Clinical trial NCT04045145
Conditions: CAH - Congenital Adrenal Hyperplasia
Sponsor: Neurocrine Biosciences
Start date: 2019-12-12; Completion date: 2021-07-02
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 2, open-label, multiple-dose, study to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of NBI-74788 (crinecerfont) in pediatric participants (14 to 17 years of age) with a documented medical diagnosis of classic 21-hydroxylase deficiency congenital adrenal hyperplasia (CAH).

Detailed description:

Arms: arm 1: Crinecerfont administered orally for 14 consecutive days.
Interventions: intervention 1: Crinecerfont
Intervention descriptions: intervention 1: Crinecerfont administered orally for 14 consecutive days.

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
Final Version Date:  10 May 2019 
A Phase 2, Open-Label, Multiple-Dose Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics of NBI-74788 in 
Pediatric Subjects with Congenital Adrenal Hyperplasia 
Study No.:  NBI-74788-CAH2008 
Development Phase:  Phase 2 
Sponsor: 
Neurocrine Biosciences, Inc. 
12780 El Camino Real 
San Diego, CA 92130 
Telephone:  (858) 617-7600 
Facsimile:   (858) 617-7705 
CONFIDENTIAL 
This document is a confidential communication of Neurocrine Biosciences, Inc.  It is agreed that 
no unpublished information contained herein will be published or disclosed without prior approval 
from the Sponsor.  However, this document can be disclosed to an appropriate Institutional Review 
Board/Ethics Committee (IRB/EC) or authorized representatives of national regulatory authorities 
under the condition that they respect its confidential nature. 
NCT #: NCT04045145


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SIGNATURES:  
I agree to conduct this study in accordance with the requirements of this clinical study protocol 
and also in accordance with the following: 
• Established principles of Good Clinical Practice (GCP) (Harmonized) 
• United States (US) Code of Federal Regulations (CFR); US Food and Drug Administration 
(FDA) 
• Canada Food and Drugs Act and Regulations; Health Canada 
 
CLINICAL STUDY TITLE: 
A Phase 2, Open-Label, Multiple-Dose Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of NBI-74788 in Pediatric Subjects with Congenital 
Adrenal Hyperplasia 
 
Study No.: 
NBI-74788-CAH2008 
 
 
As Agreed: 
 
____________________________________ 
_______________________ 
Principal Investigator Signature 
Date 
 
PRINCIPAL INVESTIGATOR: 
 
______________________________________________________________ 
(Print Principal Investigator Name) 
 
SITE:   
 
________________________________________________________ 
(Print Site Name) 
 
 


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Accepted for the Sponsor:
SPONSOR:
Neurocrine Biosciences, Inc.
12780 El Camino Real
San Diego, CA  92130
Phone:
(858) 617-7600
Facsimile: (858) 617-7705
___________________
______
Date


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LIST OF SPONSOR PERSONNEL 
Neurocrine Biosciences, Inc. 
12780 El Camino Real 
San Diego, CA 92130 
Medical Monitor:  
 
Telephone: 
 
Facsimile: 
 
Cell Phone: 
 
Vice President, Clinical Development:  
 
Telephone: 
 
Facsimile: 
 
Serious Adverse Event Reporting: 
Telephone: 
(866) 626-7792 or (858) 617-7792 
Facsimile: 
(888) 617-7551 
Email:  
cds@neurocrine.com 
 


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1. 
SYNOPSIS 
Title of study:  A Phase 2, Open-Label, Multiple-Dose Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of NBI-74788 in Pediatric Subjects with Congenital Adrenal 
Hyperplasia 
Study number:  NBI-74788-CAH2008 
Study center(s):  Approximately 5 study centers in North America 
Objectives: 
• 
To assess the safety and tolerability of NBI-74788 in pediatric subjects 14 to 17 years of age with 
congenital adrenal hyperplasia (CAH). 
• 
To evaluate the effect of repeated doses of NBI-74788 on endogenous levels of pharmacodynamic (PD) 
biomarkers in pediatric subjects with CAH. 
• 
To evaluate the pharmacokinetics (PK) of NBI-74788 and metabolites in pediatric subjects with CAH. 
Methodology:  This is a Phase 2, open-label, multiple-dose study to assess the safety, tolerability, PK, and PD 
of NBI-74788 in approximately 12 pediatric female and male subjects (14 to 17 years of age) with a 
documented medical diagnosis of classic 21-hydroxylase deficiency CAH.  NBI-74788 50 mg twice daily (bid) 
will be administered for 14 consecutive days with breakfast and evening meals beginning on the evening of 
Day 1. 
Parental or legal guardian informed consent with signed and witnessed study subject assent will be obtained 
prior to any study-related procedures.  Subjects will then be screened for up to approximately 3 weeks (Days -28 
to -8) for eligibility to participate in the study.  During screening, subjects will provide a blood sample in the 
morning between 0700 and 1000 hours (prior to first morning dose of hydrocortisone) to determine their 
17-hydroxyprogesterone (17-OHP) levels for study entry. 
Eligible subjects who have a screening 17-OHP level ≥800 ng/dL will be admitted to the study center on Day -7 
for 1 night and have baseline serial PD samples collected over a 24-hour period beginning that evening.  
Baseline serial PD samples will be collected at approximately 1845, 2000, 2300, 0100, 0300, 0700, 1000, 1500, 
and 1900 hours. 
The subjects’ usual morning dose of steroidal treatments will be administered after the 1000 hours PD sample is 
collected on Day -6.  Subjects will be discharged on Day -6 after the last PD sample is collected. 
Subjects will be admitted to the study center on Days 1 and 14 (first and last day of dosing).  Subjects will have 
a blood sample collected on Day 1 for 
.  Baseline safety assessments 
will be collected on Day 1 prior to the first dose of study drug.  The first dose of study drug, NBI-74788 50 mg, 
will be administered at approximately 1900 hours with subjects’ evening meal on Day 1.  Study drug will be 
administered at the study center on Days 2 and 14 with subjects’ breakfast and evening meals, respectively.  The 
subjects’ usual morning dose of concurrent steroidal treatments, study drug dosing, and breakfast (snacks will be 
allowed prior to breakfast) will be delayed until after the 15-hour postdose PD samples are collected (ie, at 
approximately 1000 hours) on Day 2.  The subjects’ usual morning dose of concurrent steroidal treatments will 
be administered after the 15-hour postdose PD samples are collected (ie, at approximately 1000 hours) on Day 
15.  Subjects will be discharged from the study center in the evening on Days 2 and 15 following completion of 
all study-related procedures for those days.  Study drug will be self-administered at home under parent/guardian 
supervision at approximately 0700 hours (with breakfast) and 1900 hours (with evening meal) on Days 3 to 13. 
On Day 7 during the treatment period, PK, PD, and safety assessments will be conducted in an outpatient setting 
at the study center.  
Follow-up visits on Days 17 and 21 will be conducted at the study center or by a qualified home healthcare 
provider at the subject’s home (based on the subject’s preference).  A final study visit will be conducted at the 
study center approximately 3 weeks after the last dose of study drug (on Day 35 or early termination).  There 
will be a visit window of -8 hours for Day 7, -8 hours/+3 days for Days 17 and 21, and +7 days for the final 
study visit (Day 35 or early termination).  Safety, tolerability, PK, and PD will be assessed at scheduled times 
throughout the study.  


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Study Population:  Approximately 12 pediatric female and male subjects (14 to 17 years of age) with a 
documented medical diagnosis of classic 21-hydroxylase deficiency CAH, who meet all protocol eligibility 
criteria, will be enrolled. 
Duration of treatment:  The expected duration of study participation for each subject is approximately 
9 weeks, including up to approximately 3 weeks for screening, a 24-hour PD baseline period (approximately 
7 days prior to the first day of dosing), 14 days of dosing, and a follow-up period of approximately 3 weeks. 
Test product, dose, and mode of administration:  NBI-74788 will be supplied as capsules containing 50 mg 
of NBI-74788 
 for oral administration.  One capsule of study drug will be administered orally at 
approximately 0700 hours with breakfast and at approximately 1900 hours with evening meal. 
Reference therapy, dose, and mode of administration:  Not applicable. 
Criteria for evaluation  
Pharmacokinetics:   
Blood samples for PK analysis will be collected at the following times: 
• 
Days 1 and 14: 15 minutes pre-evening dose and at 1, 4, and 6 hours post-evening dose (±5 minute 
window). 
• 
Days 2 and 15:  8, 12, and 24 hours post-evening dose (±15 minute window; 24-hour post-evening dose 
blood sample on Day 15 only). 
• 
Day 7:  12 hours (±2 hour window) after the Day 6 evening dose, prior to the Day 7 morning dose. 
• 
Days 17 and 21:  72 hours (-8 hours/+3 days) and 168 hours (-8 hours/+3 days) post-final dose. 
• 
Final study visit (+7 days; Day 35 or early termination). 
The following plasma PK parameters will be calculated for NBI-74788 and metabolites for the Day 1 to 2 and 
the Day 14 to 15 sampling intervals: 
• 
Area under the plasma concentration versus time curve from 0 to 12 hours (AUC0–12). 
• 
Observed maximum plasma concentration (Cmax). 
• 
Time to Cmax (tmax). 
Additional PK parameters for Days 14 to 15 only: 
• 
Average plasma concentration at steady state (Cavg). 
• 
Percent fluctuation at steady state (%fluctuation). 
• 
Accumulation ratio at steady state. 
• 
Apparent terminal half-life (t½). 
• 
Apparent terminal rate constant (λz). 
• 
Apparent mean residence time (MRT). 
• 
Apparent systemic clearance after oral administration (CL/F) (NBI-74788 only). 
Pharmacodynamics:   
Blood samples for PD parameters will be collected at the following times: 
• 
Screening (must be collected prior to first morning dose of hydrocortisone). 


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• 
Day -7 to Day -6 (24-hour PD baseline):  at approximately 1845, 2000, 2300, 0100, 0300, 0700, 1000, 
1500, and 1900 hours. 
• 
Days 1 and 14: 15 minutes pre-evening dose and at 1, 4, and 6 hours post-evening dose (±5 minute 
window). 
• 
Days 2 and 15:  8, 12, 15, 20, and 24 hours post-evening dose (±15 minute window). 
• 
Day 7:  12 hours (±2 hour window) after the Day 6 evening dose and prior to the Day 7 morning dose. 
• 
Day 21:  168 hours (-8 hours/+3 days) following last dose. 
  Morning 17-OHP (serum; ng/dL) from the 8- and 12-hour postdose samples (collected at 
0300 and 0700 hours). 
  17-OHP at all other times, androstenedione (serum; ng/dL), testosterone (serum; ng/dL), 
cortisol (serum; μg/dL), and adrenocorticotropic hormone (ACTH; plasma; pg/mL). 
Safety:  Safety and tolerability will be monitored throughout the study and will include the following 
assessments: 
• 
Treatment-emergent adverse events. 
• 
Clinical laboratory tests (clinical chemistry, hematology, 
 and urinalysis). 
• 
Vital signs. 
• 
Physical examinations (including musculoskeletal exam). 
• 
12-lead electrocardiograms (ECGs). 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS), Children’s Version 
• 
Brief Psychiatric Rating Scale for Children (BPRS-C). 
Statistical methods:  Safety, PK, and PD data will be summarized using descriptive statistics.  Summaries of 
safety measures will include both observed values and changes from baseline.  Summaries of PD measures will 
include both observed values and changes from timepoint-matched PD baseline values. 
 


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TABLE OF CONTENTS 
1. 
SYNOPSIS ...................................................................................................................5 
TABLE OF CONTENTS .................................................................................................................8 
LIST OF TABLES .........................................................................................................................11 
LIST OF FIGURES .......................................................................................................................11 
2. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................12 
3. 
ETHICS ......................................................................................................................14 
4. 
INTRODUCTION ......................................................................................................14 
4.1. 
Background .................................................................................................................14 
4.2. 
NBI-74788 ..................................................................................................................15 
4.3. 
Study and Dose Rationale ...........................................................................................17 
5. 
OBJECTIVES .............................................................................................................17 
6. 
STUDY DESIGN .......................................................................................................17 
7. 
STUDY POPULATION .............................................................................................21 
7.1. 
Subject Inclusion Criteria ...........................................................................................21 
7.2. 
Subject Exclusion Criteria ..........................................................................................22 
7.3. 
Subject Identification and Replacement .....................................................................24 
7.4. 
Randomization ............................................................................................................24 
8. 
STUDY EVALUATIONS ..........................................................................................24 
8.1. 
Schedule of Assessments ............................................................................................24 
8.2. 
Screening and Baseline Assessments .........................................................................27 
8.2.1. 
Serum 17-Hydroxyprogesterone .................................................................................27 
8.2.2. 
 ..........................................................................27 
8.3. 
Pharmacokinetic Assessments ....................................................................................27 
8.4. 
Pharmacodynamic Assessments: Pharmacodynamic Biomarkers..............................28 
8.5. 
Safety Assessments .....................................................................................................28 
8.5.1. 
Vital Sign Measurements ............................................................................................28 
8.5.2. 
Medical History and Physical Examination ...............................................................29 
8.5.3. 
12-Lead Electrocardiogram ........................................................................................29 
8.5.4. 
Clinical Laboratory Assessments ...............................................................................30 
8.5.5. 
Brief Psychiatric Rating Scale for Children ...............................................................31 
8.5.6. 
Columbia-Suicide Severity Rating Scale Children’s Versions ..................................31 


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8.5.7. 
Estimated Total Blood Sample Volume Required by Study ......................................31 
8.6. 
Subject Study Diary ....................................................................................................32 
8.7. 
Specific Study Period Information .............................................................................32 
8.7.1. 
Screening Period (Study Days -28 to -8) ....................................................................32 
8.7.2. 
Day -7 to Day -6:  24-Hour Baseline Pharmacodynamics .........................................33 
8.7.3. 
Treatment Period ........................................................................................................33 
8.7.3.1. 
Day 1 to Day 2 ............................................................................................................33 
8.7.3.2. 
Day 7 ...........................................................................................................................36 
8.7.3.3. 
Day 14 to Day 15 ........................................................................................................36 
8.7.4. 
Follow-Up Period .......................................................................................................38 
8.7.4.1. 
Follow-Up Visits:  Days 17 and 21 ............................................................................38 
8.7.4.2. 
Final Study Visit:  (Day 35 or Early Termination) .....................................................38 
8.8. 
Study Duration ............................................................................................................39 
8.9. 
Prohibitions and Restrictions ......................................................................................39 
8.9.1. 
Prior and Concomitant Medications ...........................................................................39 
8.9.2. 
Dietary and Other Restrictions ...................................................................................40 
8.10. 
Withdrawal Criteria ....................................................................................................40 
8.10.1. 
Reasons for Withdrawal .............................................................................................40 
8.10.2. 
Handling of Withdrawals ............................................................................................41 
8.10.3. 
Sponsor’s Termination of Study .................................................................................41 
9. 
STUDY DRUG ...........................................................................................................41 
9.1. 
Study Drug Supplies ...................................................................................................41 
9.2. 
Study Drug Packaging and Labeling ..........................................................................41 
9.3. 
Study Drug Administration.........................................................................................42 
9.4. 
Study Drug Storage and Return ..................................................................................42 
9.5. 
Blinding ......................................................................................................................42 
9.6. 
Study Compliance and Accountability .......................................................................43 
10. 
ADVERSE EVENTS..................................................................................................43 
10.1. 
Definition ....................................................................................................................43 
10.2. 
Intensity of Adverse Events ........................................................................................44 
10.3. 
Relationship to Study Drug ........................................................................................44 
10.4. 
Recording Adverse Events .........................................................................................44 
10.5. 
Post-Study Follow-Up of Adverse Events ..................................................................45 


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10.6. 
Serious Adverse Events ..............................................................................................45 
10.6.1. 
Definition of a Serious Adverse Event .......................................................................45 
10.6.2. 
Managing Serious Adverse Events .............................................................................46 
10.6.3. 
Reporting Serious Adverse Events and Other Immediately Reportable 
Events .........................................................................................................................46 
10.6.4. 
Expedited Safety Reports ...........................................................................................46 
10.7. 
Pregnancy ...................................................................................................................47 
11. 
DOCUMENTATION OF DATA ...............................................................................47 
11.1. 
Case Report Forms .....................................................................................................47 
11.2. 
Data Capture, Review, and Validation .......................................................................48 
11.3. 
Coding Dictionaries ....................................................................................................48 
12. 
STATISTICAL AND ANALYTICAL PLAN ...........................................................48 
12.1. 
Analysis Sets ...............................................................................................................49 
12.2. 
Sample Size ................................................................................................................49 
12.3. 
Handling of Missing Data ...........................................................................................49 
12.4. 
Disposition of Subjects ...............................................................................................49 
12.5. 
Demographics and Baseline Characteristics ...............................................................49 
12.6. 
Pharmacokinetic Data .................................................................................................49 
12.7. 
Pharmacodynamic Data ..............................................................................................50 
12.8. 
Safety Data ..................................................................................................................50 
12.9. 
Interim Analysis ..........................................................................................................50 
13. 
REGULATORY AND ETHICAL ISSUES ...............................................................50 
13.1. 
General Legal References ...........................................................................................50 
13.2. 
Institutional Review Board .........................................................................................50 
13.3. 
Protocol Adherence and Amendments .......................................................................51 
13.4. 
Required Documents ..................................................................................................51 
13.5. 
Informed Consent .......................................................................................................51 
13.6. 
Study Monitoring ........................................................................................................51 
13.7. 
Quality Assurance .......................................................................................................52 
13.8. 
Record Retention ........................................................................................................52 
13.9. 
Confidentiality ............................................................................................................52 
14. 
STUDY COMMENCEMENT AND DISCONTINUATION ....................................52 
15. 
REFERENCES ...........................................................................................................54 


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LIST OF TABLES 
Table 1: 
Study Drug Dosing and Blood Draw Timepoints Schematic .....................................20 
Table 2: 
Schedule of Assessments ............................................................................................25 
Table 3: 
Estimated Total Blood Sample Volume .....................................................................32 
Table 4: 
Intensity of Adverse Events ........................................................................................44 
Table 5: 
Relationship of Adverse Events to Study Drug ..........................................................44 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................................19 
 


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2. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
17-OHP 
17-hydroxyprogesterone 
ACTH 
adrenocorticotropic hormone 
AE 
adverse event 
ALT 
alanine aminotransferase 
 
 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration versus time curve 
β-hCG 
β-human chorionic gonadotropin 
bid 
twice daily 
BPRS-C 
Brief Psychiatric Rating Scale for Children 
CAH 
congenital adrenal hyperplasia 
CFR 
Code of Federal Regulations 
CK 
creatine kinase 
Cmax 
observed maximum plasma concentration 
CRF1 
corticotropin releasing factor 1 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
 
 
DSM 
Diagnostic and Statistical Manual of Mental Disorders 
DSPV 
Drug Safety and Pharmacovigilance 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
HbsAg 
hepatitis B surface antigen 
HCV-Ab 
hepatitis C antibody 
HIV-Ab 
human immunodeficiency virus antibody 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
 
 
IRB 
institutional review board 


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MedDRA 
Medical Dictionary for Regulatory Activities 
NBI 
Neurocrine Biosciences, Inc. 
NOAEL 
no observed adverse effect level 
PD 
pharmacodynamics 
P-gp 
P-glycoprotein 
PK 
pharmacokinetics 
QTcF 
QT interval corrected for heart rate using Fridericia’s correction 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
t½ 
apparent terminal half-life 
TEAE 
treatment-emergent adverse event 
tmax 
time to reach observed maximum plasma concentration 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cell 
 


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3. 
ETHICS 
The study will be conducted in accordance with Neurocrine Biosciences, Inc. (NBI) standards 
that meet regulations relating to Good Clinical Practice (GCP).  These standards respect the 
following guidelines: 
• GCP:  Consolidated Guideline (International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use [ICH; current version]). 
• United States (US) Code of Federal Regulations (CFR) dealing with clinical studies (21 CFR 
parts 50, 54, 56, 312, and 314). 
• Canada Food and Drugs Act and Regulations Part C, Division 5:  Drugs for Clinical Trials 
Involving Human Subjects. 
• Guidance for Clinical Trial Sponsors:  Clinical Trial Applications, Effective March 2016, 
Health Canada Therapeutic Products Directorate, Health Products and Food Branch. 
The ethical requirements of Institutional Review Boards (IRBs)/Ethics Committees and the 
informed consent forms (ICFs) are discussed in Section 13. 
4. 
INTRODUCTION 
4.1. 
Background 
NBI-74788 is a selective corticotropin releasing factor 1 (CRF1) receptor antagonist that is being 
developed by NBI as a novel oral treatment for classic congenital adrenal hyperplasia (CAH) due 
to 21-hydroxylase deficiency, a condition that results in little or no cortisol biosynthesis.  One 
clinical manifestation of the absence of cortisol is the lack of feedback inhibition of pituitary 
adrenocorticotropic hormone (ACTH) secretion.  Increased ACTH levels cause adrenal 
hyperplasia and the enzyme mutation causes a shunting of cortisol precursor steroids to alternate 
pathways.  Most notably, the shunting of androgens leads to virilization and other developmental 
complications in females and the over-accumulation of ACTH is associated with the formation 
of testicular adrenal rest tumors in males.  In addition, since the same enzyme (21-hydroxylase) 
is used in the pathway for the biosynthesis of the mineralocorticoids, a number of these patients 
suffer from aldosterone deficiency which can result in dehydration and death due to salt-wasting.  
The prevalence of classic 21-hydroxylase deficiency CAH in the US general population, based 
on newborn screening, has been documented as 1:10,000 to 1:20,800 (Trakakis et al., 2010; 
Hertzberg et al., 2011), a figure that supports orphan drug designation. 
Pediatric patients from birth through adolescence, and females in particular, appear to be the 
most vulnerable population of CAH sufferers and represent the subgroup of patients with the 
greatest unmet medical need (Cheng and Speiser, 2012; Merke and Poppas, 2013).  Excessive 
androgen production in these younger patients results in early onset puberty and adrenarche, 
changes in skeletal maturation patterns, short stature caused by premature growth plate fusion, as 
well as significant hirsutism and acne problems.  While survival is properly ensured through 
steroid replacement strategies based on physiologic dosing of glucocorticoids 
(eg, hydrocortisone) and mineralocorticoids (eg, fludrocortisone), these doses are often 
inadequate to suppress the accumulating ACTH and overproduction of progestogens and 


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androgens (eg, 17-hydroxyprogesterone [17-OHP], androstenedione, and testosterone).  The 
uncontrolled symptoms of androgen excess, indeed, have a substantial impact on the day-to-day 
functioning and development of these patients.  The glucocorticoid doses required to treat the 
androgen excess are typically well above the normal physiologic dose used for cortisol 
replacement alone (as in patients with Addison’s disease).  This increased exposure to 
glucocorticoids can lead to iatrogenic Cushing’s syndrome, increased cardiovascular risk factors, 
glucose intolerance, reduced growth velocity, and decreased bone mineral density in CAH 
patients (Elnecave et al., 2008; King et al., 2006; Migeon and Wisniewski, 2001). 
Corticotropin releasing factor is a hypothalamic hormone released directly into the hypophyseal 
portal vasculature and acts on specific CRF1 receptors on corticotropes in the anterior pituitary 
to stimulate the release of ACTH.  Blockade of these receptors has been shown to decrease the 
release of ACTH in both animals and humans.  Therefore, compounds that block CRF1 receptors 
have the potential to directly inhibit the excessive ACTH release that occurs in CAH and thereby 
allow for normalization of androgen production while using lower, more physiologic doses of 
hydrocortisone.  The novel CRF1 receptor antagonist, NBI-74788, may provide an important 
therapeutic approach to treat patients with CAH. 
4.2. 
NBI-74788 


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4.3. 
Study and Dose Rationale 
The present Phase 2 study is designed to evaluate the safety, tolerability, pharmacokinetics (PK), 
and pharmacodynamics (PD) of NBI-74788 in pediatric subjects 14 to 17 years of age with 
classic CAH following multiple days of dosing twice daily 50 mg.  
 
 
 
 
 
 
 
 
 
 
 
 
 
5. 
OBJECTIVES 
The objectives of the study are as follows: 
• To assess the safety and tolerability of NBI-74788 in pediatric subjects 14 to 17 years of 
age with CAH. 
• To evaluate the effect of repeated doses of NBI-74788 on endogenous levels of PD 
biomarkers in pediatric subjects with CAH. 
• To evaluate the PK of NBI-74788 and metabolites in pediatric subjects with CAH. 
6. 
STUDY DESIGN 
This is a Phase 2, open-label, multiple-dose study to assess the safety, tolerability, PK, and PD of 
NBI-74788 in approximately 12 pediatric female and male subjects (14 to 17 years of age) with a 
documented medical diagnosis of classic 21-hydroxylase deficiency CAH.  NBI-74788 50 mg 
bid will be administered for 14 consecutive days with breakfast and evening meals beginning on 
the evening of Day 1. 
Parental or legal guardian informed consent with signed and witnessed study subject assent will 
be obtained prior to any study-related procedures.  Subjects will then be screened for up to 
approximately 3 weeks (Days -28 to -8) for eligibility to participate in the study.  During 


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screening, subjects will provide a blood sample in the morning between 0700 and 1000 hours 
(prior to first morning dose of hydrocortisone) to determine their 17-OHP levels for study entry. 
Eligible subjects who have a screening 17-OHP level ≥800 ng/dL will be admitted to the study 
center on Day -7 for 1 night and have baseline serial PD samples collected over a 24-hour period 
beginning that evening.  Baseline serial PD samples will be collected at approximately 1845, 
2000, 2300, 0100, 0300, 0700, 1000, 1500, and 1900 hours.    
The subjects’ usual morning dose of steroidal treatments will be administered after the 
1000 hours PD sample is collected on Day -6.  Subjects will be discharged on Day -6 after the 
last PD sample is collected. 
Subjects will be admitted to the study center on Days 1 and 14 (first and last day of dosing).  
Subjects will have a blood sample collected on Day 1 for 
.  Baseline safety 
assessments will be collected on Day 1 prior to the first dose of study drug.  The first dose of 
study drug, NBI-74788 50 mg, will be administered at approximately 1900 hours with subjects’ 
evening meal on Day 1.  Study drug will be administered at the study center on Days 2 and 14 
with subjects’ breakfast and evening meals, respectively.  The subjects’ usual morning dose of 
concurrent steroidal treatments, study drug dosing, and breakfast (snacks will be allowed prior to 
breakfast) will be delayed until after the 15-hour postdose PD samples are collected (ie, at 
approximately 1000 hours) on Day 2.  The subjects’ usual morning dose of concurrent steroidal 
treatments will be administered after the 15-hour postdose PD samples are collected (ie, at 
approximately 1000 hours) on Day 15.  Subjects will be discharged from the study center in the 
evening on Days 2 and 15 following completion of all study-related procedures for those days.  
Study drug will be self-administered at home under parent/guardian supervision at approximately 
0700 hours (with breakfast) and 1900 hours (with evening meal) on Days 3 to 13. 
On Day 7 during the treatment period, PK, PD, and safety assessments will be conducted in an 
outpatient setting at the study center. 
Follow-up visits on Days 17 and 21 will be conducted at the study center or by a qualified home 
healthcare provider at the subject’s home (based on the subject’s preference).  A final study visit 
will be conducted at the study center approximately 3 weeks after the last dose of study drug (on 
Day 35 or early termination).  There will be a visit window of -8 hours for Day 7, -8 hours/+3 
days for Days 17 and 21, and +7 days for the final study visit (Day 35 or early termination).  
Safety, tolerability, PK, and PD will be assessed at scheduled times throughout the study. 
The study design schematic is shown in Figure 1.  A schematic of study drug dosing and blood 
draw timepoints is shown in Table 1. 


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Figure 1: 
Study Design Schematic 
 
bid=twice daily; ET=early termination; PD=pharmacodynamic. 
Screening
PD Baseline
14-Day Dosing Period
Final Study 
Visit/ET
Follow-Up 
Period
Day
-28 to -8
-7 to -6
1
15
2
14
7
35
17
21
NBI-74788
(50 mg bid)


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Table 1: 
Study Drug Dosing and Blood Draw Timepoints Schematic 
Screening 
PD 
Baseline 
(Day -7) 
PD 
Baseline 
(Day -6) 
Day 1 
Day 2 
Day 3 
– Day 
6 
Day 7 
Day 8 
– Day 
13 
Day 14 
Day 15 
Day 
17 
Day 21 
Day 35 
 
 
PD:  
0100, 
0300, 
0700 hr 
 
PK/PD:  8, 
12 hr post 
 
PK/PD:  
Predose 
 
 
PK/PD:  8, 
12 hr post 
 
 
 
AM DOSING 
1000 hr 
Delayed 
Dosing 
with Meal 
0700 hr 
0700 hr 
0700 hr 
0700 hr 
 
PD/Labs:  
0700 – 
1000 hr 
(+ 
 & 
Serology) 
 
PD:  
1000, 
1500, 
1900 hr 
PK/PD/Labs:  
Predose 
+
 
 
PD:  15, 20, 
24 hr post 
 
 
 
PK/PD:  
Predose 
PD:  15, 
20 hr post 
PK/PD/Labs:  
24 hr post 
PK:  
72 hr 
post 
PK/PD:  
168 hr 
post 
PK/Labs:  
504 hr 
post 
PM DOSING 
1900 hr 
1900 hr 
1900 hr 
1900 hr 
1900 hr 
1900 hr 
 
 
PD:  
1845, 
2000, 
2300 hr 
 
PK/PD:  1, 
4, 6 hr post 
 
 
 
 
PK/PD:  
1, 4, 6 hr 
post 
 
 
 
 
 PD=pharmacodynamic; PK=pharmacokinetic. 
Note:  blood draws (pre- and post-dose) are relative to evening dosing. 
 


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7. 
STUDY POPULATION 
This study will be conducted in approximately 12 pediatric female and male subjects (14 to 
17 years of age) with a documented medical diagnosis of classic 21-hydroxylase deficiency 
CAH.  Subjects must meet all inclusion criteria and no exclusion criteria in order to be enrolled.  
7.1. 
Subject Inclusion Criteria 
To participate in this study, subjects must meet the following criteria:  
1. Have documentation of informed consent by the subject's parent(s) or legal guardian, and of 
assent by the study subject. 
2. Be female or male between 14 to 17 years of age (inclusive).  
3. Have a body weight (in kg) greater than or equal to the 10th percentile of his/her age- and 
gender-matched weight percentile at screening. 
4. Be in good general health, as determined by medical history, physical examination, clinical 
laboratory assessments, and 12-lead ECG. 
5. Have a medically confirmed diagnosis of classic 21-hydroxylase deficiency CAH that 
includes a serum 17-OHP level of ≥800 ng/dL at screening.  A medically confirmed 
diagnosis will be satisfied if the subject is able to provide a medical record of the CAH 
diagnosis or the investigator can confirm the CAH diagnosis. 
6. Have a serum cortisol concentration <5 μg/dL and plasma ACTH concentration ≥20 pg/mL 
at screening, consistent with the classic 21-hydroxylase deficiency CAH diagnosis. 
7. Be on a stable regimen of steroidal treatment for CAH
 
 
 that is expected to remain 
stable throughout the study.  
 
 
 
8. Subjects of childbearing potential must agree to use contraception consistently from 
screening until 30 days (females) or 90 days (males) after the last dose of study drug.  A 
female subject of childbearing potential is defined as a female capable of becoming pregnant, 
which includes subjects who have had their first menstrual cycle (ie, menarche) and are not 
surgically sterile (ie, bilateral oophorectomy, hysterectomy or bilateral tubal ligation for at 
least 3 months prior to screening).  A male subject of childbearing potential is defined as a 
subject who has reached spermarche and has not been vasectomized for at least 3 months 
prior to screening. 
 
 
 
 
 
 
  


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9. Female subjects of childbearing potential must have a negative serum β-human chorionic 
gonadotropin (β-hCG) pregnancy test at screening and negative urine pregnancy test at Day 1 
(baseline).    
10. Subjects must have a negative urine drug screen (negative for amphetamines, barbiturates, 
benzodiazepine, phencyclidine, cocaine, opiates, or cannabinoids) and negative alcohol 
breath test at screening, at the start of the 24-hour PD baseline period (Day -7), and on Day 1 
(Day -7 and Day 1 eligibility based on urine drug screen and alcohol breath test conducted at 
the site).  Subjects with a positive urine drug screen due to a stable medication regimen to 
treat a medical condition may participate in the study. 
11. Be willing and able to adhere to the study regimen and study procedures described in the 
protocol and informed consent/assent forms, including all requirements at the study center 
and return for the follow-up visits. 
7.2. 
Subject Exclusion Criteria 
Subjects will be excluded from the study if they: 
1. Are currently pregnant or lactating. 
2. Are unable to swallow the study drug capsule. 
3. Have a clinically significant unstable medical condition or chronic disease (including history 
of neurological, hepatic, renal, cardiovascular, gastrointestinal, pulmonary, psychiatric or 
endocrine disease [excluding CAH]), or malignancy that could confound interpretation of 
study outcome. 
4. Had a clinically significant illness within 30 days of screening. 
5. Have a known or suspected differential diagnosis of any of the other known classic forms of 
CAH including
 
 
6. Have a history that includes bilateral adrenalectomy, hypopituitarism, or other condition 
requiring daily therapy with orally administered glucocorticoids (eg, asthma, arthritis, or 
systemic lupus erythematosus). 
7. Have any clinically significant acute or unstable chronic abnormal finding in physical 
examination, neurological assessment, vital signs, ECGs, or clinical laboratory tests, as 
determined by the investigator. 
8. Have a history of epilepsy or serious head injury (eg, traumatic brain injury or post-
concussive syndrome). 


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9. Have a known history of long QT syndrome or cardiac tachy-arrhythmia. 
10. Have a screening or Day 1 (baseline) average ECG QT interval corrected for heart rate using 
Fridericia’s correction (QTcF) of >450 msec or the presence of any clinically significant 
cardiac abnormality. 
11. Have an exaggerated pharmacological sensitivity (ie, hypersensitivity) to any corticotropin 
releasing hormone (CRH) antagonists. 
12. Test positive at screening for hepatitis B surface antigen (HBsAg), hepatitis C antibody 
(HCV-Ab), or human immunodeficiency virus antibody (HIV-Ab) or have a history of a 
positive result. 
18. Have used any other investigational drug within 30 days or 5 half-lives (whichever is longer) 
before initial screening or plan to use an investigational drug (other than the study drug) 
during the study. 
19. Currently use any excluded concomitant medication (refer to Section 8.9.1) and cannot 
discontinue use of these medications for the duration of the study. 


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20. Have a history of substance (drug or alcohol) dependence or abuse within the 3 months 
before Day 1 (baseline), as defined in the Diagnostic and Statistical Manual of Mental 
Disorders (DSM)-IV (Substance Dependence or Abuse) or DSM-5 (Substance Use 
Disorder). 
21. Have ingested foods containing poppy seeds within 7 days before screening, the start of the 
24-hour PD baseline period (Day -7), and Day 1. 
 
23. Have had a blood loss ≥250 mL due to a surgical procedure or blood donation within 56 days 
before Day 1 (baseline). 
24. Have a significant risk of suicidal or violent behavior.  Subjects will be excluded if they 
have: 
• Any lifetime history of suicidal behavior or 
• Suicidal ideation of type 4 (active suicidal ideation with some intent to act, without 
specific plan) or type 5 (active suicidal ideation with specific plan and intent) in the 
1 year before screening based on the Columbia-Suicide Severity Rating Scale (C-SSRS) 
Children’s Version. 
25. In the investigator’s opinion, the subject is not capable of adhering to the protocol 
requirements.  
7.3. 
Subject Identification and Replacement 
Subjects will be identified during the study by a unique subject identification number.  The 
identification number will be written on all source documentation and laboratory specimens and 
populated on all electronic Case Report Forms (eCRFs).  Subjects who discontinue the study due 
to causes other than TEAEs may be replaced. 
7.4. 
Randomization  
This is a single-arm study. 
8. 
STUDY EVALUATIONS 
8.1. 
Schedule of Assessments 
Table 2 summarizes the frequency and timing of all study assessments and procedures for the 
study.  Parent(s) or legal guardian(s) will provide informed consent with signed (or verbal, if 
applicable) and witnessed study subject assent before the performance of any study-related 
procedures.  Subject-related activities and events including specific instructions, procedures, 
concomitant medications, dispensing of study drug, and descriptions of AEs will be recorded in 
the appropriate source documents and eCRFs. 


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Table 2: 
Schedule of Assessments 
Assessment 
Screening 
PD Baseline 
14-Day Dosing Period 
Follow-Up Period 
Final Study Visita 
Study Day  
-28 to -8 
-7 to -6 
1b 
2 
3-6 
7 
8-13 
14 
15 
17 
21 
35 (+7 days) 
Informed consent and assent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
Update 
Update 
 
 
 
 
 
 
 
 
 
Medical history 
X 
Update 
Update 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
X 
X 
 
X 
 
 
X 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
X 
Weight 
X 
 
X 
 
 
 
 
 
X 
 
 
X 
Vital signs 
X 
X 
X 
Xc 
 
X 
 
X 
Xc 
 
 
X 
12-lead ECGd 
X 
 
X 
X 
 
 
 
X 
X 
 
 
X 
Pregnancy teste 
X(s) 
X(u) 
X(u) 
 
 
X(u) 
 
 
X(u) 
 
 
X (u) 
Serology (HBsAg, HCV-Ab and HIV-Ab) 
X 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory testf 
X 
 
X 
 
 
 
 
 
X 
 
 
X 
UDS and alcohol breath testh 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
PD blood samplesi 
X 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
C-SSRS, Children’s Version 
X 
 
X 
 
 
 
 
 
X 
 
 
X 
PK plasma samplesk 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Study drug dosingl 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Subject study diarym 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Study drug reconciliationn 
 
 
 
 
 
X 
 
X 
 
 
 
 
AE monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Outpatient visit 
X 
 
 
 
 
Xo 
 
 
 
Xp 
Xp 
X 
Inpatient center stays 
 
X 
X 
X 
 
 
 
X 
X 
 
 
 
Definitions: 17-OHP=17-hydroxyprogesterone; ACTH=adrenocorticotropic hormone; AE=adverse event; 
; 
C-SSRS=Columbia-Suicide Severity Rating Scale; 
 ECG=electrocardiogram; HBsAg=hepatitis B surface antigen; HCV-Ab=hepatitis C 
virus antibody; HIV-Ab=human immunodeficiency virus antibody; PD=pharmacodynamic; PK=pharmacokinetic; s=serum; u=urine; UDS=urine drug screen. 
Footnotes are on the following page. 
 


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a Final study visit for subjects who complete the study (or early termination). The final study visit will be conducted approximately 3 weeks (+7 days) after the last dose of study 
drug. 
b Day 1 occurs 1 week after the Day -7 visit. Day 1 assessments will be collected predose unless otherwise noted below. Safety assessments collected predose on Day 1 will serve 
as the baseline. 
c Vital signs will be collected on Days 2 and 15 between 8 and 10 and 22 and 24 hours post-evening dose (ie, morning and evening). 
d A standard 12-lead ECG will be conducted in triplicate (1 to 3 minutes apart) after subject has rested supine for at least 5 minutes at screening, pre-evening dose on Days 1 and 
14, prior to visit completion or discharge on Days 2 and 15, and at the final study visit (Day 35 or early termination). 
e Pregnancy tests will be conducted for female subjects of childbearing potential.  A serum pregnancy test will be conducted at screening, and urine pregnancy tests will be 
conducted at other timepoints.  The pregnancy test will be conducted prior to dosing on Day 1 (for eligibility). 
f Includes hematology, clinical chemistry (including creatine kinase, myoglobin, total and conjugated bilirubin), and urinalysis (including quantitative myoglobin, casts and 
crystals).  Samples will be obtained under nonfasted conditions. 
 
 
h Urine testing kits will be provided by the central laboratory to confirm negative drug screen prior to Day -7 PD collection and Day 1 dosing.  Separate urine sample will also be 
sent to the central laboratory for analysis. 
i Blood samples for analyses of 17-OHP, androstenedione, testosterone, cortisol, and ACTH will be collected at the following times: 
• Screening (between 0700 and 1000 hours; must be collected prior to first morning dose of hydrocortisone). 
• Day -7 to Day -6 (24-hour PD baseline):  at approximately 1845, 2000, 2300, 0100, 0300, 0700, 1000, 1500, and 1900 hours. 
• Days 1 and 14: 15 minutes pre-evening dose and at 1, 4, and 6 hours post-evening dose (±5 minute window). 
• Days 2 and 15:  8, 12, 15, 20, and 24 hours post-evening dose (±15 minute window).  The subjects’ usual morning dose of concurrent steroidal treatments, study drug dosing, 
and breakfast (snacks will be allowed prior to breakfast) will be delayed until after the 15 hour postdose PD samples are collected (ie, at approximately 1000 hours) on Day 2.  
The subjects’ usual morning dose of concurrent steroidal treatments will be administered after the 15 hour postdose samples are collected (ie, at approximately 1000 hours) on 
Day 15. 
• Day 7:  12 hours (±2 hour window) after the Day 6 evening dose and prior to the Day 7 morning dose (study drug dosing should not occur until after the blood sample has been 
collected). 
• Day 21:  168 hours (-8 hours/+3 days) following last dose. 
 
 
k Pharmacokinetic plasma samples will be collected at the following times: 
• Days 1 and 14: 15 minutes pre-evening dose and at 1, 4, and 6 hours post-evening dose (±5 minute window). 
• Days 2 and 15:  8, 12, and 24 hours post-evening dose (±15 minute window; 24-hour post-evening dose blood sample on Day 15 only). 
• Day 7:  12 hours (±2 hour window) after the Day 6 evening dose, prior to the Day 7 morning dose (study drug dosing should not occur until after the blood sample has been 
collected). 
• Days 17 and 21:  72 hours (-8 hours/+3 days) and 168 hours (-8 hours/+3 days) post-final dose. 
• Final study visit (+7 days; Day 35 or early termination). 
l The first dose of study drug will be administered at approximately 1900 hours with subjects’ evening meal on Day 1.  Study drug will be administered at the study center on Days 
2 and 14 with subjects’ breakfast and evening meals, respectively.  The subjects’ usual morning dose of concurrent steroidal treatments, study drug dosing, and breakfast (snacks 
will be allowed prior to breakfast) will be delayed until after the 15-hour postdose PD samples are collected (ie, at approximately 1000 hours) on Day 2.  Study drug will be self-
administered at home under parent/guardian supervision at approximately 0700 hours (with breakfast) and 1900 hours (with evening meal) on Days 3 to 13. 
m Subject study diary will be provided to subjects on Day 1 prior to dosing.  The date and time of study drug administration, the number of capsules taken, and confirmation that 
study drug was taken with breakfast and the evening meal will be documented each day.  The diary will be reviewed for completeness at the Day 7 visit.  The subject will return 
the diary at the Day 14 visit. 
n A compliance check will be performed by counting the number of capsules returned. 
o Sites should call subjects between the Day 2 and Day 7 visits to remind them to complete the subject study diary, check on compliance, and remind them to bring subject study 
diary and remaining study drug to the Day 7 visit.  
p Subjects will have the option of having the Days 17 and 21 assessments conducted at home by a qualified home healthcare provider or at the study center.


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8.2. 
Screening and Baseline Assessments 
8.2.1. 
Serum 17-Hydroxyprogesterone 
A blood sample will be collected at screening (approximately 7 mL) to measure morning serum 
17-OHP (and other PD analytes) between 0700 and 1000 hours (prior to first morning dose of 
hydrocortisone) to determine subject eligibility.  Subjects must have serum 17-OHP level of 
≥800 ng/dL at screening to be eligible for study enrollment. 
8.2.2. 
 
  
 
8.3. 
Pharmacokinetic Assessments  
Approximately 2 mL of blood will be collected for each sample.  PK samples will be sent to a 
central laboratory which will provide instructions and supplies to the study staff before study 
initiation. 
For blood sample collection performed while subjects are asleep, every effort should be made to 
minimize disturbances to the subjects. 
PK plasma samples for analyses of NBI-74788 will be collected at the following times:   
• Days 1 and 14: 15 minutes pre-evening dose and at 1, 4, and 6 hours post-evening dose 
(±5 minute window). 
• Days 2 and 15:  8, 12, and 24 hours post-evening dose (±15 minute window; 24-hour post-
evening dose blood sample on Day 15 only). 
• Day 7:  12 hours (±2 hour window) after the Day 6 evening dose, prior to the Day 7 
morning dose (study drug dosing should not occur until after the blood sample has been 
collected). 
• Days 17 and 21:  72 hours (-8 hours/+3 days) and 168 hours (-8 hours/+3 days) post-final 
dose. 
• Final study visit (+7 days; Day 35 or early termination). 
The exact time of sampling in hour and minutes will be recorded. 
The blood samples will be processed to plasma, which will be stored as specified in the 
laboratory manual.  These samples will be shipped on dry ice to the central laboratory for 
analysis.  Refer to the laboratory manual for additional details. 
Plasma samples remaining at the end of the study may be used for exploratory assessments of 
NBI-74788 metabolites.  
An in-home service (phlebotomist) will be available for blood draws on Days 17 and 21. 


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8.4. 
Pharmacodynamic Assessments: Pharmacodynamic Biomarkers 
Approximately 7 mL of blood will be collected for each sample.  PD biomarker samples will be 
sent to a central laboratory which will provide instructions and supplies to the study staff before 
study initiation.   
Blood samples to measure cortisol (serum; μg/dL), 17-OHP (serum; ng/dL), androstenedione 
(serum; ng/dL), testosterone (serum; ng/dL), and ACTH (plasma; pg/mL) will be collected at: 
• Screening (between 0700 and 100 hours; must be collected prior to first morning dose of 
hydrocortisone). 
• Day -7 to Day -6 (24-hour PD baseline):  at approximately 1845, 2000, 2300, 0100, 0300, 
0700, 1000, 1500, and 1900 hours. 
• Days 1 and 14: 15 minutes pre-evening dose and at 1, 4, and 6 hours post-evening dose (±5 
minute window). 
• Days 2 and 15:  8, 12, 15, 20, and 24 hours post-evening dose (±15 minute window). 
• Day 7:  12 hours (±2 hour window) after the Day 6 evening dose and prior to the Day 7 
morning dose (study drug dosing should not occur until after the blood sample has been 
collected). 
• Day 21:  168 hours (-8 hours/+3 days) following last dose. 
The exact time of sampling in hour and minutes will be recorded. 
The blood samples will be processed and stored as specified in the laboratory manual.  These 
samples will be shipped on dry ice to the central laboratory for analysis.  Refer to the laboratory 
manual for additional details. 
An in-home service (phlebotomist) will be available for blood draws on Day 21. 
8.5. 
Safety Assessments 
Concomitant medication use and AEs will be monitored throughout the study as described in 
Section 8.9.1 and Section 10, respectively.  Additional safety assessments are described in the 
following sections. 
Appropriate psychiatric evaluation and intervention will be provided for any treatment-emergent 
suicidal behavior or clinically significant suicidal ideation. 
For any abnormal safety assessment deemed clinically significant, the investigator will perform 
appropriate follow-up assessments (eg, repeat analysis), until the cause of the abnormality is 
determined and/or until the value returns to baseline (or within normal limits), or the investigator 
deems the abnormality to be of no clinical significance. 
8.5.1. 
Vital Sign Measurements 
Vital sign measurements, including orthostatic systolic and diastolic blood pressures, orthostatic 
heart rate, respiratory rate, and oral body temperature will be conducted.  Blood pressure will be 
measured using a calibrated automatic blood pressure cuff after the subject has been supine for at 


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least 5 minutes and after approximately 2 minutes of standing.  The automatic blood pressure 
cuff will also provide pulse rate measurement. 
As much as possible, vital sign measurements will be collected before scheduled blood sample 
collection.  Vital sign measurements will be collected at the following times: 
• Screening. 
• Day -7 (PD baseline). 
• Day 1. 
• Day 2 (between 8 and 10 and 22 and 24 hours post-evening dose [ie, morning and evening]). 
• Day 7. 
• Day 14. 
• Day 15 (between 8 and 10 and 22 and 24 hours post-evening dose [ie, morning and 
evening]). 
• Day 35 (or early termination). 
8.5.2. 
Medical History and Physical Examination 
A medical history will be taken at the screening visit and updated on Day -7 and Day 1. 
A complete physical examination will be conducted at screening and on Days 1, 2, 7, 15, and 35 
(or early termination).  The complete physical examination will consist of an assessment of 
general appearance, skin and mucosae, head, eyes, ears, nose, throat, neck (including thyroid), 
lymph nodes, chest/lungs, cardiovascular, abdomen, extremities, neurological and 
musculoskeletal systems.  Height and weight will be measured with subjects not wearing shoes.  
Height will be measured at screening and Day 35 (or early termination).  Weight will be 
measured at screening and on Days 1, 15, and 35 (or early termination).  
8.5.3. 
12-Lead Electrocardiogram 
12-lead ECG will be conducted in triplicate (1 to 3 minutes apart) after the subject has rested 
supine for at least 5 minutes at the following times: 
• Screening. 
• Days 1 and 14 (pre-evening dose). 
• Days 2 and 15:  prior to visit completion or discharge. 
• Day 35 (or early termination). 
The ECG parameters that will be assessed include heart rate, PR interval, QRS duration, QT 
interval, and QTcF (machine readings).  Additionally, the occurrence of de- and re-polarization 
and rhythm disorders or other abnormalities will be assessed.  Based on the review of these 
parameters, the investigator or designee will note if the ECG is Normal, Abnormal Not Clinically 
Significant, or Abnormal Clinically Significant.  If the ECG is Abnormal Clinically Significant, 
the investigator will provide a description of the abnormality recorded on the AE eCRF. 


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8.5.4. 
Clinical Laboratory Assessments 
All clinical laboratory assessments will be conducted by a central laboratory, which will provide 
instructions and supplies to the study staff before study initiation.  The instructions will be 
included in a laboratory manual.  The laboratory test battery will include routine and screening 
laboratory tests.  Samples will be obtained under nonfasted conditions. 
Clinical laboratory assessments will be conducted at the following times: 
• Screening.  
• Day 1. 
• Day 15. 
• Day 35 (or early termination; 
). 
The following clinical safety laboratory assays will be conducted: 
Hematology:  complete blood count including WBC count with differential, red blood cell count, 
hemoglobin, hematocrit, platelet count, mean corpuscular hemoglobin (MCH), mean corpuscular 
volume (MCV), mean corpuscular hemoglobin concentration (MCHC), red cell distribution 
width (RDW), mean platelet volume (MPV). 
Clinical chemistry:  sodium, potassium, calcium, magnesium, chloride, blood urea nitrogen, 
bicarbonate, creatinine, uric acid, albumin, alkaline phosphatase, lactate dehydrogenase, AST, 
ALT, gamma-glutamyl transferase (GGT), CK, myoglobin, total and conjugated bilirubin, total 
cholesterol, triglycerides, total protein, and glucose. 
Urinalysis:  specific gravity, nitrite, ketones, protein, urobilinogen, glucose, bilirubin, leukocyte 
esterase, occult blood, pH, and quantitative myoglobin.  Microscopic examination of sediment 
will include evaluation for casts and crystals. 
The following additional laboratory tests will be conducted: 
 
Serology:  Blood will be collected for HBsAg, HCV-Ab, and HIV-Ab testing at screening. 
Urine drug screen and alcohol breath test:  The urine drug screen will test for amphetamines 
barbiturates, phencyclidine, benzodiazepines, cannabinoids, cocaine, and opiates.  A urine drug 
screen and alcohol breath test will be conducted at screening, Day -7, Day 1, and Day 14.  Urine 
testing kits will be provided by the central laboratory to confirm negative drug screen prior to 
Day -7 PD collection and Day 1 dosing.  Separate urine sample will also be sent to the central 
laboratory for analysis. 
Pregnancy test:  Pregnancy tests will be conducted for female subjects of childbearing potential.  
Serum pregnancy tests (β-hCG) will be conducted at screening and urine pregnancy tests will be 
conducted on Day -7, prior to dosing on Day 1 (for eligibility), Day 7, Day 15, and at the final 
study visit (Day 35 or early termination). 


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For any abnormal tests deemed clinically significant, repeat analysis will be conducted until the 
cause of the abnormality is determined or until the value returns to baseline (or within normal 
limits), or the investigator deems the abnormality to be of no clinical significance. 
8.5.5. 
Brief Psychiatric Rating Scale for Children 
The Brief Psychiatric Rating Scale for Children (BPRS-C) was created to provide a concise 
profile of childhood behavioral and emotional symptomatology (Hughes et al., 2001; 
Overall and Pfefferbaum, 1982).  The BPRS-C includes 21 items that assess behavioral 
problems, depression, thinking disturbance, psychomotor excitation, withdrawal, anxiety, and 
organicity.  The severity of each of the 21 items of the BPRS-C is rated on a scale of 0 (not 
present) to 6 (extremely severe) (total score range:  0 to 126).  Higher scores represent greater 
symptom severity. 
 
 
 
8.5.6. 
Columbia-Suicide Severity Rating Scale Children’s Versions 
The C-SSRS is a validated instrument to prospectively assess suicidal ideation and behavior 
(http://www.cssrs.columbia.edu).  There are versions of the questionnaire designed for use at 
screening (Children’s Screening/Baseline version) and at visits throughout the study (Children’s 
Since Last Visit version).  All versions of the C-SSRS include a series of screening questions 
related to suicidal ideation and suicidal behavior.  Subject responses of ‘yes’ to one or more 
screening questions will prompt additional questions that evaluate frequency and intensity of 
suicidal ideation and/or behavior.  Subjects with any suicidal behavior or suicidal ideation of 
type 4 (active suicidal ideation with some intent to act, without specific plan) or type 5 (active 
suicidal ideation with specific plan and intent) in the past 1 year before screening based on the 
C-SSRS Children’s Version should be excluded (see exclusion criterion #24). 
The C-SSRS will be administered and scored by the investigator or other qualified site personnel 
who completed C-SSRS certification.  The C-SSRS will be administered at screening, Day 1, 
Day 15, and at the final study visit (Day 35 or early termination).  The “Children’s 
Screening/Baseline” version of the scale will be used to evaluate subject eligibility at screening 
and the “Children’s Since Last Visit” version will be used at all other times. 
8.5.7. 
Estimated Total Blood Sample Volume Required by Study 
The estimated total blood sample volume for each subject for the entire study is presented in 
Table 3.  These estimates include samples to be collected during screening and throughout the 
study. 


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Table 3: 
Estimated Total Blood Sample Volume 
Parameter 
Number of Samples 
Required 
Approximate Volume 
(mL) 
Approximate Total Volume 
(mL) 
Clinical laboratorya 
4 
7 
28 
 
3 
4.5 
13.5 
Serology 
1 
9 
9 
 
1 
2 
2 
Pharmacodynamics 
30 
7 
210 
Pharmacokinetics  
17 
2 
34 
Approximate Maximum Total Blood Sample Volume per Subject (mL): 
296.5 
a Includes clinical chemistry, hematology, and serum pregnancy samples. 
8.6. 
Subject Study Diary 
The site will provide each subject with a subject study diary on Day 1 prior to dosing.  The date 
and time of study drug administration, the number of capsules taken, and confirmation that study 
drug was taken with breakfast and evening meal will be documented each day.  The diary will be 
reviewed for completeness at the Day 7 visit.  The subject will return the diary at the Day 14 
visit. 
8.7. 
Specific Study Period Information 
8.7.1. 
Screening Period (Study Days -28 to -8) 
After obtaining informed consent by the subject’s parent(s) or legal guardian, and study subject 
assent, subjects will undergo screening procedures within 21 days of Day -7.   
The following study evaluations and tasks will be performed during screening:  
• Assess inclusion/exclusion criteria. 
• Collect medical history. 
• Perform a physical examination including height and weight. 
• Collect vital signs. 
• Perform 12-lead ECG in triplicate (1 to 3 minutes apart). 
• Perform a serum pregnancy test (β-hCG) for female subjects of childbearing potential. 
• Collect blood sample for serology testing (HIV-Ab, HBsAg, and HCV-Ab). 
• Collect blood sample for clinical laboratory and 
 parameters. 
• Collect urine sample for urinalysis. 
• Collect urine for drug screen (central laboratory) and perform alcohol breath test. 


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• Collect blood sample for PD biomarkers between 0700 and 1000 hours (prior to first morning 
dose of hydrocortisone).  Subject must have serum 17-OHP level ≥800 ng/dL to be enrolled 
in the study. 
• Administer the C-SSRS (Children’s Screening/Baseline version). 
• AE monitoring. 
• Record prior and concomitant medications. 
Eligible subjects will be instructed to return to the study center on Day -7. 
8.7.2. 
Day -7 to Day -6:  24-Hour Baseline Pharmacodynamics  
Subjects who continue to meet eligibility requirements will return to the study center for a 
24-hour in-patient stay, during which blood samples will be collected for PD analysis.  Subjects 
will not take their usual morning dose of steroidal treatment until after the 1000 hours PD sample 
is collected on Day -6. 
The following study evaluations and tasks will be performed on Day -7 to Day -6:  
• Update inclusion/exclusion criteria and medical history. 
• Collect vital signs. 
• Perform a urine pregnancy test (β-hCG) for female subjects of childbearing potential. 
• Collect urine for drug screen and perform alcohol breath test.  Urine testing kits will be 
provided by the central laboratory to confirm negative drug screen prior to PD collection.  A 
separate urine sample will also be sent to the central laboratory for analysis. 
• Collect blood samples for PD biomarkers at approximately 1845, 2000, 2300, 0100, 0300, 
0700, 1000, 1500, and 1900 hours. 
• AE monitoring. 
• Record prior and concomitant medications. 
Eligible subjects will be instructed to return to the study center on Day 1. 
8.7.3. 
Treatment Period 
The study will consist of a 14-day treatment period and will include 2 overnight in-patient stays 
(on Day 1 to Day 2 and Day 14 to Day 15) and a study center visit on Day 7.   
8.7.3.1. 
Day 1 to Day 2 
Subjects will be admitted to the study center on Day 1 and will be discharged in the evening of 
Day 2 after the 24-hour postdose procedures have been performed.  Standard meals and snacks 
will be provided during the in-patient stay.  The procedures to be conducted on these days are 
described in the following sections. 


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Day 1 
Subjects will report to the study center on Day 1.  The following study evaluations and tasks will 
be performed prior to dosing on Day 1: 
• Update inclusion/exclusion criteria and medical history. 
• Perform a physical examination including weight.  
• Collect vital signs.  
• Perform 12-lead ECG in triplicate (1 to 3 minutes apart).  
• Perform a urine pregnancy test (β-hCG) for female subjects of childbearing potential.  
• 
  
• Collect blood sample for clinical laboratory and 
 parameters.  
• Collect urine sample for urinalysis.  
• Collect urine for drug screen and perform alcohol breath test. Urine testing kits will be 
provided by the central laboratory to confirm negative drug screen prior to dosing. A separate 
urine sample will also be sent to the central laboratory for analysis.  
• Collect blood sample for PD biomarkers at 15 minutes predose (±5 minute window).  
• Collect blood sample for PK at 15 minutes predose (±5 minute window).  
• 
  
• Administer the C-SSRS (Children’s Since Last Visit version). 
• AE monitoring. 
• Record prior and concomitant medications.  
• Provide subject with a subject study diary and instruct him/her to document in the diary the 
date and time of study drug administration, the number of capsules taken, and confirmation 
that study drug was taken with breakfast and evening meal each day. 
At approximately 1900 hours, each subject will receive study drug with the evening meal as 
described in Section 9.3. 
The following study evaluations and tasks will be performed after dosing on Day 1 while the 
subject remains in bed (as applicable): 
• Collect blood samples for PD biomarkers at 1, 4, and 6 hours postdose (±5 minute window). 
• Collect blood samples for PK at 1, 4, and 6 hours postdose (±5 minute window). 
• AE monitoring. 
• Record concomitant medications. 


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Day 2 
The subjects’ usual morning dose of concurrent steroidal treatments, study drug dosing, and 
breakfast (snacks will be allowed prior to breakfast) will be delayed until after the 15 hour 
postdose PD samples are collected (ie, at approximately 1000 hours).  
The following study evaluations and tasks will be performed on Day 2: 
• Perform a physical examination. 
• Collect vital signs between 8 and 10 and 22 and 24 hours post-evening dose (ie, morning and 
evening). 
• Perform 12-lead ECG in triplicate (1 to 3 minutes apart) predose. 
• Collect blood samples for PD biomarkers at 8, 12, 15, 20, and 24 hours post-evening dose 
(±15 minute window). 
• Collect blood samples for PK at 8 and 12 hours post-evening dose (±15 minute window). 
• 
 
• AE monitoring.  
• Record concomitant medications. 
The following procedures will be conducted before subjects may be discharged from the study 
center:  
• At approximately 1900 hours, each subject will receive study drug with their evening meal as 
described in Section 9.3. 
• Instruct male subjects and female subjects of childbearing potential who do not practice total 
abstinence to continue using contraception. 
• Instruct subjects to notify the investigator or study staff by telephone if they experience any 
AEs and before taking any concomitant medications. 
• Instruct subjects to continue taking study drug with breakfast (approximately 0700 hours) 
and with their evening meal (approximately 1900 hours) through Day 13 as described in 
Section 9.3, and to document in the diary the date and time of study drug administration, the 
number of capsules taken, and confirmation that study drug was taken with breakfast and the 
evening meal each day. 
• Instruct subjects to bring the subject study diary as well as the remaining study drug back for 
the Day 7 visit. 
Sites should call subjects between the Day 2 and Day 7 visits to remind them to complete the 
subject study diary, check on compliance, and remind them to bring subject study diary and 
remaining study drug to the Day 7 visit. 


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8.7.3.2. 
Day 7 
The following procedures will be performed at the study center on Day 7: 
• Perform a physical examination. 
• Collect vital signs. 
• Perform a urine pregnancy test (β-hCG) for female subjects of childbearing potential.  
• Collect blood samples for PD biomarkers at approximately 12 hours (±2 hour window) after 
the Day 6 evening dose and prior to the Day 7 morning dose. 
• Collect blood samples for PK at approximately 12 hours (±2 hour window) after the Day 6 
evening dose and prior to the Day 7 morning dose. 
• Check subject study diary. 
• Study drug reconciliation. 
• AE monitoring. 
• Record concomitant medications. 
The following additional procedures will be conducted on Day 7:  
• Instruct subjects to perform study drug dosing (as described in Section 9.3) and subject study 
diary entry at home. 
• Instruct subjects to return to the study center on Day 14 before evening dosing and to bring 
their study drug bottle including any unused study drug, and their subject study diary. 
8.7.3.3. 
Day 14 to Day 15 
Subjects will return to the study center on Day 14 and will be discharged in the evening of 
Day 15 after the 24-hour postdose procedures have been performed.  Standard meals and snacks 
will be provided.  The procedures to be conducted on these days are described in the following 
sections. 
Day 14 
Subjects will return to the study center on Day 14.  The following study evaluations and tasks 
will be performed prior to evening dosing on Day 14: 
• Collect vital signs.  
• Perform 12-lead ECG in triplicate (1 to 3 minutes apart).  
• Collect blood sample for PD biomarkers at 15 minutes predose (±5 minute window).  
• Collect blood sample for PK at 15 minutes predose (±5 minute window).  
• Collect urine for drug screen and perform alcohol breath test.  
• 
 
• Collect the study drug bottle including any unused study drug. 


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• Study drug reconciliation. 
• AE monitoring.  
• Record concomitant medications.  
At approximately 1900 hours, each subject will receive study drug with their evening meal as 
described in Section 9.3.  After study drug dosing, subjects will record in the subject study diary 
the date and time of study drug administration, the number of capsules taken, and confirmation 
that study drug was taken with the evening meal.  The subject study diary will then be collected.  
Subjects will then go to bed. 
The following procedures will be conducted after evening dosing on Day 14 while the subject 
remains in bed (as applicable): 
• Collect blood samples for PD biomarkers at 1, 4, and 6 hours post-evening dose (±5 minute 
window). 
• Collect blood samples for PK at 1, 4, and 6 hours post-evening dose (±5 minute window). 
• AE monitoring. 
• Record concomitant medications. 
Day 15 
The subjects’ usual morning dose of concurrent steroidal treatments will be administered after 
the 15 hour postdose PD samples are collected (ie, at approximately 1000 hours) on Day 15.   
The following procedures will be performed on Day 15:  
• Perform a physical examination including weight. 
• Collect vital signs between 8 and 10 and 22 and 24 hours post-evening dose (ie, morning and 
evening). 
• Perform 12-lead ECG in triplicate (1 to 3 minutes apart). 
• Perform a urine pregnancy test (β-hCG) for female subjects of childbearing potential.  
• Collect blood sample for clinical laboratory and 
 parameters.  
• Collect urine sample for urinalysis.  
• Collect blood samples for PD biomarkers at 8, 12, 15, 20, and 24 hours post-evening dose 
(±15 minute window). 
• Collect blood samples for PK at 8, 12, and 24 hours post-evening dose (±15 minute window). 
• 
 
• Administer the C-SSRS (Children’s Since Last Visit version). 
• AE monitoring. 
• Record concomitant medications. 


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The following procedures will be conducted before subjects may be discharged from the study 
center:  
• Instruct male subjects and female subjects of childbearing potential who do not practice total 
abstinence to continue using contraception. 
• Instruct subjects to notify the investigator or study staff by telephone if they experience any 
AEs and before taking any concomitant medications. 
• Confirm if the subject prefers to have the Days 17 and 21 visits conducted at home instead of 
at the study center. 
− If the subject elects to have a home visit, instruct him/her that the qualified home 
healthcare provider will contact him/her to schedule the visit. 
− If the subject elects to come into the study center, instruct him/her to return on Days 17 
and 21. 
8.7.4. 
Follow-Up Period 
Follow-up visits will be conducted on Days 17 and 21 with a final study visit on Day 35 (or early 
termination).  Based on their preference, the subject will either come into the study center, or the 
qualified home healthcare provider will come to the subject’s home on Days 17 and 21.  The 
final study visit will be conducted at the study center. 
8.7.4.1. 
Follow-Up Visits:  Days 17 and 21  
The following procedures will be performed on Days 17 and 21 (-8 hours/+3 days):  
• Collect blood sample for PD biomarkers at approximately 168 hours (-8 hours/+3 days; 
Day 21 only) following the last dose.  
• Collect blood samples for PK at approximately 72 hours (-8 hours/+3 days) and 168 hours 
(-8 hours/+3 days) following the last dose. 
• AE monitoring.  
• Record concomitant medications. 
At each visit, subjects will be reminded to notify the investigator or study staff by telephone if 
they experience any AEs and before taking any concomitant medications.  
At the Day 21 visit, subjects will be reminded to report to the study center on Day 35 (+7 days) 
for the final study visit (or at early termination). 
8.7.4.2. 
Final Study Visit:  (Day 35 or Early Termination) 
Subjects will return to the study center for the final study visit (Day 35 or early termination 
[+7 days]). 
The following procedures will be conducted at the final study visit: 
• Perform a physical examination including height and weight. 


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• Collect vital signs.  
• Perform 12-lead ECG in triplicate (1 to 3 minutes apart). 
• Perform a urine pregnancy test (β-hCG) for female subjects of childbearing potential.  
• Collect blood sample for clinical laboratory parameters.  
• Collect urine sample for urinalysis.  
• Collect blood sample for PK.  
• 
  
• Administer the C-SSRS (Children’s Since Last Visit version). 
• AE monitoring. 
• Record concomitant medications.  
8.8. 
Study Duration 
The expected duration of study participation for each subject is approximately 9 weeks, 
including up to approximately 3 weeks for screening, a 24-hour PD baseline period 
(approximately 7 days prior to the first day of dosing), 14 days of dosing, and a follow-up period 
of approximately 3 weeks. 
8.9. 
Prohibitions and Restrictions 
8.9.1. 
Prior and Concomitant Medications 
All prescription and over-the-counter medications, dietary supplements (including vitamins), and 
herbal supplements taken by the subject during the 30 days before screening will be recorded on 
the Prior and Concomitant Medications page of the eCRF.   
Subjects must be on a stable regimen of steroidal treatment for CAH for a minimum of 30 days 
before PD baseline (Day -7) and the regimen should remain stable throughout the study.  
 
 
 
 
 
  Female 
subjects of childbearing potential may use hormonal contraception during the study if taken for 
at least 3 months prior to screening.  Subjects who are on stable medication regimens to treat 
stable medical conditions (other than CAH) are allowed to participate in the study. 
The following medications are prohibited from 30 days before screening until the final study 
visit (or early termination): 
• Orally administered glucocorticoids for indications other than CAH. 
 
 


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• As-needed doses of anxiolytics. 
 
 
 
Any concomitant medication taken during the study will be recorded on the Prior and 
Concomitant Medications page of the eCRF with indication, total daily dose, route, and dates of 
drug administration. 
Any additions, deletions, or changes in the dose of medications during the study should be 
recorded on the appropriate eCRF page. 
8.9.2. 
Dietary and Other Restrictions 
Subjects may be confined to the study center for approximately 24 hours three times during the 
study:  on Days -7 to -6 (for PD baseline sample collection), Days 1 to 2, and Days 14 to 15.  In 
these instances, subjects will be discharged from the study center after completion of the 
required procedures. 
 
  Foods containing poppy seeds are prohibited from 7 days before screening until the 
final study visit.  
Strenuous activity beyond what is customary for the subject is prohibited during the study. 
Subjects must not donate blood or blood products from 30 days before Day -7 until 30 days after 
the final study visit (or early termination).  Male subjects must agree to refrain from donating 
sperm for 90 days after the last dose of study drug. 
Participation in another investigational drug study is prohibited for at least 30 days after the last 
dose of study drug in the current study. 
8.10. 
Withdrawal Criteria 
8.10.1. 
Reasons for Withdrawal 
Subjects are free to discontinue their participation in the study at any time.  The investigator 
must withdraw any subject from the study if that subject requests to be withdrawn. 
The investigator must withdraw the subject from the study if the subject experiences any of the 
following: 
• If the type, frequency, or severity of any AE becomes unacceptable/intolerable. 
• QTcF value >500 msec (one or more value; cardiologist verified). 
• Is lost to follow up. 
• Subject is confirmed to be pregnant. 
The investigator or NBI may withdraw the subject from the study for other reasons as described 
below.  


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• Develops an ECG abnormality. 
• Liver function test values for AST or ALT exceed 2.5 times ULN, GGT exceeds 3 times 
ULN, or total bilirubin exceeds 2 times ULN. 
• Creatinine value exceeds 1.5 times ULN. 
 
 
 
 
 
 
 
 
• Positive urine drug screen or alcohol breath test. 
• Requires a medication that is prohibited by the protocol (refer to Section 8.9.1). 
All subjects prematurely discontinuing the study, regardless of cause, should have all early 
termination assessments performed (see Section 8.7.4.2). 
8.10.2. 
Handling of Withdrawals 
If a subject prematurely withdraws from the study, either at his/her request or at the 
investigator’s discretion, the investigator will record the reason for withdrawal on the relevant 
eCRF.  All subjects who withdraw from the study prematurely will be asked to have all early 
termination assessments performed within 4 weeks. 
It is crucial to obtain follow-up data for any subject withdrawn because of an AE, abnormal 
laboratory test, vital sign measurement, physical examination, or ECG finding.  In any case, 
every effort must be made to undertake safety follow-up procedures. 
8.10.3. 
Sponsor’s Termination of Study 
NBI reserves the right to discontinue the study at any time for clinical or administrative reasons.  
Such a termination must be implemented by the investigator if instructed to do so by NBI in a 
time frame that is compatible with the subjects’ well-being. 
9. 
STUDY DRUG 
NBI-74788 will be supplied as capsules containing 50 mg of NBI-74788 
 for oral 
administration. 
9.1. 
Study Drug Supplies 
NBI or its designee will provide the study center with sufficient capsule supplies for the 
completion of the study.  Study drug will be supplied in 
. 
9.2. 
Study Drug Packaging and Labeling 
All packaging and labeling operations will be conducted according to Good Manufacturing 
Practice (GMP) and GCP.  The study drug will be sent to designated staff at the study center who 


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must complete and return the Drug Supply Confirmation to NBI or its designee verifying the 
receipt of the drug. 
Study drug will be labeled with the following information, including, but not limited to:  protocol 
number, dosage form, route of administration, Sponsor name, and the statement “Caution – New 
Drug:  Limited by Federal law to investigational use.” 
9.3. 
Study Drug Administration 
Subjects will take a study drug capsule by mouth starting at approximately 1900 hours beginning 
on Day 1, and then at approximately 0700 hours and 1900 hours for 14 consecutive days.  Study 
drug will be administered at the study center on Days 2 and 14 with subjects’ breakfast and 
evening meals, respectively, and on Day 1 with subjects’ evening meal.  The subjects’ usual 
morning dose of concurrent steroidal treatments, study drug dosing, and breakfast (snacks will be 
allowed prior to breakfast) will be delayed until after the 15 hour postdose PD samples are 
collected (ie, at approximately 1000 hours) on Day 2. 
Each dose of study drug is to be administered a meal (breakfast or the evening meal); each meal 
should be completed within 
.  The date and time of study drug 
administration, the number of capsules taken, and confirmation that study drug was taken with 
breakfast and the evening meal will be documented each day.   
9.4. 
Study Drug Storage and Return 
NBI-74788 
 
 and in a locked area accessible only to the pharmacist or designee until dispensing.   
Study drug should be stored and inventoried according to applicable state and federal regulations 
and study procedures. 
Written documentation to account for study drug and study drug materials is mandatory; all 
unused study drug and study drug materials must be kept in a secure location for final 
accountability and reconciliation.  Returned study drug and study drug materials must be 
accounted for on a study drug return form provided by NBI or the designee.  The investigator 
must provide a written explanation for any destroyed or missing study drug or study drug 
materials. 
Returns will be shipped to NBI or its designee at the completion of the study according to 
instructions provided by NBI or its designee.  Study drug return forms must be completed for the 
shipment of returns and sent with the study drug and study drug materials.  One copy of the 
study drug return form will be retained in the investigator’s study file.  All returned study drug 
and study drug materials should be stored, inventoried, reconciled, and returned according to 
applicable state and federal regulations and study procedures. 
9.5. 
Blinding 
This is an open-label study. 


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9.6. 
Study Compliance and Accountability 
All doses of the study drug ingested in the study center will be taken in the presence of study 
center personnel who will check the subject’s hands and mouth to confirm that the dose has been 
swallowed.   
The quantity of study drug dispensed, used, and returned will be recorded on a dispensing log or 
otherwise documented.  The quantity of study drug lost or destroyed, must also be accounted for 
and documented.  The designated pharmacist or qualified personnel will be responsible for 
maintaining accurate records of the quantity and dates of all study drug supplies received, 
dispensed, and returned.   
The exact time of medication dosing will be recorded on the eCRF and in the subject diary. 
10. 
ADVERSE EVENTS 
All AEs, whether observed by the investigator, reported by the subject, noted from laboratory 
findings, or by other means, will be recorded from the time the subject has signed the ICF until 
the subject’s final study visit. 
10.1. 
Definition 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
AEs include, but are not limited to:  (1) a worsening or change in nature, severity, or frequency 
of conditions present at the start of the study; (2) subject deterioration due to primary illness; (3) 
intercurrent illness; and (4) drug interaction. 
All suicidal behaviors and clinically significant suicidal ideations will be documented as an AE. 
Subjects should be questioned in a general way, without asking about the occurrence of any 
specific symptom.  The investigator should attempt to establish a diagnosis of the event based on 
signs, symptoms, and/or other clinical information.  In such cases, the diagnosis should be 
documented as the AE and not the individual signs/symptoms.  Following questioning and 
evaluation, all AEs, whether believed by the investigator to be related or unrelated to the study 
drug, must be documented in the subject’s medical records, in accordance with the investigator’s 
normal clinical practice and on the AE eCRF.  Each AE is to be evaluated for duration, intensity, 
frequency, seriousness, outcome, other actions taken, and relationship to the study drug.  
The following are not considered AEs: 
• Continuous persistent disease/symptom present before drug administration, unless it 
unexpectedly progresses, or increases in severity following drug administration. 
• Pregnancy. 


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10.2. 
Intensity of Adverse Events 
AEs must be graded for intensity.  An intensity category of mild, moderate, or severe, as defined 
in Table 4, must be entered on the AE eCRF.  It should be noted that the term “severe” used to 
grade intensity is not synonymous with the term “serious.” 
Table 4: 
Intensity of Adverse Events 
Grade  
Intensity 
Mild 
An AE that is usually transient and may require only minimal treatment or 
therapeutic intervention.  The event does not generally interfere with usual activities 
of daily living. 
Moderate 
An AE that is usually alleviated with additional specific therapeutic intervention.  
The event interferes with usual activities of daily living, causing discomfort but 
poses no significant or permanent risk of harm to the research participant. 
Severe 
An AE that interrupts usual activities of daily living, or significantly affects clinical 
status, or may require intensive therapeutic intervention. 
10.3. 
Relationship to Study Drug 
The investigator will document his/her opinion of the relationship of the AE to treatment with 
study drug using the criteria outlined in Table 5.  An AE is deemed associated with the use of the 
study drug “if there is a reasonable possibility that the drug caused the AE” (otherwise referred 
to as a suspected adverse reaction).  Reasonable possibility means there is evidence to suggest a 
causal relationship between the drug and the AE (Title 21 CFR 312.32 [a]). 
Table 5: 
Relationship of Adverse Events to Study Drug 
Relationship 
Description 
Definite 
A reaction that follows a reasonable temporal sequence from administration of the drug or in 
which the drug level has been established in body fluids or tissue; that follows a known or 
expected response pattern to the suspected drug; and that is confirmed by improvement on 
stopping or reducing the dosage of the drug, and reappearance of the reaction on repeated 
exposure. 
Possible 
An AE in which there is reasonable possibility that the drug caused the event.  Reasonable 
possibility means there is evidence to suggest a causal relationship between the drug and the 
AE. 
Unlikely 
A reaction that follows a reasonable temporal sequence from administration of the drug; that 
follows a known or suspected response pattern to the suspected drug; but that could 
reasonably be explained by known characteristics of the subject’s clinical state. 
Not Related 
Any event that does not meet the above criteria. 
10.4. 
Recording Adverse Events 
For enrolled subjects, each AE will be listed as a separate entry on an AE eCRF.  Screen failure 
subjects will have AE information noted in the source documentation.  The investigator (or 
designee) will provide information on dates and times of onset and resolution, intensity, 
seriousness, frequency, action(s) taken, changes in study drug usage, relationship to study drug, 
and outcome. 
The following categories of medical events that could occur during participation in a clinical 
study must be reported within 24 hours to NBI or its designee: 


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• SAE, including death (Section 10.6). 
• Pregnancy (Section 10.7). 
• Events of suicidal behavior or suicidal ideation type 4 (active suicidal ideation with some 
intent to act, without specific plan) or type 5 (active suicidal ideation with specific plan and 
intent) based on the C-SSRS. 
10.5. 
Post-Study Follow-Up of Adverse Events 
All AEs, including clinically significant changes in ECGs, physical examination findings, or 
isolated clinically significant laboratory findings must be followed until the event resolves, the 
condition stabilizes, the event is otherwise explained, or the subject is lost to follow-up. 
AEs ongoing at the final study visit (or upon early termination) will be followed for as long as 
necessary to adequately evaluate the subject’s safety or until the event stabilizes or resolves or 
until the subject is lost to follow up.  The investigator is responsible for ensuring that follow-up 
includes any supplemental investigations as may be indicated to elucidate the nature and/or 
causality of the AE.  This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals, as is 
practical. 
10.6. 
Serious Adverse Events 
All SAEs will be recorded from the time the subject has signed the ICF until the final study visit.   
Investigators are not obligated to actively seek SAEs after a subject has withdrawn from or 
completed the study. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been withdrawn from or has completed the study, and the investigator 
considers the event to be reasonably related to the study intervention or study participation, the 
investigator must promptly notify the Sponsor as described in Section 10.6.3. 
10.6.1. 
Definition of a Serious Adverse Event 
An SAE is any AE that results in any of the following outcomes: 
• Death. 
• A life-threatening AE.  Life threatening means that the subject was, in the view of the 
investigator or Sponsor, at immediate risk of death from the reaction as it occurred.  It does 
not mean that hypothetically the event might have caused death if it occurred in a more 
serious form. 
• Inpatient hospitalization or prolongation of existing hospitalization.  Hospitalization for 
elective treatment or a pre-existing condition that did not worsen during the clinical 
investigation is not considered an AE.  Hospitalization or nursing home admission for the 
purpose of caregiver respite is not considered an AE.  Complications that occur during 
hospitalization are AEs, and if a complication prolongs hospitalization, the event is 
considered serious.  Treatment in a hospital emergency room is not a hospitalization. 
• A persistent or significant incapacity or substantial disruption of a person’s ability to conduct 
normal life functions. 


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• A congenital anomaly/birth defect. 
• Important medical events that may not result in death, be life threatening, or require 
hospitalization.  These events may be considered serious when, based on appropriate medical 
judgment, they may jeopardize the health of the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed.  Any other event thought by the 
investigator to be serious should also be reported, following the reporting requirements 
detailed in this section.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias, 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
10.6.2. 
Managing Serious Adverse Events 
Subjects experiencing an SAE or an emergency situation will be examined by a physician as 
soon as possible.  The physician in attendance will do whatever is medically needed for the 
safety and well-being of the subject.  The subject will remain under observation as long as 
medically indicated.  Appropriate laboratory studies will be conducted until all parameters return 
to normal or are otherwise explained or stable.  The subject will be followed until the SAE 
resolves or until the subject is medically stabilized.  The investigator (or designee) will notify the 
NBI Medical Monitor (and the IRB, if necessary) immediately (within 24 hours) of the SAE and 
the outcome of the SAE. 
10.6.3. 
Reporting Serious Adverse Events and Other Immediately Reportable Events 
Serious AEs and other immediately reportable events (defined in Section 10.4) must be reported 
within 24 hours of first knowledge of the event by study personnel to the NBI Medical Monitor 
or NBI Drug Safety and Pharmacovigilance (DSPV) Department.  Reports of SAEs or 
pregnancies should be followed by a fax or email of the SAE or Pregnancy Form.  It is important 
that the investigator provide his or her assessment of relationship to study drug at the time of the 
initial SAE report.  
For SAEs or Other Immediately Reportable Events, contact DSPV: 
 
DSPV telephone: 
 
 
DSPV facsimile: 
 
 
DSPV e-mail:  
 
 
NBI Medical Monitor: 
 
Telephone: 
 
 
 
 
 
 
 
Cell phone: 
 
10.6.4. 
Expedited Safety Reports 
NBI or its representatives will submit an Expedited Safety Report for any suspected adverse 
reaction (as defined in Section 10.3) that is considered both serious and unexpected within 
15 calendar days and for any unexpected fatal or life threatening experience within 7 calendar 
days via telephone or facsimile; or according to country specific regulations. 


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NBI or its representatives will send copies of each safety report submitted to regulatory 
authorities to the investigators.  The safety report must be submitted to the appropriate IRB as 
soon as possible.  Documentation of the submission to the IRB and receipt by the IRB (if 
applicable) must be retained for each safety report. 
10.7. 
Pregnancy 
Females of childbearing potential will be enrolled in this study.  In the event of a pregnancy, the 
following instructions should be followed. 
Pregnancy is neither an AE nor an SAE unless the criteria for an SAE are met.  However, all 
pregnancies in female subjects who received NBI-74788 will be followed to assess for 
congenital anomaly.  Subjects of childbearing potential must be counseled at all visits to 
continue using contraception (see inclusion criterion #8) until 30 days (females) or 90 days 
(males) after the last dose of study drug.  If at any time between the time the subject signs the 
ICF and the last study visit a subject believes she is pregnant, the subject will be instructed to 
return to the study center within 24 hours and undergo a serum pregnancy test to confirm 
pregnancy. 
All confirmed pregnancies in subjects who received study drug must be immediately reported to 
NBI (refer to Section 10.6.3 for contact information), followed by fax or email of the pregnancy 
form to NBI DSPV.  A first trimester ultrasound will be requested for all confirmed pregnancies.  
Pregnancies in subjects who received NBI-74788 will be followed until resolution (ie, 
termination [voluntary or spontaneous] or birth). 
11. 
DOCUMENTATION OF DATA 
11.1. 
Case Report Forms 
The case report form data for this study are being collected with an electronic data capture 
(EDC) system 
  The EDC 
system and the study-specific eCRFs will comply with Title 21 CFR Part 11.  The documentation 
related to the validation of the EDC system is available through the vendor, 
 while the 
validation of the study specific eCRFs will be conducted by NBI and the required documentation 
will be maintained in the Trial Master File. 
The investigator will document subject data in his/her own subject files.  These subject files will 
serve as source data for the study.  All eCRF data required by this protocol will be recorded by 
authorized study personnel in the EDC system, with the exception of data captured in an 
electronic format, which will be loaded electronically into the appropriate eCRFs.  All data 
entered into the eCRF will be supported by source documentation.  The eCRF for each subject 
must be reviewed by the investigator and signed on the appropriate eCRF page(s).  This should 
be done as soon as possible after the subject completes the study.   
The investigator or an authorized member of the investigator's staff will make any necessary 
additions/corrections to the eCRF.  All change information, including the date, person 
performing the corrections, and reason for the change will be available via the electronic audit 


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trail, which is part of the EDC system.  The eCRFs will be reviewed periodically for 
completeness, legibility, and acceptability by NBI (or designee).  NBI will also be allowed 
access to all source documents and medical records pertinent to the study in order to verify eCRF 
entries.  The Principal Investigator will review the eCRFs for completeness and accuracy and 
enter his or her electronic signature on the eCRFs as evidence thereof. 
 will provide access to the NBI portal of the EDC system for the duration of the study 
through a password-protected method of internet access.  Such access will be removed from 
investigator sites at the end of the site's participation in the study.  Data from the EDC system 
will be archived on appropriate data media and provided to the investigator at that time as a 
durable record of the site's eCRF data.  Although not required, the investigator may make paper 
printouts from that media. 
All clinical work conducted under this protocol is subject to GCP regulations.  This includes an 
inspection by NBI and/or health authority representatives at any time.  The Principal Investigator 
will agree to the inspection of study-related records by health authority representatives and/or 
NBI. 
11.2. 
Data Capture, Review, and Validation 
Data entered in the EDC system will be verified against the source data by NBI (or designee).  
Any discrepancies will be corrected on-line by authorized site personnel.  Automated (computer-
generated) logic checks will run in order to identify items such as inconsistent study dates.  In 
addition, manual review/checks may be conducted by NBI on the data.  Any 
inconsistencies/errors/omissions identified will be sent to the site (via an electronic query) for the 
necessary corrections to be made to the eCRF.  Once entered and saved in an eCRF, data 
immediately become part of the study database and are available to NBI. 
11.3. 
Coding Dictionaries 
AEs and medical history will be coded using the chosen version of the Medical Dictionary for 
Regulatory Activities (MedDRA).  Prior and concomitant medications will be coded using the 
chosen version of the World Health Organization Drug Dictionary (WHODrug). 
12. 
STATISTICAL AND ANALYTICAL PLAN 
Descriptive statistical methods will be used to summarize the data from this study.  The term 
“descriptive statistics” refers to the number of subjects (n), mean, median, SD, SEM, minimum, 
and maximum for continuous variables, and refers to the number of subjects (or events) and 
percentage for categorical variables.  Confidence intervals may be presented for selected 
variables as well.   
Detailed descriptions of the data summaries that will be presented for this study will be provided 
in the expanded Statistical Analysis Plan (SAP).  The SAP will be developed prior to locking the 
study database. 


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12.1. 
Analysis Sets 
Data summaries for this study will be based on the safety analysis set, which will include all 
subjects who receive a dose of study drug.  Additional analysis sets may be specified in the SAP.   
12.2. 
Sample Size 
The sample size for this study is based on practical clinical considerations with no formal 
statistical power calculations. 
12.3. 
Handling of Missing Data 
All available study data will be included in relevant summaries and data displays, including any 
available data for subjects with incomplete or missing data. 
12.4. 
Disposition of Subjects 
A summary of subject disposition will be prepared that displays the number of subjects who 
were enrolled, received study drug, and completed the study.  The number of subjects who did 
not complete the study will be displayed both overall and by reason for discontinuation. 
12.5. 
Demographics and Baseline Characteristics 
Age, height, weight, BMI, gender, race, ethnic group, 
, and screening 
17-OHP levels will be summarized with descriptive statistics. 
12.6. 
Pharmacokinetic Data 
Descriptive statistics and graphical displays will be presented for NBI-74788 and metabolites 
plasma concentrations by scheduled sampling time.  For these summaries, values that are below 
the limit of quantitation (BLQ) will be set equal to zero. 
Individual subject plasma concentration vs. time plots will also be presented. 
The following plasma PK parameters will be calculated for NBI-74788 and metabolites using 
noncompartmental methods and summarized by dose cohort using descriptive statistics: 
• Area under the plasma concentration versus time curve from 0 to 12 hours (AUC0–12) 
• Cmax 
• Time to reach Cmax (tmax). 
Additional PK parameters for Day 14 to 15 only: 
• Average plasma concentration at steady state (Cavg) 
• Percent fluctuation at steady state (%fluctuation) 
• Accumulation ratio at steady state 
• t½ 
• Apparent terminal rate constant (λz) 
• Apparent mean residence time (MRT)  


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• Apparent systemic clearance after oral administration (CL/F) (NBI-74788 only). 
12.7. 
Pharmacodynamic Data 
  Morning 17-OHP (serum; ng/dL) from the 8- and 12-hour postdose samples 
(collected at 0300 and 0700 hours). 
  17-OHP at all other times, androstenedione (serum; ng/dL), testosterone 
(serum; ng/dL), cortisol (serum; μg/dL), and adrenocorticotropic hormone (ACTH; plasma; 
pg/mL).  Summaries of PD measures will include both observed values and changes from 
timepoint-matched PD baseline values. 
12.8. 
Safety Data 
TEAEs, categorized by system organ class (SOC) and/or preferred term as defined by MedDRA, 
will be summarized.  A TEAE is defined as any AE that occurs after the first dose of study drug.  
Any AE that occurred before the first dose of study drug will be considered a pretreatment AE.  
The TEAE tables will include the number and percentage of unique subjects experiencing each 
event.  
Clinical laboratory data, vital sign measurements, ECG data, and other safety data will be 
summarized by timepoint (as appropriate) with descriptive statistics.  
12.9. 
Interim Analysis 
An interim analysis is not planned for this study. 
13. 
REGULATORY AND ETHICAL ISSUES 
13.1. 
General Legal References 
The study will be carried out according to the provision of the US CFR, the US Food and Drug 
Administration (FDA), Canada Food and Drugs Act and Regulations, Health Canada, and the 
ICH Guidelines for GCP.  All clinical work conducted under this protocol is subject to GCP 
rules.  This includes an inspection by NBI or its representative, health authority, or IRB 
representatives at any time.  The investigator must agree to the inspection of study-related 
records by health authority representatives and/or NBI or its designee. 
13.2. 
Institutional Review Board 
The final approved protocol and the consent/assent documents will be reviewed by the IRB for 
the clinical site.  The committee’s decision concerning conduct of the study will be sent in 
writing to the investigator and a copy will be forwarded to NBI.  The investigator must agree to 
make any required progress reports to the IRB, as well as reports of SAEs, life threatening 
problems, or death.  


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13.3. 
Protocol Adherence and Amendments 
The protocol must be read thoroughly, and the instructions must be followed exactly.  Any 
changes in the protocol will require a formal amendment.  Such amendments will be agreed upon 
and approved in writing by the investigator and NBI.  The IRB will be notified of all 
amendments to the protocol.  Amendments to the protocol will not be implemented until written 
IRB approval has been received. 
13.4. 
Required Documents 
The investigator must provide NBI or its representatives with the following documents before 
the enrollment of any subject (originals should be kept by the investigator in the investigator’s 
regulatory document binder): 
• Signed copy of the approved protocol signature page. 
• Investigator’s Brochure acknowledgement page. 
• Completed and signed statement of investigator (Form FDA 1572) and/or Clinical Trial Site 
Information Form, as applicable. 
• Curriculum vitae and current medical license of the investigator and subinvestigators. 
• Financial disclosure information as required. 
• Letter of approval from the IRB for the protocol and consent documents. 
• Copy of the IRB approved written ICF to be used. 
• Laboratory documents (certifications/accreditations, normal ranges) if not provided by a 
central laboratory. 
13.5. 
Informed Consent 
Parent(s) or legal guardian(s) will provide informed consent with signed (or verbal, if applicable) 
and witnessed study subject assent before the performance of any study-related procedures. 
Each subject’s chart will include the signed ICF with signed and witnessed study subject assent 
(or confirmation of verbal assent) for study participation.  When the study treatment is completed 
and the eCRF has been monitored, the ICF and signed and witnessed study subject assent will be 
kept in the investigator’s central study file.  Regulatory authorities may check the existence of 
the signed ICF and the signed and witnessed study subject assent in this central study folder. 
13.6. 
Study Monitoring 
Throughout the course of the study, the study monitor will make frequent contacts with the 
investigator.  This will include emails, telephone calls, and on-site visits.  During the on-site 
visits, the eCRFs will be reviewed for completeness and adherence to the protocol.  As part of 
the data audit, source documents will be made available for review by the study monitor.  The 
study monitor will also perform drug accountability checks and may periodically request review 
of the investigator study file to ensure completeness of documentation in all respects of clinical 
study conduct. 


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Upon completion of the study, the study monitor will arrange for a final review of the study files 
after which the files should be secured for the appropriate time period.  The investigator or 
appointed delegate will receive the study monitor during these on-site visits, will cooperate in 
providing the documents for inspection, and respond to inquiries.  In addition, the investigator 
will permit inspection of the study files by authorized representatives of the regulatory agencies. 
13.7. 
Quality Assurance 
The study will be conducted in accordance with NBI’s standard operating procedures designed to 
ensure that all procedures are in compliance with GCP, FDA Guidelines, Health Canada 
Guidelines, and according to national law.  Quality assurance audits may be conducted at the 
discretion of NBI. 
13.8. 
Record Retention 
Federal regulations require that records of drug disposition, eCRFs, and all reports of this 
investigation shall be retained by the investigator for a minimum of 2 years after notification by 
NBI that the regulatory authorities have been notified of the study's termination, or 2 years after 
approval of the marketing application.  If the investigator is unable to retain the study documents 
for the required amount of time, NBI must be informed of the individual who will be assuming 
this responsibility. 
13.9. 
Confidentiality 
NBI and the clinical site affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy.  Throughout this study, all data will be identified only by an 
identification number. 
All information concerning this study and which was not previously published is considered 
confidential information.  This confidential information shall remain the sole property of NBI; it 
shall not be disclosed to others without written consent of NBI; and shall not be used except in 
the performance of this study. 
The information compiled during the conduct of this clinical study is also considered 
confidential and may be disclosed and/or used only by NBI as deemed necessary.  To allow the 
use of the information derived from this clinical study and to ensure compliance with current 
federal regulations, the investigator is obliged to furnish NBI with the complete test results and 
all data compiled in this study. 
14. 
STUDY COMMENCEMENT AND DISCONTINUATION 
Upon satisfactory receipt of all required regulatory documents, NBI (or designee) will arrange 
that all study material be delivered to the study center.  Subject entry should not begin until after 
the required regulatory documents are confirmed as received, and the Investigator 
Meeting/Initiation Meeting has occurred.  All personnel expected to be involved in the conduct 
of the study will undergo orientation to include review of study protocol, instructions for eCRF 


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completion, AE reporting, and overall responsibilities including those for drug accountability 
and study file maintenance. 
If the study is discontinued, all subjects should undergo a complete follow up examination.  Any 
clinically relevant finding, including laboratory values of potential clinical concern, and adverse 
experiences will be followed until they resolve or return to a clinically acceptable level. 


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15. 
REFERENCES 
Cheng TQ, Speiser PW. Treatment outcomes in congenital adrenal hyperplasia. Adv Pediatr. 
2012;59(1):269-81. 
Elnecave RH, Kopacek C, Rigatto M, Keller Brenner J, Sisson de Castro JA. Bone mineral 
density in girls with classical congenital adrenal hyperplasia due to CYP21 deficiency. J Pediatr 
Endocrinol Metab. 2008 Dec;21(12):1155-62. 
Hertzberg VS, Hinton CF, Therrell BL, Shapira SK. Birth prevalence rates of newborn screening 
disorders in relation to screening practices in the United States. J Pediatr. 2011 Oct;159(4):555-
60. 
Hughes CW, Rintelmann J, Emslie GJ, Lopez M, MacCabe N. A revised anchored version of the 
BPRS-C for childhood psychiatric disorders. J Child Adolesc Psychopharmacol. 2001 
Spring;11(1):77-93. 
King JA, Wisniewski AB, Bankowski BJ, Carson KA, Zacur HA, Migeon CJ. Long-term 
corticosteroid replacement and bone mineral density in adult women with classical congenital 
adrenal hyperplasia. J Clin Endocrinol Metab. 2006 Mar;91(3):865-9. 
Merke DP, Poppas DP. Management of adolescents with congenital adrenal hyperplasia. Lancet 
Diabetes Endocrinol. 2013 Dec;1(4):341-52. 
Migeon CJ, Wisniewski AB. Congenital adrenal hyperplasia owing to 21-hydroxylase 
deficiency. Growth, development, and therapeutic considerations. Endocrinol Metab Clin North 
Am. 2001 Mar;30(1):193-206. 
Overall JE, Pfefferbaum B. The Brief Psychiatric Rating Scale for Children. Psychopharmacol 
Bull. 1982 Apr;18(2):10-6. 
Trakakis E, Basios G, Trompoukis P, Labos G, Grammatikakis I, Kassanos D. An update to 21-
hydroxylase deficient congenital adrenal hyperplasia. Gynecol Endocrinol. 2010 Jan;26(1):63-
71. 

SAP_001.pdf: 
Neurocrine Biosciences, Inc. 
NBI-74788-CAH2008 
Statistical Analysis Plan 
19Oct2021 
1 
STATISTICAL ANALYSIS PLAN 
PHASE 2 
VERSION: 
1.0 
DATE OF PLAN: 
19Oct2021 
BASED ON: 
Original Protocol Final Version Date: 10 May 2019 
STUDY DRUG: 
Crinecerfont (NBI-74788) 
PROTOCOL NUMBER: 
NBI-74788-CAH2008 
STUDY TITLE: 
A Phase 2, Open-Label, Multiple-Dose Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of NBI-74788 in Pediatric Subjects with Congenital 
Adrenal Hyperplasia 
SPONSOR: 
Neurocrine Biosciences, Inc. 
12780 El Camino Real 
San Diego, CA 92130 
858-617-7600
This study is being conducted in compliance with good clinical practice, including the archiving 
of essential documents. 
CONFIDENTIAL 
NCT #: NCT04045145


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SIGNATURE PAGE 
 
This document was prepared by:  
 
 
 
 
 
eSigned and Dated 
 
 
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Signature 
 
Date 
 
 
 
 
 
 
This document has been reviewed by: 
 
 
 
 
 
eSigned and Dated 
 
 
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Signature 
 
Date 
 
 
 
 
eSigned and Dated 
 
 
  
Neurocrine Biosciences, Inc 
 
Signature 
 
Date 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS.......................................................................................6 
2. 
INTRODUCTION ........................................................................................................8 
3. 
STUDY OBJECTIVES ................................................................................................9 
3.1. 
Study Objectives ...........................................................................................................9 
4. 
STUDY DESIGN .......................................................................................................10 
4.1. 
Summary of Study Design ..........................................................................................10 
4.2. 
Sample Size Considerations .......................................................................................11 
4.3. 
Clinical Assessments ..................................................................................................11 
5. 
PLANNED ANALYSES ............................................................................................13 
5.1. 
Interim Analyses .........................................................................................................13 
5.2. 
Final Analyses ............................................................................................................13 
6. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING ...............................................................................................................14 
6.1. 
General Statistical Procedures ....................................................................................14 
6.2. 
Analysis Sets ...............................................................................................................14 
6.2.1. 
Definition of Analysis Sets .........................................................................................14 
6.2.2. 
Summary of Analysis Sets ..........................................................................................15 
6.2.3. 
Application of Analysis Sets ......................................................................................15 
6.3. 
Baseline Definitions ....................................................................................................15 
6.3.1. 
Study Baseline ............................................................................................................15 
6.3.2. 
Pharmacodynamic Baseline ........................................................................................15 
6.4. 
Derived and Transformed Data ..................................................................................16 
6.4.1. 
Study Day ...................................................................................................................16 
6.4.2. 
Change and Percent Change from Baseline ................................................................16 
6.4.3. 
Handling of Pharmacodynamic BLQ Data .................................................................16 
6.4.4. 
Handling of Early Termination Visit Data .................................................................16 
6.5. 
Handling of Missing Data ...........................................................................................16 
6.5.1. 
Missing Dates .............................................................................................................16 
7. 
IMPACT OF COVID-19 PANDEMIC ......................................................................18 
8. 
STUDY POPULATION .............................................................................................19 
8.1. 
Subject Disposition .....................................................................................................19 


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8.2. 
Protocol Deviations ....................................................................................................19 
8.3. 
Demographic and Baseline Characteristics ................................................................19 
8.4. 
CAH History ...............................................................................................................20 
9. 
PHARMACODYNAMIC DATA ..............................................................................21 
9.1. 
Timepoint Summaries .................................................................................................21 
9.2. 
Morning Window Summaries.....................................................................................21 
9.3. 
Responder Summaries ................................................................................................21 
9.4. 
Pharmacodynamic/Pharmacokinetic Relationship .....................................................22 
10. 
PHARMACOKINETIC DATA..................................................................................23 
10.1. 
Plasma Concentrations ................................................................................................23 
10.2. 
Plasma PK Parameters ................................................................................................23 
11. 
SAFETY .....................................................................................................................24 
11.1. 
Adverse Events ...........................................................................................................24 
11.1.1. 
Adverse Events Resulting in Premature Discontinuation from Study........................24 
11.1.2. 
Deaths and Other Serious Adverse Events .................................................................25 
11.2. 
Clinical Laboratory Data ............................................................................................25 
11.3. 
Vital Signs ..................................................................................................................26 
11.4. 
Body Weight ...............................................................................................................27 
11.5. 
Electrocardiogram .......................................................................................................27 
11.6. 
Columbia-Suicide Severity Rating Scale ....................................................................28 
11.7. 
Brief Psychiatric Rating Scale for Children ...............................................................29 
12. 
DEVIATIONS FROM PROTOCOL PLANNED ASSESSMENTS AND 
ANALYSIS.................................................................................................................30 
13. 
PERFORMANCE QUALIFICATION OF SAS® PROGRAMS ...............................31 
14. 
REFERENCES ...........................................................................................................32 
15. 
APPENDIX.................................................................................................................33 
 
LIST OF TABLES 
Table 1: List of Abbreviations .........................................................................................................6 
Table 2: Data Summaries by Analysis Set .....................................................................................15 
Table 3: Potentially Clinically Significant Criteria for Clinical Laboratory Variables .................26 
Table 4: Potentially Clinically Significant Criteria for Vital Signs Variables...............................27 


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Table 5: Hydrocortisone Dose Equivalent Conversion .................................................................33 
 
LIST OF FIGURES  
Figure 1: Study Design Schematic .................................................................................................10 


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1. 
LIST OF ABBREVIATIONS 
Table 1: List of Abbreviations 
17-OHP 
17-hydroxyprogesterone 
ACTH 
Adrenocorticotropic hormone 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ALP 
Alkaline phosphatase  
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration versus time curve 
AUC0-12 
AUC from 0 to 12 hours 
BMI 
Body mass index 
BPRS-C 
Brief Psychiatric Rating Scale for Children 
BSA 
Body surface area 
CAH 
Congenital adrenal hyperplasia 
Cavg 
Average plasma concentration at steady state 
CL/F 
Apparent systemic clearance after oral administration 
Cmax 
Maximum plasma concentration 
CSR 
Clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale, Children’s Version 
CV 
Coefficient of variation 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ET 
Early termination 
GGT 
Gamma-glutamyl transferase 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
IPD 
 
Important protocol deviation 
λz 
Apparent terminal rate constant 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRT 
Mean residence time 
NBI 
Neurocrine Biosciences, Inc. 
PD 
Pharmacodynamic(s) 


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PK 
Pharmacokinetic(s) 
PT 
Preferred term 
QTcF 
Corrected QT interval using Fridericia’s formula 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SE 
Standard error 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
t1/2 
Terminal half life 
tmax  
Time to maximum plasma concentration 
ULN 
Upper limit of normal 
WHO 
World Health Organization 
 


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2. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and data 
displays that will be prepared to summarize the data from the Phase 2 study described in 
Neurocrine Biosciences, Inc. (NBI) Protocol NBI-74788-CAH2008. 
This SAP was developed in accordance with ICH (International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use) E9 guidance. All decisions 
regarding the final analysis, as defined in this SAP document, will be made prior to database 
lock. Changes made to the planned analyses after finalization of this SAP and database lock will 
be described in the clinical study report (CSR). Further information related to study design and 
methodology can be found in the protocol. 
 


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3. 
STUDY OBJECTIVES  
3.1. 
Study Objectives 
The objectives of the study are as follows: 
• To assess the safety and tolerability of crinecerfont (NBI-74788) in pediatric subjects 14 to 
17 years of age with congenital adrenal hyperplasia (CAH). 
• To evaluate the effect of repeated doses of crinecerfont on endogenous levels of 
pharmacodynamic (PD) biomarkers in pediatric subjects with CAH. 
• To evaluate the pharmacokinetics (PK) of crinecerfont and metabolites in pediatric subjects 
with CAH. 
 


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4. 
STUDY DESIGN 
4.1. 
Summary of Study Design 
This is a Phase 2, open-label, multiple-dose study to assess the safety, tolerability, PK, and PD of 
crinecerfont in approximately 12 pediatric female and male subjects (14 to 17 years of age) with 
a documented medical diagnosis of classic 21-hydroxylase deficiency CAH. Crinecerfont 50 mg 
bid will be administered for 14 consecutive days with breakfast and evening meals beginning on 
the evening of Day 1. 
Eligible subjects who have a screening 17-OHP level ≥800 ng/dL will be admitted to the study 
center on Day -7 for 1 night and have baseline serial PD samples collected over a 24-hour period 
beginning that evening.  Baseline serial PD samples will be collected at approximately 1845, 
2000, 2300, 0100, 0300, 0700, 1000, 1500, and 1900 hours.    
The subjects’ usual morning dose of steroidal treatments will be administered after the 
1000 hours PD sample is collected on Day -6.  Subjects will be discharged on Day -6 after the 
last PD sample is collected. 
Subjects will be admitted to the study center on Days 1 and 14 (first and last day of dosing).    
The first dose of study drug, crinecerfont 50 mg, will be administered at approximately 1900 
hours with subjects’ evening meal on Day 1.  Study drug will be administered at the study center 
on Days 2 and 14 with subjects’ breakfast and evening meals, respectively.  The subjects’ usual 
morning dose of concurrent steroidal treatments, study drug dosing, and breakfast (snacks will be 
allowed prior to breakfast) will be delayed until after the 15-hour postdose PD samples are 
collected (ie, at approximately 1000 hours) on Day 2.  The subjects’ usual morning dose of 
concurrent steroidal treatments will be administered after the 15-hour postdose PD samples are 
collected (ie, at approximately 1000 hours) on Day 15. Study drug will be self-administered at 
home under parent/guardian supervision at approximately 0700 hours (with breakfast) and 1900 
hours (with evening meal) on Days 3 to 13. 
The study design schematic is shown in Figure 1. 
Figure 1: Study Design Schematic 
 
bid=twice daily; ET=early termination; PD=pharmacodynamic; NBI-74788=crinecerfont. 
Screening
PD Baseline
14-Day Dosing Period
Final Study 
Visit/ET
Follow-Up 
Period
Day
-28 to -8
-7 to -6
1
15
2
14
7
35
17
21
NBI-74788
(50 mg bid)


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4.2. 
Sample Size Considerations 
The sample size for this study is based on practical clinical considerations with no formal 
statistical power calculations. 
4.3. 
Clinical Assessments 
Pharmacodynamic assessments include: 
• 
  Morning 17-OHP (serum; ng/dL) from the 12- and 15-hour postdose 
samples (collected at 0700 and 1000 hours). 
• 
  17-OHP at all other times, androstenedione (serum; ng/dL), 
testosterone (serum; ng/dL), cortisol (serum; μg/dL), and adrenocorticotropic hormone 
(ACTH; plasma; pg/mL). 
 
Pharmacokinetic assessments include:  
The following plasma PK parameters will be calculated for crinecerfont and metabolites for the 
Day 1 to 2 and the Day 14 to 15 sampling intervals: 
• Area under the plasma concentration versus time curve from 0 to 12 hours (AUC0–12). 
• Observed maximum plasma concentration (Cmax). 
• Time to Cmax (tmax). 
Additional PK parameters for Days 14 to 15 only: 
• Average plasma concentration at steady state (Cavg). 
• Percent fluctuation at steady state (%fluctuation). 
• Accumulation ratio at steady state. 
• Apparent terminal half-life (t½). 
• Apparent terminal rate constant (λz). 
• Apparent mean residence time (MRT). 
• Apparent systemic clearance after oral administration (CL/F) (crinecerfont only). 
 
Safety assessments include:   
• Adverse events (AEs). 
• Clinical laboratory tests (clinical chemistry, hematology, 
 and urinalysis). 
• Vital signs. 
• Physical examinations (including musculoskeletal exam). 
• 12-lead electrocardiograms (ECGs). 
• Columbia-Suicide Severity Rating Scale (C-SSRS), Children’s Version 


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• Brief Psychiatric Rating Scale for Children (BPRS-C). 
 
See Table 2 of the study protocol for a complete schedule of assessments. 


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5. 
PLANNED ANALYSES 
5.1. 
Interim Analyses 
No interim analysis is planned for this study. 
5.2. 
Final Analyses 
Final analyses, as specified in the protocol and in this SAP, will be performed after the study 
database has been locked. 


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6. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING 
All analyses described in this plan are considered a priori analyses in that they have been defined 
prior to locking the study database. Analyses defined subsequent to locking the database will be 
considered post hoc analyses and will be applied as exploratory methodology. Any post hoc 
analyses will be clearly identified in the CSR. 
6.1. 
General Statistical Procedures 
Descriptive statistical methods will be used to summarize the data from this study. The term 
“descriptive statistics” refers to the number of subjects, mean, median, standard deviation (SD) 
or standard error (SE), minimum, and maximum for continuous and ordinal categorical variables; 
and refers to the number and percentage of subjects (or events) for categorical variables. 
Additional descriptive statistics, such as the coefficient of variation (CV), will be presented for 
selected PK data.  
Unless otherwise noted, data will be summarized by a single dose group (crinecerfont 50 mg 
bid). For the purposes of PD data summaries, serial sampling that starts at the 15 minutes pre-
evening dose on Study Day 1 and continues until the 24 hours post-evening dose on Study Day 2  
will be referred to as “Day 1”; serial sampling that starts at the 15 minutes pre-evening dose on 
Study Day 14 and continues until the 24 hours post-evening dose on Study Day 15 will be 
referred to as “Day 14” in the data summaries.   
Summary statistics will be displayed using the following decimal precision rules: the minimum 
and maximum will have the same number of decimal places as the data; the mean, median, SD, 
and SE will have one more decimal place than the data being summarized. Percentages will be 
displayed using one decimal place; percentages for 0 counts will be omitted. These rules may be 
modified if warranted, based on practical considerations.  
6.2. 
Analysis Sets  
6.2.1. 
Definition of Analysis Sets 
6.2.1.1. 
Safety Analysis Set 
The safety analysis set will include all subjects who take at least one dose of study drug and have 
any postbaseline safety data. The safety analysis set will be used for all summaries of safety data 
(e.g., AEs, clinical laboratory data) and pharmacokinetic data. 
6.2.1.2. 
Pharmacodynamic Analysis Set  
The pharmacodynamic analysis set will include all subjects who take at least one dose of study 
drug and have at least one PD parameter measurement at PD baseline (Days -7 to -6) and at least 
one PD parameter measurement at Day 1 or Day 14.  The pharmacodynamic analysis set will be 
used for all summaries of pharmacodynamic data. 


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6.2.2. 
Summary of Analysis Sets 
A summary of the number and percentage of subjects included in (and excluded from, as 
applicable) each analysis set will be provided. The number and percentage of subjects excluded 
from each analysis set by reason for exclusion will also be provided. 
6.2.3. 
Application of Analysis Sets 
Summaries of subject disposition, analysis set inclusion/exclusion status, and Important Protocol 
Deviations (IPDs) will include all enrolled subjects. All other summaries by analysis set are 
identified in Table 2. 
Table 2: Data Summaries by Analysis Set 
Data Summary/Analysis 
Analysis Set 
Safety 
Pharmacodynamic  
Demographics[1] 
X  
X 
Baseline subject characteristics[1] 
X  
X 
CAH history 
X 
 
Pharmacodynamic data 
 
X 
Plasma concentrations 
X 
 
PK parameters 
X 
 
Adverse events 
X 
 
Clinical laboratory data 
X 
 
Vital signs 
X 
 
Weight 
X 
 
ECG 
X 
 
C-SSRS, Children’s Version 
X 
 
BPRS-C 
X 
 
[1] if the safety analysis set and the pharmacodynamic analysis set are the same, only one set of tables will be created 
using the safety analysis set.  
6.3. 
Baseline Definitions 
6.3.1. 
Study Baseline 
Study baseline will be defined as the last reported value prior to study drug dosing for all safety 
assessments. The assessments collected at the Day 1 study visit will serve as the baseline value 
for all assessments. With the exception of C-SSRS, if a Day 1 visit value is not available, then 
the last measurement collected on or prior to the date of the Day 1 study visit will serve as 
baseline. C-SSRS values that are missing at Day 1 will remain missing.   
6.3.2. 
Pharmacodynamic Baseline 
For all pharmacodynamic data analyses, baseline will be defined as the PD values collected 
during the 24 hour PD baseline on Days -7 to -6 of the study.  The specific timepoints that will 
be used to represent PD baseline from Days -7 to -6 are further explained in Section 9 of this 
SAP.  


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6.4. 
Derived and Transformed Data 
6.4.1. 
Study Day 
Study day is calculated relative to the date of the Day 1 visit. If the date of interest occurs on or 
after the Day 1 visit, then the study day will be calculated as: date of interest – date of Day 1 visit 
+ 1. If the date of interest occurs prior to the Day 1 visit, then the study day will be calculated as: 
date of interest – date of Day 1 visit. 
6.4.2. 
Change and Percent Change from Baseline 
Change from baseline is calculated as (postbaseline value – baseline value). 
Percent change from baseline is calculated as (change from baseline/baseline value * 100). 
If either the baseline or postbaseline value is missing, the change from baseline and percent 
change from baseline will also be missing. The percent change from baseline will also be 
missing if the baseline value is equal to zero.   
6.4.3. 
Handling of Pharmacodynamic BLQ Data 
Pharmacodynamic data with values that are below the limit of quantification (BLQ) will be set 
equal to the lower limit of quantification (LLQ) unless the value is between two quantifiable 
measurements, in which case it will be set to missing.   
6.4.4. 
Handling of Early Termination Visit Data 
An early termination (ET) visit occurs when a subject discontinues from the study prior to 
completing the scheduled Day 35 visit. The data collected at ET visits will be included in 
summary tables and figures if they correspond to a protocol-specified visit or timepoint.  
Early termination visit data which are not captured at a protocol-specified visit or timepoint will 
not be included in by-visit analyses and summaries. They will be included in any analyses that 
look across all available assessments during the treatment period, including unscheduled visits. 
They will also be included in any applicable by-subject data listings. 
6.5. 
Handling of Missing Data 
6.5.1. 
Missing Dates  
6.5.1.1. 
Start Dates for Adverse Events and Prior and Concomitant Medications 
Missing and incomplete (“partial”) dates for adverse events (AEs) and concomitant medications 
will be imputed for the purpose of estimating the time of the event or medication usage in 
relationship to study treatment. Any data listings will display the original dates as reported in the 
database.   
The imputation rules for AE start dates are as follows: 
• If the date is completely missing, the date will be imputed as the date of the first dose of 
study drug; 


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• If only the day is missing, the date will be imputed as the date of the first dose of study 
drug if the month and year match the month and year of the first dose of study drug; 
otherwise, the missing day will be imputed as the first day of the month; 
• If both the day and month are missing, the date will be imputed as the date of the first 
dose of study drug if the date is in the same year as the first dose of study drug; 
otherwise, the missing day and month will be imputed as 01 January; 
• If any of the above imputations result in a start date that is later than an existing (not 
imputed) end date for the event, the start date will be imputed as the end date. 
The imputation rules for concomitant medication start dates are as follows: 
• If the date is completely missing, the date will be imputed as 01 January in the year of the 
subject’s screening vital signs assessment; 
• If only the day is missing, the date will be imputed as the date of the first dose of study 
drug if the date is in the same month and year as the first dose of study drug; otherwise, 
the missing day will be imputed as the first day of the month; 
• If both the day and month are missing, the date will be imputed as the date of the first 
dose of study drug if the date is in the same year as the first dose of study drug; 
otherwise, the missing day and month will be imputed as 01 January; 
• If any of the above imputations result in a start date which is later than an existing (not 
imputed) medication stop date, the start date will be imputed as the stop date. 


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7. 
IMPACT OF COVID-19 PANDEMIC 
This section describes analyses and summaries that will be produced to help determine the 
potential impact of the COVID-19 pandemic on the study conduct/data and additional details 
regarding how data that is potentially impacted by the COVID-19 pandemic will be handled in 
the analysis plan. It is in alignment with the guidance put forth by the US Food and Drug 
Administration (FDA; Conduct of Clinical Trials of Medical Products During the COVID-19 
Public Health Emergency [March 2020, updated January 2021]) and European Medicines 
Agency (EMA; Points to consider on implications of Coronavirus disease [COVID-19] on 
methodological aspects of ongoing clinical trials [March 2020]). 
To help understand the impact of the COVID-19 pandemic on the clinical trial data, the 
following listings will be generated: 
• A listing of all subjects affected by the COVID-19 pandemic. The listing will identify 
subjects who experience at least one of the following situations due to the COVID-19 
pandemic (additional situations may be included): 
o Discontinued study treatment or withdrew from study 
o Presumed or confirmed diagnosis of COVID-19 
o Had at least one COVID-19 pandemic-related major protocol deviation 
o Missed at least one study visit or assessment  
o Required at least one assessment to be collected using a method other than what is 
defined in the protocol (eg, remotely) 
o Had at least one known study drug interruption  
• A listing of subjects who discontinued study treatment and/or withdrew from study due to 
the COVID-19 pandemic, which will include the specific reasons. 
• A listing by subject of visits and assessments affected by the COVID-19 pandemic (eg, 
missing, partial, collected remotely).  
Further classification and summaries of protocol deviations related to the COVID-19 pandemic 
are detailed in Section 8.2. All assessments (eg, C-SSRS, BPRS-C) that are collected remotely 
will be included in the analysis.  
Additional summaries may be generated to address the potential impact of the COVID-19 
pandemic on the efficacy and safety data, as needed, based on ongoing data review or during the 
final analysis of study data. 
 


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8. 
STUDY POPULATION 
8.1. 
Subject Disposition 
The summary of subject enrollment and disposition will display the number and percentage of 
subjects who were enrolled, who completed through Day 14 of study drug dosing, and who 
completed the study (ie, up to Day 35). The number of subjects who did not complete the study 
will also be summarized, both overall and according to the reason for early discontinuation. 
A listing of lot numbers used in the study will be provided. 
8.2. 
Protocol Deviations 
Protocol deviations described in the study-specific Protocol Deviation Plan will be entered into 
the clinical trial management system. Prior to database lock, all major protocol deviations that 
have been entered into the clinical trial management system will be exported to a file and 
integrated into the study data. 
IPDs are protocol deviations that might significantly affect the completeness, accuracy and/or 
reliability of the study data or that might significantly affect a subject’s rights, safety, or well-
being. An assessment of IPDs will be performed by a committee composed of NBI Clinical 
Development project team members prior to database lock. This committee will review a listing 
of all major protocol deviations reported in the study database and determine which deviations 
are IPDs. 
A summary of the number and percentage of subjects with IPDs by deviation category will be 
provided using all enrolled subjects. The summary will be repeated for the subset of IPDs that 
are related to the COVID-19 pandemic.  
All major protocol deviations will be presented in a data listing and any that are classified as 
IPDs will be flagged in the listing. Any major PDs related to the COVID-19 pandemic will also 
be flagged in the listing.  
8.3. 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics data will be summarized using descriptive statistics. 
Demographics include: 
• Age (years) 
• Sex 
• Ethnicity 
• Race 
 
  
Baseline subject characteristics include: 
• 17-OHP levels at screening  
• Body surface area (BSA; calculated using the DuBois formula and height collected at 
the screening visit and weight collected at the Day 1 visit; m2) 


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• Total daily glucocorticoid dose at screening, expressed in hydrocortisone equivalents 
(mg/day) (See Table 5) 
• Total daily glucocorticoid dose at screening, expressed in hydrocortisone equivalents 
(See Table 5) and adjusted for BSA (mg/m2/day) 
• Glucocorticoid type (hydrocortisone alone; prednisone or equivalent with or without 
hydrocortisone; dexamethasone with or without another glucocorticoid) 
• Height (measured at screening; cm) 
• Weight (presented in both pounds and kilograms) 
• Body mass index (BMI; calculated using height collected at the screening visit and 
weight collected at the Day 1 visit; kg/m2) 
8.4. 
CAH History  
CAH history will be summarized using descriptive statistics. 
CAH history assessments include: 
• How the CAH diagnosis was made 
• Number of adrenal crises within the past 2 years 
• Age at menarche (female subjects only) 
• Menstrual cycle frequency (in days; female subjects only) 


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9. 
PHARMACODYNAMIC DATA 
PD biomarker data include measurements of ACTH, 17-OHP, androstenedione, testosterone, and 
cortisol.  Note that all summaries of testosterone will be stratified by sex. The following sections 
describe the summaries and analyses of the PD biomarker data. 
9.1. 
Timepoint Summaries 
Observed values for the PD biomarker data will be summarized with descriptive statistics by 
parameter, visit, and timepoint.  This summary will also include the changes from PD baseline to 
postdose values with the same timepoint (eg, change from Day -7/-6, 6 hours post-evening dose 
to Day 14, 6 hours post-evening dose).  Descriptive statistics for the 24 hour average values of 
the PD parameters at each visit (excluding Day 7 and Day 21) will also be displayed. Figures of 
mean (+SE) versus time curves will be generated for each parameter by visit. In addition, these 
data will be displayed as individual subject observed values versus time curves for each 
parameter by visit. 
9.2. 
Morning Window Summaries   
The peak morning period for ACTH, 17-OHP, androstenedione, and testosterone levels is 
between 0700 and 1000 hours. For the purposes of analysis, this timeframe will be referred to as 
the “morning window” and includes all PD biomarker measurements (excluding cortisol) taken 
during this time.  Specifically, the morning window timepoints for PD draws are 12- and 15-
hours post-evening crinecerfont dose. This group of timepoints will be summarized using the 
average of the two morning window timepoints at each visit. If only one timepoint is available, 
this value will be used as the morning window value. If both timepoints are missing, the morning 
window value for that subject/visit will be reported as missing.  
The morning window values will be summarized with descriptive statistics by PD parameter and 
visit.  In addition to the observed values, descriptive statistics will also be generated for the 
change from PD baseline to Day 1 and from PD baseline to Day 14, as well as the percent 
change from PD baseline to Day 1 and from PD baseline to Day 14. Percent change from PD 
baseline to Day 1 and Day 14 for each subject will be presented as waterfall plots by PD 
parameter.   
9.3. 
Responder Summaries 
The PD biomarker data will also be summarized based on responder definitions for ACTH, 17-
OHP, androstenedione, and testosterone (female subjects only).  The first responder definition 
will be composed of subjects who have a 50% or greater reduction from PD baseline to Day 14 
in the average of their morning window values.  The second responder definition will be 
composed of subjects who have a 50% or greater reduction from PD baseline to Day 14 for at 
least one timepoint in the morning window period. The frequency and percentage of subjects 
meeting each of these responder definitions will be summarized by parameter.  
Additionally, a responder definition for the ratio of androstenedione to testosterone (A4/T) in 
male subjects will be composed of male subjects who have an A4/T ratio greater than or equal to 
0.5 (based on the average of the morning window values for androstenedione and testosterone) at 
PD baseline and who achieve an A4/T ratio less than 0.5 (based on the average of the morning 


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window values for androstenedione and testosterone) at Day 14. The frequency and percentage 
of male subjects meeting this responder definition will be summarized.  
9.4. 
Pharmacodynamic/Pharmacokinetic Relationship 
The relationship between pharmacodynamic and pharmacokinetic data will be depicted 
graphically. Scatter plots of percent change from PD baseline to Day 14 in the average of 
morning window values vs. crinecerfont AUC0-12 will be generated for ACTH, 17-OHP, and 
androstenedione. These plots will also be generated for Cmax.  
 
 
 


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10. 
PHARMACOKINETIC DATA 
10.1. 
Plasma Concentrations 
Plasma concentrations of crinecerfont and its metabolite, NBI-756179, will be summarized by 
visit, and nominal (scheduled) timepoint with descriptive statistics, which will include the 
coefficient of variation (CV [%]), geometric mean, and geometric CV (%). Figures of arithmetic 
mean (+SD) concentration vs. time curves will be generated by visit (Day 1, Day 14, and Day 14 
through Day 35), and timepoint on both the linear and log (base10) scales.  
In addition, these data will be displayed as individual subject plasma concentration vs. time 
curves by visit on both the linear and log (base 10) scales.  Actual times from dosing rather than 
nominal timepoints will be displayed in the by-subject graphs.   
All BLQ values (crinecerfont < 5.00 ng/mL; NBI-756179 < 0.500 ng/mL) will be set equal to 
zero (0) in the plasma concentration summaries, with the exception of the geometric mean and 
geometric CV (%) which will be treated as missing.  
Subjects with significant deviations that could impact the interpretation of study data (eg, missed 
study drug dosing, emesis) will be excluded from summaries. 
10.2. 
Plasma PK Parameters  
The plasma PK parameters listed in Section 4.3 will be summarized with descriptive statistics.  
These statistics will include the arithmetic mean, SD, median, geometric mean, geometric 
CV(%), and range for each parameter. PK parameters will be calculated using 
 
. 
It should be noted that the handling of BLQ concentration values for the calculation of t1/2 and 
the AUC parameters with the 
 
 software package differs from the approach 
described above (Section 10.1) for the summary of plasma concentrations.  For the calculation of 
these parameters, BLQ values will be set equal to zero with the exception of BLQ values 
bounded by quantifiable values.  BLQ values between quantifiable concentrations will be 
ignored (i.e., treated as missing values) for the calculation of these parameters. 
 


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11. 
SAFETY 
Results will be presented using the safety analysis set, as described in Section 6.2.1.1. 
11.1. 
Adverse Events 
Adverse events are recorded in the electronic case report form (eCRF). Each AE will be coded to 
a SOC and PT using MedDRA (version 24.0).   
A treatment-emergent adverse event (TEAE) is an adverse event not present prior to the 
initiation of study drug dosing or is an already present event that worsens either in intensity or 
frequency following the initiation of study drug dosing and also occurs on or before the last dose 
of study drug.  Investigators will be asked to respond “Yes” or “No” on the CRF as to whether 
the AE started after the subject took the first dose of study drug.  An AE with a response of 
“Yes”, and that occurs on or before the last dose of study drug, will be classified as a TEAE.  If 
the investigator’s response is missing on the CRF, then the treatment emergent status will be 
derived based on the AE onset date and time relative to the date and time of the subject’s first 
and last dose of study drug.  If the AE onset date and time are unknown, it will be assumed that 
the AE is a TEAE.  If the AE onset time is unknown but the AE onset date is the same date as the 
first dose of study drug, it will be assumed that the AE is a TEAE. Adverse events that occur 
after the last dose of study drug but on or before the last dose plus 21 days will be considered 
post-treatment emergent (post-TEAEs).  Adverse events with an onset date after the last dose 
plus 21 days will not be considered treatment emergent (non-TEAEs). 
TEAEs, post-TEAEs, and non-TEAEs categorized by MedDRA SOC and/or PT, will be 
summarized in frequency tables. The frequency tables will include the number and percentage of 
unique subjects experiencing each event one or more times. 
Two similar frequency tables will be generated for TEAEs – one including both SOC and PT 
(each sorted in alphabetical order), and one including PT only, with PTs sorted in order of 
decreasing frequency of subjects reporting the PT. Post-TEAEs and non-TEAEs will be 
summarized by SOC and PT only (each in alphabetical order). 
An overall summary table will be provided which summarizes the number and percentage of 
unique subjects with any TEAE, any TEAE leading to study discontinuation, any serious TEAE, 
and any TEAE resulting in death. The summary table will also include the frequency distribution 
of the maximum TEAE intensity (mild, moderate, severe). A subject with more than one event 
coded to the same PT will be classified according to the most severe event. 
11.1.1. 
Adverse Events Resulting in Premature Discontinuation from Study 
Summary tables of TEAEs resulting in early discontinuation from the study will be presented. 
The number and percentage of subjects with a TEAE resulting in study discontinuation will be 
presented by PT within SOC (presented in the same method as the analogous primary TEAE 
table).  More than one AE can contribute to study discontinuation per subject. The first line of 
the table will display the number and percentage of subjects with at least one TEAE leading to 
study discontinuation.   


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A listing of TEAEs resulting in premature study discontinuation will be provided which includes 
subject ID, treatment, study day of the discontinuation, and other relevant information from the 
AE eCRF.  
11.1.2. 
Deaths and Other Serious Adverse Events 
Summary tables of serious adverse events (SAEs) will be presented.  The number and percentage 
of subjects with an SAE will be presented by PT within SOC (each sorted in alphabetical order).  
The first line of the table will display the number and percentage of subjects with at least one 
SAE.   
Separate listings of SAEs and fatal TEAEs will also be provided. Each listing will include 
subject ID, treatment group, study day of the SAE or fatal TEAE, and any additional relevant 
information from the AE eCRF. 
11.2. 
Clinical Laboratory Data 
The hematology, clinical chemistry, and 
 data will be summarized with descriptive 
statistics by visit. Both observed values and changes from baseline will be summarized.  
A shift table from baseline to Day 15 will be presented for selected clinical laboratory variables 
based on the reference range-based categories of “Low,” “Normal,” or “High.” A clinical 
laboratory variable value will be assigned to one of these three categories according to the 
reference ranges provided by the central clinical laboratory. The shift table will have three rows 
and three columns, with rows reflecting the reference range category at baseline, and columns 
reflecting the reference range category at Day 15. A “Total” row and “Total” column will also be 
included. Subjects with a missing baseline value or who do not have Day 15 data will not be 
included in the tables for that variable. The number and percentage of subjects in each shift 
category will be displayed in the table; percentages will be based on the number of subjects 
included in the table. 
The shift table will be presented for the following clinical laboratory variables:  
• aspartate aminotransferase (AST),  
• alanine aminotransferase (ALT),  
• alkaline phosphatase (ALP),  
• gamma-glutamyl transferase (GGT),  
• total bilirubin,  
• creatine kinase,  
• creatinine,  
• blood urea nitrogen,  
• white blood cell count,  
• absolute neutrophil count,  
• hemoglobin,  


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• platelet count, 
 
 
 
 
Summaries of sponsor-defined potentially clinically significant (PCS) values will be presented 
for the following clinical laboratory variables: ALT, AST, creatine kinase, GGT, total bilirubin, 
white blood cell count, absolute neutrophil count, creatinine, and BUN. The number and 
percentage of subjects with PCS values that are reported at any postbaseline visit (scheduled or 
unscheduled) will be summarized. The criteria for identifying PCS clinical laboratory values are 
provided in Table 3. 
Table 3: Potentially Clinically Significant Criteria for Clinical Laboratory Variables 
Variable  
PCS Threshold 
ALT 
>3 x ULN (upper limit of normal) 
AST 
>3 x ULN 
Creatine kinase 
>5 x ULN 
GGT 
>3 x ULN 
Total bilirubin 
>1.5 x ULN 
White blood cell count 
≤2.8 x 1000/µL 
Absolute neutrophil count 
<1.5 x 1000/µL 
Creatinine 
>1.5 x baseline value or > 1.5 x ULN 
BUN 
>30 mg/dL (> 10.71 mmol/L) 
Repeat clinical laboratory samples may be collected at any time during this study due to either 
missing or abnormal results. The general rule for summarizing these data is to include the 
original sample results in summary tables. Exceptions to this rule are: (1) all available lab values 
will be used in the PCS tables and (2) if there are missing results from the original lab samples at 
screening, the results of a repeat screening sample will be substituted for the missing results in 
summary tables.  
11.3. 
Vital Signs 
The vital signs data, including orthostatic blood pressures and heart rate (calculated as standing 
value minus supine value), will be summarized with descriptive statistics by visit.  Observed and 
change from baseline values will be summarized.  
Summaries of sponsor-defined PCS values will be presented for systolic blood pressure, diastolic 
blood pressure, and heart rate. The number and percentage of subjects with PCS values that are 
reported at any postbaseline visit (scheduled or unscheduled) will be summarized. The criteria 
for identifying PCS vital signs values are provided in Table 4. 


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Table 4: Potentially Clinically Significant Criteria for Vital Signs Variables 
Variable Name 
PCS – Low if: 
PCS – High if: 
Observed 
Value is: 
 
AND 
Decrease from 
Baseline is: 
Observed 
Value is: 
 
AND 
Increase from 
Baseline is: 
Systolic Blood 
Pressure 
 <90 mmHg 
 
≥20 mmHg 
>180 mmHg 
 
≥20 mmHg 
Diastolic Blood 
Pressure 
 <50 mmHg 
  
≥15 mmHg 
>105 mmHg 
 
≥15 mmHg 
Heart Rate 
 <50 bpm 
 
≥15 bpm 
>120 bpm 
 
≥15 bpm 
Both supine and standing values of blood pressures and heart rate will be included in the 
identification and summary of PCS values. 
11.4. 
Body Weight  
The body weight data (in units of kilograms) will be summarized with descriptive statistics at 
baseline and each scheduled postbaseline visit. Both observed values and changes from baseline 
will be summarized.  
11.5. 
Electrocardiogram 
The triplicate ECG parameter values recorded at each timepoint for heart rate, PR interval, QRS 
duration, QT interval, and QTcF (corrected QT interval using Fridericia's formula) interval will 
be averaged (and rounded to the nearest whole number) for each subject and timepoint for the 
purpose of statistical summarization.  Additionally, for the triplicate investigator overall 
categorical assessment (ie, Normal, Abnormal not Clinically Significant, or Abnormal Clinically 
Significant) at each timepoint, the outcome representing the greatest degree of abnormality will 
be selected for summarization.   
Descriptive statistics for the observed values and changes from baseline will be presented for 
each of the ECG parameters by timepoint.  
Frequency tables (number and percentage of subjects) will be presented for the overall 
categorical assessment at each timepoint. 
Two additional categorical summaries (frequency tables displaying number and percentage of 
subjects) will be presented for the QTcF interval.  For the first summary, the observed QTcF 
values at each timepoint will be classified as follows: 
• Greater than 450 msec 
• Greater than 480 msec 
• Greater than 500 msec 
For the second categorical summary, the changes from baseline to each subsequent timepoint 
will be classified as follows: 
• Increase greater than 30 msec 
• Increase greater than 60 msec 


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The same categorical summaries will be presented in frequency tables for values at any postdose 
timepoint (including unscheduled assessments) meeting the aforementioned criteria.  
11.6. 
Columbia-Suicide Severity Rating Scale 
The C-SSRS (Children’s Version) data will be presented in the following summaries: 
• Screening/lifetime assessment  
• Screening/past 1 year assessment  
• Baseline (Day 1) assessment  
• Postbaseline assessments  
Each summary will display the number and percentage of subjects who report “Yes” to specific 
C-SSRS items or categories of items (a category is assigned a “Yes” value if a “Yes” is reported 
for any item in the category). These C-SSRS items and categories are as follows: 
• Suicidal Ideation Items 
(1) 
Wish to be dead 
(2) 
Non-specific active suicidal thoughts 
(3) 
Active suicidal ideation with any methods (not plan) without intent to act 
(4) 
Active suicidal ideation with some intent to act, without specific plan 
(5) 
Active suicidal ideation with specific plan and intent 
• Suicidal Ideation Category: Any of items (1) through (5) 
• Suicidal Behavior Items (not included for screening/past 1 year assessment) 
(6) 
Preparatory acts or behavior 
(7) 
Aborted attempt 
(8) 
Interrupted attempt 
(9) 
Non-fatal suicide attempt 
(10) 
Completed suicide (not reported for the screening/lifetime assessment) 
• Suicidal Behavior Category: Any of items (6) through (10) 
• Suicidal Ideation or Behavior Category: Any of items (1) through (10) 
For the “all postbaseline assessments” summary, each subject’s C-SSRS responses for all 
postbaseline assessments will be evaluated, and a “Yes” response for any assessment will be 
considered as a “Yes” for the subject. 
In addition to the summaries described above, shift tables comparing postbaseline suicidal 
ideation scores to baseline scores will be presented. The shift table scores are defined as the 
following: 
0 = No suicidal ideation 
1 = Wish to be dead 
2 = Non-specific active suicidal thoughts 
3 = Active suicidal ideation with any methods (not plan) without intent to act 
4 = Active suicidal ideation with some intent to act, without specific plan 


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5 = Active suicidal ideation with specific plan and intent 
The shift tables will display the number and percentage of subjects within each cell of a 6 x 6 
table for each treatment group, with the rows representing the baseline score and the columns 
representing the maximum score recorded across all postbaseline assessments (including both 
scheduled and unscheduled visits). Subjects missing either a baseline score or all postbaseline 
scores will not appear in the table.  
11.7. 
Brief Psychiatric Rating Scale for Children 
The Brief Psychiatric Rating Scale for Children (BPRS-C) includes 21 items and the severity of 
each item is rated on a 7-point scale (1=not present, 2=very mild, 3=mild, 4=moderate, 
5=moderately severe, 6=severe, 7=extremely severe).  The BPRS-C total score is calculated as 
the sum of the scores for the 21 items (total score range: 21 to 147).  If any one of the 21 items is 
not scored (ie, has a missing value), the BPRS total score will be set equal to missing. 
BPRS total score observed values and change from baseline values will be summarized with 
descriptive statistics by visit. 
 


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12. 
DEVIATIONS FROM PROTOCOL PLANNED ASSESSMENTS 
AND ANALYSIS 
 
 


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13. 
PERFORMANCE QUALIFICATION OF SAS® PROGRAMS 
The analysis and summary of data from this study will be performed using SAS® 9.4 (or a later 
release if available).  All SAS® programs used in the production of statistical analyses, tables, 
listings, and figures described in this SAP will undergo performance qualification (verification 
that the program produces the intended output) in accordance with department standard operating 
procedures.  The performance qualification may include independent programming and/or peer 
review of the SAS® log files. In addition, tables, figures, listings, and statistical analysis output 
will be independently reviewed for completeness and accuracy. 
 


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14. 
REFERENCES 
Auchus RJ, Arlt W. Approach to the patient: the adult with congenital adrenal hyperplasia. J Clin 
Endocrinol Metab. 2013 Jul;98(7):2645-55. 
European Medicines Agency. Points to consider on implications of Coronavirus disease 
(COVID-19) on methodological aspects of ongoing clinical trials. March 2020. 
United States Food and Drug Administration. Conduct of Clinical Trials of Medical Products 
During the COVID-19 Public Health Emergency. Guidance for Industry, Investigators, and 
Institutional Review Boards. March 2020, updated January 2021. 
 


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15. 
APPENDIX 
The following table provides the conversion factors for different types of glucocorticoids to 
hydrocortisone dose equivalents. This will be used to calculate the total daily glucocorticoid dose. 
Table 5: Hydrocortisone Dose Equivalent Conversion 
Glucocorticoid 
Hydrocortisone dose equivalent conversion 
Methylprednisolone 
4× 
Prednisolone 
4× 
Prednisone 
4× 
Dexamethasone 
60× 
Auchus and Arlt, 2013; Speiser et al., 2018. 


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Date of signature: 19-Oct-2021 21:26:21 GMT+0000
Reason for signing: Approved
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