hematology, chemistry (including liver function tests AST, ALT, ALP, GGT, total and direct bilirubin, and 
total bile acids), thyroid panel. Fasting is not required.  
6 As needed based upon safety concerns, per Investigator discretion. 
7 For Cohorts 1 and 2, serial blood samples at 3 timepoints to assess PD (ACTH, 17-OHP, A4, testosterone and 11KT) cortisol and tildacerfont concentrations:  pre-dose (prior to 
GC dosing and tildacerfont dosing), 0.5 to 1.5 hours post GC and tildacerfont dose, and 3 to 5 hours post-GC and tildacerfont dose. 
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8 PD Samples (ACTH, 17-OHP, A4, testosterone, 11KT). They must be drawn prior to GC dosing, at approximately 8 AM (± 1 h). Fasting is not required. 
9 Tildacerfont concentration collected prior to GC dosing. Fasting is not required.  
10 In all cohorts, GC dose (frequency or total daily dose) may be adjusted based on A4 levels collected at Weeks 4 and 8 (all participants) and Week 12 (for those participants 
continuing in the optional EP). If a change in GC is warranted by the A4 algorithm, sites will contact participants by telephone after receipt of results (within approximately 2 
weeks) after each applicable study visit. 
11Urinalysis should include the following: specific gravity, pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, by dipstick. Microscopic examination should be 
obtained if blood or protein is abnormal. For visits in which tildacerfont is administered, urinalysis should be performed pre-dose. 
12 Systolic and diastolic blood pressure, pulse rate, body temperature, and respiration rate. Height will only be collected at Screening.  
13 Full physical exam is performed at Visit 2, Visit 6, and ET Visit; an abbreviated/directed physical exam is performed at all other visits.  
14 Day 1 ECGs are conducted pre-dose. Day 14 ECG is dose independent, as participants should be at steady state. 
15 Historical bone age and predicted adult height calculation may be used if performed ч6 months prior to Screening. If no appropriate image is available, x-ray of left hand and 
wrist will be performed to assess bone age and calculate predicted adult height. 
16 The C-SSRS, to assess suicidality, is only conducted for participants aged 6 to 17 years. 
17 PROMIS, to assess anxiety and depression, is conducted for participants aged 5 to 17 years.  
18 The SWYC to assess anxiety and depression is only conducted in Cohort 3 participants ч5 years of age. 
19 A 12-week supply of study drug will be dispensed at Visit 2 (Day 1). Participants should bring study drug to all visits for accountability. Upon receipt of study drug, the 
pharmacy will hold/store two doses to ensure that in-clinic dosing can occur at Visit 3 (Week 2) in the event a participant does not bring study drug to the visit.   
20 Cohorts 1 and 2 dosing:   
    Cohorts 1 and 2 (and 1a if indicated) will dose with a morning meal for the first 14 days of the study. Cohorts 1 and 2 (and 1a if indicated) will take the study drug at the clinic 
on Day 1 (Visit 2) (to allow for a 1-hour safety observational period and serial tildacerfont concentrations), and on Day 14 (to allow for serial tildacerfont concentrations). 
Starting on Day 15, Cohorts 1 and 2 will switch to taking the study drug with their evening meal for the duration of the study. 
    Cohort 3 dosing:   
    Cohort 3 will dose with a morning meal at the study clinic on Day 1 (Visit 2) to allow for a 1-hour observational period. All subsequent doses for Cohort 3 will occur with 
evening meals. 
 
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APPENDIX 2. 
SCHEDULE OF ACTIVITIES FOR OPEN-LABEL EXTENSION FOR COHORTS 1, 1A, 2, AND 3 
 
Week 12 Week 24 Week 36 Week 48 
 
 
Week 60 
 
Week 72 
 
 
Week 84 
 
Week 96 
(EOT) 
 
Early  
Termination 
Safety  
Follow-
up 
(Phone 
call) 
VISIT NUMBER 
6 
7 
8 
9 
10 
11 
12 
13 
 
 
Visit windows 
±2  
weeks 
±2 
weeks 
±2 
weeks 
±2 
weeks 
 
±2  
weeks 
 
±2 
weeks 
 
±2 
weeks 
 
±2  
weeks 
 
Last 
dose  
+30 
days 
Informed consent/assent 
X 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test for FOCP 1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Laboratory assessments 2, 3  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 X4 
PD and tildacerfont samples 5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 X4 
A4-based GC dose adjustment6 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Weight-based tildacerfont dose 
adjustment 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Urinalysis 7 
 
 
 
X 
 
X 
 
X 
X 
 X4 
Vital signs 8, body weight  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 X4 
Abbreviated/directed physical 
exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 X4 
C-SSRS 9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 X4 
PROMIS 10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 X4 
SWYC11 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Week 12 Week 24 Week 36 Week 48 
 
 
Week 60 
 
Week 72 
 
 
Week 84 
 
Week 96 
(EOT) 
 
Early  
Termination 
Safety  
Follow-
up 
(Phone 
call) 
VISIT NUMBER 
6 
7 
8 
9 
10 
11 
12 
13 
 
 
Visit windows 
±2  
weeks 
±2 
weeks 
±2 
weeks 
±2 
weeks 
 
±2  
weeks 
 
±2 
weeks 
 
±2 
weeks 
 
±2  
weeks 
 
Last 
dose  
+30 
days 
Bone age and predicted adult 
height12 
 
X 
 
X 
 
X 
 
X 
 
 
Dispense study drug 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Review any AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug accountability 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Abbreviations: 11KT=11-ketotestosterone; A4=androstenedione; ACTH=adrenocorticotropin hormone; AEs=adverse events; ALT=alanine aminotransferase; ALP=alkaline 
phosphatase; AST=aspartate aminotransferase; C-SSRS=Columbia–Suicide Severity Rating Scale; ECG=electrocardiogram; EOT= end of treatment; ET=early termination; 
FOCP=female of childbearing potential; GC=glucocorticoid; GGT=gamma-glutamyl transferase; PD=pharmacodynamics; PROMIS= Patient Reported Outcomes Measurement 
Information System; 17-OHP=17-hydroxyprogesterone; SWYC=Survey of Well-being of Young Children; T=testosterone. 
1 A serum pregnancy test will be performed at Screening for FOCP only. All subsequent tests will be urine pregnancy tests 
2 Labs will be drawn at 8 AM (±1 h) before any morning dose of GC medication.  
3 Laboratory assessments include: hematology, chemistry (including liver function tests AST, ALT, ALP, GGT, total and direct bilirubin, and total bile acids), thyroid panel. Fasting 
is not required. 
4 As needed based upon any safety concerns, per Investigator discretion. 
5 PD Samples (ACTH, 17-OHP, A4, testosterone, and 11KT). They must be drawn prior to GC dosing. Fasting is not required. Single samples for plasma concentration of 
tildacerfont will be drawn at all visits. 
6  GC dose (frequency or total daily dose) may be adjusted based on A4 levels collected at each visit. If a change in GC is warranted by the A4 algorithm, sites will contact 
participants by telephone after receipt of results (within approximately 2 weeks) after each applicable study visit. 
7 Urinalysis should include the following:  specific gravity, pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, by dipstick. Microscopic examination should be 
obtained if blood or protein is abnormal. 
8 Systolic and diastolic blood pressure, pulse rate, body temperature, and respiration rate. 
9 The C-SSRS, to assess suicidality, is only conducted for participants aged 6 to 17 years. 
10 PROMIS, to assess anxiety and depression, is conducted for participants aged 5 to 17 years.  
11 The SWYC to assess anxiety and depression is only conducted in Cohort 3 participants under 5 years of age. 
12 Historical bone age and predicted adult height calculation will be performed by an x-ray of left hand and wrist to assess bone age and calculate predicted adult height.
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APPENDIX 3. 
SCHEDULE OF ACTIVITIES FOR COHORTS 4, 5, 6, 8, 7, and 9 
 
Screening1 
Treatment Period 
Early  
Termination 
Safety  
Follow-up2 
Day 1 Week 2  Week 4 
(EOT) 
 
 
VISIT NUMBER 
1 
2 
3 
4 
 
5 
STUDY DAY 
чϭϰĚĂǇƐ
before V2 
1 
14 
28 
 
Last dose  
+30 days 
Visit windows 
 
 
+3 days ±3 days 
 
± 7 days 
Informed consent/assent 
X 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
Demography & medical history 
X 
 
 
 
 
 
Review of prior medications from past year 
X 
 
 
 
 
 
Review of concomitant medications 
X 
X 
X 
X 
X 
X 
Hepatitis B & C and HIV Screening 
X 
 
 
 
 
 
Pregnancy test for FOCP 3 
X 
X 
X 
X 
X 
X6 
Laboratory assessments 4, 5  
X 
X 
X 
X 
X 
X6 
Pharmacodynamics and Tildacerfont Concentration Samples 
(by Cohort) 
 
 
 
 
 
 
Cohorts 4, 5, 6, and 7 PD markers and tildacerfont 
concentration (serial, drawn together) 7 (also 8 and 9 if 
indicated) 
 
X 
X 
 
 
 
Cohorts 4, 5, 6, and 7 PD markers and tildacerfont 
concentration (single sample) 8 (also 8 and 9 if indicated) 
 
 
 
X 
X 
X6 
A4-based GC dose adjustment10 
 
 
 
X 
 
 
Weight-based tildacerfont dose adjustment 
X 
 
 
 
 
 
Urinalysis 11 
X 
 
X 
 
X 
X6 
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Screening1 
Treatment Period 
Early  
Termination 
Safety  
Follow-up2 
Day 1 Week 2  Week 4 
(EOT) 
 
 
VISIT NUMBER 
1 
2 
3 
4 
 
5 
STUDY DAY 
чϭϰĚĂǇƐ
before V2 
1 
14 
28 
 
Last dose  
+30 days 
Visit windows 
 
 
+3 days ±3 days 
 
± 7 days 
Vital signs 12, body weight 
X 
X 
X 
X 
X 
X6 
Physical exam 13 
X 
X 
X 
X 
X 
X6 
12-lead ECG  
X 
 
X14 
 
X 
X6 
Bone age and predicted adult height15 
X 
 
 
 
 
 
C-SSRS 16 
X 
 
X 
X 
X 
X6 
PROMIS 17  
X 
 
X 
X 
X 
X6 
SWYC18 
X 
 
X 
X 
X 
X6 
Dispense study drug19 
 
X 
 
 
 
 
Study drug accountability 
 
 
X 
X 
X 
 
Clinic drug administration 20 
 
X 
X 
 
 
 
Review any AEs 
 
X 
X 
X 
X 
X 
Abbreviations: 11KT=11-ketotestosterone; A4=androstenedione; ACTH=adrenocorticotropin hormone; AEs=adverse events; ALT=alanine aminotransferase; ALP=alkaline 
phosphatase; AST=aspartate aminotransferase; CRO=contract research organization; C-SSRS= Columbia–Suicide Severity Rating Scale; ECG=electrocardiogram; 
eGFR=estimated glomerular filtration rate; EOT=end of treatment; ET=early termination; FOCP=female of childbearing potential; GC=glucocorticoid; GGT=gamma-glutamyl 
transferase; HIV=human immunodeficiency virus; EP=open-label extension; PD=pharmacodynamics; PK=pharmacokinetics; PROMIS=Patient Reported Outcomes Measurement 
Information System; 17-OHP=17-hydroxyprogesterone; SWYC=Survey of Well-being of Young Children; T=testosterone. 
1 The Screening Period may be extended as approved by the Sponsor or CRO designee. 
2 For participants continuing in the EP period, the Safety Follow-up Visit will be 30 days after their last dose in the EP Period. 
3 A pregnancy test will be performed at every visit for FOCP. The Screening Visit will include a serum pregnancy test. All subsequent visits will include urine pregnancy tests. Any 
positive urine pregnancy test must be followed up by a serum pregnancy test for confirmation. 
4 Labs will be drawn at approximately 8 AM (±1 h) before any morning dose of GC medication.  
5 Laboratory assessments include: A4, coagulation panel (Screening only), hematology, chemistry (including liver function tests AST, ALT, ALP, GGT, total and direct bilirubin, and 
total bile acids), thyroid panel. Fasting is not required.  
6 As needed based upon safety concerns, per Investigator discretion. 
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7 For Cohorts 4, 5, 6, 8, 7, and 9 serial blood samples at 3 timepoints to assess PD (ACTH, 17-OHP, A4, testosterone, 11KT, cortisol) and tildacerfont concentrations following the 
morning (1st) dose:  pre-dose (prior to GC dosing and tildacerfont dosing), 0.5 to 1.5 hours post GC and tildacerfont dose, and 3 to 5 hours post-GC and tildacerfont dose. Serial 
samples should be attempted in all cases but may be declined in Cohort 7 & 9 at Investigator’s discretion (e.g., unable to establish IV, behavioral challenges impede collection 
and risk other assessments). 
8 For Cohorts 4, 5, 6, 8, 7, and 9 single blood sample to assess PD (ACTH, 17-OHP, A4, testosterone, and 11KT) and cortisol and tildacerfont concentration. Pre-dose at 
approximately 8 AM (±1 h), prior to GC dosing and tildacerfont dosing. 
9 Tildacerfont concentration collected prior to the morning tildacerfont and GC dose. Fasting is not required.  
10 In all cohorts, GC dose (frequency or total daily dose) may be adjusted based on A4 levels collected at Week 4 (for those participants continuing in the optional EP). If a change 
in GC is warranted by the A4 algorithm, sites will contact participants by telephone after receipt of results (within approximately 2 weeks) after each applicable study visit. 
11Urinalysis should include the following: specific gravity, pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, by dipstick. Microscopic examination should be 
obtained if blood or protein is abnormal. For visits in which tildacerfont is administered, urinalysis should be performed pre-dose. 
12 Systolic and diastolic blood pressure, pulse rate, body temperature, and respiration rate. Height will only be collected at Screening.  
13 Full physical exam is performed at Visit 2, EOT, and the ET Visit; an abbreviated/directed physical exam is performed at all other visits.  
14 Day 1 ECGs are conducted pre-dose. Day 14 ECG is dose independent, as participants should be at steady state. 
15 ,ŝƐƚŽƌŝĐĂůďŽŶĞĂŐĞĂŶĚƉƌĞĚŝĐƚĞĚĂĚƵůƚŚĞŝŐŚƚĐĂůĐƵůĂƚŝŽŶŵĂǇďĞƵƐĞĚŝĨƉĞƌĨŽƌŵĞĚчϲŵŽŶƚŚƐƉƌŝŽƌƚŽ^ĐƌĞĞŶŝŶŐ͘/ĨŶŽĂƉƉƌŽpriate image is available, x-ray of left hand and 
wrist will be performed to assess bone age and calculate predicted adult height. This may not be performed if deemed inappropriate by the investigator (based on maturation 
level). This will not be performed in adults (Cohorts 4 & 5). 
16 The C-^^Z^͕ƚŽĂƐƐĞƐƐƐƵŝĐŝĚĂůŝƚǇ͕ŝƐŽŶůǇĐŽŶĚƵĐƚĞĚĨŽƌƉĂƌƚŝĐŝƉĂŶƚƐĂŐĞĚшϲǇĞĂƌƐ͘ 
17 WZKD/^͕ƚŽĂƐƐĞƐƐĂŶǆŝĞƚǇĂŶĚĚĞƉƌĞƐƐŝŽŶ͕ŝƐĐŽŶĚƵĐƚĞĚĨŽƌƉĂƌƚŝĐŝƉĂŶƚƐĂŐĞĚшϱǇĞĂƌƐ͘ 
18 The SWYC to assess anxiety and depression is only conducted in Cohort 7 (and 9 ŝĨŝŶĚŝĐĂƚĞĚͿĨŽƌƉĂƌƚŝĐŝƉĂŶƚƐчϱǇĞĂƌƐŽĨĂŐĞ͘ 
19 A 4-week supply of study drug will be dispensed at Visit 2 (Day 1). Participants should bring study drug to all visits for accountability. Upon receipt of study drug, the pharmacy 
will hold/store two doses to ensure that in-clinic dosing can occur at Visit 3 (Week 2) in the event a participant does not bring study drug to the visit. 
20 All cohorts will dose in clinic with a morning meal for their first dose to allow observation 1 hour post dose. 
 
 
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APPENDIX 4. 
SCHEDULE OF ACTIVITIES FOR EXTENSION PERIOD FOR COHORTS 4, 5, 6, 8, 7, AND 9 
 
Week 
4 
Week  
8 
Week 
12 
Week 
24 
Week 
36 
Week 
48  
Week 
60 
Week 
72 
Week 
84 
Week 96 
(EOT) 
Early  
Termination 
Safety  
Follow-
up 
(Phone 
call) 
VISIT NUMBER 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
 
 
Visit windows 
 
±2 
weeks 
 
±2 
weeks 
 
±2 
weeks 
 
±2 
weeks 
 
±2 
weeks 
 
±2 
weeks 
 
±2 
weeks 
 
±2 
weeks 
 
±2 
weeks 
 
±2 
weeks 
 
Last 
dose  
+30 days 
Informed consent/assent 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test for FOCP 1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Laboratory assessments 2, 3  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 X4 
PD and tildacerfont 
samples 5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 X4 
A4-based GC dose 
adjustment6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Urinalysis 7 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 X4 
Vital signs 8, body weight  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 X4 
Abbreviated/directed 
physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 X4 
C-SSRS 9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 X4 
PROMIS 10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 X4 
SWYC11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Bone age and predicted 
adult height12 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
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Week 
4 
Week  
8 
Week 
12 
Week 
24 
Week 
36 
Week 
48  
Week 
60 
Week 
72 
Week 
84 
Week 96 
(EOT) 
Early  
Termination 
Safety  
Follow-
up 
(Phone 
call) 
VISIT NUMBER 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
 
 
Visit windows 
 
±2 
weeks 
 
±2 
weeks 
 
±2 
weeks 
 
±2 
weeks 
 
±2 
weeks 
 
±2 
weeks 
 
±2 
weeks 
 
±2 
weeks 
 
±2 
weeks 
 
±2 
weeks 
 
Last 
dose  
+30 days 
Weight/Efficacy 
Tildacerfont Dose 
Adjustment 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Dispense study drug 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Review any AEs 
X 
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 
 
Abbreviations: 11KT=11-ketotestosterone; A4=androstenedione; ACTH=adrenocorticotropin hormone; AEs=adverse events; ALT=alanine aminotransferase; ALP=alkaline 
phosphatase; AST=aspartate aminotransferase; C-SSRS=Columbia–Suicide Severity Rating Scale; ECG=electrocardiogram; EOT= end of treatment; ET=early termination; 
FOCP=female of childbearing potential; GC=glucocorticoid; GGT=gamma-glutamyl transferase; PD=pharmacodynamics; PROMIS= Patient Reported Outcomes Measurement 
Information System; 17-OHP=17-hydroxyprogesterone; SWYC=Survey of Well-being of Young Children; T=testosterone. 
1 A serum pregnancy test will be performed at Screening for FOCP only. All subsequent tests will be urine pregnancy tests 
2 Labs will be drawn at 8 AM (±1 h) before any morning dose of GC medication.  
3 Laboratory assessments include: hematology, chemistry (including liver function tests AST, ALT, ALP, GGT, total and direct bilirubin, and total bile acids), thyroid panel. Fasting 
is not required. 
4 As needed based upon any safety concerns, per Investigator discretion. 
5 PD Samples (ACTH, 17-OHP, A4, testosterone, and 11KT). They must be drawn prior to GC dosing. Fasting is not required. Single samples for plasma concentration of 
tildacerfont will be drawn at all visits. 
6  GC dose (frequency or total daily dose) may be adjusted based on A4 levels collected at each visit. If a change in GC is warranted by the A4 algorithm, sites will contact 
participants by telephone after receipt of results (within approximately 2 weeks) after each applicable study visit. 
7 Urinalysis should include the following:  specific gravity, pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, by dipstick. Microscopic examination should be 
obtained if blood or protein is abnormal. 
8 Systolic and diastolic blood pressure, pulse rate, body temperature, and respiration rate. 
9 The C-SSRS, to assess suicidality, is only conducted for participants aged ш6 years. 
10 PROMIS, to assess anxiety and depression, is conducted for participants aged ш5 years.  
11 The SWYC to assess anxiety and depression is only conducted in Cohort 7 (and 9 if indicated) for participants ч5 years of age. 
12 Historical bone age and predicted adult height calculation will be performed by an x-ray of left hand and wrist to assess bone age and calculate predicted adult height. This 
may not be performed if deemed inappropriate by the investigator (based on maturation level). This will not be performed in adults (Cohorts 4 & 5).
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APPENDIX 5. 
PROHIBITED CONCOMITANT MEDICATIONS 
Refer to Section 5.3.2 for more information on prohibited concomitant medications. 
The following is a non-exhaustive list of medications that are prohibited because of their potential for metabolic interactions with tildacerfont. 
Most children in this study will not be taking the medications listed below. Any drugs of concern should be discussed with the MM. 
alfentanil 
darifenacin 
itraconazole  
paxlovida 
rivaroxaban 
apixaban 
diltiazem  
ketoconazole 
phenobarbital 
sildenafil  
atorvastatin 
elagolix  
lesinurad 
phenytoin 
simvastatin 
avanafil 
eletriptan 
loperamide 
posaconazole 
St John's wort 
avasimibe 
ethinyl estradiol 
(>20 mcg) 
lovastatin 
pravastatin  
teneligliptin 
buspirone  
felodipine 
mibefradil  
quetiapine 
ticagrelor 
carbamazepine 
fluconazole 
midazolam 
repaglinide 
triazolam 
cenobamate 
glyburide 
nefazodone 
rifampin 
vardenafil  
ciprofloxacin 
isavuconazole 
oseltamivir  
rifapentine 
voriconazole 
a Study drug should be held during paxlovid treatment but can be re-started 24 hours after last paxlovid dose. 
Many oncology drugs and medications used to treat the hepatitis C virus and HIV are strong inhibitors of CYP3A4 but are not listed above simply 
because individuals with active cancer, hepatitis C, and/or HIV are excluded from this study. 
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CONFIDENTIAL 
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APPENDIX 6. 
CLINICAL LABORATORY TESTS 
Refer to Section 7.1.5 for more information on clinical laboratory tests. 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet count  
RBC count 
RBC indices: MCV, MCH, % reticulocytes 
 
Hemoglobin 
Hematocrit 
WBC count  
Differential: neutrophils, lymphocytes, monocytes, eosinophils, basophils 
Clinical Chemistry1 
Potassium 
  
Calcium 
Sodium 
BUN 
Creatinine 
Total protein 
 
ALP 
ALT/SGPT 
AST/SGOT  
GGT 
Total and direct bilirubin  
Total bile acids 
 
Coagulation 
INR, PT, PTT 
Thyroid Panel 
T3 (free and total), T4 (free and total), TSH 
Other Tests 
Testosterone, ACTH, 17-OHP, A4, 11KT, and cortisol 
 
Routine Urinalysis 
Specific gravity 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, by dipstick 
Microscopic examination (if blood or protein is abnormal) 
Abbreviations: 11KT=11-ketotestosterone; A4=androstenedione; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea 
nitrogen; GGT=gamma-glutamyl transferase; INR=international normalized ratio; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume; PT=prothrombin time; 
PTT=partial thromboplastin time; RBC=red blood cell; SAE=serious adverse event; SGOT=serum glutamic-oxaloacetic transaminase; SGPT=serum glutamic-pyruvic 
transaminase; TSH=thyroid-stimulating hormone; WBC=white blood cell. 
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