Clinical trial NCT03525886
Conditions: CAH - Congenital Adrenal Hyperplasia
Sponsor: Neurocrine Biosciences
Start date: 2018-04-10; Completion date: 2020-04-07
Enrollment: 18 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a Phase 2, open-label, multiple-dose, dose-escalation study to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of NBI-74788 in up to 30 adult female and male subjects (18 to 50 years of age) with a documented medical diagnosis of classic 21-hydroxylase deficiency congenital adrenal hyperplasia (CAH). The study will include a sequential-cohort design with four NBI-74788 dosing regimens, with each regimen administered for 14 days.

Detailed description:

Arms: arm 1: NBI-74788 50 mg once daily at bedtime (QHS) administered orally for 14 consecutive days. arm 2: NBI-74788 100 mg once daily at bedtime (QHS) administered orally for 14 consecutive days. arm 3: NBI-74788 100 mg once daily in the evening (QPM) administered orally for 14 consecutive days. arm 4: NBI-74788 100 mg twice daily (BID) administered orally for 14 consecutive days.
Interventions: intervention 1: NBI-74788
Intervention descriptions: intervention 1: Capsule, administered daily.

Protocol documents:
Prot_SAP_000.pdf: 
CLINICAL STUDY PROTOCOL 
 
Amendment No. 3 Final Version Date:  14 May 2019 
Amendment No. 2 Final Version Date:  05 October 2018 
Amendment No. 1 Final Version Date:  02 February 2018 
Original Protocol Final Version Date:  14 June 2017 
 
 
A Phase 2, Open-Label, Multiple-Dose Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics of NBI-74788 in 
Adult Subjects with Congenital Adrenal Hyperplasia 
 
 
Study No.:  NBI-74788-CAH2001 
 
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no unpublished information contained herein will be published or disclosed without prior approval 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. 


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 Adult Subjects with Congenital 
Adrenal Hyperplasia 
 
Study No.: 
NBI-74788-CAH2001 
 
 
As Agreed: 
 
____________________________________ 
_______________________ 
Principal Investigator Signature 
Date 
 
PRINCIPAL INVESTIGATOR: 
 
______________________________________________________________ 
(Print Principal Investigator Name) 
 
SITE:   
 
________________________________________________________ 
(Print Site Name) 
 
 
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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 Adult Subjects with Congenital Adrenal 
Hyperplasia 
Study number:  NBI-74788-CAH2001 
Study center(s):  Approximately 7 study centers in North America 
Objectives: 
• To assess the safety and tolerability of different dosing regimens of NBI-74788 in adult 
subjects with congenital adrenal hyperplasia (CAH). 
• To evaluate the effect of repeated doses of NBI-74788 on endogenous levels of 
pharmacodynamic (PD) biomarkers in adult subjects with CAH. 
• To evaluate the impact of different dosing regimens of NBI-74788 on endogenous levels of 
PD biomarkers. 
• To evaluate plasma exposures following repeated doses of NBI-74788. 
Methodology:  This is a Phase 2, open-label, multiple-dose, dose-escalation study to assess the 
safety, tolerability, pharmacokinetics (PK), and PD of NBI-74788 in approximately 30 adult female 
and male subjects (18 to 50 years of age) with a documented medical diagnosis of classic 
21-hydroxylase deficiency CAH.  The study will include a sequential-cohort design with 
4 NBI-74788 dosing regimens, with each regimen administered for 14 consecutive days: 
• 
Cohort 1:  NBI-74788 50 mg once daily with a bottle of vanilla-flavored 
 
(~237 mL) at approximately 2200 hours. 
• 
Cohort 2:  NBI-74788 100 mg once daily with a bottle of vanilla-flavored 
 
(~237 mL) at approximately 2200 hours. 
• 
Cohort 3:  NBI-74788 100 mg once daily with the evening meal at approximately 1900 hours. 
• 
Cohort 4:  NBI-74788 100 mg twice daily with breakfast at approximately 0700 hours and 
with the evening meal at approximately 1900 hours. 
There will be an approximate 2-week period to evaluate safety and tolerability data before proceeding 
from Cohort 1 to Cohort 2.  Subjects who previously completed the current study in Cohort 1 or 
Cohort 2 may reenroll to participate in Cohorts 3 or 4 (in addition to new subjects).  The following 
table depicts the cohorts, doses, and number of subjects per cohort: 
Cohort 
NBI-74788 Dose 
Approximate Dosing 
Time(s) 
Number of Subjects  
1 
50 mg 
2200 hours 
8-10 
2 
 100 mg 
2200 hours 
8-10 
3 
100 mg 
1900 hours 
8-10 
4 
100 mg 
0700 and 1900 hours 
Up to 8 
Subjects must provide informed consent prior to any study-related procedures.  Subjects will then be 
screened for eligibility to participate in the study for up to approximately 3 weeks (Days -28 to -8).  
Subjects who reenroll and have had a stable medication regimen for CAH since their last visit in this 
study do not have to undergo screening; those who reenroll and have had a change to their medication 
regimen for CAH must undergo a second screening visit.  During screening, subjects will provide a 
single 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. 
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Eligible subjects who have a screening 17-OHP level ≥1,000 ng/dL will be admitted to the study 
center for 1 night and have baseline serial PD samples collected over a 24-hour period beginning in 
the evening of Day -7.  Baseline serial PD samples will be collected at approximately 2145, 2300, 
2400, 0100, 0200, 0400, 0600, 0800, 1000, 1200, 1400, 1800, and 2200 hours for Cohorts 1 and 2 and 
at approximately 1845, 2000, 2100, 2200, 2300, 2400, 0100, 0200, 0400, 0600, 0800, 1000, 1200, 
1400, 1800, 1900, and 2200 hours for Cohorts 3 and 4.  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 in Cohorts 1 and 2 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.  Study drug (NBI-74788 50 mg or 100 mg) will be administered at approximately 2200 hours.  
The subjects’ usual morning dose of concurrent steroidal treatments will be administered after the 
12-hour postdose PK/PD samples are collected (ie, at approximately 1000 hours) on Day 2 and after 
the 16-hour postdose PK/PD samples are collected (ie, at approximately 1400 hours) on Day 15.  
Subjects will be discharged from the study center the evening on Days 2 and 15 following completion 
of all study-related procedures for those days.  Prior to this discharge on Day 2, study drug will be 
administered at the study center at approximately 2200 hours.  Study drug will then be 
self-administered nightly at home at approximately 2200 hours on Days 3 to 13.  Subjects will take 
their usual morning dose of concurrent steroidal treatments at approximately 1000 hours on Days 3 to 
14.  On Day 7 during the treatment period, PK, PD, and safety assessments will be conducted in an 
outpatient setting at the study center. 
Subjects in Cohorts 3 and 4 will have a blood sample collected on Day 1 for 
 
(only for subjects who have not previously participated in Cohorts 1 or 2).  Baseline safety 
assessments will be collected on Day 1 prior to the first dose of study drug.  For Cohort 3, study drug 
(NBI-74788 100 mg) will be administered at home on Days 1 to 13 at approximately 1900 hours with 
each subject’s evening meal.  For Cohort 4, study drug (NBI-74788 100 mg) will be administered at 
home on Days 2 to 14 at approximately 0700 hours with each subject’s breakfast and on Days 1 to 13 
at approximately 1900 hours with each subjects’ evening meal.  For both cohorts, the Day 14 evening 
dose will be administered at the study site.  Subjects will take their usual morning dose of concurrent 
steroidal treatments at approximately 1000 hours on Days 1 to 14.  On Day 7 during the treatment 
period, PK, PD, and safety assessments will be conducted in an outpatient setting at the study center.  
Subjects will be admitted to the study center on Day 14 (last day of dosing).  On Day 14, subjects will 
receive study drug in the study center at approximately 1900 hours with a standard (moderate 
fat/moderate calorie) evening meal.  The subjects’ usual morning dose of concurrent steroidal 
treatments will be administered after PK/PD samples are collected at approximately 1400 hours on 
Day 15.  Subjects will be discharged from the study center the evening on Day 15 following 
completion of all study-related procedures.    
For all cohorts, follow-up visits on Days 21, 28, and 35 will be conducted at the study center or the 
subject’s home by a qualified home healthcare provider (based on the subject’s preference).  A final 
study visit will be conducted at the study site approximately 5 weeks after the last dose of study drug 
(on Day 49 or early termination).  There will be a visit window of -8 hours for day 7, -8 hours/+3 days 
for Days 21, 28, and 35, and +7 days for the final study visit.  Safety, tolerability, PK, and PD will be 
assessed at scheduled times throughout the study. 
Dose Escalation Procedure 
Cohort 1 will consist of approximately 8 to 10 subjects who will receive a daily dose of NBI-74788 
50 mg at approximately 2200 hours for 14 days (subjects will receive study drug at the site on Days 1, 
2, and 14, and self-administer study drug at home on Days 3 to 13).  Following the completion of 
Day 15 assessments for all subjects in Cohort 1, a medical monitor will review the accumulated safety 
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and tolerability results to ensure there are no safety concerns with proceeding to the 100 mg dose 
(Cohorts 2 and 3), and to determine if a maximum tolerated dose (MTD) has been reached.  If the 
MTD is reached, no dose escalation will occur.  There will be an approximate 2-week period between 
Cohorts 1 and 2 to accommodate this safety review.  A similar procedure will be used prior to 
proceeding to the 100 mg twice daily dose (Cohort 4). 
If the medical monitor determines that it is safe to proceed to NBI-74788 100 mg, subjects in Cohort 2 
will be administered NBI-74788 100 mg daily for 14 days.  Dosing for Cohorts 3 and 4 may begin 
simultaneously with Cohort 2. 
During the 14-day dosing period for any cohort, dosing may be postponed or halted if one or more 
subjects experience a severe or serious adverse event (AE), or if the type, frequency, or severity of 
AEs becomes unacceptable.  If dosing is postponed, the medical monitor will review all available 
safety, tolerability, and PK data before allowing any further subjects to receive study drug.   
Study Population:  Approximately 30 adult female and male subjects (18 to 50 years of age) with a 
documented medical diagnosis of classic 21-hydroxylase deficiency CAH, who meet all protocol 
eligibility criteria, will be enrolled.  Subjects who previously completed the current study in Cohort 1 
or Cohort 2 may reenroll to participate in Cohorts 3 or 4 (in addition to new subjects). 
Duration of treatment:  The expected duration of study participation for each subject is 
approximately 11 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 5 weeks.  The total duration of the study will be an additional 8 to 11 weeks 
for subjects who reenroll. 
Test product, dose, and mode of administration:  NBI-74788 will be supplied as capsules 
containing 50 mg of NBI-74788 
 for oral administration.  Doses of NBI-74788 are 50 mg and 
100 mg, administered in oral capsule form.  Each dose of study drug for Cohorts 1 and 2 is to be 
administered with a bottle of vanilla-flavored 
 (~237 mL) at approximately 2200 hours.  
Each dose of study drug for Cohort 3 is to be administered with each subject’s evening meal at 
approximately 1900 hours.  Each dose of study drug for Cohort 4 is to be administered with each 
subject’s breakfast at approximately 0700 hours and evening meal at approximately 1900 hours (ie, a 
total daily dose of 200 mg). 
Reference therapy, dose, and mode of administration:  Not applicable. 
CRITERIA FOR EVALUATION:  
Cohorts 1 and 2 
Blood samples to evaluate 24-hour PD baseline will be collected on Days -7 to -6 at approximately 
2145, 2300, 2400, 0100, 0200, 0400, 0600, 0800, 1000, 1200, 1400, 1800, and 2200 hours.  Blood 
samples to evaluate PK and PD parameters of NBI-74788 will be collected on Days 1 to 2 and 
Days 14 to 15 at:  15 minutes predose and at 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours postdose; 
Day 7 (at approximately 24 hours postdose); Days 21, 28, and 35 (at approximately 168, 336, and 
504 hours postdose); and at the final study visit (Day 49 or early termination).  
Cohorts 3 and 4 
Blood samples to evaluate 24-hour PD baseline will be collected on Days -7 to -6 at approximately 
1845, 2000, 2100, 2200, 2300, 2400, 0100, 0200, 0400, 0600, 0800, 1000, 1200, 1400, 1800, 1900, 
and 2200 hours.  Blood samples to evaluate PK and PD parameters of NBI-74788 will be collected on 
Days 14 to 15 at the following times (for Cohort 4, all times are relative to evening dosing unless 
otherwise indicated):  15 minutes predose and at 1, 2, 3, 4, 5, 6, 7, 9, 11, 13, 15, 17, 19, 23, 24, and 
27 hours postdose; Day 7 (at 24 hours postdose for Cohort 3 or at 12 hours post morning dose but 
prior to the evening dose for Cohort 4); Days 21, 28, and 35 (at approximately 168, 336, and 
504 hours postdose); and at the final study visit (Day 49 or early termination).  
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Pharmacokinetics:   
The following plasma PK parameters will be calculated for NBI-74788 and metabolites: 
• 
Area under the plasma concentration versus time curve from 0 hours to last measurable 
concentration (AUC0-tlast) 
• 
Area under the plasma concentration versus time curve from 0 to 24 hours (AUC0–24) 
(Cohorts 1, 2, and 3) 
• 
Area under the plasma concentration versus time curve from 0 to 12 hours (AUC0–12) 
(Cohort 4) 
• 
Maximum plasma concentration (Cmax) 
• 
Time to maximum plasma concentration (tmax) 
• 
Delay time between time of dosing and time of appearance of measurable test article (Tlag) 
• 
Terminal half-life (t½) 
• 
Apparent terminal rate constant (λz)  
• 
Apparent mean residence time (MRT) 
Additional PK parameters for Day 14 only: 
• 
Average plasma concentration at steady state (Cavg) 
• 
Percent fluctuation at steady state (%fluctuation) 
• 
Accumulation index at steady state 
• 
Apparent systemic clearance after oral administration (CL/F) (NBI-74788 only) 
Pharmacodynamics: 
  Morning 17-OHP (serum; ng/dL) from the 0600, 0800, and 1000 hour samples (8-, 10-, and 
12-hour postdose samples from Cohorts 1 and 2 and 11-, 13-, and 15-hour postdose samples from 
Cohorts 3 and 4). 
  17-OHP at all other times, androstenedione (serum; ng/dL), testosterone (serum; ng/dL), 
cortisol (serum; μg/dL), and adrenocorticotropic hormone (plasma ACTH; pg/mL). 
Safety:   
Safety and tolerability will be monitored throughout the study and will include the following 
assessments: 
• 
Adverse events 
• 
Clinical laboratory tests - clinical chemistry (including creatine kinase, myoglobin, total and 
conjugated bilirubin), hematology, coagulation (prothrombin time, aPTT, d-dimer, 
fibrinogen), and urinalysis (including quantitative myoglobin, casts and crystals) 
• 
Vital signs 
• 
Physical examinations (including musculoskeletal exam) 
• 
12-lead electrocardiograms (ECGs) 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
• 
Brief Psychiatric Rating Scale (BPRS) 
Statistical methods:  Safety, PK, and PD variables will be summarized within each cohort using 
descriptive statistics.  Summaries of PD measures will include both observed values and changes from 
predose. 
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TABLE OF CONTENTS 
1. 
SYNOPSIS ...................................................................................................................5 
TABLE OF CONTENTS .................................................................................................................9 
LIST OF TABLES .........................................................................................................................12 
LIST OF FIGURES .......................................................................................................................12 
2. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................13 
3. 
ETHICS ......................................................................................................................15 
4. 
INTRODUCTION ......................................................................................................15 
4.1. 
Background .................................................................................................................15 
4.2. 
NBI-74788 ..................................................................................................................16 
4.3. 
Study and Dose Rationale ...........................................................................................18 
5. 
OBJECTIVES .............................................................................................................18 
6. 
STUDY DESIGN .......................................................................................................18 
6.1. 
Overview of Study Design ..........................................................................................18 
6.2. 
Dose Escalation Procedure .........................................................................................21 
7. 
STUDY POPULATION .............................................................................................22 
7.1. 
Subject Inclusion Criteria ...........................................................................................22 
7.2. 
Subject Exclusion Criteria ..........................................................................................23 
7.3. 
Subject Identification and Replacement .....................................................................25 
7.4. 
Randomization ............................................................................................................25 
8. 
STUDY EVALUATIONS ..........................................................................................26 
8.1. 
Schedule of Assessments ............................................................................................26 
8.2. 
Screening and Baseline Assessments .........................................................................33 
8.2.1. 
Serum 17-Hydroxyprogesterone .................................................................................33 
8.2.2. 
 ..........................................................................33 
8.3. 
Pharmacokinetic Assessments ....................................................................................33 
8.4. 
Pharmacodynamic Assessments: Pharmacodynamic Biomarkers..............................34 
8.5. 
Safety Assessments .....................................................................................................35 
8.5.1. 
Vital Sign Measurements ............................................................................................35 
8.5.2. 
Medical History and Physical Examination ...............................................................36 
8.5.3. 
12-Lead Electrocardiogram ........................................................................................36 
8.5.4. 
Clinical Laboratory Assessments ...............................................................................37 
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8.5.5. 
Brief Psychiatric Rating Scale ....................................................................................38 
8.5.6. 
Columbia-Suicide Severity Rating Scale ....................................................................38 
8.6. 
Subject Study Diary ....................................................................................................39 
8.7. 
Specific Study Period Information for Cohorts 1 and 2 .............................................39 
8.7.1. 
Screening Period (Study Days -28 to -8) ....................................................................39 
8.7.2. 
Day -7 to Day -6:  24-Hour Baseline Pharmacodynamics .........................................40 
8.7.3. 
Treatment Period for Each Dose Cohort ....................................................................40 
8.7.3.1. 
Day 1 to Day 2 ............................................................................................................40 
8.7.3.2. 
Day 7 ...........................................................................................................................43 
8.7.3.3. 
Day 14 to Day 15 ........................................................................................................43 
8.7.4. 
Follow-Up Period .......................................................................................................45 
8.7.4.1. 
Follow-Up Visits:  Days 21, 28, and 35 .....................................................................45 
8.7.4.2. 
Final Study Visit:  (Day 49 or Early Termination) .....................................................45 
8.8. 
Specific Study Period Information for Cohorts 3 and 4 .............................................46 
8.8.1. 
Screening Period (Study Days -28 to -8) ....................................................................46 
8.8.2. 
Day -7 to Day -6:  24-Hour Baseline Pharmacodynamics .........................................47 
8.8.3. 
Treatment Period ........................................................................................................47 
8.8.3.1. 
Day 1 ...........................................................................................................................48 
8.8.3.2. 
Day 7 ...........................................................................................................................49 
8.8.3.3. 
Day 14 to Day 15 ........................................................................................................49 
8.8.4. 
Follow-Up Period .......................................................................................................51 
8.8.4.1. 
Follow-Up Visits:  Days 21, 28, and 35 .....................................................................51 
8.8.4.2. 
Final Study Visit:  (Day 49 [+7 Days] or Early Termination) ....................................52 
8.9. 
Study Duration ............................................................................................................52 
8.10. 
Prohibitions and Restrictions ......................................................................................52 
8.10.1. 
Prior and Concomitant Medications ...........................................................................52 
8.10.2. 
Dietary and Other Restrictions ...................................................................................53 
8.11. 
Withdrawal Criteria ....................................................................................................54 
8.11.1. 
Reasons for Withdrawal .............................................................................................54 
8.11.2. 
Handling of Withdrawals ............................................................................................55 
8.11.3. 
Sponsor’s Termination of Study .................................................................................55 
9. 
STUDY DRUG ...........................................................................................................55 
9.1. 
Study Drug Supplies ...................................................................................................55 
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9.2. 
Study Drug Packaging and Labeling ..........................................................................55 
9.3. 
Study Drug Administration.........................................................................................55 
9.4. 
Study Drug Storage and Return ..................................................................................56 
9.5. 
Blinding ......................................................................................................................56 
9.6. 
Study Compliance and Accountability .......................................................................56 
10. 
ADVERSE EVENTS..................................................................................................57 
10.1. 
Definition ....................................................................................................................57 
10.2. 
Intensity of Adverse Events ........................................................................................57 
10.3. 
Relationship to Study Drug ........................................................................................58 
10.4. 
Recording Adverse Events .........................................................................................58 
10.5. 
Post-Study Follow-Up of Adverse Events ..................................................................59 
10.6. 
Serious Adverse Events ..............................................................................................59 
10.6.1. 
Definition of a Serious Adverse Event .......................................................................59 
10.6.2. 
Managing Serious Adverse Events .............................................................................60 
10.6.3. 
Reporting Serious Adverse Events and Other Immediately Reportable 
Events .........................................................................................................................60 
10.6.4. 
Expedited Safety Reports ...........................................................................................60 
10.7. 
Pregnancy ...................................................................................................................61 
11. 
DOCUMENTATION OF DATA ...............................................................................61 
11.1. 
Case Report Forms .....................................................................................................61 
11.2. 
Data Capture, Review, and Validation .......................................................................62 
11.3. 
Coding Dictionaries ....................................................................................................62 
12. 
STATISTICAL AND ANALYTICAL PLAN ...........................................................62 
12.1. 
Analysis Sets ...............................................................................................................62 
12.2. 
Sample Size ................................................................................................................62 
12.3. 
Handling of Missing Data ...........................................................................................63 
12.4. 
Disposition of Subjects ...............................................................................................63 
12.5. 
Demographics and Baseline Characteristics ...............................................................63 
12.6. 
Pharmacokinetic Data .................................................................................................63 
12.7. 
Pharmacodynamic Data ..............................................................................................64 
12.8. 
Safety Data ..................................................................................................................64 
12.9. 
Interim Analysis ..........................................................................................................64 
13. 
REGULATORY AND ETHICAL ISSUES ...............................................................64 
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13.1. 
General Legal References ...........................................................................................64 
13.2. 
Institutional Review Board .........................................................................................65 
13.3. 
Protocol Adherence and Amendments .......................................................................65 
13.4. 
Required Documents ..................................................................................................65 
13.5. 
Informed Consent .......................................................................................................65 
13.6. 
Study Monitoring ........................................................................................................66 
13.7. 
Quality Assurance .......................................................................................................66 
13.8. 
Record Retention ........................................................................................................66 
13.9. 
Confidentiality ............................................................................................................66 
14.
STUDY COMMENCEMENT AND DISCONTINUATION ....................................67
15.
REFERENCES ...........................................................................................................68
16.
APPENDICES ............................................................................................................69
APPENDIX A. BRIEF PSYCHIATRIC RATING SCALE .......................................................69 
APPENDIX B. COLUMBIA-SUICIDE SEVERITY RATING SCALE ...................................72 
LIST OF TABLES 
Table 1: 
Dose Cohorts, Doses, and Number of Subjects ..........................................................19 
Table 2: 
Schedule of Assessments for Cohorts 1 and 2 ............................................................27 
Table 3: 
Schedule of Assessments for Cohorts 3 and 4 ............................................................30 
Table 4: 
Intensity of Adverse Events ........................................................................................58 
Table 5: 
Relationship of Adverse Events to Study Drug ..........................................................58 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................................21 
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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 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration versus time curve 
AUC0-12 
AUC from 0 to 12 hours 
AUC0-24 
AUC from 0 to 24 hours 
β-hCG 
β-human chorionic gonadotropin 
BMI 
Body mass index 
BPRS 
Brief Psychiatric Rating Scale 
CAH 
Congenital adrenal hyperplasia 
CDS 
Clinical Drug Safety 
CFR 
Code of Federal Regulations 
CK 
Creatine kinase 
Cmax 
Maximum plasma concentration 
CRF1 
Corticotropin releasing factor 1 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
 
 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
FDA 
Food and Drug Administration 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
HBsAg 
Hepatitis B surface antigen 
HCV-Ab 
Hepatitis C virus antibody 
HIV-Ab 
Human immunodeficiency virus antibody 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
INR 
International normalized ratio 
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IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
Maximum tolerated dose 
NBI 
Neurocrine Biosciences, Inc. 
NOAEL 
No adverse effect dose level 
PD 
Pharmacodynamic(s) 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetic(s) 
QTcF 
Corrected QT interval using Fridericia’s formula 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
TEAE 
Treatment-emergent adverse event 
tmax  
Time to maximum plasma concentration 
ULN 
Upper limit of normal 
US 
United States 
 
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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: 
• Good Clinical Practice:  Consolidated Guideline (International Conference on Harmonisation 
[ICH] of Technical Requirements for the Registration of Pharmaceuticals for Human Use 
[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 (FDAR) 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/Ethics Committees (IRBs/ECs) 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 
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deficiency CAH.  The study will include a sequential-cohort design with 4 NBI-74788 dosing 
regimens, with each regimen administered for 14 consecutive days: 
• Cohort 1:  NBI-74788 50 mg once daily with a bottle of vanilla-flavored 
 
(~237 mL) at approximately 2200 hours. 
• Cohort 2:  NBI-74788 100 mg once daily with a bottle of vanilla-flavored 
 
(~237 mL) at approximately 2200 hours. 
• Cohort 3:  NBI-74788 100 mg once daily with the evening meal at approximately 
1900 hours. 
• Cohort 4:  NBI-74788 100 mg twice daily with breakfast at approximately 0700 hours and 
with the evening meal at approximately 1900 hours.   
There will be an approximate 2-week period to evaluate safety and tolerability data before 
proceeding from Cohort 1 to Cohort 2.  Subjects who previously completed the current study in 
Cohort 1 or Cohort 2 may reenroll to participate in Cohorts 3 or 4 (in addition to new subjects).  
Table 1 depicts the cohorts, doses, and number of subjects per cohort. 
Table 1: 
Dose Cohorts, Doses, and Number of Subjects 
Cohort 
NBI-74788 Dose 
Approximate Dosing Time(s) 
Number of Subjects 
1 
50 mg 
2200 hours 
8-10 
2 
100 mg 
2200 hours 
8-10 
3 
100 mg 
1900 hours 
8-10 
4 
100 mg 
0700 and 1900 hours 
Up to 8 
Subjects must provide informed consent prior to any study-related procedures.  Subjects will 
then be screened for eligibility to participate in the study for up to approximately 3 weeks 
(Days -28 to -8).  Subjects who reenroll and have had a stable medication regimen for CAH since 
their last visit in this study do not have to undergo screening; those who reenroll and have had a 
change to their medication regimen for CAH must undergo a second screening visit.  During 
screening, subjects will provide a single 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 ≥1,000 ng/dL will be admitted to the study 
center for 1 night and have baseline serial PD samples collected over a 24-hour period beginning 
in the evening of Day -7.  Baseline serial PD samples will be collected at approximately 2145, 
2300, 2400, 0100, 0200, 0400, 0600, 0800, 1000, 1200, 1400, 1800, and 2200 hours for 
Cohorts 1 and 2 and at approximately 1845, 2000, 2100, 2200, 2300, 2400, 0100, 0200, 0400, 
0600, 0800, 1000, 1200, 1400, 1800, 1900, and 2200 hours for Cohorts 3 and 4.  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 in Cohorts 1 and 2 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 
.  
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Baseline safety assessments will be collected on Day 1 prior to the first dose of study drug.  
Study drug (NBI-74788 50 or 100 mg) will be administered at approximately 2200 hours.  The 
subjects’ usual morning dose of concurrent steroidal treatments will be administered after the 
12-hour postdose PK/PD samples are collected (ie, at approximately 1000 hours) on Day 2 and 
after the 16-hour postdose PK/PD samples are collected (ie, at approximately 1400 hours) on 
Day 15.  Subjects will be discharged from the study center the evening on Days 2 and 15 
following completion of all study-related procedures for those days.  Prior to this discharge on 
Day 2, study drug will be administered at the study center at approximately 2200 hours.  Study 
drug will then be self-administered nightly at home at approximately 2200 hours on Days 3 to 
13.  Subjects will take their usual morning dose of concurrent steroidal treatments at 
approximately 1000 hours on Days 3 to 14.  On Day 7 during the treatment period, PK, PD, and 
safety assessments will be conducted in an outpatient setting at the study center. 
Subjects in Cohorts 3 and 4 will have a blood sample collected on Day 1 for 
 
 (only for subjects who have not previously participated in Cohorts 1 or 2).  Baseline 
safety assessments will be collected on Day 1 prior to the first dose of study drug.  For Cohort 3, 
study drug (NBI-74788 100 mg) will be administered at home on Days 1 to 13 at approximately 
1900 hours with each subject’s evening meal.  For Cohort 4, study drug (NBI-74788 100 mg) 
will be administered at home on Days 2 to 14 at approximately 0700 hours with each subject’s 
breakfast and on Days 1 to 13 at approximately 1900 hours with each subjects’ evening meal.  
For both cohorts, the Day 14 evening dose will be administered at the study site.  Subjects will 
take their usual morning dose of concurrent steroidal treatments at approximately 1000 hours on 
Days 1 to 14.  On Day 7 during the treatment period, PK, PD, and safety assessments will be 
conducted in an outpatient setting at the study center.  Subjects will be admitted to the study 
center on Day 14 (last day of dosing).  On Day 14, subjects will receive study drug in the study 
center at approximately 1900 hours with a standard (moderate fat/moderate calorie) evening 
meal.  The subjects’ usual morning dose of concurrent steroidal treatments will be administered 
after PK/PD samples are collected at approximately 1400 hours on Day 15.  Subjects will be 
discharged from the study center the evening on Day 15 following completion of all study-
related procedures.   
Standard meals and snacks will be provided by the study center during the in-patient stays.  
For all cohorts, follow-up visits on Days 21, 28, and 35 will be conducted at the study center or 
the subject’s home by a qualified home healthcare provider (based on the subject’s preference).  
A final study visit will be conducted at the study site approximately 5 weeks after the last dose of 
study drug (on Day 49 or early termination).  There will be a visit window of -8 hours for 
Day 7, -8 hours/+3 days for Days 21, 28, and 35, and +7 days for the final study visit.  Safety, 
tolerability, PK, and PD will be assessed at scheduled times throughout the study. 
The study design schematic is shown in Figure 1. 
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Figure 1: 
Study Design Schematic 
 
bid=twice daily. 
Visits on Days 21 (+3 days), 28 (+3 days), and 35 (+3 days); final study visit on Day 49 (+7 days) or early 
termination. 
6.2. 
Dose Escalation Procedure 
Cohort 1 will consist of approximately 8 to 10 subjects who will receive a daily dose of 
NBI-74788 50 mg at approximately 2200 hours for 14 days (subjects will receive study drug at 
the site on Days 1, 2, and 14, and self-administer study drug at home on Days 3 to 13).  
Following the completion of Day 15 assessments for all subjects in Cohort 1, a medical monitor 
will review the accumulated safety and tolerability results to ensure there are no safety concerns 
with proceeding to the 100 mg dose (Cohorts 2 and 3), and to determine if a maximum tolerated 
dose (MTD) has been reached.  If the MTD is reached, no dose escalation will occur.  There will 
be an approximate 2-week period between Cohorts 1 and 2 to accommodate this safety review.  
A similar procedure will be used prior to proceeding to the 100 mg twice daily dose (Cohort 4). 
If the medical monitor determines that it is safe to proceed to NBI-74788 100 mg, subjects in 
Cohort 2 will be administered NBI-74788 100 mg daily for 14 days.  Dosing for Cohorts 3 and 4 
may begin simultaneously with Cohort 2. 
During the 14-day dosing period for any cohort, dosing may be postponed or halted if one or 
more subjects experience a severe or serious adverse event (AE), or if the type, frequency, or 
severity of AEs becomes unacceptable.  If dosing is postponed, the medical monitor will review 
all available safety, tolerability, and PK data before allowing any further subjects to receive 
study drug.   
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8. 
STUDY EVALUATIONS 
8.1. 
Schedule of Assessments 
Table 2 summarizes the frequency and timing of all study assessments and procedures for 
Cohorts 1 and 2; Table 3 summarizes the frequency and timing of all study assessments and 
procedures for Cohorts 3 and 4.  Subjects will provide written informed consent before any 
study-related procedures are conducted, including the cessation of prohibited concomitant 
medications.  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 for Cohorts 1 and 2 
Procedure 
Screening 
PD 
Baseline 
14-Day Dosing Period 
Follow-Up Period (-8 hour/+3 day 
window for each visit) 
Final Study 
Visita 
 
Study Day 
-28 to -8 
-7 to -6b 
DAY 
1b 
2 
3-
6 
7 
8-
13 
14 
15 
21 
28 
35 
49 
(+7 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
Update 
Update 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
Update 
Update 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
X 
X 
 
X 
 
 
X 
 
 
 
X 
Height  
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) 
Screening FSH (postmenopausal 
females only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serology (HBsAg, HCV-Ab, HIV-Ab) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Morning 17-OHPf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory testsg 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Urine drug screen & alcohol breath 
testh 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
 
PD blood samplesi 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Brief Psychiatric Rating Scalej 
 
 
X 
X 
 
 
 
X 
X 
 
 
 
X 
C-SSRS 
X 
 
X 
 
 
 
 
 
X 
 
 
 
X 
PK plasma samplesk 
 
 
X 
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 
X 
Prior and concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Center visit  
X 
 
 
 
X 
 
 
Xo 
Xo 
Xo 
X 
Inpatient center stay 
 
X 
X 
X 
 
 
 
X 
X 
 
 
 
 
Definitions and footnotes are on the next page. 
 
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Definitions:  17-OHP=17-hydroxyprogesterone; AE=adverse event; C-SSRS=Columbia Suicide Severity Rating Scale; 
; 
ECG=electrocardiogram; FSH=follicle stimulating hormone; 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.   
a Final study visit for subjects who complete the study (or early termination).  The final study visit will be conducted approximately 5 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 8-10 and 22-24 hours postdose (ie, morning and evening). 
d A standard 12-lead ECG will be conducted in triplicate (1-3 minutes apart) after subject has rested supine for at least 5 minutes at screening, at 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 49 or early termination).   
e Pregnancy tests will be conducted for female subjects of childbearing potential.  Serum pregnancy tests will be conducted at screening and urine pregnancy 
tests will be conducted on Day -7, prior to dosing on Day 1 (for eligibility), Day 14, and at the final study visit (Day 49 or early termination). 
f Blood sample for determination of study-qualifying levels of 17-OHP should be collected between 0700 and 1000 hours (prior to first morning dose of 
hydrocortisone). 
g Includes hematology, clinical chemistry (including creatine kinase, myoglobin, total and conjugated bilirubin), coagulation (prothrombin time, activated partial 
thromboplastin time [aPTT], d-dimer, fibrinogen), 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 adrenocorticotropic hormone [ACTH] will be collected at the following 
times: 
• Screening (for all biomarkers except 17-OHP). 
• Day -7 to Day -6 (24-hour PD baseline):  at approximately 2145, 2300, 2400, 0100, 0200, 0400, 0600, 0800, 1000, 1200, 1400, 1800, and 2200 hours. 
• Days 1 and 14: 15 minutes predose and at 1, 2, 3, 4, and 6 hours postdose (±5 minute window). 
• Days 2 and 15:  8, 10, 12, 14, 16, 20, and 24 hours postdose (±15 minute window). 
• Day 7:  approximately 24 hours (-8 hour window) after the Day 6 dose and prior to the Day 7 dose. 
• Days 21, 28, and 35:  approximately 168 hours (-8 hours/+3 days), 336 hours (-8 hours/+3 days) and 504 hours (-8 hours/+3 days) postdose. 
• Final study visit (Day 49 [+7 days] or early termination). 
j The Brief Psychiatric Rating Scale will be administered predose on Days 1 and 14, on Days 2 and 15, and at the final study visit (Day 49 or early termination). 
k Pharmacokinetic plasma samples for analyses of NBI-74788 will be collected at the following times: 
• Days 1 and 14:  15 minutes predose and at 1, 2, 3, 4, and 6 hours postdose (±5 minute window). 
• Days 2 and 15:  8, 10, 12, 14, 16, 20, and 24 hours postdose (±15 minute window). 
• Day 7:  24 hours (-8 hour window) after the Day 6 dose, prior to the Day 7 dose. 
• Days 21, 28, and 35:  approximately 168 hours (-8 hours/+3 days), 336 hours (-8 hours/+3 days) and 504 hours (-8 hours/+3 days) postdose. 
• Final study visit (Day 49 [+7 days] or early termination). 
l Study drug will be administered at the study center on Days 1, 2, and 14, and at home on Days 3 to 13 at approximately 2200 hours.  Sites should call subjects 
between the Day 3 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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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 
 was taken will be documented each day (subjects should finish consuming the entire bottle of 
 within 30 minutes of 
taking study drug).  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 Subjects will have the option of having the Days 21, 28, and 35 assessments conducted at home by a qualified home healthcare provider or at the study center.   
 
 
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Table 3: 
Schedule of Assessments for Cohorts 3 and 4 
Procedure 
Screeninga 
PD 
Baseline 
14-Day Dosing Period 
Follow-Up Period (-8 hour/+3 day 
window for each visit) 
Final Study 
Visitb 
 
Study Day 
-28 to -8 
-7 to -6c 
DAY 1c 
2-
6 
7 
8-
13 
14 
15 
21 
28 
35 
49 
(+7 days) 
Informed consent 
X 
Xd 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
Updatee 
Updatee 
 
 
 
 
 
 
 
 
 
Medical history 
X 
Updatee 
Updatee 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
X 
 
X 
 
 
X 
 
 
 
X 
Height  
X 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
Vital Signs 
X 
X 
X 
 
X 
 
X 
Xf 
 
 
 
X 
12-lead ECGg 
X 
 
X 
 
 
 
X 
X 
 
 
 
X 
Pregnancy testh 
X (s) 
X (s/u) 
X (u) 
 
 
 
X 
(u) 
 
 
 
 
X (u) 
Screening FSH (postmenopausal 
females only) 
X 
 
 
 
 
 
 
 
 
 
 
 
Serology (HBsAg, HCV-Ab, HIV-Ab) 
X 
 
 
 
 
 
 
 
 
 
 
 
Morning 17-OHPj 
X 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory testsk 
X 
 
X 
 
X 
 
 
X 
 
 
X 
Urine drug screen & alcohol breath testl 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
PD blood samplesm 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Brief Psychiatric Rating Scalen 
 
 
X 
 
 
 
X 
X 
 
 
 
X 
C-SSRS 
X 
Xo 
X 
 
 
 
 
X 
 
 
 
X 
PK plasma samplesp 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Study drug dosingq 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Subject study diaryr 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Study drug reconciliations 
 
 
 
 
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 
Center visit  
X 
 
X 
 
X 
 
 
Xt 
Xt 
Xt 
X 
Inpatient center stay 
 
X 
 
 
 
X 
X 
 
 
 
 
Definitions and footnotes are on the next page. 
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Definitions:  17-OHP=17-hydroxyprogesterone; AE=adverse event; C-SSRS=Columbia-Suicide Severity Rating Scale; 
; 
ECG=electrocardiogram; FSH=follicle stimulating hormone; 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.   
a Subjects who reenroll and have had a stable medication regimen for CAH since their last visit in this study do not have to undergo screening; those who 
reenroll and have had a change to their medication regimen for CAH must undergo a second screening visit. 
b Final study visit for subjects who complete the study (or early termination).  The final study visit will be conducted approximately 5 weeks (+7 days) after the 
last dose of study drug. 
c 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. 
d Only for subjects who reenroll and who do not undergo screening. 
e Only for subjects who undergo screening. 
f Vital signs will be collected on Day 15 between 8-10 and 22-24 hours postdose (ie, morning and evening) (for Cohort 4, timing is relative to evening dosing). 
g A standard 12-lead ECG will be conducted in triplicate (1-3 minutes apart) after subject has rested supine for at least 5 minutes at screening, at pre-evening 
dose on Days 1 and 14, prior to visit completion or discharge on Day 15, and at the final study visit (Day 49 or early termination).   
h Pregnancy tests will be conducted for female subjects of childbearing potential.  For subjects who undergo screening, serum pregnancy tests will be conducted 
at screening and urine pregnancy tests will be conducted on Day -7, prior to dosing on Day 1 (for eligibility), Day 14, and at the final study visit (Day 49 or 
early termination).  For subjects who do not undergo screening, serum pregnancy tests will be conducted on Day -7 and urine pregnancy tests will be conducted 
prior to dosing on Day 1 (for eligibility), Day 14, and at the final study visit (Day 49 or early termination). 
i Only for subjects who have not previously enrolled in Cohorts 1 or 2. 
j Blood sample for determination of study-qualifying levels of 17-OHP should be collected between 0700 and 1000 hours (prior to first morning dose of 
hydrocortisone). 
k Includes hematology, clinical chemistry (including creatine kinase, myoglobin, total and conjugated bilirubin), coagulation (prothrombin time, activated partial 
thromboplastin time [aPTT], d-dimer, fibrinogen), and urinalysis (including quantitative myoglobin, casts and crystals).  Samples will be obtained under 
nonfasted conditions. 
l 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. 
m Blood samples for analyses of 17-OHP, androstenedione, testosterone, cortisol, and adrenocorticotropic hormone [ACTH] will be collected at the following 
times: 
• Screening (for all biomarkers except 17-OHP). 
• Day -7 to Day -6 (24-hour PD baseline):  at approximately 1845, 2000, 2100, 2200, 2300, 2400, 0100, 0200, 0400, 0600, 0800, 1000, 1200, 1400, 1800, 1900, 
and 2200 hours.  
• Day 7:  24 hours (-8 hour window) after the Day 6 dose and prior to the Day 7 dose (Cohort 3); 12 hours post morning dose but prior to the evening dose for 
Cohort 4 (-4 hour window). 
• Day 14 (for Cohort 4, all times are relative to the evening dose):  15 minutes predose and at 1, 2, 3, 4, and 5 hours postdose (±5 minute window). 
• Day 15 (for Cohort 4, all times are relative to the evening dose):  6, 7, 9, 11, 13, 15, 17, 19, 23, 24, and 27 hours postdose (±15 minute window). 
• Days 21, 28, and 35 (for Cohort 4, all times are relative to the evening dose):  approximately 168 hours (-8 hours/+3 days), 336 hours (-8 hours/+3 days) and 
504 hours (-8 hours/+3 days) postdose. 
• Final study visit (Day 49 [+7 days] or early termination). 
n The Brief Psychiatric Rating Scale will be administered pre-evening dose on Day 14, on Day 15, and at the final study visit (Day 49 or early termination). 
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o Only for subjects who reenroll and who do not undergo screening.  The Screening/Baseline version should be administered. 
p Pharmacokinetic plasma samples for analyses of NBI-74788 will be collected at the following times: 
• Day 7:  24 hours (-8 hour window) after the Day 6 dose, prior to the Day 7 dose (Cohort 3); 12 hours post morning dose but prior to the evening dose for 
Cohort 4 (-4 hour window). 
• Day 14 (for Cohort 4, all times are relative to evening dosing):  15 minutes predose and at 1, 2, 3, 4, and 5 hours postdose (±5 minute window). 
• Day 15 (for Cohort 4, all times are relative to evening dosing):  6, 7, 9, 11, 13, 15, 17, 19, 23, 24, and 27 hours postdose (±15 minute window). 
• Days 21, 28, and 35 (for Cohort 4, all times are relative to evening dosing):  approximately 168 hours (-8 hours/+3 days), 336 hours (-8 hours/+3 days) and 
504 hours (-8 hours/+3 days) postdose. 
• Final study visit (Day 49 [+7 days] or early termination). 
q For Cohort 3, study drug will be administered at home on Days 1 to 13 at approximately 1900 hours with each subject’s evening meal.  For Cohort 4, study 
drug will be administered at home on Days 2 to 14 at approximately 0700 hours with each subject’s breakfast and on Days 1 to 13 at approximately 1900 hours 
with each subject’s evening meal.  For both cohorts, the Day 14 evening dose will be administered at the study site.  Sites should call subjects between the Day 
3 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. 
r 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 (Cohort 4 only) 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. 
s A compliance check will be performed by counting the number of capsules returned. 
t Subjects will have the option of having the Days 21, 28, and 35 assessments conducted at home by a qualified home healthcare provider or at the study center.   
 
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• Day 7:  24 hours (-8 hour window) after the Day 6 dose and prior to the Day 7 dose for 
Cohort 3; 12 hours post morning dose but prior to the evening dose for Cohort 4 (-4 hour 
window). 
• Day 14:  15 minutes predose and at 1, 2, 3, 4, and 5 hours postdose (±5 minute window). 
• Day 15:  6, 7, 9, 11, 13, 15, 17, 19, 23, 24, and 27 hours postdose (±15 minute window). 
• Days 21, 28, and 35:  approximately 168 hours (-8 hours/+3 days), 336 hours 
(-8 hours/+3 days), and 504 hours (-8 hours/+3 days) postdose. 
• Final study visit (Day 49 [+7 days] or early termination). 
A PK sample should be collected from subjects who terminate early.  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.  
At any time during the study, an in-home service (phlebotomist) may be available under certain 
circumstances for blood draws. 
8.4. 
Pharmacodynamic Assessments: Pharmacodynamic Biomarkers 
Approximately 7 mL of blood will be collected for each sample.  Pharmacodynamic 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) for Cohorts 1 and 2 
will be collected at: 
• Screening (for all biomarkers except 17-OHP; Section 8.2.1 describes sample collection for 
17-OHP at screening). 
• Day -7 to -6 (24-hour PD baseline):  at approximately 2145, 2300, 2400, 0100, 0200, 0400, 
0600, 0800, 1000, 1200, 1400, 1800, and 2200 hours.  
• Days 1 and 14:  15 minutes predose and 1, 2, 3, 4, and 6 hours postdose (±5 minute window). 
• Days 2 and 15:  8, 10, 12, 14, 16, 20, and 24 hours postdose (±15 minute window). 
• Day 7:  approximately 24 hours (-8 hour window) after the Day 6 dose and prior to the Day 7 
dose. 
• Days 21, 28, and 35:  approximately 168 hours (-8 hours/+3 days), 336 hours 
(-8 hours/+3 days), and 504 hours (-8 hours/+3 days) postdose. 
• Final study visit (Day 49 [+7 days] or early termination). 
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) for Cohorts 3 and 4 
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will be collected at (for Cohort 4, all times are relative to evening dosing unless otherwise 
noted): 
• Screening (for all biomarkers except 17-OHP; Section 8.2.1 describes sample collection for 
17-OHP at screening) (only for subjects who undergo screening). 
• Day -7 to -6 (24-hour PD baseline):  at approximately 1845, 2000, 2100, 2200, 2300, 2400, 
0100, 0200, 0400, 0600, 0800, 1000, 1200, 1400, 1800, 1900, and 2200 hours.  
• Day 7:  24 hours (-8 hour window) after the Day 6 dose and prior to the Day 7 dose for 
Cohort 3; 12 hours post morning dose but prior to the evening dose for Cohort 4 (-4 hour 
window). 
• Day 14:  15 minutes predose and at 1, 2, 3, 4, and 5 hours postdose (±5 minute window). 
• Day 15:  6, 7, 9, 11, 13, 15, 17, 19, 23, 24, and 27 hours postdose (±15 minute window). 
• Days 21, 28, and 35:  approximately 168 hours (-8 hours/+3 days), 336 hours 
(-8 hours/+3 days), and 504 hours (-8 hours/+3 days) postdose. 
• Final study visit (Day 49 [+7 days] or early termination). 
For the 24-hour serial blood draws, blood samples should be collected using an intravenous 
catheter inserted into a peripheral vein.  Individual venipunctures can be used if there are 
complications with the intravenous catheter.  Individual blood samples on other days should be 
collected by venipuncture. 
Samples may be used for an exploratory assessment of changes in biomarkers associated with 
treatment with NBI-74788 (eg, metabolomics; these biomarkers do not include testing for 
specific genes).  Data collected as part of this exploratory analysis will not be reported as part of 
the study results. 
At any time during the study, an in-home service (phlebotomist) may be available for blood 
draws. 
8.5. 
Safety Assessments 
Concomitant medication use and AEs will be monitored throughout the study as described in 
Section 8.10.1 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 
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measured using a calibrated automatic blood pressure cuff after the subject has been supine for at 
least 5 minutes and after approximately 2 minutes of standing.  The automatic blood pressure 
cuff will also provide pulse rate measurement. 
Vital sign measurements will be collected once per day (other than on Days 2 and 15, as 
indicated below) and will generally be obtained before scheduled blood sample collection.  Vital 
sign measurements will be collected at the following times (for Cohort 4, all times are relative to 
evening dosing): 
• Screening. 
• Day -7 (PD baseline). 
• Day 1. 
• Days 2 and 15 (between 8-10 and 22-24 hours postdose [ie, morning and evening]) (Day 2 
only applies to Cohorts 1 and 2). 
• Day 7. 
• Day 14. 
• Day 49 (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 (only for 
subjects who undergo screening). 
A complete physical examination including weight will be conducted at screening, on Day 1, 
Day 2 (Cohorts 1 and 2 only), Day 7, Day 15, and Day 49 (or final study visit for subjects who 
terminate early).  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 only at screening.  Weight will be measured at screening, on Day 1, Day 15, and 
Day 49 (or final study visit for subjects who terminate early). 
8.5.3. 
12-Lead Electrocardiogram 
12-lead ECG will be conducted in triplicate (1-3 minutes apart) after the subject has rested 
supine for at least 5 minutes at the following times (for Cohort 4, all times are relative to evening 
dosing): 
• Screening. 
• Days 1 and 14 (predose). 
• Days 2 and 15:  prior to visit completion or discharge (Day 2 only applies to Cohorts 1 
and 2). 
• Day 49 (or final study visit for subjects who terminate early). 
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 
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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.  
For subjects who undergo screening, 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 14, and at the final study visit (Day 49 or early termination).  For subjects who 
do not undergo screening, serum pregnancy tests (β-hCG) will be conducted on Day -7 and urine 
pregnancy tests will be conducted prior to dosing on Day 1 (for eligibility), Day 14, and at the 
final study visit (Day 49 or early termination). 
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. 
At any time during the study, an in-home service (phlebotomist) may be available under certain 
circumstances for blood draws. 
8.5.5. 
Brief Psychiatric Rating Scale 
The Brief Psychiatric Rating Scale (BPRS) is a clinician-rated tool designed to assess the 
severity of psychopathology in patients with schizophrenia and other psychotic disorders 
(Overall and Gorham, 1962, 1988).  The BPRS includes 18 items that address somatic concern, 
anxiety, emotional withdrawal, conceptual disorganization, guilt feelings, tension, mannerisms 
and posturing, grandiosity, depressive mood, hostility, suspiciousness, hallucinatory behaviors, 
motor retardation, uncooperativeness, unusual though content, blunt affect, excitement, and 
disorientation.  The severity of each of the 18 items of the BPRS is rated on a scale of 1 (not 
present) to 7 (extremely severe) (total score range:  18 to 126).  Higher scores represent greater 
symptom severity. 
The investigator or other qualified site personnel will administer and score the BPRS 
pre-evening dose on Days 1 and 14, on Days 2 (Cohorts 1 and 2 only) and 15, and at the final 
study visit (Day 49 or early termination).  A copy of the BPRS is provided in Appendix A. 
8.5.6. 
Columbia-Suicide Severity Rating Scale 
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 (Screening/Baseline version) and at visits throughout the study (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 6 months before screening based on the C-SSRS should be 
excluded (see exclusion criterion #20). 
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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, during 
PD baseline (only for subjects who reenroll and who do not undergo screening), Day 1, Day 15, 
and at the final study visit (Day 49 or early termination).  The “Screening/Baseline” version of 
the scale will be used to evaluate subject eligibility at screening (or at PD baseline for subjects in 
Cohorts 3 and 4 who do not undergo screening) and the “Since Last Visit” version will be used at 
all other times. 
A copy of both versions of the C-SSRS are provided in Appendix B. 
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 
 was taken (Cohorts 1 and 2), that the study drug was taken with the evening meal 
(Cohort 3), or that the study drug was taken with breakfast and the evening meal (Cohort 4), 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 for Cohorts 1 and 2 
8.7.1. 
Screening Period (Study Days -28 to -8) 
After providing subject informed consent, 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 (1-3 minutes apart). 
• Perform a serum pregnancy test (β-hCG) for female subjects of childbearing potential. 
• Collect blood sample for FSH testing only if subject is postmenopausal. 
• Collect blood sample for serology testing (HBsAg, HCV-Ab, and HIV-Ab,). 
• Collect blood sample for morning serum 17-OHP measurement between 0700 and 
1000 hours (prior to first morning dose of hydrocortisone).  Subject must have serum 
17-OHP level ≥1,000 ng/dL to be enrolled in the study. 
• Collect blood sample for hematology and clinical chemistry. 
• 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 other PD biomarkers (androstenedione, testosterone, cortisol, and 
ACTH). 
• Administer the C-SSRS (Screening/Baseline version). 
• AE monitoring. 
• Record prior 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 (17-OHP, androstenedione, testosterone, cortisol, 
and ACTH) at:  approximately 2145, 2300, 2400, 0100, 0200, 0400, 0600, 0800, 1000, 1200, 
1400, 1800, and 2200 hours. 
• AE monitoring. 
• Record prior medications. 
Eligible subjects will be instructed to return to the study center on Day 1. 
8.7.3. 
Treatment Period for Each Dose Cohort  
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 (1-3 minutes apart).  
• Perform a urine pregnancy test (β-hCG) for female subjects of childbearing potential.  
 
  
• Collect blood sample for hematology and clinical chemistry.  
• 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.  
• Collect blood sample for PK at 15 minutes predose.  
• Administer the BPRS.  
• Administer the C-SSRS (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 
 was taken each day. 
At approximately 2200 hours, each subject will receive study drug as described in Section 9.3.  
Subjects will go to bed after study drug dosing. 
The following study evaluations and tasks will be performed after dosing on Day 1 while the 
subject remains in bed: 
• Collect blood samples for PD biomarkers at 1, 2, 3, 4, and 6 hours postdose (±5 minute 
window). 
• Collect blood samples for PK at 1, 2, 3, 4, and 6 hours postdose (±5 minute window). 
• AE monitoring. 
• Record concomitant medications. 
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Day 2 
Subjects will be awakened at approximately 0600 hours.  Subjects will delay their usual morning 
dose of steroidal treatment until after the 12-hour postdose PK/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 8-10 and 22-24 hours postdose (ie, morning and evening). 
• Perform 12-lead ECG in triplicate (1-3 minutes apart). 
• Collect blood samples for PD biomarkers at 8, 10, 12, 14, 16, 20, and 24 hours postdose 
(±15 minute window). 
• Collect blood samples for PK at 8, 10, 12, 14, 16, 20, and 24 hours postdose (±15 minute 
window). 
• Administer the BPRS. 
• AE monitoring.  
• Record concomitant medications. 
The following procedures will be conducted before subjects may be discharged from the study 
center:  
• At approximately 2200 hours, each subject will receive study drug 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 nightly at approximately 2200 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 
 was 
taken each day. 
• Instruct subjects to bring the subject study diary as well as the remaining study drug back for 
the Day 7 visit. 
• Instruct subjects to delay their usual morning dose of concurrent steroidal treatments until 
approximately 1000 hours on Days 3 to 14. 
Sites should call subjects between the Day 3 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. 
• Collect blood sample for hematology and clinical chemistry.  
• Collect urine sample for urinalysis.  
• Collect blood samples for PD biomarkers at 24 hours (-8 hour window) after the Day 6 dose 
and prior to the Day 7 dose. 
• Collect blood samples for PK at 24 hours (-8 hour window) after the Day 6 dose and prior to 
the Day 7 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 dosing and to bring with them 
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 dosing on Day 14: 
• Collect vital signs.  
• Perform 12-lead ECG in triplicate (1-3 minutes apart).  
• Perform a urine pregnancy test (β-hCG) for female subjects of childbearing potential. 
• Collect urine for drug screen and perform alcohol breath test.  
• Collect blood sample for PD biomarkers at 15 minutes predose.  
• Collect blood sample for PK at 15 minutes predose.  
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• Administer the BPRS.  
• Collect the study drug bottle including any unused study drug. 
• Study drug reconciliation. 
• AE monitoring.  
• Record concomitant medications.  
At approximately 2200 hours, each subject will receive study drug 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 
 was taken.  
The subject study diary will then be collected.  Subjects will then go to bed. 
The following procedures will be conducted after dosing on Day 14 while the subject remains in 
bed: 
• Collect blood samples for PD biomarkers at 1, 2, 3, 4, and 6 hours postdose (±5 minute 
window). 
• Collect blood samples for PK at 1, 2, 3, 4, and 6 hours postdose (±5 minute window). 
• AE monitoring. 
• Record concomitant medications. 
Day 15 
Subjects will be awakened at approximately 0600 hours.  Subjects will delay their usual morning 
dose of steroidal treatment until after the 16-hour postdose PK/PD samples are collected (ie, at 
approximately 1400 hours).   
The following procedures will be performed on Day 15:  
• Perform a physical examination including weight. 
• Collect vital signs between 8-10 and 22-24 hours postdose (ie, morning and evening). 
• Perform 12-lead ECG in triplicate (1-3 minutes apart). 
• Collect blood sample for hematology and clinical chemistry.  
• Collect urine sample for urinalysis.  
• Collect blood samples for PD biomarkers at 8, 10, 12, 14, 16, 20, and 24 hours postdose 
(±15 minute window). 
• Collect blood samples for PK at 8, 10, 12, 14, 16, 20, and 24 hours postdose (±15 minute 
window). 
• Administer the BPRS. 
• Administer the C-SSRS (Since Last Visit version). 
• AE monitoring. 
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• Record concomitant medications. 
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 21, 28, and 35 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 21, 
28, and 35. 
8.7.4. 
Follow-Up Period 
Follow-up visits will be conducted on Days 21, 28, and 35 with a final study visit on Day 49 (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 21, 28, and 
35.  The final study visit will be conducted at the study center. 
8.7.4.1. 
Follow-Up Visits:  Days 21, 28, and 35  
The following procedures will be performed on Days 21, 28, and 35 (-8 hours/+3 days for 
Days 21, 28, and 35):  
• Collect blood samples for PD biomarkers at approximately 168 hours (-8 hours/+3 days), 
336 hours (-8 hours/+3 days), and 504 hours (-8 hours/+3 days) postdose.  
• Collect blood samples for PK at approximately 168 hours (-8 hours/+3 days), 336 hours 
(-8 hours/+3 days), and 504 hours (-8 hours/+3 days) postdose. 
• 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 35 visit, subjects will be reminded to report to the study center on Day 49 (+7 days) 
for the final study visit (or at early termination). 
8.7.4.2. 
Final Study Visit:  (Day 49 or Early Termination) 
Subjects will return to the study center for the final study visit. 
The following procedures will be conducted at the final study visit: 
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• Perform a physical examination including weight. 
• Collect vital signs.  
• Perform 12-lead ECG in triplicate (1-3 minutes apart). 
• Perform a urine pregnancy test (β-hCG) for female subjects of childbearing potential.  
• Collect blood sample for hematology and clinical chemistry.  
• Collect urine sample for urinalysis.  
• Collect blood sample for PD biomarkers.  
• Collect blood sample for PK.  
• Administer the BPRS.  
• Administer the C-SSRS (Since Last Visit version). 
• AE monitoring. 
• Record concomitant medications.  
8.8. 
Specific Study Period Information for Cohorts 3 and 4 
8.8.1. 
Screening Period (Study Days -28 to -8) 
Subjects who reenroll and have had a stable medication regimen for CAH since their last visit in 
this study (in Cohorts 1 or 2) do not have to undergo screening; those who reenroll and have had 
a change to their medication regimen for CAH must undergo a second screening visit.  After 
providing subject informed consent, 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 (1-3 minutes apart). 
• Perform a serum pregnancy test (β-hCG) for female subjects of childbearing potential. 
• Collect blood sample for FSH testing only if subject is postmenopausal. 
• Collect blood sample for serology testing (HBsAg, HCV-Ab, and HIV-Ab). 
• Collect blood sample for morning serum 17-OHP measurement between 0700 and 
1000 hours (prior to first morning dose of hydrocortisone).  Subject must have serum 
17-OHP level ≥1,000 ng/dL to be enrolled in the study. 
• Collect blood sample for hematology and clinical chemistry. 
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• Collect urine sample for urinalysis. 
• Collect urine for drug screen (central laboratory) and perform alcohol breath test. 
• Collect blood sample for other PD biomarkers (androstenedione, testosterone, cortisol, and 
ACTH). 
• Administer the C-SSRS (Screening/Baseline version). 
• AE monitoring. 
• Record prior medications. 
Eligible subjects will be instructed to return to the study center on Day -7. 
8.8.2. 
Day -7 to Day -6:  24-Hour Baseline Pharmacodynamics  
Subjects who reenroll and do not undergo screening must provide subject informed consent. 
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 (only for subjects who undergo 
screening). 
• Collect vital signs. 
• Perform a urine (for subjects who undergo screening) or serum (for subjects who did not 
undergo screening) 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 (17-OHP, androstenedione, testosterone, cortisol, 
and ACTH) at:  approximately 1845, 2000, 2100, 2200, 2300, 2400, 0100, 0200, 0400, 0600, 
0800, 1000, 1200, 1400, 1800, 1900, and 2200 hours. 
• Administer the C-SSRS (Screening/Baseline version) only for subjects who reenroll and who 
do not undergo screening. 
• AE monitoring. 
• Record prior medications. 
Eligible subjects will be instructed to return to the study center on Day 1. 
8.8.3. 
Treatment Period 
The study will consist of a 14-day treatment period and will include an overnight in-patient stay 
(on Day 14 to Day 15) and study center visits on Days 1 and 7.   
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Sites should call subjects between the Day 3 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. 
8.8.3.2. 
Day 7 
The following procedures will be performed at the study center on Day 7: 
• Perform a physical examination. 
• Collect vital signs. 
• Collect blood sample for hematology and clinical chemistry.  
• Collect urine sample for urinalysis.  
• Collect blood samples for PD biomarkers at 24 hours (-8 hour window) after the Day 6 dose 
and prior to the Day 7 dose for Cohort 3; 12 hours post morning dose but prior to the evening 
dose for Cohort 4 (-4 hour window). 
• Collect blood samples for PK at 24 hours (-8 hour window) after the Day 6 dose and prior to 
the Day 7 dose for Cohort 3; 12 hours post morning dose but prior to the evening dose for 
Cohort 4 (-4 hour window). 
• 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 dosing and to bring with them 
their study drug bottle including any unused study drug, and their subject study diary. 
8.8.3.3. 
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 (subjects in Cohort 4 will take their morning 
study drug dose at home).  The following study evaluations and tasks will be performed prior to 
evening dosing on Day 14: 
• Collect vital signs.  
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• Perform 12-lead ECG in triplicate (1-3 minutes apart).  
• Perform a urine pregnancy test (β-hCG) for female subjects of childbearing potential. 
• Collect urine for drug screen and perform alcohol breath test.  
• Collect blood sample for PD biomarkers at 15 minutes predose.  
• Collect blood sample for PK at 15 minutes predose.  
• Administer the BPRS.  
• Collect the study drug bottle including any unused study drug. 
• Study drug reconciliation. 
• AE monitoring.  
• Record concomitant medications.  
At approximately 1900 hours, each subject will receive study drug as described in Section 9.3 
with a moderate fat/moderate calorie meal.  Subjects should complete their evening meal within 
30 minutes of taking study drug.  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.   
The following procedures will be conducted after dosing on Day 14: 
• Collect blood samples for PD biomarkers at 1, 2, 3, 4, and 5 hours postdose (±5 minute 
window). 
• Collect blood samples for PK at 1, 2, 3, 4, and 5 hours postdose (±5 minute window). 
• AE monitoring. 
• Record concomitant medications. 
Day 15 
Subjects will delay their usual morning dose of steroidal treatment until after the 19-hour 
postdose PK/PD samples are collected (ie, at approximately 1400 hours). 
The following procedures will be performed on Day 15:  
• Perform a physical examination including weight. 
• Collect vital signs between 8-10 and 22-24 hours post-evening dose (ie, morning and 
evening). 
• Perform 12-lead ECG in triplicate (1-3 minutes apart). 
• Collect blood sample for hematology and clinical chemistry.  
• Collect urine sample for urinalysis.  
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• Collect blood samples for PD biomarkers at 6, 7, 9, 11, 13, 15, 17, 19, 23, 24, and 27 hours 
postdose (±15 minute window) (for Cohort 4, all times are relative to evening dosing). 
• Collect blood samples for PK at 6, 7, 9, 11, 13, 15, 17, 19, 23, 24, and 27 hours postdose 
(±15 minute window) (for Cohort 4, all times are relative to evening dosing). 
• Administer the BPRS. 
• Administer the C-SSRS (Since Last Visit version). 
• AE monitoring. 
• Record concomitant medications. 
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 21, 28, and 35 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 21, 
28, and 35. 
8.8.4. 
Follow-Up Period 
Follow-up visits will be conducted on Days 21, 28, and 35 with a final study visit on Day 49 (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 21, 28, and 
35.  The final study visit will be conducted at the study center. 
8.8.4.1. 
Follow-Up Visits:  Days 21, 28, and 35  
The following procedures will be performed on Days 21, 28, and 35 (-8 hours/+3 days for 
Days 21, 28, and 35):  
• Collect blood samples for PD biomarkers at approximately 168 hours (-8 hours/+3 days), 
336 hours (-8 hours/+3 days), and 504 hours (-8 hours/+3 days) postdose (for Cohort 4, all 
times are relative to evening dosing).   
• Collect blood samples for PK at approximately 168 hours (-8 hours/+3 days), 336 hours 
(-8 hours/+3 days), and 504 hours (-8 hours/+3 days) postdose (for Cohort 4, all times are 
relative to evening dosing). 
• AE monitoring.  
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• 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 35 visit, subjects will be reminded to report to the study center on Day 49 (+7 days) 
for the final study visit (or at early termination). 
8.8.4.2. 
Final Study Visit:  (Day 49 [+7 Days] or Early Termination) 
Subjects will return to the study center for the final study visit. 
The following procedures will be conducted at the final study visit: 
• Perform a physical examination including weight. 
• Collect vital signs.  
• Perform 12-lead ECG in triplicate (1-3 minutes apart). 
• Perform a urine pregnancy test (β-hCG) for female subjects of childbearing potential.  
• Collect blood sample for hematology and clinical chemistry.  
• Collect urine sample for urinalysis.  
• Collect blood sample for PD biomarkers.  
• Collect blood sample for PK.  
• Administer the BPRS.  
• Administer the C-SSRS (Since Last Visit version). 
• AE monitoring. 
• Record concomitant medications.  
8.9. 
Study Duration 
The total duration of the study (including screening, a 24-hour PD baseline period, treatment 
periods, and follow-up) will be approximately 11 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 5 weeks.  The total duration 
of the study will be an additional 8 to 11 weeks for subjects who reenroll. 
8.10. 
Prohibitions and Restrictions 
8.10.1. 
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.   
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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. 
8.11. 
Withdrawal Criteria 
8.11.1. 
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.  These should be discussed on a case-by-case basis with the NBI medical monitor (or 
designee) prior to withdrawing the subject from the study. 
• 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 or alcohol screen. 
• Requires a medication that is prohibited by the protocol (refer to Section 8.10.1). 
All subjects prematurely discontinuing the study, regardless of cause, should have all early 
termination assessments performed (see Section 8.7.4.2). 
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Cohort 3 
Subjects will take study drug capsules by mouth at approximately 1900 hours for 14 consecutive 
days beginning on Day 1.  Each dose of study drug is to be administered with their evening meal; 
subjects should complete their evening meal within 30 minutes of taking study drug.  The 
designated NBI-74788 dose (100 mg) will be administered as 2 NBI-74788 50 mg capsules. 
Cohort 4 
Subjects will take study drug capsules by mouth for 14 consecutive days beginning at 
approximately 1900 hours on Day 1; subsequently, study drug will be taken at approximately 
0700 hours (with breakfast) and approximately 1900 hours (with evening meal).  Subjects should 
complete their respective meals within 30 minutes of taking study drug.  The designated 
NBI-74788 dose (100 mg) will be administered as 2 NBI-74788 50 mg capsules (200 mg total 
daily dose). 
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 material 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. 
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 site 
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 
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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. 
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 associated with the use of a drug in humans, whether 
or not considered drug related.  During the study, clinically significant adverse changes in 
clinical status, ECGs, laboratory values (not associated with an AE or concurrent medical 
condition), or physical examinations are considered AEs.  Any subject complaint associated with 
such an abnormal finding will also be reported as an AE. 
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. 
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.” 
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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: 
• SAE, including death (Section 10.6). 
• Pregnancy (Section 10.7). 
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• 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.  If 
resolved, a resolution date should be documented on the eCRF.   
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 
or 30 days after the last dose of study drug, whichever is longer in duration. 
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. 
• 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 
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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. 
If an investigator becomes aware of an SAE within the time of informed consent until the final 
study visit or 30 days after the last dose of study drug (whichever is longer in duration), then the 
event must be documented and reported as described in Section 10.6.3. 
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 Clinical Drug Safety (CDS) 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 CDS: 
 
CDS telephone: 
 
 
CDS facsimile: 
 
 
CDS 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. 
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. 
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10.7. 
Pregnancy 
Women 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.  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 site 
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 CDS.  A first trimester ultrasound will be required 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 
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 
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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 dose cohort and 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 hours to last measurable 
concentration (AUC0-tlast) 
• Area under the plasma concentration versus time curve from 0 to 24 hours (AUC0-24) 
(Cohorts 1, 2, and 3) 
• Area under the plasma concentration versus time curve from 0 to 12 hours (AUC0-12) 
(Cohort 4) 
• Maximum plasma concentration (Cmax) 
• Time to maximum plasma concentration (tmax) 
• Delay time between time of dosing and time of appearance of measurable test article (Tlag) 
• Terminal half-life (t½) 
• Apparent terminal rate constant (λz) 
• Apparent mean residence time (MRT) 
Additional PK parameters for Day 14 only: 
• Average plasma concentration at steady state (Cavg) 
• Percent fluctuation at steady state (%fluctuation) 
• Accumulation index at steady state 
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• Apparent systemic clearance after oral administration (CL/F) (NBI-74788 only) 
12.7. 
Pharmacodynamic Data 
The primary PD assessments are:  morning 17-OHP (serum; ng/dL) from the 0600, 0800, and 
1000 hour samples (8-, 10-, and 12-hour postdose samples from Cohorts 1 and 2 and 11-, 13-, 
and 15-hour postdose samples from Cohorts 3 and 4).  Secondary PD assessments are:  17-OHP 
at all other times, androstenedione (serum; ng/dL), testosterone (serum; ng/dL), cortisol (serum; 
μg/dL), and ACTH (plasma; pg/mL). 
The PD assessments listed above will be summarized with descriptive statistics (including 
change from predose) and in graphical displays by dose cohort and timepoint. 
12.8. 
Safety Data 
TEAEs, categorized by system organ class (SOC) and/or preferred term as defined by MedDRA, 
will be summarized by dose cohort as well as overall.  A TEAE is defined as any AE that occurs 
after the first dose of study drug within a dose cohort.  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.  The TEAEs will also be tabulated in 
terms of the number and percentage of subjects experiencing events by relationship to study drug 
if a sufficient number of TEAEs is reported. 
Data listings will be presented for SAEs, deaths, and AEs leading to premature discontinuation 
from the study. 
Clinical laboratory data, vital sign measurements, ECG data, and other safety data will be 
summarized by dose cohort and timepoint (as appropriate) with descriptive statistics.  Prior and 
concomitant medications and physical examination data will be presented in data listings. 
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. 
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13.2. 
Institutional Review Board 
The final approved protocol and the ICF 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.  
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 form. 
• 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 
All subjects will provide informed consent before the performance of any study-related 
procedures. 
Each subject’s chart will include the signed ICF for study participation.  When the study 
treatment is completed and the eCRF has been monitored, the ICF will be kept in the 
investigator’s central study file.  Regulatory authorities may check the existence of the signed 
ICF in this central study folder. 
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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. 
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 and, where applicable, subject’s initials and birth date. 
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. 
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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 site.  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 
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. 
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, Gorham DR. The Brief Psychiatric Rating Scale (BPRS). Psychological Reports. 
1962;10:799-812.  
Overall JE, Gorham DR. The Brief Psychiatric Rating Scale (BPRS): Recent Developments in 
Ascertainment and Scaling.  Psychopharmacol Bull. 1988;24:97-9. 
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. 
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16. 
APPENDICES 
APPENDIX A. BRIEF PSYCHIATRIC RATING SCALE 
 
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APPENDIX B. COLUMBIA-SUICIDE SEVERITY RATING SCALE 
Two versions of the C-SSRS will be used in this study:  the Screening/Baseline version and the 
Since Last Visit version. 
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COLUMBIA-SUICIDE SEVERITY
RATING SCALE
(C-SSRS)
Baseline/Screening Version 
Version 1/14/09 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J.  
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. The questions contained in 
the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of suicidal 
ideation or behavior depends on the judgment of the individual administering the scale. 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History Form, 
developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside Drive, New 
York, New York, 10032; inquiries and training requirements contact posnerk@nyspi.columbia.edu 
© 2008 The Research Foundation for Mental Hygiene, Inc. 
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COLUMBIA-SUICIDE SEVERITY
RATING SCALE
(C-SSRS) 
Since Last Visit 
Version 1/14/09 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J.  
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. The questions contained 
in the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of 
suicidal ideation or behavior depends on the judgment of the individual administering the scale. 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History 
Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside Drive, New 
York, New York, 10032; inquiries and training requirements contact posnerk@nyspi.columbia.edu 
© 2008 The Research Foundation for Mental Hygiene, Inc.
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