Clinical trial NCT03687242
Conditions: Congenital Adrenal Hyperplasia CAH - Congenital Adrenal Hyperplasia CAH - 21-Hydroxylase Deficiency
Sponsor: Spruce Biosciences
Start date: 2018-09-06; Completion date: 2019-08-09
Enrollment: 11 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 2 study of SPR001 for the treatment of classic CAH that will provide 12 weeks of open-label treatment to eligible subjects.

Detailed description:
This is a Phase 2 study of SPR001 for the treatment of classic CAH that will provide 12 weeks of open-label treatment to eligible subjects. To be eligible for this study, an individual must either have completed Study SPR001-201 or meet eligibility criteria for SPR001-naïve subjects. The expected duration of study participation for each subject is up to approximately 5 months. This includes a screening period of ≤30 days, a treatment period of 12 weeks, and a safety follow-up period of 30 days.

Arms: arm 1: SPR001 at Dose A
Interventions: intervention 1: SPR001
Intervention descriptions: intervention 1: Open label SPR001

Protocol documents:
Prot_000.pdf: 
Protocol #: SPR001-202 
CLINICAL STUDY PROTOCOL 
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Version 1.1NIH 
CONFIDENTIAL 
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TITLEPAGE 
A 3-Month Phase 2 Study  
to Evaluate the Safety and Efficacy of SPR001  
in Subjects with Classic Congenital Adrenal Hyperplasia 
 US IND Number: 131761 
Study Number: SPR001-202 
Document Type: Clinical Study Protocol 
Protocol Version: 1.1NIH 
Protocol Date: 20 December 2018 
Investigational Medicinal Product: SPR001 
Indication: Classic congenital adrenal hyperplasia (CAH) 
Sponsor: Spruce Biosciences, Inc. 
1700 Montgomery St, Suite 212 
San Francisco, CA 94111  
Principal Investigator: Deborah Merke, MD, MS 
Registry: ClinicalTrials.gov 
Statement of Confidentiality 
This document contains proprietary and confidential information of Spruce Biosciences, Inc. Acceptance of this 
document constitutes agreement by the recipient that no previously unpublished information contained herein 
will be published or disclosed without the prior written approval of Spruce Biosciences, Inc., with the exception 
that this document may be disclosed to study personnel under your supervision who need to know the contents 
for conducting the study and to appropriate Institutional Review Boards (IRBs) or Ethics Committees (ECs) under 
the condition that the personnel have agreed to keep this information confidential. The foregoing shall not apply 
to disclosure required by governmental regulations or laws; however, Spruce Biosciences, Inc. shall be promptly 
notified of any such disclosure.  
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NCT03687242


Protocol #: SPR001-202 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE 
A 3-Month Phase 2 Study to Evaluate the Safety and Efficacy of SPR001 in 
Subjects with Classic Congenital Adrenal Hyperplasia 
Study Number: SPR001-202 
Protocol Version: 1.1 
Protocol Date: 20 Dec 2018 
I have reviewed the protocol and the attachments, and I agree to conduct this trial in 
accordance with all stipulations of the protocol, including all statements regarding 
confidentiality. I will ensure that no deviation from, or changes to, the protocol will take place 
without prior agreement from the Sponsor and documented approval from the Institutional 
Review Board (IRB), except where necessary to eliminate an immediate hazard(s) to the trial 
participants or when change(s) involves only logistical or administrative aspects of the study. 
I agree to conduct this trial in accordance with International Council for Harmonisation Good 
Clinical Practice (ICH GCP), the most recent version of the Declaration of Helsinki, and all 
applicable local and federal legal and regulatory requirements.  
I agree to provide sufficient time and adequate numbers of qualified staff and facilities for the 
foreseen duration of the clinical study to conduct the study properly, ethically, and safely. All 
personnel involved in the conduct of this study have completed Human Subjects Protection and 
ICH GCP Training. 
I agree to permit periodic site monitoring of case report forms and source documents by the 
Sponsor or designee and by appropriate regulatory authorities. 
I agree to supply the Sponsor with any information regarding ownership interest and financial 
ties with the Sponsor for the purpose of complying with regulatory requirements. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB for review and approval. Approval of both the protocol and the consent 
form must be obtained before any participant is enrolled. Any amendment to the protocol will 
require review and approval by the IRB before the changes are implemented to the study. All 
changes to the consent form will be IRB approved; a determination will be made regarding 
whether participants who provided previous consent need to be re-consented using the 
updated consent form. 
 
Site Name:  National Institutes of Health  
Principal Investigator Name: Deborah P. Merke, M.D., M.S. 
__________________________________________________________     _________________ 
Investigator’s Signature  
 
 
 
 
 
 
Date 
 
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Protocol #: SPR001-202 
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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................... 1 
INVESTIGATOR PROTOCOL AGREEMENT PAGE .............................................................................. 2 
TABLE OF CONTENTS....................................................................................................................... 3 
TABLE OF TABLES ............................................................................................................................ 8 
LIST OF ABBREVIATIONS ................................................................................................................. 9 
1 
PROTOCOL SUMMARY ............................................................................................................ 13 
1.1 
Protocol Synopsis ............................................................................................................. 13 
1.2 
Schema............................................................................................................................. 22 
1.3 
Schedule of Activities ....................................................................................................... 23 
2 
INTRODUCTION ....................................................................................................................... 27 
2.1 
Study Rationale ................................................................................................................ 27 
2.2 
Background ...................................................................................................................... 27 
2.2.1 
Congenital Adrenal Hyperplasia ............................................................................... 27 
2.2.2 
SPR001 for the Treatment of CAH ............................................................................ 29 
2.2.3 
Nonclinical Toxicology of SPR001 ............................................................................. 29 
2.2.4 
Clinical Experience with SPR001 ............................................................................... 30 
2.3 
Risk/Benefit Assessment ................................................................................................. 31 
2.3.1 
Known Potential Risks .............................................................................................. 31 
2.3.2 
Known Potential Benefits ......................................................................................... 32 
2.3.3 
Assessment of Potential Risks and Benefits ............................................................. 32 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 33 
4 
STUDY DESIGN ........................................................................................................................ 34 
4.1 
Overall Design .................................................................................................................. 34 
4.2 
Scientific Rationale for Study Design ............................................................................... 34 
4.3 
Justification for Dose ....................................................................................................... 35 
4.4 
End of Study Definition .................................................................................................... 36 
5 
STUDY POPULATION ............................................................................................................... 37 
5.1 
Eligibility Criteria for Subjects Who Completed Study SPR001-201 ................................ 37 
5.1.1 
Inclusion Criteria for Subjects Who Completed Study SPR001-201 ......................... 37 
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5.1.2 
Exclusion Criteria for Subjects Who Completed Study SPR001-201 ........................ 37 
5.2 
Eligibility Criteria for SPR001-Naïve Subjects .................................................................. 39 
5.2.1 
General Inclusion Criteria for All SPR001-Naïve Subjects ........................................ 39 
5.2.2 
Additional Inclusion Criteria for Enriched Population of SPR001-Naïve Subjects .... 40 
5.2.3 
Exclusion Criteria for All SPR001-Naïve Subjects ...................................................... 40 
5.3 
Lifestyle Considerations ................................................................................................... 41 
5.3.1 
Shift Work ................................................................................................................. 41 
5.3.2 
Meals and Dietary Restrictions ................................................................................. 41 
5.3.3 
Caffeine, Alcohol, and Tobacco ................................................................................ 42 
5.3.4 
Activity ...................................................................................................................... 42 
5.3.5 
Contraception Guidelines ......................................................................................... 42 
5.4 
Screen Failures ................................................................................................................. 43 
6 
STUDY INTERVENTION ............................................................................................................ 44 
6.1 
Study Intervention Administration .................................................................................. 44 
6.1.1 
Study Intervention Description ................................................................................ 44 
6.1.2 
Dosing and Administration ....................................................................................... 44 
6.2 
Preparation/Handling/Storage/Accountability ............................................................... 45 
6.2.1 
Acquisition and Accountability ................................................................................. 45 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 45 
6.2.3 
Product Storage and Stability ................................................................................... 45 
6.3 
Treatment Assignment .................................................................................................... 45 
6.4 
Study Intervention Compliance ....................................................................................... 45 
6.5 
Concomitant Therapy ...................................................................................................... 46 
6.5.1 
Glucocorticoid Replacement Therapy ...................................................................... 46 
6.5.2 
Prohibited Concomitant Medications and Concomitant Medications of Concern .. 46 
7 
DOSE REDUCTION, STUDY DRUG DISCONTINUATION, AND PARTICIPANT WITHDRAWAL ... 48 
7.1 
Dose-Limiting Toxicity and Dose Reduction .................................................................... 48 
7.2 
Study Drug Discontinuation ............................................................................................. 48 
7.2.1 
Liver Chemistry Stopping Criteria ............................................................................. 48 
7.2.2 
QT Stopping Criteria ................................................................................................. 49 
7.2.3 
Suicidality Stopping Criteria ...................................................................................... 49 
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7.2.4 
Adrenal Insufficiency Stopping Criteria .................................................................... 50 
7.2.5 
Depression Stopping Criteria .................................................................................... 50 
7.2.6 
Reproductive Hormone Stopping Criteria ................................................................ 50 
7.2.7 
Potentially Clinically Significant Adverse Events ...................................................... 50 
7.3 
Participant Withdrawal from the Study .......................................................................... 51 
7.4 
Lost to Follow-up ............................................................................................................. 51 
8 
STUDY ASSESSMENTS AND PROCEDURES .............................................................................. 53 
8.1 
Safety Assessments ......................................................................................................... 53 
8.1.1 
Physical Examination ................................................................................................ 53 
8.1.2 
Vital Signs .................................................................................................................. 53 
8.1.3 
Body Weight, Height, and BMI ................................................................................. 53 
8.1.4 
Electrocardiogram .................................................................................................... 54 
8.1.5 
Clinical Laboratory .................................................................................................... 54 
8.1.6 
Psychiatric Evaluations ............................................................................................. 54 
8.2 
Adverse Events and Serious Adverse Events ................................................................... 55 
8.2.1 
Definition of Adverse Event ...................................................................................... 55 
8.2.2 
Definition of Serious Adverse Event ......................................................................... 56 
8.2.3 
Classification of an Adverse Event ............................................................................ 57 
8.2.4 
Time Period and Frequency for Event Assessment and Follow-up .......................... 59 
8.2.5 
Adverse Event Reporting .......................................................................................... 60 
8.2.6 
Serious Adverse Event Reporting ............................................................................. 60 
8.2.7 
Reporting of Pregnancy ............................................................................................ 61 
8.2.8 
Adverse Events of Special Interest ........................................................................... 61 
8.2.9 
Disease-Related Events ............................................................................................. 62 
8.3 
Efficacy Assessments ....................................................................................................... 62 
8.3.1 
Hormone Assessments ............................................................................................. 62 
8.4 
Pharmacokinetic Assessments ........................................................................................ 63 
8.5 
Exploratory Assessments ................................................................................................. 63 
8.5.1 
Quality of Life Assessments ...................................................................................... 63 
8.5.2 
Metabolic Assessments ............................................................................................ 64 
8.5.3 
Exploratory Adrenal Hormones ................................................................................ 64 
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8.5.4 
Sex-Specific Assessments ......................................................................................... 64 
8.5.5 
Metabolite Identification .......................................................................................... 65 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 66 
9.1 
Sample Size Determination ............................................................................................. 66 
9.2 
Populations for Analyses and Missing Data .................................................................... 66 
9.3 
Statistical Analyses .......................................................................................................... 66 
9.3.1 
General Approach ..................................................................................................... 66 
9.3.2 
Demographics and Baseline Descriptive Statistics ................................................... 66 
9.3.3 
Subject Disposition ................................................................................................... 67 
9.3.4 
Subject Compliance .................................................................................................. 67 
9.3.5 
Safety Analyses ......................................................................................................... 67 
9.3.6 
Efficacy Analyses ....................................................................................................... 67 
9.3.7 
Pharmacokinetics Analyses ...................................................................................... 68 
9.3.8 
Planned Interim Analyses ......................................................................................... 68 
9.3.9 
Subgroup Analyses .................................................................................................... 68 
9.3.10 
Exploratory Analyses .............................................................................................. 68 
10 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS .................................. 69 
10.1 
Informed Consent .......................................................................................................... 69 
10.2 
Study Discontinuation and Closure ............................................................................... 69 
10.3 
Confidentiality and Privacy ............................................................................................ 69 
10.4 
Future Use of Stored Specimens and Data ................................................................... 69 
10.5 
Key Roles and Study Governance .................................................................................. 70 
10.6 
Safety Oversight ............................................................................................................ 70 
10.7 
Clinical Monitoring ........................................................................................................ 70 
10.8 
Quality Assurance and Quality Control ......................................................................... 70 
10.9 
Data Handling and Record Keeping ............................................................................... 71 
10.9.1 
Data Collection and Management Responsibilities ............................................... 71 
10.9.2 
Study Records Retention ........................................................................................ 71 
10.10 
Protocol Deviations ..................................................................................................... 71 
10.11 
Publication and Data Sharing Policy ............................................................................ 72 
10.12 
Amendments ............................................................................................................... 72 
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11 
REFERENCES .......................................................................................................................... 73 
12 
APPENDICES .......................................................................................................................... 75 
12.1 
Appendix of Prohibited Concomitant Medications and Concomitant Medications of 
Concern ..................................................................................................................................... 75 
12.1.1 
List of Prohibited Concomitant Medications ......................................................... 75 
12.1.2 
List of Concomitant Medications of Concern ......................................................... 76 
12.2 
Appendix of Liver Safety ................................................................................................ 77 
12.2.1 
Liver Chemistry Stopping Criteria and Follow-up Assessments ............................. 77 
12.2.2 
Criterion for Increased Liver Chemistry Monitoring While Continuing Study Drug
 
78 
12.2.3 
Restart Following Transient Resolving Liver Chemistry Events Not Related to Study 
Drug 
79 
12.3 
Appendix of Potentially Clinically Significant Adverse Events ...................................... 80 
12.3.1 
List of Potentially Clinically Significant Signs and Symptoms ................................. 80 
12.3.2 
List of Potentially Clinically Significant Laboratory Findings .................................. 80 
12.4 
Appendix of Clinical Laboratory Tests ........................................................................... 82 
 
 
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TABLE OF TABLES 
Table 1. Severity of Adverse Events .............................................................................................. 57 
Table 2. Relatedness of Adverse Event to Study Drug .................................................................. 58 
Table 3. Outcome of Adverse Event ............................................................................................. 59 
 
 
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LIST OF ABBREVIATIONS 
11oxC19 
11-oxygenated 19-carbon (steroids) 
17-OHP 
17-hydroxyprogesterone 
ACTH 
adrenocorticotropin hormone, corticotropin 
ADL 
activities of daily living 
ADR 
adverse drug reaction 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase  
AUC 
area under the concentration-time curve 
BDI-II 
Beck Depression Inventory-II 
BID 
twice a day 
BMI 
body mass index 
BUN 
blood urea nitrogen 
BW 
body weight 
C-SSRS        Columbia-Suicide Severity Rating Scale 
CAH 
congenital adrenal hyperplasia 
Cmax 
maximum concentration 
CNS 
central nervous system 
CONSORT Consolidated Standards of Reporting Trials 
CRF 
corticotropin-releasing factor 
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CRF1  
corticotropin-releasing factor type-1 
CTCAE 
Common Terminology Criteria for Adverse Events  
CYP 
cytochrome P450 
DILI 
drug-induced liver injury 
DLT 
dose-limiting toxicity 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyltransferase 
HADS 
Hospital Anxiety and Depression Scale 
HbA1c 
hemoglobin A1c 
HDPE 
high-density polyethylene 
HEENT 
head, eyes, ears, neck, and throat 
HIV 
human immunodeficiency virus 
HPA 
hypothalamic-pituitary-adrenal 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IGA 
Investigator’s Global Assessment (of acne severity) 
INR 
international normalized ratio 
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IRB 
Institutional Review Board 
IUD 
intrauterine device 
IUS 
intrauterine system 
LFT 
liver function test 
LH 
luteinizing hormone 
MCH 
mean corpuscular hemoglobin 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mFG 
modified Ferriman Gallwey (score for hirsutism) 
M.I.N.I. 
Mini International Neuropsychiatric Interview 
NCI 
National Cancer Institute 
NOAEL 
no-observed-adverse-effect level 
OTC 
over the counter 
PD 
pharmacodynamic(s) 
PGIC 
Patient Global Impression of Change 
PK 
pharmacokinetic(s) 
QD 
once a day 
QoL 
quality of life 
QTcF 
Fridericia-corrected QT interval 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SF-36 
Short Form 36 
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SGOT 
serum glutamic-oxaloacetic transaminase 
SGPT 
serum glutamic-pyruvic transaminase 
SHBG 
sex hormone–binding globulin 
SRC 
safety review committee 
TART 
testicular adrenal rest tumor 
TEAE 
treatment-emergent adverse event 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
WBC 
white blood cell 
WOCP 
woman/women of childbearing potential 
 
 
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1 PROTOCOL SUMMARY 
1.1 Protocol Synopsis 
Study Number:  SPR001-202 
Study Title 
A 3-Month Phase 2 Study to Evaluate the Safety and Efficacy of SPR001 in Subjects with 
Classic Congenital Adrenal Hyperplasia 
Study Rationale 
Congenital adrenal hyperplasia (CAH) is a chronically debilitating genetic disorder caused by a 
critical enzymatic deficiency in the steroidogenic pathways that synthesize the corticosteroids 
aldosterone and cortisol within the adrenal gland. The hallmark of CAH is cortisol deficiency, 
which disrupts the balance of the hypothalamic-pituitary-adrenal (HPA) axis by removing the 
negative feedback to the hypothalamus provided by normal levels of cortisol. This leads to 
the overproduction of corticotropin-releasing factor (CRF) by the hypothalamus, consequent 
overproduction of adrenocorticotropin hormone (ACTH) by the pituitary gland, and 
consequent adrenal hyperplasia and overproduction of cortisol precursors such as 
17-hydroxyprogesterone (17-OHP) by the adrenal gland, leading to androgen overproduction. 
Androgen excess may result in precocious puberty; seborrhea; impaired fertility; irregular 
menses, amenorrhea, acne, hirsutism, and virilization in females; and testicular adrenal rest 
tumors (TARTs) in males. Additionally, patients with the salt-wasting form of CAH have severe 
aldosterone deficiency, which leads to sodium depletion, potassium elevation, decreased 
blood volume, dehydration, and hypotension that can be life threatening in early infancy. 
Current treatment for CAH centers around using chronic high-dose glucocorticoids to replace 
cortisol, a problematic therapy with significant side effects, a narrow therapeutic window, 
and overall poor treatment effectiveness. Given the serious nature of CAH and the limitations 
and risks of chronic steroid therapy, new treatment modalities are needed for patients with 
CAH. 
SPR001, a high-affinity and selective small-molecule antagonist of CRF type 1 (CRF1) receptors 
in the pituitary gland, is being studied for the treatment of CAH on the basis of its ability to 
reduce the hypothalamic drive of CRF on the pituitary, thereby reducing ACTH 
overproduction by the pituitary and consequently reducing the overproduction of 17-OHP 
and androgens by the adrenal glands. This mechanism of action has been validated in a 
previous proof-of-concept study using a similar small-molecule CRF1 receptor antagonist, 
which produced reductions in ACTH and 17-OHP in subjects with CAH (Turcu et al, 2016). 
SPR001 has been shown to have an acceptable safety and tolerability profile in nonclinical 
toxicology studies, 2 completed Phase 1 clinical studies in healthy volunteers, and an ongoing 
Phase 2 clinical study in which subjects with CAH are treated for 2 weeks with any particular 
dose level of study drug (Study SPR001-201). Given that patients with CAH may require 
long-term treatment with SPR001, this study will investigate the extended use of SPR001 over 
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a 3-month period in combination with replacement glucocorticoids and mineralocorticoids in 
the treatment of CAH. 
Objectives 
Endpoints 
Primary 
 
• To evaluate the safety of SPR001 
in subjects with CAH  
• Adverse events (AEs), serious adverse events (SAEs), 
AEs leading to discontinuation/withdrawal, 
dose-limiting toxicities (DLTs), and AEs of special 
interest (AESIs) 
• Physical examination findings 
• Vital signs 
• Changes in electrocardiogram (ECG) 
• Changes in clinical laboratory values 
• Changes in the Columbia-Suicide Severity Rating 
Scale (C-SSRS) and the Hospital Anxiety and 
Depression Scale (HADS) 
Secondary 
 
• To evaluate the efficacy of 
SPR001 in subjects with CAH in 
terms of changes in hormones 
• Changes in ACTH, 17-OHP, androstenedione, and 
testosterone 
Exploratory  
 
• To evaluate the effect of SPR001 
on quality of life (QoL), metabolic 
parameters, exploratory adrenal 
hormones, and sex-specific 
outcomes in subjects with CAH 
• Changes in QoL as measured using the Short Form 36 
(SF-36), Patient Global Impression of Change (PGIC), 
bother score, and CAH signs and symptoms interview 
• Changes in fasting glucose, hemoglobin A1c (HbA1c), 
fasting insulin, and lipid profile 
• Changes in body weight (BW) and body mass index 
(BMI) 
• Changes in exploratory adrenal hormones 
• Changes in TARTs and on semen analysis in male 
subjects 
• Changes in acne, hirsutism, and menstrual cyclicity in 
female subjects 
Study Design 
This is a Phase 2 study of SPR001 for the treatment of classic CAH that will provide 12 weeks 
of open-label treatment to eligible subjects. To be eligible for this study, an individual must 
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either have completed Study SPR001-201 or meet criteria for SPR001-naïve subjects outlined 
under Eligibility Criteria.  
Initial subjects who enroll in this study will be treated with SPR001 at 400 mg once a day (QD) 
during the treatment period. For subjects who enroll later on in this study, the dose strength 
may be increased or decreased (by no more than 2-fold) and/or the dose regimen may be 
adjusted (e.g., to twice-daily [BID] dosing, a regimen being tested in Study SPR001-201). In 
general, subjects are expected to complete the study at the dose strength and on the dose 
regimen at which they started the study, unless they experience a clinically significant AE that 
would warrant a dose reduction. 
A safety review committee (SRC) will review the available safety, pharmacokinetics (PK), and 
pharmacodynamics (PD) data from Study SPR001-201 Cohorts B/C/D and from this study on 
an ongoing basis and provide recommendations to the Sponsor, who will ultimately decide on 
any dosing adjustments in this study. 
The Schedule of Activities is provided in Section 1.3. Study visits will occur every 2 weeks 
during the treatment period and should be scheduled for the morning, to accommodate 8am 
laboratory assessments. Study visits for screening and at Day 1 (baseline), Week 4, Week 8, 
and Week 12 (end of treatment) will be conducted as outpatient clinic visits. Study visits at 
Week 2, Week 6, and Week 10 may be conducted as either outpatient clinic visits or in-home 
visits by qualified study personnel. A final safety follow-up outpatient clinic visit will occur 
30 days after the last dose of study drug.  
To reduce subject burden, the final safety follow-up visit in Study SPR001-201 for subjects 
completing that study and rolling over into this study may coincide with the screening visit of 
this study (with any overlapping assessments conducted only once). Subjects who completed 
the final follow-up visit in Study SPR001-201 >3 months before screening in this study and 
subjects naïve to SPR001 must complete anew all specified screening assessments for this 
study. Subjects will maintain a stable dose and regimen of glucocorticoids throughout this 
study. 
Study Population 
This study will enroll up to approximately 24 eligible subjects with classic CAH who either 
previously completed Study SPR001-201 or meet criteria for SPR001-naïve subjects outlined 
under Eligibility Criteria. The study will be conducted at approximately 8 investigative sites in 
the United States. 
Eligibility Criteria 
For Subjects Who Completed Study SPR001-201 
Inclusion Criteria for Subjects Who Completed Study SPR001-201 
• Is approved by the Sponsor’s Medical Monitor 
• Is on a stable regimen of glucocorticoid replacement for ≥12 weeks before baseline that 
is expected to remain stable throughout the study 
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• If screening for this study occurs >3 months after the subject’s final follow-up visit in 
Study SPR001-201, the subject will have serum 17-OHP measured at screening. On the 
day of screening, the subject should take any morning glucocorticoid medication after 
the screening blood draw to allow for an unimpeded assessment of 17-OHP. The subject 
will be included if screening shows 17-OHP ≥800 ng/dL. 
• Agrees to follow contraception guidelines (Section 5.3.5). Male subjects must also agree 
to refrain from donating sperm throughout the treatment period and for 90 days after 
the last dose of study drug. 
• Is able to understand all study procedures and risks involved and provides written 
informed consent indicating willingness to comply with all aspects of the protocol 
Exclusion Criteria for Subjects Who Completed Study SPR001-201 
• Experienced a clinically significant AE (defined in Section 7.2.7) considered at least 
possibly related to SPR001 in Study SPR001-201 
• If screening for this study occurs >3 months after the subject’s final follow-up visit in 
Study SPR001-201, the subject will be screened for any clinically significant unstable 
medical condition, medically significant illness, or chronic disease occurring within 
30 days of screening, including but not limited to the following: 
o A malignancy or <3 years of remission history from any malignancy, other than 
successfully treated localized skin cancer 
o Presence of clinically significant renal disease, as evidenced by an estimated 
glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2 
o Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert’s syndrome or asymptomatic gallstones) 
o Confirmed positive test at screening for active hepatitis B, hepatitis C, or human 
immunodeficiency virus (HIV) 
• If screening for this study occurs >3 months after the subject’s final follow-up visit in 
Study SPR001-201, the subject will be screened for clinically significant psychiatric 
disorders by history and from the Mini International Neuropsychiatric Interview (M.I.N.I.) 
conducted at screening. The subject will be excluded if screening reveals evidence of 
current major depressive episode, bipolar disorder, schizophrenia, schizoaffective 
disorder, major depressive disorder with psychotic features, or any other psychotic 
disorder within the preceding 6 months. 
• Is at increased risk of suicide on the basis of the Investigator’s judgment or the results of 
the C-SSRS conducted at screening and baseline (e.g., C-SSRS Type 3, 4, or 5 ideation 
during the preceding 6 months or any suicidal behavior within the past 12 months) 
• Has a HADS score >12 for either depression or anxiety at screening or baseline 
• Clinically significant abnormal clinical or laboratory assessments must be discussed with 
the Medical Monitor to determine eligibility for this study. Abnormal assessments that 
must be reviewed to determine eligibility include but are not limited to: 
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o Clinically meaningful abnormal ECG results, in the opinion of the Investigator 
o Fridericia-corrected QT interval (QTcF) >450 msec for male participants or >470 msec 
for female participants 
o Alanine aminotransferase (ALT) >2x upper limit of normal (ULN) 
o Bilirubin >1.5x ULN (isolated bilirubin >1.5x ULN is acceptable if bilirubin is 
fractionated and direct bilirubin is <35%) 
• Subjects who routinely work overnight shifts require Medical Monitor approval for 
enrollment 
• Females who are pregnant or lactating 
• Use of any other investigational drug within 30 days or 5 half-lives (whichever is longer) 
before screening 
• Use of prohibited concomitant medications (see Section 6.5.2.1), including rosiglitazone, 
testosterone, and strong inhibitors and/or inducers of CYP3A4 (with the exception of 
glucocorticoids and birth control) within 30 days or 5 half-lives (whichever is longer) of 
baseline. Medications metabolized by CYP3A4, 2C8, 2C9, or 2C19, especially those that 
are sensitive substrates or substrates with narrow therapeutic ranges (see 
Section 6.5.2.2), should be discussed on a case-by-case basis with the Medical Monitor to 
determine whether the medication should be discontinued or may be continued with 
caution. If washout is feasible, then the medication should be withdrawn at least 30 days 
or 5 half-lives (whichever is longer) before baseline. 
• Donation of blood within 60 days before baseline or donation of platelets, white blood 
cells, or plasma within 15 days before baseline 
For SPR001-Naïve Subjects 
This study will offer enrollment to SPR001-naïve subjects with eligibility criteria similar to 
those of Study SPR001-201 but will also seek to include an enriched population of subjects 
with CAH who exhibit clinically significant sequelae of androgen excess, specifically males 18 
to 35 years old with TARTs and adult females with clinically significant acne, hirsutism, and/or 
ovulatory dysfunction. This study will initially allow enrollment of at least 3 subjects who 
meet general eligibility criteria for all SPR001-naïve subjects and who may or may not meet 
additional inclusion criteria for an enriched population of SPR001-naïve subjects. At any time 
thereafter, the Sponsor may decide to require all SPR001-naïve subjects who enroll 
subsequently to satisfy the additional inclusion criteria for an enriched population of 
SPR001-naïve subjects. 
Inclusion Criteria for All SPR001-Naïve Subjects 
• Male and female subjects ≥18 years old 
• Has a documented historical diagnosis of classic CAH due to 21-hydroxylase deficiency 
based on documented genetic mutation or elevated 17-OHP 
• Known or suspected differential diagnosis of any of the other known forms of CAH, 
including non-classic CAH, requires Medical Monitor approval for enrollment 
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• Has serum 17-OHP ≥800 ng/dL at screening. On the day of screening, the subject should 
take any morning glucocorticoid medication after the screening blood draw to allow for 
an unimpeded assessment of 17-OHP. 
• Is on a stable regimen of glucocorticoid replacement for ≥12 weeks before baseline that 
is expected to remain stable throughout the study 
• Agrees to follow contraception guidelines (Section 5.3.5). Male subjects must also agree 
to refrain from donating sperm throughout the treatment period and for 90 days after 
the last dose of study drug. 
• Is able to understand all study procedures and risks involved and provides written 
informed consent indicating willingness to comply with all aspects of the protocol 
Additional Inclusion Criteria for Enriched Population of SPR001-Naïve Subjects 
• If male, must be 18 to 35 years old, inclusive. 
• If male, must have a diagnosis of TART(s) confirmed via scrotal ultrasound at screening 
with at least 1 lesion having a diameter ≥4 mm 
• If female, must have at least one of the following clinically significant sequelae of 
androgen excess: 
o Clinically significant acne defined as an Investigator’s Global Assessment (IGA) score 
≥2 at screening 
o Clinically significant hirsutism defined as a modified Ferriman-Gallwey (mFG) score 
≥6 at screening 
o Verifiable history (based on medical records or ability to obtain an accurate history 
from the individual) of ovulatory dysfunction defined as having at least 1 year of 
menstrual cycles that last ≥45 days or having ≤8 menstrual periods within the past 
year, if the subject is not on a hormonal contraceptive 
Exclusion Criteria for All SPR001-Naïve Subjects 
• Has had a clinically significant unstable medical condition, medically significant illness, or 
chronic disease within 30 days of screening, including but not limited to: 
o A malignancy or <3 years of remission history from any malignancy, other than 
successfully treated localized skin cancer 
o Presence of clinically significant renal disease, as evidenced by an eGFR of 
<60 mL/min/1.73 m2 
o Current or chronic history of liver disease or known hepatic or biliary abnormalities 
(with the exception of Gilbert’s syndrome or asymptomatic gallstones) 
o Confirmed positive test at screening for active hepatitis B, hepatitis C, or HIV 
• Had or has a clinically significant psychiatric disorder either by history or from the M.I.N.I. 
conducted at screening. The subject will be excluded if screening reveals evidence of 
current major depressive episode, bipolar disorder, schizophrenia, schizoaffective 
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disorder, major depressive disorder with psychotic features, or any other psychotic 
disorder within the preceding 6 months. 
• Is at increased risk of suicide on the basis of the Investigator’s judgment or the results of 
the C-SSRS conducted at screening and baseline (e.g., C-SSRS Type 3, 4, or 5 ideation 
during the preceding 6 months or any suicidal behavior within the past 12 months) 
• Has a HADS score >12 for either depression or anxiety at screening or baseline 
• Clinically significant abnormal clinical or laboratory assessments must be discussed with 
the Medical Monitor to determine eligibility for this study. Abnormal assessments that 
must be reviewed to determine eligibility include but are not limited to: 
o Clinically meaningful abnormal ECG results, in the opinion of the Investigator 
o QTcF >450 msec for male participants or >470 msec for female participants 
o ALT >2x ULN 
o Bilirubin >1.5x ULN (isolated bilirubin >1.5x ULN is acceptable if bilirubin is 
fractionated and direct bilirubin is <35%) 
• Has a history that includes bilateral adrenalectomy or hypopituitarism 
• Subjects who routinely work overnight shifts require Medical Monitor approval for 
enrollment 
• Females who are pregnant or nursing 
• Use of any other investigational drug within 30 days or 5 half-lives (whichever is longer) 
before screening 
• Use of prohibited concomitant medications (see Section 6.5.2.1), including rosiglitazone, 
testosterone, and strong inhibitors and/or inducers of CYP3A4 (with the exception of 
glucocorticoids and birth control) within 30 days or 5 half-lives (whichever is longer) of 
baseline. Medications metabolized by CYP3A4, 2C8, 2C9, or 2C19, especially those that 
are sensitive substrates or substrates with narrow therapeutic ranges (see 
Section 6.5.2.2), should be discussed on a case-by-case basis with the Medical Monitor to 
determine whether the medication should be discontinued or may be continued with 
caution. If washout is feasible, then the medication should be withdrawn at least 30 days 
or 5 half-lives (whichever is longer) before baseline. 
• Donation of blood within 60 days before baseline or donation of platelets, white blood 
cells, or plasma within 15 days before baseline 
Investigational Drug 
The drug product SPR001 is a small-molecule CRF1 receptor antagonist and will be supplied as 
white, hard-gelatin capsules containing either 50 mg or 200 mg of drug substance with no 
excipients. 
Dose, Route, Regimen 
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Initial subjects who enroll in this study will be treated with oral study drug at 400 mg QD at 
10pm for 12 weeks. This dose is within the range of doses that were well tolerated and 
reduced key hormones (ACTH, 17-OHP, and androstenedione) in subjects with CAH in 
Cohort A of Study SPR001-201. For subjects who enroll later on in this study, the dose 
strength may be increased or decreased (by no more than 2-fold) and/or the dose regimen 
may be adjusted (e.g., to BID dosing, a regimen being tested in Study SPR001-201). In general, 
subjects are expected to complete the study at the dose strength and on the dose regimen at 
which they started the study, unless they experience a clinically significant AE that would 
warrant a dose reduction. An SRC will review the available safety, PK, and PD data from Study 
SPR001-201 Cohorts B/C/D and from this study on an ongoing basis and provide 
recommendations to the Sponsor, who will ultimately decide on any dosing adjustments in 
this study. 
Study drug will be taken with a meal or 5 to 15 minutes after consumption of a standardized 
snack. On the mornings of all study visits, including the screening visit, subjects should hold 
off on taking any morning glucocorticoid medication (and on taking study drug, if a morning 
dose is added and if applicable to the visit) until after laboratory assessments are completed. 
On all other days during the study, subjects should take any morning glucocorticoid 
medication (and morning dose of study drug, if applicable) at their usual time. 
If a subject experiences a DLT (defined as a Grade 3 or higher treatment-emergent adverse 
event [TEAE] considered at least possibly related to study drug), the Investigator may reduce 
the subject’s daily dose of SPR001 (by 50 to 200 mg), depending on the TEAE and upon 
discussion with the Sponsor’s Medical Monitor. Study drug will be discontinued in subjects 
who experience clinically significant liver chemistry, QTcF, or other individual treatment 
stopping criteria (Section 7.2). 
Study Duration 
The expected duration of study participation for each subject is up to approximately 
7 months. This includes a screening period of 12 weeks, a treatment period of 12 weeks, and 
a safety follow-up period of 30 days. 
Statistical Analyses 
Sample Size 
The total sample size of up to approximately 24 subjects in this study is based on an estimate 
of the number of subjects who may enroll either after completing Study SPR001-201 or as 
SPR001-naïve subjects. There is no statistical basis for the total sample size. 
General Approach 
Changes in primary, secondary, and exploratory endpoints will be analyzed over time, with 
change from baseline summarized for each post-baseline time point measured. If SPR001 
dosing is adjusted for subjects who enroll later on in this study, data will be presented by 
SPR001 dose. 
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Demographics and Background  
Demographics and subject background information such as disease characteristics will be 
summarized using descriptive statistics, including the number of subjects (n), mean, standard 
deviation, median, and range for continuous variables and count and percentage for 
categorical variables. 
Safety Analyses 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 20 
or higher and presented by System Organ Class and Preferred Term. TEAEs will be listed by 
subject and summarized overall and by SPR001 dose, if applicable. The incidence of each 
TEAE will be tabulated and presented by maximum severity. The frequency (number and 
percentage) of subjects who experience ≥1 TEAE will be summarized. TEAEs potentially 
related to study drug, SAEs, AEs leading to study drug discontinuation/study withdrawal, 
DLTs, and AESIs will be summarized by frequency of subjects who experience ≥1 event and/or 
tabulated by incidence for each event. 
Physical examination findings will be listed. Vital signs, ECG parameters, and clinical 
laboratory values will be listed and summarized using descriptive statistics. Investigators’ 
assessments of ECG results will be listed and summarized in a frequency table. Clinical 
laboratory values may be presented in shift tables. Prior and concomitant medications will be 
listed. C-SSRS data will be listed. Data for the HADS (including anxiety and depression 
subscales) will be summarized using descriptive statistics. 
An SRC will review safety data at regular intervals throughout the study (see Section 10.6). 
Efficacy Analyses 
Changes over time in hormones (ACTH, 17-OHP, androstenedione, testosterone, and 
exploratory adrenal hormones) will be summarized using descriptive statistics and presented 
in tables and/or graphs. Parametric (paired t test) or nonparametric (Wilcoxon signed rank) 
tests will be used to test the change from baseline depending on the data distribution. 
Data for the SF-36 (including individual domain scores and summary scores) will be 
summarized using descriptive statistics. Data for the PGIC, the bother score, and the CAH 
signs and symptoms interview will be summarized using counts and percentages. Shifts in 
status from baseline to each post-baseline visit will be presented. 
Changes over time in metabolic parameters (including fasting glucose, HbA1c, fasting insulin, 
lipid profile, BW, and BMI) will be summarized using descriptive statistics. 
Changes over time in measures of TARTs and on semen analysis in male subjects and in 
measures of acne, hirsutism, and menstrual cyclicity in female subjects will be summarized 
using descriptive statistics. 
Pharmacokinetic Analyses 
PK may be assessed using a population PK approach. 
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1.2 Schema 
 
 
 
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1.3 Schedule of Activities 
 
Screening 
Period 
Treatment Period 
Follow-
up/ET 
VISIT NUMBER 
11 
Screening 
2 
Baseline 
3 
4 
5 
6 
7 
8 
9 
STUDY WEEK 
 
0 
2 
4 
6 
8 
10 
12 
16 
STUDY DAY2 
12 weeks 
before Day 1 
1 
15 
29 
43 
57 
71 
85 
Last dose 
+30 days 
Site Visits3 
X 
X 
 
X 
 
X 
 
X 
X 
Home Visits4 
 
 
X 
 
X 
 
X 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
Demography5 
X 
 
 
 
 
 
 
 
 
Medical history6 
X 
 
 
 
 
 
 
 
 
Prior medications6 
X 
 
 
 
 
 
 
 
 
Concomitant medications7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
                                                      
1 For subjects rolling over from Study SPR001-201, the final safety follow-up visit of Study SPR001-201 may 
coincide with the screening visit of this study (with any overlapping assessments conducted only once). If a subject 
completed the final follow-up visit of Study SPR001-201 ≤3 months before the screening period of this study, 
overlapping assessments conducted at that final follow-up visit need not be repeated at screening for this study. If 
a subject completed the final follow-up visit of Study SPR001-201 >3 months before the screening period of this 
study, all screening assessments must be conducted anew, including some additional screening assessments 
specified for such subjects. 
2 All visits should be performed on the indicated study days. In cases where this is not possible, the following visit 
windows apply: ±3 days for Visits 3 to 8 and ±7 days for the safety follow-up visit (Visit 9). All visits, including the 
early termination visit, should be scheduled for the morning, to accommodate 8am laboratory assessments. 
3 Study visits for screening; at Weeks 0, 4, 8, and 12; and at final follow-up must be conducted as in-clinic 
outpatient visits. 
4 Study visits at Weeks 2, 6, and 10 may be conducted as either in-clinic outpatient visits or in-home visits by 
qualified study personnel. 
5 Demographic information needs to be collected only for SPR001-naïve subjects. 
6 Full medical history and prior medications from the past year will be collected for SPR001-naïve subjects. If a 
subject completed the final follow-up visit in Study SPR001-201 before the screening period for this study, any 
significant medical history and medications taken during the intervening period should be captured. 
7 Subjects should be on a stable regimen of glucocorticoid replacement for a minimum of 12 weeks before baseline 
and throughout the treatment period. On the mornings of all study visits, including screening, subjects should hold 
off on taking any morning glucocorticoid medication until after laboratory assessments have been completed. On 
all other days during the study, subjects may take any morning dose of glucocorticoid medication at their usual 
time. 
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Screening 
Period 
Treatment Period 
Follow-
up/ET 
VISIT NUMBER 
11 
Screening 
2 
Baseline 
3 
4 
5 
6 
7 
8 
9 
STUDY WEEK 
 
0 
2 
4 
6 
8 
10 
12 
16 
STUDY DAY2 
12 weeks 
before Day 1 
1 
15 
29 
43 
57 
71 
85 
Last dose 
+30 days 
Site Visits3 
X 
X 
 
X 
 
X 
 
X 
X 
Home Visits4 
 
 
X 
 
X 
 
X 
 
 
Clinical laboratory8,9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HbA1c and fasting insulin8 
 
X 
 
X 
 
X 
 
X 
 
Key hormones8,10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Exploratory adrenal 
hormones8,11 
 
X 
 
X 
 
X 
 
X 
 
PK8,12 
X 
X 
 
X 
 
X 
 
X 
X 
Hepatitis B & C and HIV 
screening13 
X 
 
 
 
 
 
 
 
 
eGFR for screening13,14 
X 
 
 
 
 
 
 
 
 
Pregnancy test for WOCP15 
X 
X 
 
X 
 
X 
 
X 
X 
Vital signs16 and body 
weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination17  
X 
X 
 
X 
 
X 
 
X 
X 
                                                      
8 Samples for these lab assessments will be obtained at the beginning of each study visit (8am), after overnight fast 
(nothing to eat since the previous midnight), and before the subject has taken any morning dose of glucocorticoid 
medication. If a morning dose of study drug is added, samples for these lab assessments will be obtained before 
the morning dose of study drug for that day (where applicable). 
9 Clinical laboratory assessments include hematology, clinical chemistry, fasting glucose, lipid panel, thyroid panel, 
urinalysis, LH, FSH, inhibin B, SHBG, renin, aldosterone, and, for females only, estradiol, prolactin, and 
progesterone. 
10 ACTH, 17-OHP, androstenedione, testosterone, and background glucocorticoid levels 
(cortisol/prednisolone/dexamethasone, depending on what the subject is taking) will be measured from blood 
samples. 17-OHP will also be measured from a saliva sample. 
11 A single blood sample will be drawn for measurement of exploratory adrenal hormones at each specified visit. 
12 A single blood sample will be drawn for PK measurement at each specified visit. The PK blood sample does not 
need to be obtained from SPR001-naïve subjects at screening. 
13 These screening assessments will be performed for SPR001-naïve subjects and for subjects who completed the 
final follow-up visit in Study SPR001-201 >3 months before the screening visit for this study. 
14 eGFR for screening will be calculated from blood creatinine measured as part of clinical chemistry during 
screening. 
15 A serum pregnancy test will be performed at screening for WOCP who are SPR001-naïve and for WOCP who 
completed the final follow-up visit in Study SPR001-201 >3 months before the screening visit for this study. All 
other pregnancy tests will be urine pregnancy tests. 
16 Systolic and diastolic blood pressure, pulse rate, body temperature, and respiration rate. 
17 A full physical examination will be conducted at baseline (Day 1) and end of treatment (Week 12) for all subjects. 
A full physical examination will also be conducted at screening for SPR001-naïve subjects and subjects who 
completed the final follow-up visit in Study SPR001-201 >3 months before the screening visit for this study. The full 
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Screening 
Period 
Treatment Period 
Follow-
up/ET 
VISIT NUMBER 
11 
Screening 
2 
Baseline 
3 
4 
5 
6 
7 
8 
9 
STUDY WEEK 
 
0 
2 
4 
6 
8 
10 
12 
16 
STUDY DAY2 
12 weeks 
before Day 1 
1 
15 
29 
43 
57 
71 
85 
Last dose 
+30 days 
Site Visits3 
X 
X 
 
X 
 
X 
 
X 
X 
Home Visits4 
 
 
X 
 
X 
 
X 
 
 
Scrotal ultrasound for 
males18 
X 
X 
 
 
 
 
 
X 
 
Optional semen sample for 
males19 
 
X 
 
 
 
 
 
X 
 
Menstrual diary for 
females20 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG 
X 
X 
 
X 
 
X 
 
X 
 
MINI Version 7.0.213 
X 
 
 
 
 
 
 
 
 
C-SSRS 
X 
X 
 
X 
 
X 
 
X 
 
HADS 
X 
X 
 
X 
 
X 
 
X 
X 
SF-3621 
 
X 
 
X 
 
X 
 
X 
X 
PGIC 
 
 
 
X 
 
X 
 
X 
X 
Bother score 
 
X 
 
X 
 
X 
 
X 
 
CAH signs and symptoms 
interview 
 
X 
 
X 
 
X 
 
X 
X 
Dispense study drug22 
 
X 
 
X 
 
X 
 
 
 
                                                      
physical examination may exclude rectal, genitourinary, and breast exams. An abbreviated physical examination will be 
conducted at Weeks 4 and 8 and final follow-up. Height needs to be collected at screening only. As part of the examination of 
the skin, acne will be evaluated for all subjects using an IGA score at baseline and Weeks 4, 8, and 12; hirsutism will be 
evaluated for female subjects using an mFG score at baseline and Week 12. Female subjects will be asked about their last 
menstrual period as part of both full and abbreviated physical exams. 
18 For SPR001-naïve male subjects, a scrotal ultrasound will be conducted at the initial screening visit. For SPR001-experienced 
male subjects rolling over from Study SPR001-201, a scrotal ultrasound will be conducted at the initial screening visit only if the 
subject has not had a prior scrotal ultrasound within 3 months before screening. For all male subjects, if the prior or screening 
scrotal ultrasound reveals no evidence of TART, the scrotal ultrasound need not be repeated at either Day 1 or Week 12. If the 
prior or screening scrotal ultrasound does show evidence of TART(s), the scrotal ultrasound will be repeated at Day 1 and Week 
12. 
19 All male subjects should be encouraged (though not required) to provide a semen sample. Semen will be collected from male 
subjects for analysis of sperm count, morphology, and motility. 
20 Female subjects will record menstrual information (including start and stop dates of menses and whether the flow was light, 
moderate, or heavy) in a menstrual diary throughout the 12-week screening period and the 12-week treatment period. A 
menstrual diary will be handed out at the screening visit and collected at the Day 1 visit, and a second menstrual diary will be 
handed out at the Day 1 visit and collected at the Week 12 visit. 
21 The 4-week SF-36 will be administered. 
22 Subjects will be dispensed a 4-week supply of study drug each time. If a morning dose of study drug is added, subjects should 
hold off on taking their morning dose of study drug on the mornings of all study visits until after laboratory assessments have 
been completed. On all other days during the study, subjects should take their morning dose of study drug (if applicable) at the 
usual time. 
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Screening 
Period 
Treatment Period 
Follow-
up/ET 
VISIT NUMBER 
11 
Screening 
2 
Baseline 
3 
4 
5 
6 
7 
8 
9 
STUDY WEEK 
 
0 
2 
4 
6 
8 
10 
12 
16 
STUDY DAY2 
12 weeks 
before Day 1 
1 
15 
29 
43 
57 
71 
85 
Last dose 
+30 days 
Site Visits3 
X 
X 
 
X 
 
X 
 
X 
X 
Home Visits4 
 
 
X 
 
X 
 
X 
 
 
Study drug accountability 
 
 
X 
X 
X 
X 
X 
X 
 
Review adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: 17-OHP, 17-hydroxyprogesterone; ACTH, adrenocorticotropin hormone; CAH, congenital adrenal 
hyperplasia; C-SSRS, Columbia Suicide Severity Rating Scale; ECG, electrocardiogram; eGFR, estimated glomerular 
filtration rate; ET, early termination; FSH, follicle-stimulating hormone; HADS, Hospital Anxiety and Depression 
Scale; HbA1c, hemoglobin A1c; HIV, human immunodeficiency virus; IGA, Investigator’s Global Assessment (score 
for acne); LH, luteinizing hormone; M.I.N.I., Mini International Neuropsychiatric Interview; mFG, modified 
Ferriman-Gallwey (score for hirsutism); PD, pharmacodynamics; PGIC, Patient Global Impression of Change; PK, 
pharmacokinetics; SF-36, Short Form 36; SHBG, sex hormone–binding globulin; WOCP, women of childbearing 
potential. 
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2 INTRODUCTION 
2.1 Study Rationale 
CAH is a chronically debilitating genetic disorder caused by a critical enzymatic deficiency in the 
steroidogenic pathways that synthesize the corticosteroids aldosterone and cortisol within the 
adrenal gland. The hallmark of CAH is cortisol deficiency, which disrupts the balance of the HPA 
axis by removing the negative feedback to the hypothalamus provided by normal levels of 
cortisol. This leads to the overproduction of CRF by the hypothalamus, consequent 
overproduction of ACTH by the pituitary gland, and consequent adrenal hyperplasia and 
overproduction of cortisol precursors such as 17-OHP by the adrenal gland, leading to androgen 
overproduction. Androgen excess may result in precocious puberty; seborrhea; impaired 
fertility; irregular menses, amenorrhea, acne, hirsutism, and virilization in females; and TARTs in 
males. Additionally, patients with the salt-wasting form of CAH have severe aldosterone 
deficiency, which leads to sodium depletion, potassium elevation, decreased blood volume, 
dehydration, and hypotension that can be life threatening in early infancy. Current treatment 
for CAH centers around using chronic high-dose glucocorticoids to replace cortisol, a 
problematic therapy with significant side effects, a narrow therapeutic window, and overall 
poor treatment effectiveness. Given the serious nature of CAH and the limitations and risks of 
chronic steroid therapy, new treatment modalities are needed for patients with CAH. 
SPR001, a high-affinity and selective small-molecule antagonist of CRF1 receptors on the 
pituitary gland, is being studied for the treatment of CAH on the basis of its ability to reduce the 
hypothalamic drive of CRF on the pituitary, thereby reducing ACTH overproduction by the 
pituitary and consequently reducing the overproduction of 17-OHP and androgens by the 
adrenal glands. This mechanism of action has been validated in a previous proof-of-concept 
study using a similar small-molecule CRF1 receptor antagonist, which produced reductions in 
ACTH and 17-OHP in subjects with CAH (Turcu et al, 2016). SPR001 has been shown to have an 
acceptable safety and tolerability profile in nonclinical toxicology studies, 2 completed Phase 1 
clinical studies in healthy volunteers, and an ongoing Phase 2 clinical study in which subjects 
with CAH are treated for 2 weeks with any particular dose level of study drug (Study 
SPR001-201). Given that patients with CAH may require long-term treatment with SPR001, this 
study will investigate the extended use of SPR001 over a 3-month period in combination with 
replacement glucocorticoids and mineralocorticoids in the treatment of CAH.  
2.2 Background 
2.2.1 
Congenital Adrenal Hyperplasia 
CAH is a chronically debilitating autosomal recessive genetic disorder caused by a critical 
enzymatic deficiency in the steroidogenic pathways that synthesize the corticosteroids 
aldosterone and cortisol within the adrenal gland (White and Speiser, 2000; Bachelot et al, 
2008). CAH is typically classified as either classic (the more severe form that is usually detected 
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in infancy) or nonclassic (the milder form that may not become evident until childhood or early 
adulthood). Classic CAH can be further sub-classified as salt-wasting or simple virilizing. 
Approximately 75% of CAH patients have a mutation that leads to severe aldosterone 
deficiency, resulting in the salt-wasting form of CAH characterized by the loss of large amounts 
of sodium via their urine (hyponatremia), hyperkalemia, and elevated plasma renin activity 
indicating hypovolemia, leading to dehydration and hypotension that can be life threatening in 
early infancy. The remaining 25% of CAH patients produce sufficient aldosterone to avoid 
neonatal adrenal crisis but are nevertheless debilitated by the simple virilizing form of CAH 
resulting from impaired cortisol production. Cortisol deficiency, a hallmark of CAH, disrupts the 
balance of the HPA axis by removing the negative feedback to the hypothalamus provided by 
normal levels of cortisol. This leads to the overproduction of CRF by the hypothalamus, the 
consequent overproduction of ACTH by the pituitary gland, and the resulting adrenal 
hyperplasia and overproduction of cortisol precursors by the adrenal gland. Because CAH 
patients are deficient in enzymatic activity that converts cortisol precursors to cortisol, these 
precursors are funneled into the biosynthetic pathway for adrenal androgens, leading to 
androgen overproduction. Androgen excess may result in precocious puberty; seborrhea; 
impaired fertility; irregular menses, amenorrhea, acne, hirsutism, and virilization in females; 
and TARTs in males. 
The most common genetic cause of CAH, accounting for over 90% of cases, is mutation of the 
CYP21A2 gene, which encodes the cytochrome P450c21 enzyme, commonly known as 
21-hydroxylase, which is required for the synthesis of cortisol and aldosterone from the 
precursors 17-OHP and progesterone (White and Speiser, 2000; Bachelot et al, 2008; Auchus, 
2015; Doleschall et al, 2014). Mutations in genes that encode other enzymes critical in 
steroidogenesis (CYP17A1, HSD3B2, CYP11B1, and POR) contribute to the remaining 5% to 10% 
of CAH cases (Turcu and Auchus 2015). Severe mutations that completely ablate 21-hydroxylase 
activity lead to the salt-wasting form of CAH. Milder mutations that result in even 1% to 2% 
residual 21-hydroxylase activity enable sufficient aldosterone production to avoid neonatal 
adrenal crisis and produce the simple virilizing form of CAH. Neonatal screening of 17-OHP to 
diagnose CAH is now performed in the United States and many other countries, with the goal of 
reducing mortality and morbidity due to salt-wasting adrenal crises in newborns (Falhammar et 
al, 2015). A 17-OHP level >300 nmol/L is indicative of untreated CAH, and the patient is then 
generally genotyped to confirm the diagnosis and to help determine treatment approaches 
(Falhammar et al, 2015; Choi et al, 2016). 
Evidence-based treatment guidelines for CAH are only beginning to be developed (Reisch, 
2015), and current overall treatment effectiveness for CAH patients is poor (Mnif et al, 2012; 
Bachelot et al, 2015). Current treatment for CAH is centered around providing pharmacologic 
(supraphysiologic) doses of glucocorticoids (e.g., hydrocortisone) to replace cortisol. In patients 
with the salt-wasting form of CAH, mineralocorticoids (e.g., fludrocortisone) are also used to 
replace aldosterone; before weaning, salt supplements (NaCl) are also provided to prevent a 
potentially lethal salt-losing crisis. The challenge in using glucocorticoid therapy to manage CAH 
lies in its narrow therapeutic window and in striking the difficult balance between 
hyperandrogenism and hypercortisolism. Up to 70% of patients with CAH are considered 
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outside the acceptable bounds of biochemical control (Han et al, 2014). Among patients with 
21-hydroxylase deficiency treated with glucocorticoids, normal serum androstenedione has 
been shown to be achieved in only 36% of patients (Arlt et al, 2010). Under-treatment carries 
the risk of adrenal insufficiency and crisis (dehydration, hypotension, hypoglycemia) and allows 
androgen overproduction (precocious puberty, female virilization, TARTs, infertility). In 
contrast, over-treatment with glucocorticoids may suppress growth and cause iatrogenic 
Cushing’s syndrome, producing such metabolic symptoms as hypertension, greater BMI, 
obesity, hypercholesterolemia, and insulin resistance. Over a lifetime, the treatment of patients 
with CAH shifts from an emphasis on normal childhood growth to pubertal development to 
adult fertility and long-term health concerns, including metabolic abnormalities, cardiovascular 
disease, osteoporosis, and overall diminished quality of life (Auchus, 2015; Arlt et al, 2010). 
Numerous studies have documented diminished quality of life in patients with CAH (Han et al, 
2013; Aulinas and Webb, 2014; Gilban et al, 2014; Hummel et al, 2016). Faced with the 
debilitating effects of the disease itself, ineffective treatment, and/or the severe side effects of 
long-term high-dose glucocorticoid treatment, CAH patients may develop depression and 
anxiety. Patients with CAH have increased mortality, with 1 study documenting a mean age of 
death of 41.2 years in patients with 21-hydroxylase deficiency. The causes of death were 
adrenal crisis (42%), cardiovascular disease (32%), cancer (16%), and suicide (10%) (Falhammar 
et al, 2014). 
Refer to the Investigator’s Brochure (IB) for additional information on CAH. 
2.2.2 
SPR001 for the Treatment of CAH 
SPR001 is being studied for the treatment of CAH on the basis of its ability to antagonize CRF1 
receptors located on the pituitary gland, thereby reducing the hypothalamic drive of CRF on the 
pituitary, consequent ACTH overproduction by the pituitary, and consequent 17-OHP and 
androgen overproduction by the adrenal glands. This mechanism of action has been validated 
in a previous proof-of-concept study using a similar small-molecule CRF1 receptor antagonist, 
which produced reductions in ACTH and 17-OHP in subjects with CAH (Turcu et al, 2016). In 
vitro studies show that SPR001 binds to CRF1 receptors with high affinity and specificity and 
blocks CRF1-mediated receptor function. 
The safety profile of SPR001 has been established in nonclinical toxicology studies and in 
2 completed Phase 1 clinical studies in healthy volunteers. A Phase 2 study in subjects with CAH 
(Study SPR001-201) is currently ongoing. 
2.2.3 
Nonclinical Toxicology of SPR001 
The nonclinical safety profile of study drug substance (SPN001) has been evaluated in 
repeat-dose range-finding and definitive toxicology studies in rats and dogs administered 
SPN001 orally once daily for up to 91 consecutive days at doses up to 2000 mg/kg/day. In rats, 
SPN001-related findings were limited to the testes at 2000 mg/kg/day and the liver of both 
sexes at 5, 20, and 2000 mg/kg/day. The no observed adverse effect level (NOAEL) for SPN001 
in rats was considered to be 20 mg/kg/day in males and 2000 mg/kg/day in females. In dogs, 
SPN001-related findings were limited to the testes at 2000 mg/kg/day, the liver of both sexes at 
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70 and 2000 mg/kg/day, and the thyroid gland of both sexes at 2000 mg/kg/day. The NOAEL for 
SPN001 in dogs was considered to be 70 mg/kg/day in both sexes. All findings in both species 
were reversible following a 6-week washout period. Refer to Section 2.3.1 for a discussion of 
the potential liver, testicular, and thyroid risks associated with SPR001. 
In reproductive and developmental toxicity studies, no adverse effects on fertility or early 
embryonic development were noted when SPN001-treated male rats (dosed at 5, 20, or 
1000 mg/kg/day) were mated with untreated female rats or when SPN001-treated female rats 
(dosed at 20, 300, or 1000 mg/kg/day) were mated with untreated male rats. The NOAEL for 
SPN001 for male and female reproductive function was considered to be 1000 mg/kg/day. In an 
embryo-fetal development study conducted in rabbits (dosed at 30, 100, or 1000 mg/kg/day), 
developmental toxicity, which occurred concomitantly with maternal toxicity, was noted at 100 
and 1000 mg/kg/day. Effects included increases in resorptions and post-implantation loss and 
corresponding reductions in litter sizes and live fetuses at 1000 mg/kg/day and lower fetal body 
weight, a greater number of multiple morphological alterations, and reduced ossification in 
some bones of the paws at 100 and 1000 mg/kg/day. The NOAEL for developmental toxicity 
was considered to be 30 mg/kg/day. 
In a study conducted in juvenile rats administered SPN001 at 100, 300, or 1000 mg/kg/day for 
7 weeks beginning on postnatal day 45 (comparable to a 12-year-old human), adverse effects 
were limited to microscopic findings in the testes of males at 1000 mg/kg/day. These findings 
included minimal or mild bilateral tubular degeneration within the seminiferous tubules and 
scattered focal loss of various cell types, often segmental within a tubule, that lacked stage or 
cell-type specificity. Corresponding minimal luminal debris and reduced sperm within the 
epididymides were also noted. The NOAEL for SPN001 in juvenile rats was considered to be 
300 mg/kg/day in males and 1000 mg/kg/day in females. 
In addition, a complete battery of standard genotoxicity tests consisting of in vitro bacterial 
reverse mutation and chromosome aberration assays and an in vivo (rat) bone marrow 
micronucleus assay has been conducted. A bovine corneal opacity and permeability assay has 
also been conducted. 
2.2.4 
Clinical Experience with SPR001 
In 2 completed Phase 1 studies, a total of 53 healthy adult subjects aged 21 to 64 years were 
treated with at least 1 dose of SPR001. The first-in-human study of SPR001 (Study I3C-FW-
BLAA) evaluated single ascending doses of 2 mg to 800 mg. In this study, a small number of 
subjects experienced diarrhea and headache of mild or moderate severity. A subsequent study 
(Study I3C-FW-BLAB) evaluated repeat doses of 50 mg, 150 mg, or 200 mg SPR001 once daily 
for 14 consecutive days. A small number of subjects in the repeat-dose study experienced 
dyspnea, rhinorrhea, palpitations, and headache. The Phase 1 studies showed no clinically 
significant alterations in safety laboratory values, vital signs, or ECGs. SPR001 was well tolerated 
in healthy human subjects, with no SPR001-related SAEs / AEs leading to discontinuation or 
DLTs. 
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An ongoing Phase 2, open-label, proof-of-concept study (Study SPR001-201) is currently 
evaluating the safety and efficacy of SPR001 in adults with classic CAH. Cohort A of Study 
SPR001-201 has been completed, with 10 subjects receiving at least 1 dose of SPR001 and 
9 subjects completing the cohort. Dosing for each subject in Cohort A was to start at 200 mg QD 
(for 14 days) and to escalate to 600 mg QD (for 14 days), then 1000 mg QD (for 14 days). 
Preliminary safety data from Cohort A shows SPR001 to be generally well tolerated through 
600 mg QD and 4 weeks of dosing, with no SAEs, AEs leading to discontinuation, DLTs, or AESIs 
and no meaningful changes across clinical laboratory, ECGs, the Beck Depression Inventory-II 
(BDI-II) and C-SSRS, or physical examination findings. Refer to Section 2.3 for preliminary safety 
and efficacy data from Cohort A that speaks to the potential clinical risks and benefits of 
SPR001 as a treatment for CAH. In Cohorts B/C/D of this study, approximately 3 to 6 subjects 
are expected to be enrolled into each cohort with a 2-week treatment period. Study drug 
dosing will begin at 200 mg BID in Cohort B and may be adjusted in Cohorts C/D based on an 
adaptive multiple ascending dose design.  
2.3 Risk/Benefit Assessment 
2.3.1 
Known Potential Risks 
Reversible effects on liver function tests (LFTs) have been observed in the ongoing Phase 2 
Study SPR001-201 at the highest dose tested (1000 mg QD), after a total of 6 weeks on study 
drug. In Cohort A of Study SPR001-201, 2 subjects with CAH administered 1000 mg QD for 
2 weeks (following 2 weeks on 200 mg QD and 2 weeks on 600 mg QD) experienced transient 
ALT elevations. One subject experienced an ALT elevation of >5x ULN and another subject 
experienced a mild ALT elevation of 2.3x ULN. Both events resolved by the end of the follow-up 
period. Bilirubin levels remained within normal levels in both subjects. No LFT abnormalities 
were observed in the Phase 1 clinical studies, which treated healthy adults with single SPR001 
doses of up to 800 mg and multiple SPR001 doses of up to 200 mg QD for 14 days. No LFT 
abnormalities were observed in subjects in Cohort A dosed at up to 600 mg QD after a total of 
4 weeks on study drug (2 weeks on 200 mg QD and 2 weeks on 600 mg QD). 
Reversible testicular/spermatocyte degeneration/atrophy was observed in rats and dogs 
treated with the highest dose of SPR001 in the definitive toxicology studies (2,000 mg/kg/day). 
However, male reproductive studies in rats showed no impairment in fertility at the highest 
dose tested (1,000 mg/kg/day). Additionally, no meaningful effects on clinical laboratory 
markers of testicular function (luteinizing hormone [LH], follicle-stimulating hormone [FSH], 
inhibin B, and sex hormone–binding globulin [SHBG]) have been observed in healthy male 
volunteers in the Phase 1 studies or in male subjects with CAH in Cohort A of Study SPR001-201. 
Effects on the thyroid gland (follicular hypertrophy secondary to hepatocellular hypertrophy) 
were noted in dogs treated for 91 days at 2,000 mg/kg/day in the definitive toxicology study. 
The clinical relevance of this secondary finding is presently unclear. Thyroid function was not 
evaluated in the Phase 1 studies, and no meaningful changes in thyroid function have been 
observed in Cohort A of Study SPR001-201. 
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2.3.2 
Known Potential Benefits 
Evidence from nonclinical and early clinical studies suggests that SPR001 is effective as a CRF1 
receptor antagonist, a mechanism of action that supports the clinical investigation of SPR001 
for the treatment of CAH. This mechanism of action has been validated in a previous 
proof-of-concept study using a similar small-molecule CRF1 receptor antagonist, which 
produced reductions in ACTH and 17-OHP in subjects with CAH (Turcu et al, 2016). Preliminary 
data from Cohort A of Study SPR001-201 show clinical evidence of CRF1 receptor target 
engagement (reductions in ACTH) and reductions in key adrenal hormones (17-OHP and 
androstenedione) at all dose levels tested. 
2.3.3 
Assessment of Potential Risks and Benefits 
Multiple study design elements have been incorporated to mitigate the potential risks of LFT 
laboratory abnormalities, testicular injury, and thyroid effects described in Section 2.3.1. 
Because these risks are all associated with higher doses of SPR001, study drug will initially be 
administered in this study at 400 mg QD, which is within the range of clinical precedence that 
has been safe and well tolerated. Additionally, clinical laboratory measures of liver chemistry, 
testicular function, and thyroid function will be assessed every 2 weeks throughout the 
treatment period of this study. Liver chemistry will be monitored by measuring ALT, aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), and 
total and direct bilirubin. Testicular function will be monitored by measuring LH, FSH, inhibin B, 
and SHBG; performing scrotal ultrasounds; and conducting semen analysis. Thyroid function will 
be monitored via a thyroid panel that measures T3, T4, and thyroid-stimulating hormone (TSH). 
Finally, strict individual treatment stopping criteria for liver chemistry findings and a criterion 
for increased liver chemistry monitoring are in place (see Section 7.2.1 and Section 12.2). 
The mild and reversible toxicologic effects of SPR001 on the male reproductive tract in 
nonclinical studies occurred in the context of animals with normal, rather than elevated, 
baseline hormone function. As a CRF1 receptor antagonist, SPR001 is intended to reduce 
abnormally elevated ACTH and androgen levels. In nonclinical models where baseline hormone 
levels are within normal ranges, clinical benefits are not expected, and indeed, toxicities may be 
expected as a result of androgen reduction outside of the normal range. However, in patients 
with CAH, whose baseline ACTH and androgen levels are pathologically elevated, androgen 
reduction would be considered a positive, therapeutic effect. 
The Sponsor believes that the benefit-to-risk profile of this study is favorable. Given the serious 
nature of CAH and the limitations and risks of chronic steroid therapy, new treatment 
modalities are needed for patients with CAH. Given 1) the acceptable safety and tolerability 
profile of SPR001 in healthy volunteers from the Phase 1 program and in subjects with CAH 
administered study drug at up to 600 mg QD in Cohort A of Study SPR001-201 and 2) the 
preliminary evidence of reductions in ACTH, 17-OHP, and androstenedione at all dose levels 
tested in Cohort A of Study SPR001-201, the Sponsor believes that the benefit-to-risk profile 
favors the continued investigation of SPR001 and the investigation of extended treatment with 
SPR001 for up to 3 months in subjects with CAH. 
 
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3 OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
 
• To evaluate the safety of 
SPR001 in subjects with CAH 
• AEs, SAEs, AEs leading to discontinuation/withdrawal, 
DLTs, and AESIs 
• Physical examination findings 
• Vital signs 
• Changes in ECG 
• Changes in clinical laboratory values 
• Changes in the C-SSRS and the HADS 
Secondary 
 
• To evaluate the efficacy of 
SPR001 in subjects with CAH in 
terms of changes in hormones 
• Changes in ACTH, 17-OHP, androstenedione, and 
testosterone 
Exploratory 
 
• To evaluate the effect of 
SPR001 on QoL, metabolic 
parameters, exploratory 
adrenal hormones, and 
sex-specific outcomes in 
subjects with CAH 
• Changes in QoL as measured using the SF-36, PGIC, 
bother score, and CAH signs and symptoms interview  
• Changes in fasting glucose, HbA1c, fasting insulin, and 
lipid profile 
• Changes in BW and BMI 
• Changes in exploratory adrenal hormones 
• Changes in TARTs and on semen analysis in male 
subjects 
• Changes in acne, hirsutism, and menstrual cyclicity in 
female subjects 
 
 
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4 STUDY DESIGN 
4.1 Overall Design 
This is a Phase 2 study of SPR001 for the treatment of classic CAH that will provide 12 weeks of 
open-label treatment to eligible subjects. To be eligible for this study, an individual must either 
have completed Study SPR001-201 or meet eligibility criteria for SPR001-naïve subjects (see 
Section 5.2). The expected duration of study participation for each subject is up to 
approximately 7 months. This includes a screening period of 12 weeks, a treatment period of 
12 weeks, and a safety follow-up period of 30 days. 
Initial subjects who enroll in this study will be treated with SPR001 at 400 mg QD during the 
treatment period. For subjects who enroll later on in this study, the dose strength may be 
increased or decreased (by no more than 2-fold) and/or the dose regimen may be adjusted 
(e.g., to BID dosing, a regimen being tested in Study SPR001-201). In general, subjects are 
expected to complete the study at the dose strength and on the dose regimen at which they 
started the study, unless they experience a clinically significant AE that would warrant a dose 
reduction. 
An SRC will review the available safety, PK, and PD data from Study SPR001-201 Cohorts B/C/D 
and from this study on an ongoing basis and provide recommendations to the Sponsor, who will 
ultimately decide on any dosing adjustments in this study. 
The Schedule of Activities is provided in Section 1.3. Study visits will occur every 2 weeks during 
the treatment period and should be scheduled for the morning, to accommodate 8am 
laboratory assessments. Study visits for screening and at Day 1 (baseline), Week 4, Week 8, and 
Week 12 (end of treatment) will be conducted as outpatient clinic visits. Study visits at Week 2, 
Week 6, and Week 10 may be conducted as either outpatient clinic visits or in-home visits by 
qualified study personnel. A final safety follow-up outpatient clinic visit will occur 30 days after 
the last dose of study drug.  
To reduce subject burden, the final safety follow-up visit in Study SPR001-201 for subjects 
completing that study and rolling over into this study may coincide with the screening visit of 
this study (with any overlapping assessments conducted only once). Subjects who completed 
the final follow-up visit in Study SPR001-201 >3 months before screening in this study and 
subjects naïve to SPR001 must complete anew all specified screening assessments for this 
study. Subjects will maintain a stable dose and regimen of glucocorticoids throughout this 
study. 
4.2 Scientific Rationale for Study Design 
In the ongoing Phase 2 Study SPR001-201, subjects with CAH are treated for 2 weeks with any 
particular dose level of study drug. Given that patients with CAH may require long-term 
treatment with SPR001 to maintain antagonism of CRF1 receptors in the face of 21-hydroxylase 
deficiency, a longer-term study of the safety and efficacy of SPR001 is required. This study 
extends the duration of SPR001 treatment to 12 continuous weeks at a constant dose. The 
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treatment period of 12 weeks was chosen based on the 3-month duration of the definitive 
toxicology studies in rats and dogs. 
Individuals may qualify for this study as either SPR001-experienced or SPR001-naïve subjects. 
Individuals who previously received study drug by completing Study SPR001-201 may qualify for 
this study to receive an extended 12 weeks of study drug. SPR001-naïve individuals may also 
qualify directly for this study and will provide a bigger sample size for safety data. The Sponsor 
may decide to restrict later enrollment of SPR001-naïve individuals to those who exhibit certain 
clinically significant sequelae of hyperandrogenism due to CAH – TARTs in the case of male CAH 
patients and significant acne, hirsutism, and/or ovulatory dysfunction in the case of female CAH 
patients. This enriched population may enable better evaluation of exploratory efficacy 
endpoints to inform future studies of SPR001. 
All SPR001-experienced subjects will undergo a washout period before starting study drug in 
this study. This washout period will include, at a minimum, the 30-day safety follow-up period 
in Study SPR001-201 and the 12-week screening period in this study. Thus, SPR001-experienced 
subjects will generally undergo a washout period of at least approximately 4 months between 
their last dose of study drug in Study SPR001-201 and their first dose of study drug in this study. 
Furthermore, all subjects coming from Cohort A of Study SPR001-201 will have undergone a 
washout period of >5 months, given the interval between the completion of Cohort A in early 
2018 and the anticipated start date of this study. Based on preliminary population PK analysis 
of data from Study SPR001-201 Cohort A, a washout period of 32 to 44 days (approximately 5 to 
7 times the terminal phase for SPR001) would allow for essentially complete elimination of 
SPR001. 
The schedule of study visits every 2 weeks during the treatment period and the option for some 
study visits to be in-home visits provides an appropriate balance between closely monitoring 
subject safety / response to therapy and minimizing subject burden. The 30-day post-treatment 
washout period in this study allows for adequate safety follow-up and analysis of any HPA axis 
rebound after the last dose of study drug. 
Subjects will take study drug with a meal or after consumption of a standardized snack in order 
to improve absorption of study drug, since the Phase 1 clinical studies showed minimal study 
drug absorption when subjects were dosed in a fasted state. Specific dose reduction criteria, 
strict individual treatment stopping criteria, and appropriate laboratory and medical 
assessments have been established to ensure subject safety. 
4.3 Justification for Dose 
Study drug will initially be administered in this study at 400 mg QD. Preliminary clinical data 
support the safety and potential PD effects of this dose. 
A dose of up to 200 mg QD (for 14 days) was clinically assessed in the repeat-dose Phase 1 
Study I3C-FW-BLAB in healthy subjects and was well tolerated in that study. 
In the ongoing Phase 2 Study SPR001-201 in subjects with CAH, Cohort A has been completed. 
Dosing for each subject in Cohort A was to start at 200 mg QD (for 14 days) and to escalate to 
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600 mg QD (for 14 days), then 1000 mg QD (for 14 days). Preliminary data from Cohort A show 
evidence of CRF1 receptor target engagement (reductions in ACTH) and reductions in key 
adrenal hormones (17-OHP and androstenedione) at all dose levels tested. Preliminary safety 
data from Cohort A show SPR001 to be generally well tolerated through 600 mg QD and 
4 weeks of dosing, with no SAEs, AEs leading to discontinuation, DLTs, or AESIs and no 
meaningful changes across clinical laboratory, ECGs, BDI-II and C-SSRS, or physical examination 
findings. At 1000 mg QD and 6 weeks of dosing, transient elevations in ALT (without any 
elevations in bilirubin) were observed in 2 subjects (see Section 2.3.1). Thus, a dose of 400 mg 
QD is initially planned in this study because this dose lies within the dose range of clinical 
precedence that has both produced responses in key hormones and been safe and well 
tolerated. 
For subjects who enroll later on in this study, the dose strength may be increased or decreased 
(by no more than 2-fold) and/or the dose regimen may be adjusted based on ongoing review of 
the available safety, PK, and PD data from Study SPR001-201 Cohorts B/C/D and from this study 
by an SRC. For example, the dose regimen may be adjusted to BID dosing, a regimen being 
tested in Study SPR001-201 that may lower Cmax levels, reduce peak-to-trough fluctuation, and 
improve diurnal control of elevated hormones in subjects with CAH relative to once-daily 
dosing. 
4.4 End of Study Definition 
A subject is considered to have completed the study if the subject has completed all 12 weeks 
of treatment. The end of the study is defined as the date of the last follow-up visit of the last 
subject in the study. 
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5 STUDY POPULATION 
This study will enroll up to approximately 24 eligible subjects with classic CAH who either 
previously completed Study SPR001-201 (see Section 5.1) or meet eligibility criteria for 
SPR001-naïve subjects (see Section 5.2). The study will be conducted at approximately 
8 investigative sites in the United States.  
All applicable screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria. The Investigator will maintain a screening log to record 
details of all individuals screened and to confirm eligibility or record reasons for screening 
failure, as applicable. 
5.1 Eligibility Criteria for Subjects Who Completed Study SPR001-201 
5.1.1 
Inclusion Criteria for Subjects Who Completed Study SPR001-201 
Subjects who completed Study SPR001-201 must meet all of the following criteria to be eligible 
for this study: 
1. Is approved by the Sponsor’s Medical Monitor 
2. Is on a stable regimen of glucocorticoid replacement for ≥12 weeks before baseline that is 
expected to remain stable throughout the study 
3. If screening for this study occurs >3 months after the subject’s final follow-up visit in 
Study SPR001-201, the subject will have serum 17-OHP measured at screening. On the day 
of screening, the subject should take any morning glucocorticoid medication after the 
screening blood draw to allow for an unimpeded assessment of 17-OHP. The subject will be 
included if screening shows 17-OHP ≥800 ng/dL. 
4. Agrees to follow contraception guidelines (Section 5.3.5). Male subjects must also agree to 
refrain from donating sperm throughout the treatment period and for 90 days after the last 
dose of study drug. 
5. Is able to understand all study procedures and risks involved and provides written informed 
consent indicating willingness to comply with all aspects of the protocol 
5.1.2 
Exclusion Criteria for Subjects Who Completed Study SPR001-201 
Subjects who completed Study SPR001-201 will not be eligible for this study if they meet any of 
the following criteria: 
1. Experienced a clinically significant AE (defined in Section 7.2.7) considered at least possibly 
related to SPR001 in Study SPR001-201 
2. If screening for this study occurs >3 months after the subject’s final follow-up visit in Study 
SPR001-201, the subject will be screened for any clinically significant unstable medical 
condition, medically significant illness, or chronic disease occurring within 30 days of 
screening, including but not limited to the following: 
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a. A malignancy or <3 years of remission history from any malignancy, other than 
successfully treated localized skin cancer 
b. Presence of clinically significant renal disease, as evidenced by an eGFR of 
<60 mL/min/1.73 m2 
c. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert’s syndrome or asymptomatic gallstones) 
d. Confirmed positive test at screening for active hepatitis B, hepatitis C, or HIV 
3. If screening for this study occurs >3 months after the subject’s final follow-up visit in Study 
SPR001-201, the subject will be screened for clinically significant psychiatric disorders by 
history and from the M.I.N.I. conducted at screening. The subject will be excluded if 
screening reveals evidence of current major depressive episode, bipolar disorder, 
schizophrenia, schizoaffective disorder, major depressive disorder with psychotic features, 
or any other psychotic disorder within the preceding 6 months. 
4. Is at increased risk of suicide on the basis of the Investigator’s judgment or the results of the 
C-SSRS conducted at screening and baseline (e.g., C-SSRS Type 3, 4, or 5 ideation during the 
preceding 6 months or any suicidal behavior within the past 12 months) 
5. Has a HADS score >12 for either depression or anxiety at screening or baseline 
6. Clinically significant abnormal clinical or laboratory assessments must be discussed with the 
Medical Monitor to determine eligibility for this study. Abnormal assessments that must be 
reviewed to determine eligibility include but are not limited to: 
a. Clinically meaningful abnormal ECG results, in the opinion of the Investigator 
b. QTcF >450 msec for male participants or >470 msec for female participants 
c. ALT >2x ULN 
d. Bilirubin >1.5x ULN (isolated bilirubin >1.5x ULN is acceptable if bilirubin is fractionated 
and direct bilirubin is <35%) 
7. Subjects who routinely work overnight shifts require Medical Monitor approval for 
enrollment 
8. Females who are pregnant or lactating 
9. Use of any other investigational drug within 30 days or 5 half-lives (whichever is longer) 
before screening 
10. Use of prohibited concomitant medications (see Section 6.5.2.1), including rosiglitazone, 
testosterone, and strong inhibitors and/or inducers of CYP3A4 (with the exception of 
glucocorticoids and birth control), within 30 days or 5 half-lives (whichever is longer) of 
baseline. Medications metabolized by CYP3A4, 2C8, 2C9, or 2C19, especially those that are 
sensitive substrates or substrates with narrow therapeutic ranges (see Section 6.5.2.2), 
should be discussed on a case-by-case basis with the Medical Monitor to determine 
whether the medication should be discontinued or may be continued with caution. If 
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washout is feasible, then the medication should be withdrawn at least 30 days or 5 
half-lives (whichever is longer) before baseline. 
11. Donation of blood within 60 days before baseline or donation of platelets, white blood cells, 
or plasma within 15 days before baseline 
5.2 Eligibility Criteria for SPR001-Naïve Subjects 
This study will offer enrollment to SPR001-naïve subjects with eligibility criteria similar to those 
of Study SPR001-201 but will also seek to include an enriched population of subjects with CAH 
who exhibit clinically significant sequelae of androgen excess, specifically males 18 to 35 years 
old with TARTs and adult females with clinically significant acne, hirsutism, and/or ovulatory 
dysfunction. This study will initially allow enrollment of at least 3 subjects who meet general 
eligibility criteria for all SPR001-naïve subjects (inclusion criteria in Section 5.2.1 and exclusion 
criteria in Section 5.2.3) and who may or may not meet additional inclusion criteria for an 
enriched population of SPR001-naïve subjects. At any time thereafter, the Sponsor may decide 
to require all SPR001-naïve subjects who enroll subsequently to satisfy the additional inclusion 
criteria for an enriched population of SPR001-naïve subjects (Section 5.2.2). In particular, the 
study will attempt to enroll an enriched subpopulation of up to approximately 8 male subjects 
18 to 35 years old with TARTs, subject to the limitations of enrollment feasibility for this 
subpopulation and with consideration for the total number of accrued subjects in the study. 
5.2.1 
General Inclusion Criteria for All SPR001-Naïve Subjects 
All SPR001-naïve subjects must meet all of the following criteria to be eligible for this study: 
1. Male and female subjects ≥18 years old 
2. Has a documented historical diagnosis of classic CAH due to 21-hydroxylase deficiency 
based on documented genetic mutation or elevated 17-OHP 
3. Known or suspected differential diagnosis of any of the other known forms of CAH, 
including non-classic CAH, requires Medical Monitor approval for enrollment 
4. Has serum 17-OHP ≥800 ng/dL at screening. On the day of screening, the subject should 
take any morning glucocorticoid medication after the screening blood draw to allow for an 
unimpeded assessment of 17-OHP. 
5. Is on a stable regimen of glucocorticoid replacement for ≥12 weeks before baseline that is 
expected to remain stable throughout the study 
6. Agrees to follow contraception guidelines (Section 5.3.5). Male subjects must also agree to 
refrain from donating sperm throughout the treatment period and for 90 days after the last 
dose of study drug. 
7. Is able to understand all study procedures and risks involved and provides written informed 
consent indicating willingness to comply with all aspects of the protocol 
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5.2.2 
Additional Inclusion Criteria for Enriched Population of SPR001-Naïve Subjects 
After an initial enrollment of at least 3 SPR001-naïve subjects who must fulfill only the inclusion 
criteria in Section 5.2.1, the Sponsor may decide to require all SPR001-naïve subjects who enroll 
subsequently to satisfy all of the following additional inclusion criteria for an enriched 
population of SPR001-naïve subjects: 
1. If male, must be 18 to 35 years old, inclusive. 
2. If male, must have a diagnosis of TART(s) confirmed via scrotal ultrasound at screening with 
at least 1 lesion having a diameter ≥4 mm 
3. If female, must have at least one of the following clinically significant sequelae of androgen 
excess: 
a. Clinically significant acne defined as an IGA score ≥2 at screening 
b. Clinically significant hirsutism defined as an mFG score ≥6 at screening 
c. Verifiable history (based on medical records or ability to obtain an accurate history 
from the individual) of ovulatory dysfunction defined as having at least 1 year of 
menstrual cycles that last ≥45 days or having ≤8 menstrual periods within the past 
year, if the subject is not on a hormonal contraceptive 
5.2.3 
Exclusion Criteria for All SPR001-Naïve Subjects 
SPR001-naïve subjects will not be eligible for this study if they meet any of the following 
criteria: 
1. Has had a clinically significant unstable medical condition, medically significant illness, or 
chronic disease within 30 days of screening, including but not limited to: 
a. A malignancy or <3 years of remission history from any malignancy, other than 
successfully treated localized skin cancer 
b. Presence of clinically significant renal disease, as evidenced by an eGFR of 
<60 mL/min/1.73 m2 
c. Current or chronic history of liver disease or known hepatic or biliary abnormalities 
(with the exception of Gilbert’s syndrome or asymptomatic gallstones) 
d. Confirmed positive test at screening for active hepatitis B, hepatitis C, or HIV 
2. Had or has a clinically significant psychiatric disorder either by history or from the M.I.N.I. 
conducted at screening. The subject will be excluded if screening reveals evidence of 
current major depressive episode, bipolar disorder, schizophrenia, schizoaffective disorder, 
major depressive disorder with psychotic features, or any other psychotic disorder within 
the preceding 6 months. 
3. Is at increased risk of suicide on the basis of the Investigator’s judgment or the results of the 
C-SSRS conducted at screening and baseline (e.g., C-SSRS Type 3, 4, or 5 ideation during the 
preceding 6 months or any suicidal behavior within the past 12 months) 
4. Has a HADS score >12 for either depression or anxiety at screening or baseline 
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5. Clinically significant abnormal clinical or laboratory assessments must be discussed with the 
Medical Monitor to determine eligibility for this study. Abnormal assessments that must be 
reviewed to determine eligibility include but are not limited to: 
a. Clinically meaningful abnormal ECG results, in the opinion of the Investigator 
b. QTcF >450 msec for male participants or >470 msec for female participants 
c. ALT >2x ULN 
d. Bilirubin >1.5x ULN (isolated bilirubin >1.5x ULN is acceptable if bilirubin is fractionated 
and direct bilirubin is <35%) 
6. Has a history that includes bilateral adrenalectomy or hypopituitarism 
7. Subjects who routinely work overnight shifts require Medical Monitor approval for 
enrollment 
8. Females who are pregnant or nursing 
9. Use of any other investigational drug within 30 days or 5 half-lives (whichever is longer) 
before screening 
10. Use of prohibited concomitant medications (see Section 6.5.2.1), including rosiglitazone, 
testosterone, and strong inhibitors and/or inducers of CYP3A4 (with the exception of 
glucocorticoids and birth control) within 30 days or 5 half-lives (whichever is longer) of 
baseline. Medications metabolized by CYP3A4, 2C8, 2C9, or 2C19, especially those that are 
sensitive substrates or substrates with narrow therapeutic ranges (see Section 6.5.2.2), 
should be discussed on a case-by-case basis with the Medical Monitor to determine 
whether the medication should be discontinued or may be continued with caution. If 
washout is feasible, then the medication should be withdrawn at least 30 days or 5 
half-lives (whichever is longer) before baseline. 
11. Donation of blood within 60 days before baseline or donation of platelets, white blood cells, 
or plasma within 15 days before baseline 
5.3 Lifestyle Considerations 
5.3.1 
Shift Work 
Given the daily dosing of SPR001 at 10pm during the treatment period and the blood draws for 
laboratory assessments at 8am on study visit days, subjects who routinely work overnight shifts 
require Medical Monitor approval before enrollment. 
5.3.2 
Meals and Dietary Restrictions 
Study drug must be consumed with a meal or 5 to 15 minutes after a standardized snack. 
Standardized snacks will be provided for all dosing days. A list of acceptable alternative food 
combinations will also be provided. 
Subjects will be advised to refrain from consumption of grapefruit or grapefruit juice from 1 day 
before the first dose of study drug in this study until after the final dose. 
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5.3.3 
Caffeine, Alcohol, and Tobacco 
For study visits with 8am blood draws, subjects should abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks, or chocolate) from 5 hours before 
the blood draw (3am) until after the blood draw. Subjects will abstain from alcohol from 
12 hours before the blood draw (8pm) until after the blood draw. 
Subjects who use tobacco products should be informed that nicotine-containing products are 
not permitted while they are at the investigational site. 
5.3.4 
Activity 
Subjects should abstain from strenuous exercise for 8 hours before each study visit. 
5.3.5 
Contraception Guidelines 
5.3.5.1 Contraception Guidelines for Male Subjects 
A male enrolling in this study who has a female partner of childbearing potential, including 
those who are breastfeeding, must meet ONE of the following contraceptive criteria: 
1. Is sexually abstinent from penile-vaginal intercourse as his usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agrees to remain abstinent 
throughout the duration of the study 
2. Is vasectomized and the absence of sperm has been confirmed 
3. Agrees to use a male condom plus partner use of one of the following highly effective 
contraceptive methods for the duration of the study: 
a. Combined hormonal contraception (containing estrogen and progestogen): oral, 
intravaginal, or transdermal 
b. Progestogen-only hormonal contraception: oral, injectable, or implantable 
intrauterine device (IUD) or intrauterine system (IUS) 
c. Bilateral tubal occlusion 
5.3.5.2 Contraceptive Guidelines for Female Subjects 
A female enrolling in this study must meet ONE of the following contraceptive criteria: 
1. Is postmenopausal 
A postmenopausal state is defined as no menses for at least 1 year without an alternative 
medical cause. A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy. However, a single FSH measurement is insufficient to establish a 
postmenopausal state without at least 1 year of amenorrhea. 
2. Is premenopausal but has documentation of one of the following: 
a. Hysterectomy 
b. Bilateral salpingectomy 
c. Bilateral oophorectomy 
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3. Has only 1 male sexual partner, that partner is vasectomized, and the absence of sperm 
has been confirmed 
4. Is sexually abstinent from penile-vaginal intercourse as her usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agrees to remain abstinent 
throughout the duration of the study 
5. Agrees to use one of the following highly effective contraceptive methods for the 
duration of the study: 
a. Combined hormonal contraception (containing estrogen and progestogen): oral, 
intravaginal, or transdermal 
b. Progestogen-only hormonal contraception: oral, injectable, or implantable IUD or IUS 
c. Bilateral tubal occlusion 
5.4 Screen Failures 
Screen failures are defined as participants who consent to participate but are not subsequently 
enrolled in the study. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, and eligibility 
criteria. 
Individuals who do not meet the following criteria for participation in the study may be 
rescreened according to the following guidelines after consultation with the Sponsor’s Medical 
Monitor: 
• Individuals who do not meet the screening 17-OHP inclusion criterion may be rescreened 
after 30 days if their glucocorticoid replacement dose is reduced for clinical reasons. Any 
morning dose of glucocorticoid medication should be taken after the screening blood 
draw to allow for an unimpeded assessment of 17-OHP. 
• Individuals on incompatible or excluded concomitant medications may be rescreened 
after an appropriate washout period (e.g., 30 days or 5 half-lives, whichever is longer). 
 
 
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6 STUDY INTERVENTION 
6.1 Study Intervention Administration 
6.1.1 
Study Intervention Description 
SPR001 is a small-molecule CRF1 receptor antagonist.  
Details about the physical, chemical, and pharmaceutical properties of SPR001 are provided in 
the IB. 
6.1.2 
Dosing and Administration 
Initial subjects who enroll in this study will be treated with oral study drug at 400 mg QD at 
10pm for 12 weeks. This dose is within the range of doses that were well tolerated and reduced 
key hormones (ACTH, 17-OHP, and androstenedione) in subjects with CAH in Cohort A of Study 
SPR001-201. For subjects who enroll later on in this study, the dose strength may be increased 
or decreased (by no more than 2-fold) and/or the dose regimen may be adjusted (e.g., to BID 
dosing, a regimen being tested in Study SPR001-201). In general, subjects are expected to 
complete the study at the dose strength and on the dose regimen at which they started the 
study, unless they experience a clinically significant AE that would warrant a dose reduction. An 
SRC will review the available safety, PK, and PD data from Study SPR001-201 Cohorts B/C/D and 
from this study on an ongoing basis and provide recommendations to the Sponsor, who will 
ultimately decide on any dosing adjustments in this study. 
Only authorized site staff may dispense study drug. Sites will provide subjects with dosing 
instructions. Subjects being treated with study drug at 400 mg QD will be instructed to take 
2 capsules daily at 10pm. If dosing is adjusted to a BID regimen, subjects will be instructed on 
when to take study drug in the morning and in the evening. If a subject goes to bed earlier than 
10pm, the subject will take the 10pm dose of study drug at bedtime. Study drug will be taken 
with a meal or 5 to 15 minutes after consumption of a standardized snack. If a morning dose of 
study drug is added and a subject wishes to take his/her morning dose of study drug with 
breakfast, the Investigator should discuss the specific dosing situation with the Sponsor’s 
Medical Monitor. If a morning dose of study drug is added, subjects should hold off on taking 
their morning dose of study drug on the mornings of all applicable study visits until after 
laboratory assessments have been completed. On all other days during the treatment period, 
subjects should take their morning dose of study drug at their usual time. 
Instructions for concomitant glucocorticoid medication dosing are provided in Section 6.5.1. 
Instructions for study drug dose reduction are provided in Section 7.1. Criteria for study drug 
discontinuation are provided in Section 7.2. 
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6.2 Preparation/Handling/Storage/Accountability 
6.2.1 
Acquisition and Accountability 
The Investigator is responsible for study drug receipt and accountability, reconciliation, and 
record maintenance. 
6.2.2 
Formulation, Appearance, Packaging, and Labeling 
The drug product SPR001 is formulated as a white, hard-gelatin capsule containing either 50 mg 
or 200 mg of the drug substance SPN001 in powder form with no excipients. 
Study drug capsules containing 50 mg SPN001 are size 4 and will be packaged with 32 capsules 
per bottle in a 30-mL high-density polyethylene (HDPE) bottle with a 28-mm child-resistant cap 
and an induction foil seal. 
Study drug capsules containing 200 mg SPN001 are size 1 and will be packaged with either 
14 capsules per bottle (in a 30-mL HDPE bottle with a 28-mm child-resistant cap and an 
induction foil seal) or with 60 capsules per bottle (in a 75-mL HDPE bottle with a 33-mm 
child-resistant cap and an induction foil seal). 
Each bottle will be labeled in English with the protocol number, recommended storage 
conditions, name and address of the Sponsor, an Investigational Use Statement (“Caution: New 
Drug – Limited by Federal [USA] Law to Investigational Use”), and the instruction that the agent 
should be kept out of reach of children. Labeling will comply with all legal requirements and 
supply no information about individual subjects.  
6.2.3 
Product Storage and Stability 
Study drug capsules are stable when stored at room temperature (20 °C to 25 °C) but should be 
protected from light. Study drug must be stored in a secure, environmentally controlled area 
that is monitored (manually or automatically) and accessible only to the Investigator and 
authorized site staff. 
6.3 Treatment Assignment 
Initial subjects who enroll in this study will be treated with study drug at 400 mg QD. This dose 
strength and/or dose regimen may be adjusted for subjects who enroll later on in this study 
based on ongoing review of the available safety, PK, and PD data from Study SPR001-201 
Cohorts B/C/D and from this study by an SRC. 
6.4 Study Intervention Compliance 
Subject compliance will be assessed by maintaining adequate study drug dispensing records. 
Subjects will return bottles of study drug at each visit for a pill count. The Investigator is 
responsible for ensuring that dosing is administered in compliance with the protocol. 
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6.5 Concomitant Therapy 
Concomitant medication is any medication (including over-the-counter [OTC] medication, 
prescription medication, vaccines, vitamins, and supplements) that the subject is receiving at 
screening or receives during the study. Concomitant medications must be recorded, along with: 
• Reason for use 
• Dates of administration, including start and end dates 
• Dosage information, including dose and frequency 
All concomitant medications should be compared against the list of prohibited medications and 
the list of other medications of concern provided in Section 12.1. Subjects should be instructed 
to contact the site immediately any time a new medication is required during the course of the 
study, including prescription and OTC medications, even those to be used for only a short 
period of time (e.g., antibiotics, cold and flu remedies, gastrointestinal therapies, opioids or 
other pain relievers). The Medical Monitor should be contacted if there are any questions 
regarding concomitant or prior therapy. 
6.5.1 
Glucocorticoid Replacement Therapy 
Subjects must be on a stable regimen of glucocorticoid replacement therapy for ≥12 weeks 
before baseline to be eligible for this study. Changes in glucocorticoid dosing during the study 
are discouraged, and any changes will be recorded. 
On the mornings of all study visits, including screening, subjects should hold off on taking any 
morning dose of glucocorticoid medication until after laboratory assessments are completed. 
On all other days during the study, subjects may take any morning glucocorticoid medication at 
their usual time. 
6.5.2 
Prohibited Concomitant Medications and Concomitant Medications of Concern 
Section 12.1 outlines medications that are either prohibited or must be used with caution 
because of their potential for metabolic interactions with SPR001. In all cases, if there is a 
question or concern about a specific medication being used by the subject, it is appropriate to 
review the usage with the Medical Monitor before enrolling the subject in the study. If a 
medication is to be washed out, it should be stopped at least 30 days or 5 half-lives, whichever 
is longer, before the first dose of SPR001 in this study and cannot be resumed until after the 
safety follow-up visit. In many cases, washout will necessitate rescreening. If a prohibited 
medication such as an antibiotic or antifungal agent is required during a subject’s study 
participation, the Medical Monitor should be consulted to discuss appropriate actions, such as 
the temporary withholding of SPR001 until treatment with the prohibited agent is completed. 
6.5.2.1 Prohibited Concomitant Medications 
Other investigational drugs are prohibited during the study. 
Rosiglitazone treatment is prohibited during the study because it could affect the subject’s 
ACTH levels. Treatment with testosterone is also prohibited. In general, subjects who require 
ongoing treatment with rosiglitazone or testosterone should not be screened. 
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In vitro cytochrome P450 (CYP) reaction phenotyping has indicated that SPN001 is metabolized 
by CYP3A4. Therefore, drugs that are known strong inducers or inhibitors of CYP3A4 are 
generally prohibited during the study and require a washout period before screening. Stable 
daily doses of glucocorticoids and birth control are not restricted. 
Specifically prohibited concomitant medications are listed in Section 12.1.1. 
6.5.2.2 Concomitant Medications of Concern 
In vitro metabolism studies have indicated that SPN001 has the potential to inhibit CYP3A4, 
2C8, 2C9, and 2C19. Therefore, drugs metabolized by CYP3A4, 2C8, 2C9, and/or 2C19 should be 
avoided or used with caution, especially drugs that are sensitive substrates of these enzymes or 
that have narrow therapeutic ranges. Sensitive CYP substrates are drugs whose plasma area 
under the curve (AUC) has been shown to increase ≥5-fold when co-administered with a known 
CYP inhibitor and drugs for which the AUC in poor metabolizers is >5-fold the AUC in extensive 
metabolizers. Drugs with narrow therapeutic ranges are those for which even small increases in 
a subject’s exposure to these drugs (potentially induced by the concomitant use of the CYP 
inhibitor SPR001) could lead to serious safety concerns (e.g., torsades de pointes). 
Whenever feasible, subjects will discontinue use of a medication of concern and undergo a 
washout period before screening. However, if washout is not feasible, the Investigator should 
consult with the Medical Monitor to decide on the best course of action. If a medication of 
concern is to be continued, it must be used with caution and the subject must be carefully 
followed. 
Specific concomitant medications of concern are listed in Section 12.1.2. 
It is important to note that many commonly used medications are listed as drugs of concern, 
including certain statins (lovastatin, simvastatin), anti-inflammatory agents (celecoxib, 
felodipine), migraine remedies (ergotamine, dihydroergotamine, eletriptan), anxiolytics 
(buspirone, clobazam, midazolam), and drugs for erectile dysfunction (avanafil, sildenafil, 
vardenafil). Subjects must be willing to refrain from the use of these erectile dysfunction drugs 
during the study. It is critical that each subject’s concomitant medications are carefully 
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7 DOSE REDUCTION, STUDY DRUG DISCONTINUATION, AND PARTICIPANT 
WITHDRAWAL 
7.1 Dose-Limiting Toxicity and Dose Reduction  
A DLT is defined as a Grade 3 or higher TEAE considered at least possibly related to study drug. 
If a subject experiences a DLT, the Investigator may reduce the subject’s daily dose of SPR001 
(by 50 to 200 mg), depending on the TEAE, in order to keep the subject on study. A Grade 3 or 
higher TEAE considered related to study drug will also be considered an AESI (see Section 8.2.8). 
Potential dose reductions must be discussed with the Medical Monitor. At any time during the 
study, subjects who experience any clinically significant signs of acute adrenal insufficiency 
(e.g., postural hypotension, nausea, abdominal pain) may have their study drug dose reduced 
or withheld and/or their glucocorticoid replacement therapy modified (see Section 7.2.4). 
7.2 Study Drug Discontinuation 
Subjects may voluntarily discontinue study drug or the Investigator may discontinue a subject’s 
study drug at any time. Investigators should discuss any safety concerns with the Medical 
Monitor as soon as possible to determine whether a subject should continue or discontinue 
study drug. Study drug will be discontinued in subjects who experience clinically significant liver 
chemistry, QTcF, or other individual treatment stopping criteria described in this section. 
Subjects may discontinue study drug but remain in the study for follow-up. 
If study drug is discontinued, the Investigator will report the discontinuation to the Medical 
Monitor, document the date and reason for study drug discontinuation on the appropriate 
electronic case report form (eCRF), schedule an early termination visit for the subject (see the 
Schedule of Activities in Section 1.3), provide or arrange for appropriate follow-up, and 
document the course of the subject’s condition. 
Subjects who prematurely discontinue study drug may be replaced at the discretion of the 
Sponsor to ensure adequate numbers of evaluable subjects. 
7.2.1 
Liver Chemistry Stopping Criteria 
Liver chemistry stopping criteria schematized in Figure 1 are designed to ensure subject safety 
and to evaluate liver event etiology. Suggested actions and follow-up assessments are provided 
in Section 12.2. A significant change in liver chemistry that does not satisfy stopping criteria 
may still be considered an AESI (see Section 8.2.8). 
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Figure 1. Liver Chemistry Stopping Criteria and Increased Monitoring Algorithm 
 
7.2.2 
QT Stopping Criteria 
Study drug will be discontinued for a subject if either of the following criteria is met: 
• QTcF >500 msec OR uncorrected QT >600 msec 
• Change from screening or baseline in QTcF of >60 msec 
One repeat ECG should be performed to confirm the accuracy and persistence of an initial 
result that fulfills the QT stopping criteria. 
7.2.3 
Suicidality Stopping Criteria 
SPR001 is considered to be a central nervous system (CNS)–active study drug. Some CNS-active 
drugs may be associated with an increased risk of suicidal ideation in certain populations. 
Although SPR001 has not been shown to be associated with an increased risk of suicidal 
thinking or behavior when given to healthy volunteers, subjects will be monitored for such 
events during this study using the C-SSRS (see Section 8.1.6.1). 
Individuals who provide a positive answer to question 3, 4, or 5 of the C-SSRS (on suicidal 
ideation) at screening or baseline are not eligible for this study. The Investigator should 
immediately contact the Medical Monitor to discuss possible study drug discontinuation and 
appropriate safety follow-up for a subject who provides a positive answer to question 3, 4, or 5 
of the C-SSRS at any visit after baseline. This will also be considered an AESI (see Section 8.2.8). 
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The subject’s HADS score should also be evaluated in conjunction with the C-SSRS (see 
depression stopping criteria in Section 7.2.5). 
7.2.4 
Adrenal Insufficiency Stopping Criteria 
If a subject dosed with study drug exhibits clinically significant signs of acute adrenal 
insufficiency, such as postural hypotension, nausea, and abdominal pain, the Investigator 
should consider withholding the subject’s dose(s) of SPR001, initiate appropriate corticosteroid 
therapy, and contact the Medical Monitor. If there is no clear explanation for the subject’s 
acute adrenal insufficiency, such as inadequate corticosteroid replacement dosing or low 
circulating levels of plasma cortisol, the Investigator should review the subject with the Medical 
Monitor for possible study drug discontinuation. 
7.2.5 
Depression Stopping Criteria 
Individuals who score >12 on either the depression or anxiety subscale of the HADS (see 
Section 8.1.6.2) at screening or baseline are generally not eligible for this study. The 
Investigator should immediately contact the Medical Monitor to discuss possible study drug 
discontinuation and appropriate safety follow-up for a subject who scores >12 on either the 
depression or anxiety subscale of the HADS at any visit after baseline. This will also be 
considered an AESI (see Section 8.2.8). Reasons for an elevated HADS score (aside from clinical 
depression) include chronic pain and stress. 
7.2.6 
Reproductive Hormone Stopping Criteria 
Subjects with CAH can be expected to have abnormal reproductive hormone levels because 
deficient 21-hydroxylase enzyme activity leads 1) to elevated levels of cortisol precursors that 
are shunted into reproductive hormone biosynthetic pathways and 2) to low levels of the 
cortisol that normally provides negative feedback on the HPA axis. Standard-of-care therapy 
with glucocorticoid and mineralocorticoid replacement typically does not fully normalize 
adrenal steroid production pathways and signaling systems, including ACTH and CRF levels. 
Thus, subjects with CAH can be expected to have abnormal plasma concentrations of various 
androgens and progestogens at baseline. Therapy with an effective CRF receptor antagonist 
may in fact shift the balance between various intermediates in the steroid biosynthetic 
pathway.   
If a subject experiences changes from baseline in reproductive hormone(s), the Investigator 
should contact the Medical Monitor to discuss whether such changes represent clinically 
significant reproductive abnormalities, potential risks to the subject, possible study drug 
discontinuation, and appropriate safety follow-up. These changes include but are not limited to 
significant changes in LH, FSH, inhibin B, SHBG, estradiol, prolactin, or progesterone; testicular 
dysfunction in men; and changes in menstrual cyclicity in women. 
7.2.7 
Potentially Clinically Significant Adverse Events 
Clinically significant AEs include but are not limited to SAEs (Section 8.2.2), AEs leading to study 
drug discontinuation/study withdrawal, DLTs (Section 7.1), and AESIs (Section 8.2.8) that are 
each considered at least possibly related to study drug. The occurrence of any clinically 
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significant AE will receive special consideration in decisions regarding continuation or 
suspension of dosing or enrollment and will be reported to the SRC within 1 day of awareness 
for immediate review. 
Section 12.3 also provides a list of signs and symptoms (Section 12.3.1) and a list of laboratory 
findings (Section 12.3.2) that constitute potentially clinically significant AEs not otherwise 
specified among the foregoing individual treatment stopping criteria. These provide guidelines 
for a level of moderate-severe abnormality in safety findings that could cause harm to subject 
health and may preclude further study drug dosing. These lists are intended to guide the 
Investigator and are not meant to be a set of absolute criteria. Safety parameters not included 
in the list may be interpreted in a similar fashion according to Investigator judgment. Common 
Terminology Criteria for Adverse Events (CTCAE) severity grading should also be referenced 
(Section 8.2.3.1). 
7.3 Participant Withdrawal from the Study 
Subjects may voluntarily withdraw from the study or be withdrawn by the Investigator at any 
time. If a subject withdraws from the study, the Investigator must document the date and 
primary reason for the withdrawal on the appropriate eCRF. 
Reasons for a subject to discontinue study drug or to withdraw from this clinical study include 
but are not limited to the following:  
• Withdrawal of informed consent 
• Fulfilling individual treatment stopping criteria (see Section 7.2). 
• AE(s) 
• Protocol deviation or noncompliance with study procedures/restrictions 
• Desire or need to start a contraindicated therapy or another therapy for CAH 
• Study termination by the Sponsor 
• Lost to follow-up  
7.4 Lost to Follow-up 
A subject will be considered lost to follow-up if the subject repeatedly fails to attend scheduled 
visits and study personnel are unable to contact the subject. 
The following actions must be taken if a subject fails to attend a required study visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible, counsel the subject on the importance of maintaining the assigned visit 
schedule, and ascertain whether the subject wishes to and/or should continue in the 
study. 
• Before a subject is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the subject, including, where possible, making 
3 telephone calls to the subject and, if necessary, sending a certified letter to the 
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subject’s last known mailing address (or local equivalent methods). Attempts to contact 
the subject should be documented in the subject’s medical record. 
• If the subject continues to be unreachable, the subject will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
 
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8 STUDY ASSESSMENTS AND PROCEDURES 
This section describes what study assessments and procedures will be performed and how they 
will be conducted. The timing of study assessments and procedures is provided in the Schedule 
of Activities in Section 1.3.  
8.1 Safety Assessments 
Safety assessments will consist of monitoring and recording all AEs (including SAEs, AEs leading 
to discontinuation/withdrawal, DLTs, and AESIs), physical examination, vital signs assessment, 
ECGs, clinical laboratory, and monitoring for suicide risk and depression/anxiety. AE procedures 
are described in Section 8.2. 
8.1.1 
Physical Examination 
A full physical examination should include assessments of the cardiovascular, respiratory, 
gastrointestinal, neurological, and musculoskeletal systems; head, eyes, ears, neck, and throat 
(HEENT); thyroid, skin, and extremities. The full physical examination may exclude rectal, 
genitourinary, and breast exams. 
An abbreviated physical examination should include the following components: cardiovascular, 
respiratory, abdomen, musculoskeletal, HEENT, and skin. 
As part of both the full and abbreviated physical examinations, female subjects will be asked 
about the date, duration, and nature of their last menstrual period. 
As part of the examination of the skin where specified in the Schedule of Activities, acne will be 
evaluated in all subjects and hirsutism will be evaluated in female subjects. Acne severity will be 
graded using an Investigator’s Global Assessment (IGA) score per FDA guidance. Hirsutism will 
be graded using a modified Ferriman Gallwey (mFG) score (Yildiz et al, 2010; Martin et al, 2018). 
The mFG scores each of 9 body areas on a scale of 0 (no hair) to 4 (hairiness typical of a man), 
with the sum of the separate scores providing a hormonal hirsutism score. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
8.1.2 
Vital Signs 
Vital signs consist of systolic and diastolic blood pressure, pulse rate, respiration rate, and body 
temperature. Vital signs will be measured as specified in the Schedule of Activities and as 
clinically indicated. 
8.1.3 
Body Weight, Height, and BMI 
Body weight will be measured at every visit using a calibrated balance. The balance should be 
placed on a hard flat surface and checked for zero balance before each measurement. The 
subject should stand unassisted, in the center of the platform, and be asked to look straight 
ahead, standing relaxed but still.   
Height needs to be recorded at Visit 1 only. 
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BMI will be calculated for every visit using height and weight measurements. 
8.1.4 
Electrocardiogram 
A 12-lead ECG will be obtained using an ECG machine that automatically calculates the heart 
rate, QRS, QT, and QTc intervals, preferably using Fridericia’s formula. Any ECG measurement 
assessed by the Investigator as a clinically significant abnormality should be recorded in the AE 
section of the eCRF and monitored until resolution. 
Refer to Section 7.2.2 for QT individual treatment stopping criteria and any additional ECGs that 
may be necessary. 
8.1.5 
Clinical Laboratory 
A list of study-required clinical laboratory tests is provided in Section 12.4. A list of potentially 
clinically significant laboratory findings is provided in Section 12.3.2. 
All study-required clinical laboratory tests must be conducted in accordance with the laboratory 
manual and will be performed by a central laboratory. 
The Investigator must review the laboratory report, document the review, and record any 
clinically significant laboratory findings that occur during the study in the AE section of the 
eCRF. Laboratory reports must be filed with the source documents. Clinically significant 
laboratory findings are those that are not associated with the underlying disease, unless judged 
by the Investigator to be more severe than expected for the subject’s condition. 
All laboratory tests with values considered clinically significantly during the treatment period or 
within 30 days after the last dose of study drug should be repeated at least weekly until the 
values return to normal or baseline or are no longer considered clinically significant by the 
Investigator or Medical Monitor. If such values do not return to normal/baseline within a period 
of time judged reasonable by the Investigator, the etiology should be identified and the 
Sponsor notified. 
8.1.6 
Psychiatric Evaluations 
8.1.6.1 Columbia–Suicide Severity Rating Scale 
The C-SSRS will be used during the study to monitor suicidal ideation and behavior. The C-SSRS 
is a Food and Drug Administration (FDA)–endorsed questionnaire administered by trained study 
personnel to screen for suicidality in trials of CNS-active compounds. The Baseline/Screening 
Version of the C-SSRS, which assesses both lifetime history and history from the last 12 months, 
will be used at screening to determine subject eligibility. The Since Last Visit Version of the 
C-SSRS will be used at all subsequent visits specified. 
In addition, subjects should be observed closely, and families and caregivers of subjects should 
be instructed to monitor subjects for suicidal ideation and behavior or any other unusual 
changes in behavior. Any such symptoms should be reported immediately to the Investigator. 
Refer to Section 7.2.3 for suicidality individual treatment stopping criteria. 
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8.1.6.2 Hospital Anxiety and Depression Scale 
Subject anxiety and depression will be monitored during the study using the HADS. The HADS 
(Zigmond and Snaith, 1983) is a widely used and relatively simple subject-reported instrument 
that focuses on subjective disturbances of mood rather than physical signs. The scale consists of 
14 items, 7 items each for anxiety and depression. Each item is rated on a 4-point scale based 
on the frequency of symptoms over the preceding week and ranging from 0 (not at all) to 3 
(very often).  
Refer to Section 7.2.5 for depression individual treatment stopping criteria. 
8.2 Adverse Events and Serious Adverse Events 
8.2.1 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a clinical trial subject who has signed the 
informed consent form (ICF); the event need not necessarily have a causal relationship with the 
study drug. Examples of AEs include but are not limited to: 
• Abnormal test results 
• Clinically significant symptoms and signs 
• Changes in physical examination findings 
• Hypersensitivity 
• Progression/worsening of underlying disease 
A TEAE is an AE that is temporally associated with administration of study drug and is defined as 
an AE that occurs during or after administration of the first dose of study drug until 30 days 
after the final dose of study drug (safety follow-up visit). For AEs that occur on the date of the 
first dose of study drug, the time of onset (before or after intake of study drug) must be 
specified. 
An abnormal test result should be reported as an AE if any of the following criteria are met: 
• Test result is associated with accompanying symptoms 
• Test result requires additional diagnostic testing or medical/surgical intervention 
• Test result leads to a change in study drug dosing or study drug discontinuation, 
significant additional concomitant drug treatment, or other therapy 
• Test result is considered to be an AE by the Investigator or Sponsor 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE. Any abnormal test result that is determined to be an error does not require 
reporting as an AE. 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as AEs. However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE. For example, an acute appendicitis that 
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begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE. 
8.2.2 
Definition of Serious Adverse Event 
An SAE or serious adverse drug reaction (ADR) is any untoward medical occurrence at any dose 
that meets any of the following criteria: 
• Results in death 
• Is life threatening (immediate risk of death) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is an important medical event 
Medical and scientific judgment should be exercised in determining whether an event is an 
important medical event. An important medical event may not be immediately life threatening 
and/or result in death or hospitalization. However, if it is determined that the event may 
jeopardize the subject and may require intervention to prevent one of the other outcomes 
listed in the definition above, the important medical event should be reported as serious. If 
either the Sponsor or the Investigator believes that an event is serious, the event must be 
considered serious and evaluated by the Sponsor for expedited reporting. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
Hospitalization does not include the following: 
• Rehabilitation facilities 
• Hospice facilities 
• Respite care (e.g., caregiver relief) 
• Skilled nursing facilities 
• Nursing homes 
• Same-day surgeries (as outpatient/same day/ambulatory procedures) 
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical AE is 
not in itself an SAE. Examples include the following: 
• Admission for treatment of a pre-existing condition not associated with the development 
of a new AE or with a worsening of the pre-existing condition (e.g., for workup of 
persistent pre-treatment lab abnormality) 
• Social admission (e.g., subject has no place to sleep) 
• Administrative admission (e.g., for yearly physical exam) 
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• Protocol-specified admission during a clinical trial (e.g., for a procedure required by the 
trial protocol) 
• Optional admission not associated with a precipitating clinical AE (e.g., for elective 
cosmetic surgery) 
• Pre-planned treatments or surgical procedures should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject 
8.2.3 
Classification of an Adverse Event 
As far as possible, each AE will be described by the following: 
• Duration (start and end dates) 
• Severity grade (Section 8.2.3.1) 
• Relationship to study drug (Section 8.2.3.2) 
• Action(s) taken and, as relevant, the outcome (Section 8.2.3.3) 
8.2.3.1 Severity 
The severity of each AE will be graded according to the National Cancer Institute (NCI) CTCAE 
version 4.03, which is summarized in Table 1. 
Table 1. Severity of Adverse Events 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL (preparing meals, shopping for groceries or clothes, using 
the telephone, managing money, etc.). 
Grade 3: Severe or medically significant but not immediately life threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL (bathing, 
dressing and undressing, feeding self, using the toilet, taking medications) and not bedridden. 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
Grade 5: Death related to AE. 
Abbreviations: ADL, activities of daily living; AE, adverse event. 
If there is an increase in the severity of an ongoing AE, it will be recorded as part of the same 
event, with the worst grade of severity recorded. 
Note the distinction between the severity and the seriousness of an AE. A severe event is not 
necessarily a serious event. For example, a headache may be severe (interferes significantly 
with subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs listed in Section 8.2.2. 
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8.2.3.2 Relationship to Study Drug 
The Investigator must provide an assessment of causality for all AEs, both serious and 
non-serious, that serves to determine whether there exists a reasonable possibility that the 
study drug caused or contributed to the AE. The Investigator will assess the relatedness of each 
AE to study drug according to the categories in Table 2. AEs classified as unrelated or unlikely 
related to study drug will be considered not related to treatment, and AEs classified as possibly, 
probably, or definitely related to study drug will be considered related to treatment. 
Table 2. Relatedness of Adverse Event to Study Drug 
UNRELATED: This category applies to those AEs that are clearly and incontrovertibly due to 
extraneous causes (disease, environment, etc.). 
UNLIKELY RELATED: This category applies to those AEs that are judged to be unrelated to the 
study drug but for which no extraneous cause may be found. An AE may be considered 
unlikely to be related to the study drug if or when it meets two of the following criteria:  
(1) it does not follow a reasonable temporal sequence in relation to administration of the 
study drug;  
(2) it could readily have been produced by the subject’s clinical state, environmental or toxic 
factors, or other therapies administered to the subject;  
(3) it does not follow a known pattern of response to the study drug; or  
(4) it does not reappear or worsen when the study drug is re-administered. 
POSSIBLY RELATED: This category applies to those AEs for which a connection to study drug 
administration cannot be ruled out with certainty. An AE may be considered possibly related 
if or when it meets two of the following criteria: 
(1) it follows a reasonable temporal sequence in relation to administration of study drug; 
(2) it could not readily have been produced by the subject’s clinical state, environmental or 
toxic factors, or other therapies administered to the subject; or  
(3) it follows a known pattern of response to the study drug. 
PROBABLY RELATED: This category applies to those AEs that the Investigator thinks are 
related to the study drug with a high degree of certainty. An AE may be considered probably 
related if or when it meets three of the following criteria: 
(1) it follows a reasonable temporal sequence in relation to administration of the study drug;  
(2) it could not be reasonably explained by the known characteristics of the subject’s clinical 
state, environmental or toxic factors, or other therapies administered to the subject; 
(3) it disappears or decreases on cessation or reduction in dose of study drug. There are 
exceptions when an AE does not disappear upon discontinuation of the study drug yet 
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drug-relatedness clearly exists (e.g., as in bone marrow depression, fixed drug eruptions, or 
tardive dyskinesia); or  
(4) it follows a known pattern of response to the study drug. 
DEFINITELY RELATED: This category applies to those AEs that the Investigator thinks are 
incontrovertibly related to the study drug. An AE may be assigned an attribution of definitely 
related if or when it meets all of the following criteria:  
(1) it follows a reasonable temporal sequence in relation to administration of the study drug; 
(2) it could not be reasonably explained by the known characteristics of the subject’s clinical 
state, environmental or toxic factors, or other therapies administered to the subject; 
(3) it disappears or decreases upon cessation or reduction in dose of study drug and recurs 
with re-exposure to the study drug (if re-challenge occurs); and 
(4) it follows a known pattern of response to the study drug. 
Abbreviation: AE, adverse event. 
8.2.3.3 Outcome 
The outcome of each AE will be recorded as one of the categories in Table 3. 
Table 3. Outcome of Adverse Event 
Not recovered/not resolved: The event has not improved or recuperated. 
Recovered/resolved: The event has improved or recuperated. The subject recovered from 
the AE. Record the AE stop date. 
Recovering/resolving: The event is improving. No AE stop date should be recorded when an 
AE is recovering/resolving. 
Recovered/resolved with sequelae: The subject recuperated but retained pathological 
conditions resulting from the prior disease or injury. Record the AE stop date. The AE stop 
date will represent the date the AE stabilized with no change in event outcome anticipated. 
Unknown: There is an inability to access the subject or the subject’s records to determine the 
outcome (i.e., subject withdraws consent or is lost to follow-up). No AE stop date should be 
recorded. 
Fatal: The AE directly caused death. Record the date of death as the AE stop date. 
Abbreviation: AE, adverse event. 
8.2.4 
Time Period and Frequency for Event Assessment and Follow-up 
AEs will be recorded from the time the ICF is signed until the end of the follow-up period. AEs 
will be assessed at each study visit, and subjects should be encouraged to contact the study site 
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to report AEs that occur between scheduled visits. AEs that occur in the time period between 
informed consent and the first dose of study drug should be recorded but will not be 
considered TEAEs. If the AE occurs on the date of the first dose of study drug, the time of onset 
will be captured to determine whether the AE occurred before or after study drug 
administration.  
After the initial AE/SAE report, the Investigator is required to proactively follow each subject at 
subsequent visits/contacts. All AEs/SAEs will be followed until resolution, stabilization, the 
event has been shown to be unrelated to study drug, or the subject is lost to follow-up (as 
defined in Section 7.4). 
8.2.5 
Adverse Event Reporting 
The Investigator is to report all AEs, whether volunteered by the subject, discovered through 
questioning, or directly detected, that occur in the time period specified in Section 8.2.4 and 
according to classifications described in Section 8.2.3.  
Non-serious AEs that don’t require immediate reporting are to be reported on the AE eCRF. AEs 
that lead to permanent discontinuation of study drug must also be reported separately on the 
appropriate eCRF. 
SAEs and other potentially clinically significant AEs will receive special consideration in decisions 
regarding continuation or suspension of dosing or enrollment and will be reported to the SRC 
within 1 day of awareness for immediate review. Refer to Section 8.2.6 for reporting of SAEs. 
Refer to Section 7.2.7 for information on clinically significant AEs.  
8.2.6 
Serious Adverse Event Reporting 
Throughout the study, the Investigator is to report all SAEs, regardless of suspected causality, to 
the Sponsor within 24 hours of learning of its occurrence. Any SAE experienced after the 
follow-up period should be reported to the Sponsor only if the Investigator suspects a causal 
relationship to the study drug. Recurrent episodes, complications, or progression of the initial 
SAE, regardless of when they occur, must be reported as follow-up to the original episode 
within 24 hours of the Investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
SAE should be reported separately as a new event.   
Information about SAEs will be recorded on the SAE Report Form and sent to the Sponsor via 
fax or email using the contact information provided on the form. SAEs must be clearly 
differentiated from other types of events through the usage of the SAE Report Form. The SAE 
Report Form and completion guidelines are provided in the Investigator Site File. The 
Investigator must assess and record the relationship of each event to the study drug. SAEs must 
also be captured in the eCRF.  
Any follow-up information provided should indicate that the information is follow-up to a 
previously reported SAE. Follow-up information should describe whether the event resolved or 
continues, if and how it was treated, and whether the subject continued or withdrew from 
study participation.  
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8.2.7 
Reporting of Pregnancy 
Any subject who becomes pregnant during the study should have study drug discontinued 
immediately and be withdrawn from the study. All pregnancies in female subjects or in the 
female partners of male subjects must be reported to the Sponsor within 24 hours of the site 
learning of the pregnancy. Information about pregnancies will be recorded on the Pregnancy 
Report Form and any follow-up information will be forwarded to the Sponsor. 
For any female subject who becomes pregnant while participating in this study, the Investigator 
will collect information about the pregnancy and follow up with the subject to determine the 
outcome of the pregnancy and the status of mother and child. 
Male subjects should be instructed to notify the site in the event that any female partner 
becomes pregnant. If any female partner of a male subject who received at least 1 dose of 
study drug becomes pregnant while the male subject is participating in this study, the 
Investigator will attempt to collect information about the pregnancy. The Investigator must 
obtain informed consent from the pregnant partner before collecting such information. The 
Investigator will also attempt to follow up with the female partner to determine the outcome of 
the pregnancy and the status of mother and child.  
Generally, follow-up will not be required for longer than 6 to 8 weeks beyond the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 
Pregnancy in itself is not regarded as an AE. However, a pregnancy complication is an AE, and 
congenital abnormalities/birth defects or spontaneous miscarriages should be reported as 
SAEs. Elective termination of a pregnancy is not considered an AE. While the Investigator is not 
obligated to actively seek this information in former study subjects, he or she may learn of such 
an SAE through spontaneous reporting. 
8.2.8 
Adverse Events of Special Interest 
AESIs are those AEs that do not meet SAE criteria but must be monitored on an ongoing basis. 
These events will be reported on the SAE Report Form, allowing for the collection of additional 
information, as warranted. The following will be considered AESIs for this study: 
• Suicidality as indicated by type 3, 4, or 5 ideation on the C-SSRS (see Section 7.2.3 
regarding study drug stopping criteria and Section 8.1.6.1 regarding the C-SSRS). This 
should be reported as an AESI until it becomes serious according to the SAE definition 
(e.g. hospitalization).   
• High HADS score or other indication of worsening depression (see Section 7.2.5 regarding 
study drug discontinuation and Section 8.1.6.2 regarding the HADS) 
• Significant liver chemistry changes that do not satisfy stopping rules (see Section 7.2.1 
and Section 12.2.1). Cases of Hy’s Law should be reported as SAEs.  
• Severity Grade 3 or higher TEAE considered related to study drug (see Section 7.1 
regarding dose reduction) 
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8.2.9 
Disease-Related Events 
The following disease-related events are common in patients with CAH, and this should be 
taken into consideration when evaluating the causality of AEs during the study: 
• Acute encephalopathy 
• Adrenal crisis or insufficiency 
• Avascular necrosis 
• Memory impairment 
• Dizziness 
• Dyslipidemia; hyperlipidemia 
• Dyspepsia 
• Elevated fasting serum leptin and insulin concentrations and insulin resistance 
• Gastrointestinal effects, including gastritis, peptic ulceration, and gastrointestinal 
hemorrhage 
• Headache 
• Hyper- or hypokalemia; hyper- or hyponatremia 
• Hyper- or hypoglycemia; impaired glucose tolerance 
• Hyper- or hypotension 
• Impaired exercise tolerance 
• Infertility 
• Ischemic heart disease, subclinical atherosclerosis 
• Lower bone mineral density  
• Myopathies 
• Obesity 
• Psychiatric disorders, substance use disorders, mood swings, challenges with social 
interactions 
• Seizures have been reported during episodes of hyponatremia and of hypoglycemia 
• Weakness / lethargy / fatigue 
8.3 Efficacy Assessments 
8.3.1 
Hormone Assessments 
Blood samples will be collected for measurement of serum 17-OHP and plasma ACTH, 
testosterone, and androstenedione. Saliva samples will be collected for measurement of 
17-OHP. 
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Background glucocorticoid levels (e.g., cortisol levels if the subject takes hydrocortisone, 
prednisolone levels if the subject takes prednisone, and dexamethasone levels if the subject 
takes dexamethasone) will also be measured. 
Separate tubes of blood will be collected for serum and plasma, and each sample will be 
divided into aliquots designated for appropriate assessments and backup. Detailed instructions 
for the collection and handling of biological samples will be provided separately. 
8.4 Pharmacokinetic Assessments 
A plasma sample will be collected for measurement of SPR001 concentration at each study visit 
indicated in the Schedule of Activities. 
8.5 Exploratory Assessments 
8.5.1 
Quality of Life Assessments 
QoL will be measured using the SF-36, PGIC, bother score, and CAH signs and symptoms 
interview, all described in this section. QoL as reflected by mood will be measured using the 
HADS, which is also used as a measure of safety and is described in Section 8.1.6.2. 
8.5.1.1 Short Form 36 
The SF-36 (Ware and Sherbourne, 1992) is a widely used, validated, patient-reported survey 
that assesses subjective health status. The SF-36 consists of 36 items and the following 8 health 
domains: physical functioning, role-physical (limitations in usual role activities because of 
physical health problems), bodily pain, general health perceptions, vitality, social functioning, 
role-emotional (limitations in usual role activities because of emotional problems), and mental 
health. Domain scores range from 0 to 100, with higher scores corresponding to better 
subjective health status. The survey provides summary scores for physical health and mental 
health. 
8.5.1.2 Patient Global Impression of Change 
The PGIC (Guy, 1976) is a 1-question survey that asks subjects to evaluate whether there has 
been an improvement in overall subjective health status. Subjects select a response on a 
7-point Likert scale. 
8.5.1.3 Bother Score 
The bother score is a 1-question survey that asks subjects to evaluate the overall 
bothersomeness of their CAH symptoms. Subjects select a response on a 7-point scale. 
8.5.1.4 Congenital Adrenal Hyperplasia Signs and Symptoms Interview 
Subjects will be asked about the following aspects of health relevant to CAH signs and 
symptoms: 
• General health status 
• Fatigue 
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• Activity level 
• Concentration 
• Sleep 
• Appetite 
• Mood 
• Dizziness 
• Sweating 
• Fluid retention 
• Acne 
• Headaches 
• Nausea 
• Joint/muscle aches 
• Back pain 
• Weakness 
• Moon facies 
• Hirsutism 
Subjects will be asked to rate on a 5-point scale how frequently they experienced CAH signs and 
symptoms related to these aspects of health over the last week or since their last clinic visit, 
whichever is more recent. 
8.5.2 
Metabolic Assessments 
Metabolic assessments that will be conducted as exploratory measures of the effect of SPR001 
include fasting glucose, HbA1c, fasting insulin, and lipid panel (described as part of clinical 
laboratory in Section 12.4) and BW and BMI (described in Section 8.1.3). 
8.5.3 
Exploratory Adrenal Hormones 
A separate blood sample will be drawn at each visit specified in the Schedule of Activities and 
stored for measurement of exploratory adrenal hormones. Exploratory adrenal hormones may 
include 11-oxygenated 19-carbon (11oxC19) steroids (11β-hydroxyandrostenedione, 
11-ketoandrostenedione, 11β-hydroxytestosterone, and 11-ketotestosterone), androsterone, 
and etiocholanolone. 
8.5.4 
Sex-Specific Assessments 
Refer to Section 8.1.1 on the physical examination for information about assessments of acne 
and hirsutism in female subjects. 
8.5.4.1 Testicular Adrenal Rest Tumors 
TARTs are a common complication of CAH caused by ACTH-driven overstimulation of aberrant 
adrenal cells within the testes (Olpin and Witt, 2014) and result in pain, discomfort, impaired 
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spermatogenesis, and infertility (Chihaoui et al, 2016; Claahsen-van der Grinten et al, 2014; 
Delfino et al, 2012). Complete scrotal ultrasounds will be conducted in male subjects using a 
real-time scanner to detect and to evaluate the size and number of TARTs. Standard images 
should be obtained in the longitudinal and transverse planes. Each potential TART lesion will be 
measured in 3 planes to allow for calculation of TART volume. Detailed instructions for 
performing the scrotal ultrasound will be provided separately. Scrotal ultrasounds will be read 
by a central radiologist blinded to the study timepoint at which the ultrasounds were taken. 
For SPR001-naïve male subjects, a scrotal ultrasound will be conducted at the initial screening 
visit. For SPR001-experienced male subjects rolling over from Study SPR001-201, a scrotal 
ultrasound will be conducted at the initial screening visit only if the subject has not had a prior 
scrotal ultrasound within 3 months before screening. For all male subjects, if the prior or 
screening scrotal ultrasound reveals no evidence of TART, the scrotal ultrasound need not be 
repeated at either Day 1 or Week 12. If the prior or screening scrotal ultrasound does show 
evidence of TART(s), the scrotal ultrasound will be repeated at Day 1 and Week 12. 
8.5.4.2 Semen Analysis 
All male subjects should be encouraged (though not required) to provide a semen sample at 
each visit specified in the Schedule of Activities. Semen will be collected from male subjects to 
assess sperm count, morphology, and motility. 
8.5.4.3 Menstrual Cyclicity 
Female subjects will record menstrual information (including start and stop dates of menses 
and whether the flow was light, moderate, or heavy) in a menstrual diary throughout the 
12-week screening period and the 12-week treatment period. A menstrual diary will be handed 
out at the screening visit and collected at the Day 1 visit, and a second menstrual diary will be 
handed out at the Day 1 visit and collected at the Week 12 visit. These data will be used to 
assess the menstrual cyclicity endpoint. 
8.5.5 
Metabolite Identification 
Samples remaining after PD and PK evaluation may be stored and used for metabolite 
identification studies as deemed appropriate. 
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9 STATISTICAL CONSIDERATIONS 
A detailed description of statistical methods to be applied will be provided in the Statistical 
Analysis Plan (SAP). 
9.1 Sample Size Determination 
The total sample size of up to approximately 24 subjects in this study is based on an estimate of 
the number of subjects who may enroll either after completing Study SPR001-201 or as 
SPR001-naïve subjects. There is no statistical basis for the total sample size. 
The study will attempt to enroll an enriched subpopulation of up to approximately 8 male 
subjects 18 to 35 years old with TARTs. The sample size for this subpopulation is based on the 
following: 1) the assumptions that 10% of males with TARTs would experience TART shrinkage 
in 3 months without study treatment and that at least 50% of males with TARTs would 
experience TART shrinkage in 3 months with study treatment, 2) a power of 85%, and 3) a 
2-sided exact test with a significance level of 0.05 to detect a conservative difference of 40%. 
9.2 Populations for Analyses and Missing Data 
The Safety Population will consist of all enrolled subjects who received at least 1 dose of study 
drug in this study and will be the primary analysis population. 
The Per Protocol Population will consist of all subjects who received at least 80% of study drug 
doses planned over the entire treatment period and had no major protocol deviations. 
Additional criteria for the Per Protocol Population may be specified in the SAP. The Per Protocol 
Population will be identified prior to database lock. 
Conventions for the handling of missing data will be described in the SAP. 
9.3 Statistical Analyses 
9.3.1 
General Approach 
Summarized data will represent overall data pooled from all subjects within each analysis 
population. Changes in primary, secondary, and exploratory endpoints will be analyzed over 
time, with change from baseline summarized for each post-baseline time point measured. If 
SPR001 dosing is adjusted for subjects who enroll later on in this study, data will be presented 
by SPR001 dose. Unless otherwise specified, statistical analysis will be performed using SAS 
version 9.3 or higher. 
9.3.2 
Demographics and Baseline Descriptive Statistics 
Demographics and subject background information such as disease characteristics will be 
summarized using descriptive statistics, including the number of subjects (n), mean, standard 
deviation, median, and range for continuous variables and count and percentage for categorical 
variables. Medical history will be listed. 
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9.3.3 
Subject Disposition 
Subject disposition data such as the numbers of screen failures, enrolled subjects, subjects with 
dose reductions, subjects who discontinued study drug/withdrew from the study early, and 
subjects who completed the study will be summarized using descriptive statistics. 
9.3.4 
Subject Compliance 
The planned and actual doses of study drug administered and reason for any dose change will 
be listed by subject. Study drug compliance will be calculated for each subject and summarized 
descriptively overall and by SPR001 dose, if applicable. 
9.3.5 
Safety Analyses 
Safety analyses will be performed on the Safety Population. 
AEs will be coded using MedDRA Version 20 or higher and presented by System Organ Class and 
Preferred Term. AEs that occur before the first dose of study drug will be distinguished from 
TEAEs. TEAEs will be listed by subject and summarized overall and by SPR001 dose, if 
applicable. The incidence of each TEAE will be tabulated and presented by maximum severity. 
The frequency (number and percentage) of subjects who experience ≥1 TEAE will be 
summarized. TEAEs potentially related to study drug, SAEs, AEs leading to study drug 
discontinuation/study withdrawal, DLTs, and AESIs will be summarized by frequency of subjects 
who experience ≥1 event and/or tabulated by incidence for each event. 
Physical examination findings will be listed. Vital signs, ECG parameters, and clinical laboratory 
values will be listed and summarized using descriptive statistics. Investigators’ assessments of 
ECG results will be listed and summarized in a frequency table. Clinical laboratory values may 
be presented in shift tables. Prior and concomitant medications will be listed. C-SSRS data will 
be listed. Data for the HADS (including anxiety and depression subscales) will be summarized 
using descriptive statistics. 
An SRC will review safety data at regular intervals throughout the study (see Section 10.6). 
Additional analyses may be performed if warranted upon review of the data. 
9.3.6 
Efficacy Analyses 
Efficacy analyses will be performed on both the Safety and Per Protocol Populations. 
Changes over time in hormones (ACTH, 17-OHP, androstenedione, testosterone, and 
exploratory adrenal hormones) will be summarized using descriptive statistics and presented in 
tables and/or graphs. Parametric (paired t test) or nonparametric (Wilcoxon signed rank) tests 
will be used to test the change from baseline depending on the data distribution. 
Data for the SF-36 (including individual domain scores and summary scores) will be summarized 
using descriptive statistics. Data for the PGIC, the bother score, and the CAH signs and 
symptoms interview will be summarized using counts and percentages. Shifts in status from 
baseline to each post-baseline visit will be presented. 
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Changes over time in metabolic parameters (including fasting glucose, HbA1c, fasting insulin, 
lipid profile, BW, and BMI) will be summarized using descriptive statistics. 
Changes over time in measures of TARTs and on semen analysis in male subjects and in 
measures of acne, hirsutism, and menstrual cyclicity in female subjects will be summarized 
using descriptive statistics. 
Additional analyses may be performed if warranted upon review of the data. 
9.3.7 
Pharmacokinetics Analyses 
PK may be assessed using a population PK approach. Any population PK analysis will be 
described in a separate population PK analysis plan. 
9.3.8 
Planned Interim Analyses 
Interim ad-hoc analyses may be performed. 
An SRC will review safety data at regular intervals throughout the study (see Section 10.6). 
9.3.9 
Subgroup Analyses 
Descriptive summaries of primary, secondary, and exploratory endpoints will be provided by 
sex and by subject status as being either SPR001-naïve or SPR001-experienced on entering this 
study. Any additional subgroup analyses will be specified in the SAP. 
9.3.10 Exploratory Analyses 
Any exploratory analyses will be specified in the SAP. 
 
 
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10 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1 Informed Consent 
Eligible subjects may only be enrolled into the study after providing written (and witnessed, 
where required by law or regulation), IRB-approved informed consent. Informed consent must 
be obtained before conducting any protocol-specified procedures. The process of obtaining 
informed consent should be documented in the subject source documents. 
Any changes to the proposed consent form suggested by the Investigator must be agreed to by 
the Sponsor before submission to the IRB, and a copy of the approved version must be 
provided to the Sponsor after IRB approval. 
10.2 Study Discontinuation and Closure 
Premature study termination may occur because of a regulatory authority decision, change in 
opinion of the IRB, drug safety problems, or at the discretion of the Sponsor. In addition, the 
Sponsor retains the right to discontinue development of SPR001 at any time. 
If this study is prematurely terminated or discontinued, the Sponsor will promptly notify the 
Investigator. After notification, the Investigator must contact all participating subjects within 
7 days and have them complete final visit safety assessments. As directed by the Sponsor, all 
study materials must be collected and all eCRFs completed to the greatest extent possible. 
10.3 Confidentiality and Privacy 
All information obtained during the conduct of this study will be regarded as confidential, and 
written permission from the Sponsor is required before disclosing any information related to 
this study. 
All processing of personal data at the site and by the Sponsor must be carried out in accordance 
with any legislation concerning the protection of personal data. The Investigator must ensure 
that the subject’s privacy is maintained. The Sponsor will assign each subject a unique 
identifier. Any subject records or datasets that are transferred from the site to the Sponsor will 
contain the identifier only; subject names or any information which would make the subject 
identifiable will not be transferred. 
10.4 Future Use of Stored Specimens and Data 
Any biological samples collected for this study may be stored for up to 5 years. These samples 
may be used in the future for the discovery, analysis, verification, and/or validation of other 
biomarkers or tests for CAH. Samples will not directly identify subjects on the label. Consent 
from subjects to store the samples will be requested, and subjects may elect to opt out of 
prolonged sample storage at any time by indicating so in the ICF. 
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10.5 Key Roles and Study Governance 
A list of study contacts will be provided in a separate document. 
10.6 Safety Oversight 
An SRC composed of appropriate medical and clinical representatives will review safety data at 
regular intervals throughout the study and provide recommendations regarding further 
enrollment and dosing or any adjustments to dosing to the Sponsor, who will ultimately decide 
on any changes in this study. A separate charter will detail the responsibilities of the SRC. 
10.7 Clinical Monitoring 
Before study initiation, at a site initiation visit or at an Investigator’s meeting, a Sponsor 
representative will review the protocol and eCRFs with the Investigators and their staff. During 
the study, the field monitor will visit the site regularly to check the completeness of subject 
records, the accuracy of entries on the eCRFs, adherence to the protocol and to GCP, the 
progress of enrollment, and that study drug is being stored, dispensed, and accounted for 
according to specifications. Key study personnel must be available to assist the field monitor 
during these visits. 
The Investigator must give the monitor access to all relevant source documents to confirm their 
consistency with eCRF entries. The Sponsor’s monitoring standards require full verification for 
the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and recording of data that will be used for all primary and safety 
variables. Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan. No information in source documents about the 
identity of subjects will be disclosed. 
Refer to Section 10.9.1 for information on eCRFs and source documents. 
10.8 Quality Assurance and Quality Control 
Representatives of the Sponsor must be allowed to visit all study site locations periodically to 
assess the data, quality, and study integrity. Onsite, they will review study records and directly 
compare them with source documents, discuss the conduct of the study with the Investigator, 
and verify that the facilities remain acceptable. In addition, the study may be evaluated by 
Sponsor internal auditors and government inspectors, who must be allowed access to case 
report forms, source documents, and other study files. Spruce audit reports will be kept 
confidential. The Investigator must notify the Sponsor promptly of any inspections scheduled by 
regulatory authorities and promptly forward copies of inspection reports to Spruce. 
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10.9 Data Handling and Record Keeping 
10.9.1 Data Collection and Management Responsibilities 
An eCRF must be completed for each enrolled subject. Completed original case report forms are 
the sole property of the Sponsor and should not be made available in any form to third parties, 
except for authorized representatives of the Sponsor or appropriate regulatory authorities, 
without written permission from the Sponsor. 
It is the Investigator's responsibility to ensure completion of and to review and approve all 
eCRFs. Case report forms must be signed by the Investigator or by an authorized staff member. 
These signatures serve to attest that the information contained on the eCRFs is true. At all 
times, the Investigator has final personal responsibility for the accuracy and authenticity of all 
clinical and laboratory data entered on the eCRFs. 
For each subject in the study, the Investigator must maintain source documents at the trial site 
consisting of case and visit notes that contain demographic and medical information, laboratory 
data, ECGs, and the results of any other tests or assessments. In most cases, the source 
documents will be the hospital/clinic or physician medical records/chart. All information on 
eCRFs must be traceable to these source documents in the subject's file. In some cases, certain 
items entered on the eCRF may not require a separate written record, and the eCRF itself may 
serve as the source document. Such items will be prospectively defined between the Sponsor 
and Investigator before study start. The Investigator must also keep the original ICF signed by 
the subject (a copy of the signed ICF is given to the subject). 
10.9.2 Study Records Retention 
To enable evaluations and/or audits from regulatory authorities or the Sponsor or its designees, 
the Investigator agrees to keep records that include the identity of all subjects (sufficient 
information to link records [e.g., eCRFs and hospital records]), all original signed ICFs, copies of 
all eCRFs, SAE forms, source documents, and treatment disposition. The records should be 
retained by the Investigator for as long as ICH or local regulations or the Clinical Study 
Agreement dictates, whichever is longer.   
If the Investigator relocates, retires, or for any reason withdraws from the trial, the Sponsor 
should be prospectively notified, and the trial records must be transferred to an acceptable 
designee, such as another Investigator, another institution, or the Sponsor. The Investigator 
must obtain the Sponsor’s written permission before disposing of any records, even if retention 
requirements have been met. 
10.10 Protocol Deviations 
If a protocol deviation occurs that affects a subject’s safety, the Sponsor must be informed as 
soon as possible. 
If a protocol deviation is implemented to eliminate an immediate hazard before a protocol 
amendment can be submitted for IRB review and approval/favorable opinion (see 
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Section 10.12), the deviation will be reported as soon as possible to 1) the IRB for review and 
approval/favorable opinion, 2) the Sponsor, and 3) Regulatory Authority(ies), if required by 
local regulations. Documentation of approval signed by the chairperson or designee of the 
IRB(s) must be sent to the Sponsor. 
Protocol deviations will be included in the Clinical Study Report. 
10.11 Publication and Data Sharing Policy 
Manuscripts for publication will be prepared in accordance with the Sponsor’s publication 
policy. Manuscripts must be submitted to the Sponsor for review and comment before 
submission to a publisher. This requirement should not be construed as a means of restricting 
publication but is intended solely to ensure concurrence regarding data, evaluations, and 
conclusions and to provide an opportunity for the Sponsor to share with the Investigator any 
new or unpublished information of which the Investigator may be unaware. 
10.12 Amendments 
The study shall be conducted as described in this protocol. All revisions to the protocol must be 
discussed with and prepared by the Sponsor. The Investigator should not implement any 
change to the protocol without a prior protocol amendment that has been reviewed by and 
received documented approval/favorable opinion from the IRB, except where necessary to 
eliminate an immediate hazard(s) to study subjects. Any significant protocol deviation must be 
documented (see Section 10.10). 
If a protocol amendment is an Administrative Letter, Investigators must inform their IRB(s).   
If a protocol amendment substantially alters the study design or increases the potential risk to 
the subject, 1) the consent form must be revised and submitted to the IRB(s) for review and 
approval/favorable opinion, 2) the revised consent form must be used to obtain re-consent 
from subjects currently enrolled in the study if they are affected by the amendment, and 3) the 
revised consent form must be used to obtain consent from any new subjects prior to 
enrollment. 
 
 
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11 REFERENCES 
Arlt W, Willis DS, Wild SH, et al. Health status of adults with congenital adrenal hyperplasia: a 
cohort study of 203 patients. J Clin Endocrinol Metab. 2010;95(11):5110-5121. 
Auchus RJ. Management considerations for the adult with congenital adrenal hyperplasia. Mol 
Cell Endocrinol. 2015;408:190-197. 
Aulinas A, Webb SM. Health-related quality of life in primary and secondary adrenal 
insufficiency. Expert Rev Pharmacoecon Outcomes Res. 2014;14(6):873-888. 
Bachelot A, Chakthoura Z, Rouxel A, et al. Classical forms of congenital adrenal hyperplasia due 
to 21-hydroxylase deficiency in adults. Horm Res. 2008;69:203-211. 
Bachelot A, Golmard JL, Dulon J, et al. Determining clinical and biological indicators for health 
outcomes in adult patients with childhood onset of congenital adrenal hyperplasia. Eur J 
Endocrinol. 2015;173:175-84. 
Chihaoui M, Kanoun F, Chaker F, et al. Testicular adrenal rest tumours in young adult males 
with congenital adrenal hyperplasia: prevalence and impact on testicular function. Andrologia. 
2016;48(1):45-50. 
Choi JH, Kim GH, Yoo HW. Recent advances in biochemical and molecular analysis of congenital 
adrenal hyperplasia due to 21-hydroxylase deficiency. Ann Pediatr Endocrinol Metab. 
2016;21:1-6. 
Claahsen-van der Grinten HL, Dehzad F, Kamphuis-van Ulzen K, de Korte CL. Increased 
prevalence of testicular adrenal rest tumours during adolescence in congenital adrenal 
hyperplasia. Horm Res Paediatr. 2014;82(4):238-244. 
Delfino M, Elia J, Imbrogno N, et al. Testicular adrenal rest tumors in patients with congenital 
adrenal hyperplasia: prevalence and sonographic, hormonal, and seminal characteristics. J 
Ultrasound in Med. 2012;31(3):383-388. 
Doleschall M, Szabó JA, Pázmándi J, et al. Common genetic variants of the human steroid 
21-hydroxylase gene (CYP21A2) are related to differences in circulating hormone levels. PLoS 
One. 2014;9:e107244. 
Falhammar H, Frisén L, Norrby C, et al. Increased mortality in patients with congenital adrenal 
hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab. 2014;99(12):E2715-
2721. 
Falhammar H, Wedell A, Nordenström A. Biochemical and genetic diagnosis of 21-hydroxylase 
deficiency. Endocrine. 2015;50(2):306-314. 
Food and Drug Administration. Guidance for Industry. Acne Vulgaris: Developing Drugs for 
Treatment. Draft Guidance. September 2005. Available at: 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm06498
1.htm 
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Gilban DL, Alves Jr PA, Beserra IC. Health-related quality of life of children and adolescents with 
congenital adrenal hyperplasia in Brazil. Health Qual Life Outcomes. 2014;12:107. 
Guy W (ed). ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: US 
Department of Health, Education, and Welfare Public Health Service Alcohol, Drug Abuse, and 
Mental Health Administration; 1976. 
Han TS, Stimson RH, Rees DA, et al. Glucocorticoid treatment regimen and health outcomes in 
adults with congenital adrenal hyperplasia. Clin Endocrinol (Oxf). 2013;78(2):197-203. 
Han TS, Walker BR, Arlt W, et al. Treatment and health outcomes in adults with congenital 
adrenal hyperplasia. Nat Rev Endocrinol. 2014;10:115-124. 
Hummel SR, Sadler S, Whitaker MJ, Ara RM, Dixon S, Ross RJ. A model for measuring the health 
burden of classic congenital adrenal hyperplasia in adults. Clin Endocrinol (Oxf). 2016;85(3):361-
398. 
Martin KA, Anderson RR, Chang RJ, et al. Evaluation and treatment of hirsutism in 
premenopausal women: an Endocrine Society clinical practice guideline. J Clin Endocrinol 
Metab. 2018;103(4):1-25. 
Mnif MF, Kamoun M, Mnif F, et al. Long-term outcome of patients with congenital adrenal 
hyperplasia due to 21-hydroxylase deficiency. Am J Med Sci. 2012;344:363-73. 
Olpin JD and Witt B. Testicular adrenal rest tumors in a patient with congenital adrenal 
hyperplasia. J Radiol Case Rep. 2014;8(2):46-53. 
Reisch N. Substitution therapy in adult patients with congenital adrenal hyperplasia. Best Pract 
Res Clin Endocrinol Metab. 2015;29:33-45. 
Turcu AF, Auchus RJ. Adrenal steroidogenesis and congenital adrenal hyperplasia. Endocrinol 
Metab Clin North Am. 2015;44(2):275-296. 
Turcu AF, Spencer-Segal JL, Farber RH, et al. Single-Dose study of a corticotropin-releasing 
factor receptor-1 antagonist in women with 21-hydroxylase deficiency. J Clin Endocrinol Metab. 
2016;101(3):1174-1180. 
Ware Jr JE, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). Med Care. 
1992;30(6):473-483. 
White PC and Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. 
Endocr Rev. 2000;21:245-291. 
Yildiz BO, Bolour S, Woods K, Moore A, Azziz R. Visually scoring hirsutism. Human Reprod 
Update. 2010;16(1);51-64. 
Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 
1983;67(6):361-370. 
 
 
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12 APPENDICES 
12.1 Appendix of Prohibited Concomitant Medications and Concomitant Medications 
of Concern 
12.1.1 List of Prohibited Concomitant Medications 
Other investigational drugs are prohibited during the study. 
Rosiglitazone treatment is prohibited during the study because it could affect the subject’s 
ACTH levels. Treatment with testosterone is also prohibited. In general, subjects who require 
ongoing treatment with rosiglitazone or testosterone should not be screened. 
Potent inducers or inhibitors of CYP3A4 are generally prohibited because of their potential 
impact on the metabolism of SPR001. Stable daily doses of glucocorticoids and birth control are 
not restricted. The following CYP3A4 inducers and inhibitors are specifically prohibited: 
Butalbital 
Phenobarbital 
Carbamazepine 
Phenytoin 
Chloramphenicol Pioglitazone  
Clarithromycin 
Posaconazole 
Conivaptan 
Quercetin 
Itraconazole 
Rifabutin 
Ketoconazole 
Rifampin 
Mibefradil 
St. John's Wort 
Modafinil 
Telithromycin 
Nefazodone 
Topiramate 
Oxcarbazepine 
Voriconazole 
Many medications used to treat HCV and HIV are strong inhibitors of CYP3A4 but are not listed 
here because patients with HIV and/or HCV are excluded from this study.   
 
 
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12.1.2 List of Concomitant Medications of Concern 
The following drugs metabolized by CYP3A4, 2C8, 2C9, and/or 2C19 are sensitive substrates of 
these enzymes or substrates with narrow therapeutic windows and should be avoided as much 
as possible: 
Alfentanil 
Lovastatin 
Aprepitant 
Lurasidone 
Avanafil 
Midazolam 
Budesonide 
Nalogexol 
Buspirone 
Nisoldipine 
Capsaicin 
Omeprazole 
Celecoxib 
Pimozide 
Clobazam 
Quetiapine 
Darifenacin 
Quinidine 
Dihydroergotamine Repaglanide 
Dronedarone 
Sildenafil 
Eletriptan 
Simvastatin 
Eplerenone 
Tacrolimus  
Ergotamine 
Ticagrelor 
Felodipine 
Tolvaptan 
Fentanyl 
Triazolam 
Fluticasone  
Vardenafil 
Lansoprazole 
Warfarin 
Lomitapide 
 
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12.2 Appendix of Liver Safety 
12.2.1 Liver Chemistry Stopping Criteria and Follow-up Assessments 
Liver Chemistry Stopping Criteria 
Absolute ALT 
ALT ≥5x ULN 
Increase in ALT 
ALT ≥3x ULN persists for ≥4 weeks 
Bilirubin1,2 
ALT ≥3x ULN and bilirubin ≥2x ULN (>35% direct bilirubin) 
INR2 
ALT ≥3x ULN and INR >1.5, if INR measured 
Cannot Monitor 
ALT ≥3x ULN and cannot be monitored weekly for 4 weeks 
Symptomatic3 
ALT ≥3x ULN associated with symptoms (new or worsening) believed to be related to 
liver injury or hypersensitivity 
Suggested Actions and Follow-up Assessments  
Actions 
Follow-up Assessments 
• Immediately discontinue study drug.   
• Report the event to the Sponsor or designated CRO 
within 24 hours. 
• Complete the liver event eCRF, and complete an SAE 
data collection tool if the event also met the criteria for 
an SAE.2 
• Request list of any medications taken in last 48 hours; 
specifically question about medications that are known 
to increase liver enzymes, such as aspirin, 
acetaminophen, ibuprofen, naproxen, diclofenac, 
phenylbutazone, and any antibiotic use. 
• Perform liver chemistry follow-up assessments.   
• Monitor the participant until liver chemistry test 
abnormalities resolve, stabilize, or return to baseline 
(see MONITORING below). 
• If restart/rechallenge is not granted, permanently 
discontinue study drug and continue participant in the 
study for any protocol-specified follow-up assessments. 
MONITORING: 
If ALT ≥3x ULN AND bilirubin ≥2x ULN or INR >1.5:  
• Repeat liver chemistry tests (include ALT, AST, alkaline 
phosphatase, and bilirubin) and perform liver event 
follow-up assessments within 24 hours. 
• Viral hepatitis serology.4 
• Obtain INR and recheck with each liver 
chemistry assessment until the transaminase 
values show downward trend. 
• Obtain blood sample for PK analysis after the 
most recent dose.5 
• Serum CPK and LDH. 
• Fractionate bilirubin, if total bilirubin 
≥2x ULN. 
• Obtain complete blood count with 
differential to assess eosinophilia. 
• Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form. 
• Record use of concomitant medications 
(including acetaminophen, herbal remedies, 
and other over-the-counter medications) on 
the concomitant medications eCRF. 
• Record alcohol use on the liver event eCRF. 
If ALT ≥3x ULN AND bilirubin ≥2x ULN or INR 
>1.5: 
• Anti-nuclear antibody, anti–smooth muscle 
antibody, type 1 anti-liver kidney microsomal 
Clinical Study Report
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Protocol #: SPR001-202 
CLINICAL STUDY PROTOCOL 
Spruce Biosciences, Inc. 
Version 1.1NIH 
CONFIDENTIAL 
Page 78 of 82 
• Monitor subject twice weekly until liver chemistry test
abnormalities resolve, stabilize, or return to baseline.
• A specialist or hepatology consultation is recommended.
If ALT ≥3x ULN AND bilirubin <2x ULN and INR ≤1.5:
• Repeat liver chemistry tests (include ALT, AST, alkaline
phosphatase, bilirubin) and perform liver chemistry
follow-up assessments within 24 to 72 hours.
• Monitor subjects weekly until liver chemistry
abnormalities resolve, stabilize, or return to baseline.
antibodies, and quantitative total IgG or 
gamma globulins. 
• Serum acetaminophen adduct HPLC assay
(quantifies potential acetaminophen
contribution to liver injury) in subjects with
definite or likely acetaminophen use in the
preceding week.
• Liver imaging (ultrasound, magnetic resonance,
or computerized tomography) and/or liver
biopsy to evaluate liver disease; complete liver.
Abbreviations: AE = adverse event; ALT = alanine aminotransferase; AST = aspartate transaminase; CPK = creatine 
phosphokinase; CRO = contract research organization; HPLC = high-performance liquid chromatography; IgG = 
immunoglobulin G; INR = international normalized ratio; LDH = lactate dehydrogenase; PK = pharmacokinetic; SAE 
= serious adverse event; ULN = upper limit of normal. 
1 Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study drug if ALT ≥3x ULN and bilirubin ≥2x ULN. Additionally, if serum 
bilirubin fractionation testing is unavailable, record the absence/presence of detectable urinary bilirubin on 
dipstick, which is indicative of direct bilirubin elevations suggesting liver injury.   
2 All events of ALT ≥3x ULN and bilirubin ≥2x ULN (>35% direct bilirubin) or ALT ≥3x ULN and INR >1.5 may indicate 
severe liver injury (possible “Hy’s Law”) and must be reported as an SAE. 
3 New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or hypersensitivity (such as fever, rash, or eosinophilia). 
4 Includes hepatitis A IgM antibody, hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (HBcAb), 
hepatitis C RNA, cytomegalovirus IgM antibody, Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, 
heterophile antibody or monospot testing), and hepatitis E IgM antibody.   
5 Record the date/time of the PK blood sample draw and the date/time of the last dose of study drug before the 
blood sample draw on the eCRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping will be 
provided in the laboratory manual from the applicable central laboratory. 
12.2.2 Criterion for Increased Liver Chemistry Monitoring While Continuing Study Drug 
Criterion for Increased Liver Chemistry Monitoring and Follow-up Actions 
Criterion 
Actions 
ALT ≥3x ULN and <5x 
ULN and bilirubin <2x 
ULN, without symptoms 
believed to be related to 
liver injury or 
hypersensitivity,  
and can be monitored 
weekly for 4 weeks 
• Notify the Medical Monitor within 24 hours of learning of the abnormality to 
discuss subject safety.
• Subject can continue study drug.
• Subject must return weekly for repeat liver chemistry tests (ALT, AST, alkaline 
phosphatase, bilirubin) until the abnormalities resolve, stabilize, or return to 
baseline.
• If at any time the subject meets liver chemistry stopping criteria, proceed as 
described in Section 7.2.1 and Section 12.2.1.
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Protocol #: SPR001-202 
CLINICAL STUDY PROTOCOL 
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Version 1.1NIH 
CONFIDENTIAL 
Page 79 of 82 
• If, after 4 weeks of monitoring, ALT <3x ULN and bilirubin <2x ULN, monitor per
standard scheduling for remainder of study and follow-up period.
12.2.3 Restart Following Transient Resolving Liver Chemistry Events Not Related to Study 
Drug 
The Investigator may request the Sponsor to consider restarting study drug in a subject who 
stopped study drug because of a liver chemistry event. Approval for study drug restart can be 
considered under the following circumstances: 
• Liver chemistry events have a clear underlying cause (e.g., biliary obstruction, pancreatic
events, hypotension, acute viral hepatitis), liver chemistry tests have improved to normal
or are within 1.5x baseline, and ALT <3x ULN.
• Possible drug-induced liver injury (DILI) has been excluded by the Investigator and the
study team. This includes the absence of markers of hypersensitivity (otherwise
unexplained fever, rash, eosinophilia). Where a study medication has an identified
genetic marker associated with liver injury (e.g., lapatinib, abacavir,
amoxicillin/clavulanate), the presence of the marker should be excluded. If study drug–
related liver injury cannot be excluded, the guidance on appropriate action and follow-up
in the previous sections of this Appendix will apply.
• There is no evidence of alcoholic hepatitis.
• Medical Monitor approval of study drug restart has been obtained.
If restart of study drug is approved by the Sponsor in writing: 
• Study drug must be administered at the dose specified by the Sponsor.
• Subjects approved by the Sponsor for restart of study drug must return to the clinic twice
a week for liver chemistry tests until stable liver chemistry tests have been demonstrated,
and then standard laboratory monitoring may resume as per protocol.
• If the subject meets protocol-defined liver chemistry stopping criteria after study drug
restart, study drug should be permanently discontinued.
• The Medical Monitor must be informed of the outcome for the subject following study
drug restart.
• The Sponsor must be notified of any AEs.
Clinical Study Report
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Protocol #: SPR001-202 
CLINICAL STUDY PROTOCOL 
Spruce Biosciences, Inc. 
Version 1.1NIH 
 
 
CONFIDENTIAL 
Page 80 of 82 
 
12.3 Appendix of Potentially Clinically Significant Adverse Events 
12.3.1 List of Potentially Clinically Significant Signs and Symptoms 
Event 
Description 
Abdominal Pain 
Pain and abdominal tenderness to palpation that significantly impairs 
ambulation, food intake, and ADL for >24 hours 
Nausea/Vomiting 
>3 episodes of emesis over >4 continuous hours with continuous nausea 
Diarrhea 
>3 episodes of unformed stools and fecal urgency over >8 hours 
Dizziness/Hypotension 
Orthostatic CNS symptoms (dizziness, confusion) that prevent ambulation 
for >3 hours, associated with orthostatic SBP decrease >20 mmHg or DBP 
decrease >10 mmHg or upright heart rate >105 bpm, and are not vasovagal 
responses to provocative stimuli (e.g., phlebotomy, nausea, bowel or 
bladder function) 
Sensorium 
Disorientation to time, place, or identity. Any abnormal ideation. 
Mood 
Feelings of grief or loss that interfere with study procedures. Any suicidal 
ideation. 
Headache/Pain 
Any focal or generalized head pain that disrupts normal activities over 
>12 hours and is not responsive to 2 doses of non-steroidal analgesics 
Pruritis 
Generalized itching over >24 hours unresponsive to oral antihistamine 
Systolic Blood Pressure 
>30 mmHg increase from baseline values or an absolute level >180 mmHg 
Diastolic Blood Pressure >20 mmHg increase from baseline values or an absolute level >110 mmHg 
Heart Rate 
Resting (sitting or recumbent) HR >110 bpm 
Cardiac Rhythm 
Any rhythm other than sinus rhythm, sinus bradycardia, or mild sinus 
tachycardia 
QRS Morphology 
Significant prolongation of QRS interval or new onset of bundle branch 
block 
Skin Rash 
Pruritic rash or urticaria over >100 cm2 in area in more than one location 
simultaneously 
Neurological Signs 
New onset of readily visible tremor during normal movement, clonic 
reflexes, or motor dyscoordination, convulsions, or seizures 
Abbreviations: ADL, activities of daily living; bpm, beats per minute; CNS, central nervous system; DBP, 
diastolic blood pressure; HR, heart rate; SBP, systolic blood pressure. 
12.3.2 List of Potentially Clinically Significant Laboratory Findings 
Lab 
Criteria 
Hemoglobin 
>2 g/dL reduction from baseline or absolute value <10 g/dL 
Neutropenia 
Absolute neutrophil count <1,800/μL and >500/μL reduction from baseline 
Lymphopenia 
Absolute lymphocyte count <500/μL 
Platelet count 
<50,000/μL 
Clinical Study Report
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Protocol #: SPR001-202 
CLINICAL STUDY PROTOCOL 
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Version 1.1NIH 
 
 
CONFIDENTIAL 
Page 81 of 82 
 
Lab 
Criteria 
Creatinine 
>1.8 mg/dL or >0.4 mg/dL increase from baseline value 
BUN 
>30 mg/dL and >10 mg/dL increase from baseline values 
ALT 
>3-fold above laboratory reference upper limit value 
AST 
>3-fold above laboratory reference upper limit value 
Bilirubin (total) 
>1.5-fold above laboratory reference upper limit value 
Potassium 
<3.0 or >5.5 meq/L 
Sodium 
<130 or >150 meq/L 
Serum calcium 
>11.4 mg/dL sustained over 24 hours 
FSH 
>15 if baseline value was <5 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea 
nitrogen; FSH, follicle-stimulating hormone. 
Note: If a laboratory result meets any of these criteria, it should be confirmed by repeat measurement 
within 48 hours. 
 
Clinical Study Report
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Protocol #: SPR001-202 
CLINICAL STUDY PROTOCOL 
Spruce Biosciences, Inc. 
Version 1.1NIH 
 
 
CONFIDENTIAL 
Page 82 of 82 
 
12.4 Appendix of Clinical Laboratory Tests 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet count  
RBC count 
RBC indices: MCV, MCH, % reticulocytes 
Hemoglobin 
Hematocrit 
WBC count  
Differential: neutrophils, lymphocytes, monocytes, eosinophils, basophils 
Clinical Chemistry1 
Glucose, fasting 
Alkaline phosphatase  
Potassium 
ALT/SGPT  
Calcium 
AST/SGOT  
Sodium 
GGT 
BUN 
Total and direct bilirubin 
Creatinine 
Total protein 
Lipid Panel 
Total cholesterol, LDL, HDL, triglycerides 
Thyroid Panel 
T3, T4, TSH 
Routine Urinalysis 
Specific gravity 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, by dipstick 
Microscopic examination (if blood or protein is abnormal) 
Other Tests 
LH, FSH, inhibin B, SHBG, renin, aldosterone 
For females only: estradiol, prolactin, progesterone 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea 
nitrogen; FSH = follicle-stimulating hormone; GGT = gamma-glutamyltransferase; HDL = high-density 
lipoprotein; INR = international normalized ratio; LDL = low-density lipoprotein; LH = luteinizing 
hormone; MCH = mean corpuscular hemoglobin; MCV = mean corpuscular volume; RBC = red blood cell; 
SAE = serious adverse event; SGOT = serum glutamic-oxaloacetic transaminase; SGPT = serum glutamic-
pyruvic transaminase; SHBG = sex hormone–binding globulin; TSH = thyroid-stimulating hormone; ULN = 
upper limit of normal; WBC = white blood cell. 
1 Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver 
stopping or monitoring event are given in Section 12.2. All events of ALT ≥3x ULN plus bilirubin ≥2x ULN 
(>35% direct bilirubin) or ALT ≥3x ULN plus INR >1.5 (if INR is measured) may indicate severe liver injury 
(possible Hy’s Law) and must be reported as an SAE. 
Clinical Study Report
SPR001-202
Page 83 of 164

SAP_001.pdf: 
Spruce Biosciences 
Tildacerfont (SPR001) 
Statistical Analysis Plan- Study SPR001-202 
APR 20 2020 
Confidential Spruce Biosciences 2019 
1 
STATISTICAL ANALYSIS PLAN 
PHASE II 
VERSION: 2.0 
DATE OF PLAN: 
April 20, 2020 
BASED ON: 
Protocol Version 1.0:     24 May 2018 
STUDY DRUG: 
TILDACERFONT (SPR001) 
PROTOCOL NUMBER: 
202 
STUDY TITLE: 
A 3-Month Phase 2 Study to Evaluate the Safety and Efficacy of SPR001 in Subjects with 
Classic Congenital Adrenal Hyperplasia 
SPONSOR: 
Spruce Biosciences, Inc. 
1700 Montgomery St, Suite 212 
San Francisco, CA 94111 
This study is being conducted in compliance with good clinical practice, including the archiving 
of essential documents. 
Page 2 of 49
NCT03687242


Spruce Biosciences 
 
Tildacerfont (SPR001) 
Statistical Analysis Plan- Study SPR001-202 
 
APR 20 2020 
 
Confidential Spruce Biosciences 2019 
 
2 
 
 
  
 
SIGNATURE PAGE 
SAP Phase II 
A 3-Month Phase 2 Study to Evaluate the Safety and Efficacy of SPR001 in Subjects with Classic 
Congenital Adrenal Hyperplasia 
Plan Version: 
2.0 
Plan version reviewed: 
20 Apr 2020 
 
 
 
 
 
 
Author: 
 
 
 
 
 
 
Spruce Biosciences, Inc. 
 
Date 
 
 
 
 
Reviewer: 
 
 
 
 
 
 
Spruce Biosciences, Inc. 
 
Date 
 
 
Page 3 of 49


Spruce Biosciences 
 
Tildacerfont (SPR001) 
Statistical Analysis Plan- Study SPR001-202 
 
APR 20 2020 
 
Confidential Spruce Biosciences 2019 
 
3 
 
 
  
 
TABLE OF CONTENTS 
LE PAGE 1 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................9 
1. 
LIST OF ABBREVIATIONS.....................................................................................10 
2. 
INTRODUCTION ......................................................................................................11 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................12 
3.1. 
Study Objectives .........................................................................................................12 
3.1.1. 
Primary Objective .......................................................................................................12 
3.1.2. 
Secondary Objectives .................................................................................................12 
3.1.3. 
Exploratory Objectives ...............................................................................................12 
3.2. 
Study Endpoints ..........................................................................................................12 
3.2.1. 
Safety Endpoints .........................................................................................................12 
3.2.2. 
Secondary Efficacy Endpoints ....................................................................................12 
3.2.3. 
Exploratory Efficacy Endpoints .................................................................................13 
4. 
STUDY DESIGN .......................................................................................................14 
4.1. 
Summary of Study Design ..........................................................................................14 
4.2. 
Definition of Study Drugs ..........................................................................................14 
4.3. 
Sample Size Considerations .......................................................................................15 
4.4. 
Randomization ............................................................................................................15 
4.5. 
Clinical Assessments ..................................................................................................16 
5. 
PLANNED ANALYSES ............................................................................................19 
5.1.1. 
Changes to Protocol Specified Analyses ....................................................................19 
5.1.2. 
Revisions to Version 1.0 Statistical analysis plan ......................................................19 
5.1.3. 
Interim Analyses .........................................................................................................19 
5.1.4. 
Final Analysis .............................................................................................................19 
6. 
CONSIDERATIONS FOR DATA ANALYSES AND HANDLING .......................20 
6.1. 
Summary Table and Individual Subject Data Listing Considerations ........................20 
6.2. 
Data Management .......................................................................................................20 
6.3. 
Data Presentation Conventions ...................................................................................20 
6.4. 
Analysis Populations ..................................................................................................21 
6.4.1. 
Screen Failures ............................................................................................................21 
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4 
 
 
  
 
6.4.2. 
Enrolled Population ....................................................................................................21 
6.4.3. 
Safety Population ........................................................................................................21 
6.4.4. 
Per-Protocol (PP) Population ......................................................................................22 
6.4.5. 
Examination of Subgroups .........................................................................................22 
6.5. 
Baseline Definition .....................................................................................................22 
6.6. 
Derived and Transformed Data ..................................................................................22 
6.6.1. 
General Variable Definitions ......................................................................................22 
6.6.2. 
Safety Variable Definitions ........................................................................................23 
6.6.3. 
Efficacy Variable Definitions .....................................................................................23 
6.6.4. 
Visit Windows ............................................................................................................24 
6.6.5. 
Multiple Assessments .................................................................................................25 
6.7. 
Handling of Missing Data ...........................................................................................25 
6.7.1. 
Missing Efficacy Endpoints ........................................................................................25 
6.7.2. 
Adverse Events Severity .............................................................................................25 
6.7.3. 
Missing Start and Stop Dates for Adverse Events ......................................................26 
6.7.4. 
Missing Start and Stop Dates for Medications ...........................................................28 
6.7.5. 
Laboratory Data ..........................................................................................................28 
7. 
STUDY POPULATION .............................................................................................29 
7.1. 
Enrollment by Investigator .........................................................................................29 
7.2. 
Subjects Disposition ...................................................................................................29 
7.3. 
Protocol Deviations ....................................................................................................29 
7.4. 
Demographic and Baseline Characteristics ................................................................30 
7.5. 
Listing of Subject Inclusion and Exclusion Criteria ...................................................30 
7.6. 
Medical History and Medical Conditions Present at Entry ........................................30 
7.7. 
Prior Medication History and Medications Present at Entry ......................................30 
7.8. 
Baseline Clinical Characteristics ................................................................................31 
7.9. 
Mini International Neuropsychiatric Interview ..........................................................31 
8. 
SAFETY AND TOLERABILITY ..............................................................................32 
8.1. 
Adverse Event Preferred Term and Body/Organ System Summary Tables ...............32 
8.2. 
Total Duration of Therapy and Compliance ...............................................................33 
8.3. 
Concomitant and Other Medications ..........................................................................33 
8.4. 
Routine Laboratory Data ............................................................................................34 
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8.5. 
Vital Signs ..................................................................................................................34 
8.6. 
ECGs ...........................................................................................................................34 
8.7. 
Hospital Anxiety and Depression Scale .....................................................................35 
8.8. 
Suicidal Risk Monitoring ............................................................................................35 
8.9. 
Testicular Ultrasound ..................................................................................................36 
9. 
EFFICACY .................................................................................................................37 
9.1. 
General Considerations ...............................................................................................37 
9.2. 
Statement of the Null and Alternate Hypotheses for the Hormone Endpoints ...........37 
9.3. 
Subgroup Analyses .....................................................................................................37 
9.4. 
Multiple Comparisons and Multiplicity......................................................................37 
9.5. 
Analysis of Secondary Efficacy Endpoints ................................................................37 
9.5.1. 
Efficacy Analysis of Hormones ..................................................................................37 
9.5.2. 
Efficacy Analysis of Hormones by Subgroups ...........................................................38 
9.6. 
Analysis of the Exploratory Efficacy Endpoints ........................................................38 
9.6.1. 
Patient Reported Outcomes ........................................................................................38 
9.6.2. 
Changes in Lipid Profile .............................................................................................38 
9.6.3. 
Changes in Insulin profile ...........................................................................................38 
9.6.4. 
Changes in Body Weight ............................................................................................39 
9.6.5. 
Bother Score ...............................................................................................................39 
10. 
REFERENCES ...........................................................................................................40 
11. 
APPENDICES ............................................................................................................41 
11.1. 
Reporting Formats ......................................................................................................41 
11.2. 
Medication Logic ........................................................................................................42 
11.3. 
Tables, Figures and Listings .......................................................................................43 
 
 
 
LE PAGE 1 
1. 
LIST OF ABBREVIATIONS.....................................................................................10 
2. 
INTRODUCTION ......................................................................................................11 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................12 
3.1. 
Study Objectives .........................................................................................................12 
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3.1.1. 
Primary Objective .......................................................................................................12 
3.1.2. 
Secondary Objectives .................................................................................................12 
3.1.3. 
Exploratory Objectives ...............................................................................................12 
3.2. 
Study Endpoints ..........................................................................................................12 
3.2.1. 
Safety Endpoints .........................................................................................................12 
3.2.2. 
Secondary Efficacy Endpoints ....................................................................................12 
3.2.3. 
Exploratory Efficacy Endpoints .................................................................................13 
4. 
STUDY DESIGN .......................................................................................................14 
4.1. 
Summary of Study Design ..........................................................................................14 
4.2. 
Definition of Study Drugs ..........................................................................................14 
4.3. 
Sample Size Considerations .......................................................................................15 
4.4. 
Randomization ............................................................................................................15 
4.5. 
Clinical Assessments ..................................................................................................16 
5. 
PLANNED ANALYSES ............................................................................................19 
5.1.1. 
Changes to Protocol Specified Analyses ....................................................................19 
5.1.2. 
Revisions to Version 1.0 Statistical analysis plan ......................................................19 
5.1.3. 
Interim Analyses .........................................................................................................19 
5.1.4. 
Final Analysis .............................................................................................................19 
6. 
CONSIDERATIONS FOR DATA ANALYSES AND HANDLING .......................20 
6.1. 
Summary Table and Individual Subject Data Listing Considerations ........................20 
6.2. 
Data Management .......................................................................................................20 
6.3. 
Data Presentation Conventions ...................................................................................20 
6.4. 
Analysis Populations ..................................................................................................21 
6.4.1. 
Screen Failures ............................................................................................................21 
6.4.2. 
Enrolled Population ....................................................................................................21 
6.4.3. 
Safety Population ........................................................................................................21 
6.4.4. 
Per-Protocol (PP) Population ......................................................................................22 
6.4.5. 
Examination of Subgroups .........................................................................................22 
6.5. 
Baseline Definition .....................................................................................................22 
6.6. 
Derived and Transformed Data ..................................................................................22 
6.6.1. 
General Variable Definitions ......................................................................................22 
6.6.2. 
Safety Variable Definitions ........................................................................................23 
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6.6.3. 
Efficacy Variable Definitions .....................................................................................23 
6.6.4. 
Visit Windows ............................................................................................................24 
6.6.5. 
Multiple Assessments .................................................................................................25 
6.7. 
Handling of Missing Data ...........................................................................................25 
6.7.1. 
Missing Efficacy Endpoints ........................................................................................25 
6.7.2. 
Adverse Events Severity .............................................................................................25 
6.7.3. 
Missing Start and Stop Dates for Adverse Events ......................................................26 
6.7.4. 
Missing Start and Stop Dates for Medications ...........................................................28 
6.7.5. 
Laboratory Data ..........................................................................................................28 
7. 
STUDY POPULATION .............................................................................................29 
7.1. 
Enrollment by Investigator .........................................................................................29 
7.2. 
Subjects Disposition ...................................................................................................29 
7.3. 
Protocol Deviations ....................................................................................................29 
7.4. 
Demographic and Baseline Characteristics ................................................................30 
7.5. 
Listing of Subject Inclusion and Exclusion Criteria ...................................................30 
7.6. 
Medical History and Medical Conditions Present at Entry ........................................30 
7.7. 
Prior Medication History and Medications Present at Entry ......................................30 
7.8. 
Baseline Clinical Characteristics ................................................................................31 
7.9. 
Mini International Neuropsychiatric Interview ..........................................................31 
8. 
SAFETY AND TOLERABILITY ..............................................................................32 
8.1. 
Adverse Event Preferred Term and Body/Organ System Summary Tables ...............32 
8.2. 
Total Duration of Therapy and Compliance ...............................................................33 
8.3. 
Concomitant and Other Medications ..........................................................................33 
8.4. 
Routine Laboratory Data ............................................................................................34 
8.5. 
Vital Signs ..................................................................................................................34 
8.6. 
ECGs ...........................................................................................................................34 
8.7. 
Hospital Anxiety and Depression Scale .....................................................................35 
8.8. 
Suicidal Risk Monitoring ............................................................................................35 
8.9. 
Testicular Ultrasound ..................................................................................................36 
9. 
EFFICACY .................................................................................................................37 
9.1. 
General Considerations ...............................................................................................37 
9.2. 
Statement of the Null and Alternate Hypotheses for the Hormone Endpoints ...........37 
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Statistical Analysis Plan- Study SPR001-202 
 
APR 20 2020 
 
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9.3. 
Subgroup Analyses .....................................................................................................37 
9.4. 
Multiple Comparisons and Multiplicity......................................................................37 
9.5. 
Analysis of Secondary Efficacy Endpoints ................................................................37 
9.5.1. 
Efficacy Analysis of Hormones ..................................................................................37 
9.5.2. 
Efficacy Analysis of Hormones by Subgroups ...........................................................38 
9.6. 
Analysis of the Exploratory Efficacy Endpoints ........................................................38 
9.6.1. 
Patient Reported Outcomes ........................................................................................38 
9.6.2. 
Changes in Lipid Profile .............................................................................................38 
9.6.3. 
Changes in Insulin profile ...........................................................................................38 
9.6.4. 
Changes in Body Weight ............................................................................................39 
9.6.5. 
Bother Score ...............................................................................................................39 
10. 
REFERENCES ...........................................................................................................40 
11. 
APPENDICES ............................................................................................................41 
11.1. 
Reporting Formats ......................................................................................................41 
11.2. 
Medication Logic ........................................................................................................42 
11.3. 
Tables, Figures and Listings .......................................................................................43 
 
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Statistical Analysis Plan- Study SPR001-202 
 
APR 20 2020 
 
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LIST OF TABLES 
 
Table 1: 
List of Abbreviations ..................................................................................................10 
Table 2: 
Baseline Specifications for Specific Variables ...........................................................22 
Table 3: 
Analysis Visit Windows .............................................................................................24 
Table 4: 
Analysis Windows for Safety Endpoints ....................................................................25 
Table 5: 
Vital Signs Outlier Thresholds ...................................................................................34 
Table 6: 
ECG Outlier Thresholds .............................................................................................35 
 
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1. 
LIST OF ABBREVIATIONS 
Table 1: 
List of Abbreviations 
Abbreviation 
Term 
17-OHP 
17-hydroxyprogesterone 
A4 
Androstenedione 
ACTH 
Adrenocorticotropin hormone, corticotropin 
AE 
Adverse Event 
C 
Continuous reporting format 
CAH 
Congenital adrenal hyperplasia 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
dy 
Days 
F 
Frequency reporting format 
G 
Geometric mean reporting format 
GCP 
Good Clinical Practices 
HbA1c 
hemoglobin A1c 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat Population 
LLN 
Lower Limit of Normal 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities Terminology 
MF 
Multiple frequency reporting format 
mITT 
Modified Intent-to-Treat 
mo 
Months 
N 
Total Sample Size 
OTC 
Over the Counter Medication 
PP 
Per-Protocol Population 
SD 
Standard Deviation 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System  
SF-36 
Short Form 36 
TART 
Testicular adrenal rest tumor 
ULN 
Upper Limit of Normal 
WHO 
World Health Organization  
yr 
Years 
 
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2. 
INTRODUCTION 
This document outlines the initial plan for the summarization and analysis of clinical data 
collected in Study SPR001-202 for tildacerfont, SPR001.  
The analysis of pharmacokinetics (data derivation and summary of individual PK parameters) is 
outside the scope of this document and is not addressed here. 
This document describes the a priori plan for analysis.  Once the analysis is in progress, it may 
become apparent from the data that the planned analysis should be modified.  Any substantive 
modification to the original analysis plan will be identified in the clinical study report (CSR). 
 
 
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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
3.1.1. 
Primary Objective 
The primary objective is: 
• To evaluate the safety of SPR001 in subjects with CAH. 
3.1.2. 
Secondary Objectives 
The secondary objectives are: 
• To evaluate the efficacy of SPR001 in subjects with CAH in terms of changes in 
hormones. 
3.1.3. 
Exploratory Objectives 
The exploratory objectives are: 
• To evaluate the effect of SPR001 on quality of life (QoL), metabolic parameters, 
exploratory adrenal hormones, and sex-specific outcomes in subjects with CAH. 
3.2. 
Study Endpoints 
3.2.1. 
Safety Endpoints 
The safety endpoints of this study include the following: 
• Adverse events (AE) and Serious adverse events (SAE). 
Additional safety endpoints include the following: 
• Change from baseline in safety laboratory, vital signs, and electrocardiogram (ECG) 
parameters, 
• Clinical changes as determined by physical examinations (including testicular ultrasound 
for males), 
• Suicidality as measured by the Columbia-Suicide Severity Rating Scale (C-SSRS), and  
• Hospital Anxiety and Depression Scale (HADS) 
• Concomitant medication usage. 
3.2.2. 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints of this study are: 
• Change and percent change from baseline in plasma or serum biomarkers: 17-OHP, 
ACTH, androstenedione (A4), and testosterone. 
 
 
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3.2.3. 
Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints of this study are: 
• Changes in QoL as measured using the Short Form 36(SF-36), 
• Changes in Patient Global Impression of Change (PGIC), 
• Changes in bother score 
• Changes in CAH signs and symptoms total score, 
• Changes in fasting glucose, 
• Changes in hemoglobin A1c (HbA1c), 
• Changes in lipid profile, 
• Changes in body weight (BW) and body mass index (BMI), 
• Changes in acne, 
• Changes in hirsutism in females subjects, 
• Changes in menstrual cyclicity in female subjects, 
• Changes in TARTs and on semen analysis in male subjects. 
 
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4. 
STUDY DESIGN 
4.1. 
Summary of Study Design 
This is a Phase 2 study of SPR001 for the treatment of classic CAH that will provide 12 weeks of 
open-label treatment to eligible subjects. To be eligible for this study, an individual must either 
have completed Study SPR001-201 or meet criteria for SPR001-naïve subjects outlined under 
Eligibility Criteria.  
Subjects who enroll in this study will be treated with SPR001 at 400 mg once a day (QD) during 
the treatment period. 
Study visits will occur every 2 weeks and should be scheduled for the morning, to accommodate 
8 am laboratory assessments. Study visits for screening and at Day 1 (Baseline), Week 4, Week 
8, and Week 12 (end of treatment) will be conducted as in-clinic visits. Study visits at Week 2, 
Week 6, and Week 10 may be conducted as either in-clinic visits or in-home visits by qualified 
study personnel. A final safety follow-up outpatient clinic visit will occur 30 days after the last 
dose of study drug.  
To reduce subject burden, the final safety follow-up visit in Study SPR001-201 for subjects 
completing that study and rolling over into this study may coincide with the screening visit of 
this study (with any overlapping assessments conducted only once). Subjects who completed the 
final follow-up visit in Study SPR001-201 >3 months before screening in this study and subjects 
naïve to SPR001 must complete anew all specified screening assessments for this study. Subjects 
will maintain a stable dose and regimen of glucocorticoids throughout this study. 
Figure 1: 
Study Schema 
 
4.2. 
Definition of Study Drugs 
Study drug comprises the following: 
• SPR001 400 mg once daily (two 200 mg capsules): Taken orally for up to 12 weeks 
in the evening (approximately 10 pm or bedtime) with a snack 
Treatment Period 
Baseline 
(Day 1) 
Week 4 
Screening 
Final 
Follow-up 
Follow-up 
 Screening 
12 weeks 
≤30 days 
Week 2 
Week 8 
Week 12 (end  
of treatment) 
Week 6 
Week 10 
30 days 
SPR001-naïve  
subjects 
 
Enriched 
SPR001-naive 
subjects 
Subjects 
completing 
Study 
SPR001-201 
Males with 
TART(s) 
Females 
with acne 
hirsutism, or 
ovulatory 
dysfunction 
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4.3. 
Sample Size Considerations 
The sample size of up to approximately 24 subjects in this study is based on an estimate of the 
number of subjects who may enroll either after completing Study SPR001-201 or as SPR001-
naïve subjects. There is no statistical basis for the sample size, 
The final sample size for the study is n=11.  
4.4. 
Randomization 
This is an open label study.  All enrolled subjects receive the same treatment with no 
randomization. 
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4.5. 
Clinical Assessments 
  
 
Screening Period 
Treatment Period 
Follow-up/ET 
VISIT NUMBER 
11 
Screening 
2 
Baseline 
3 
4 
5 
6 
7 
8 
9 
STUDY WEEK 
 
0 
2 
4 
6 
8 
10 
12 
16 
STUDY DAY2 
≤30 days before Day 
1 
1 
15 
29 
43 
57 
71 
85 
Last dose  
+30 days 
Site Visits3 
X 
X 
 
X 
 
X 
 
X 
X 
Home Visits4 
 
 
X 
 
X 
 
X 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
Demography5 
X 
 
 
 
 
 
 
 
 
Medical history6 
X 
 
 
 
 
 
 
 
 
Prior medications6 
X 
 
 
 
 
 
 
 
 
Concomitant medications7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
1 For subjects rolling over from Study SPR001-201, the final safety follow-up visit of Study SPR001-201 may coincide with the screening visit of this study (with any overlapping assessments conducted 
only once). If a subject completed the final follow-up visit of Study SPR001-201 ≤3 months before the screening period of this study, overlapping assessments conducted at that final follow-up visit 
need not be repeated at screening for this study. If a subject completed the final follow-up visit of Study SPR001-201 >3 months before the screening period of this study, all screening assessments 
must be conducted anew, including some additional screening assessments specified for such subjects. 
2 All visits should be performed on the indicated study days. In cases where this is not possible, the following visit windows apply: ±3 days for Visits 3 to 8 and ±7 days for the safety follow-up visit 
(Visit 9). All visits, including the early termination visit, should be scheduled for the morning, to accommodate 8am laboratory assessments. 
3 Study visits for screening; at Weeks 0, 4, 8, and 12; and at final follow-up must be conducted as in-clinic outpatient visits. 
4 Study visits at Weeks 2, 6, and 10 may be conducted as either in-clinic outpatient visits or in-home visits by qualified study personnel. 
5 Demographic information needs to be collected only for SPR001-naïve subjects. 
6 Full medical history and prior medications from the past year will be collected for SPR001-naïve subjects. If a subject completed the final follow-up visit in Study SPR001-201 before the screening 
period for this study, any significant medical history and medications taken during the intervening period should be captured. 
7 Subjects should be on a stable regimen of glucocorticoid replacement for a minimum of 30 days before baseline and throughout the treatment period. On the mornings of all study visits, including 
screening, subjects should hold off on taking any morning glucocorticoid medication until after laboratory assessments have been completed. On all other days during the study, subjects may take any 
morning dose of glucocorticoid medication at their usual time. 
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Screening Period 
Treatment Period 
Follow-up/ET 
VISIT NUMBER 
11 
Screening 
2 
Baseline 
3 
4 
5 
6 
7 
8 
9 
STUDY WEEK 
 
0 
2 
4 
6 
8 
10 
12 
16 
STUDY DAY2 
≤30 days before Day 
1 
1 
15 
29 
43 
57 
71 
85 
Last dose  
+30 days 
Site Visits3 
X 
X 
 
X 
 
X 
 
X 
X 
Home Visits4 
 
 
X 
 
X 
 
X 
 
 
Clinical laboratory8,9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HbA1c8 
 
X 
 
X 
 
X 
 
X 
 
Key hormones8,10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Exploratory adrenal hormones8,11 
 
X 
 
X 
 
X 
 
X 
 
PK8,12 
X 
X 
 
X 
 
X 
 
X 
X 
Hepatitis B & C and HIV screening13 
X 
 
 
 
 
 
 
 
 
eGFR for screening13,14 
X 
 
 
 
 
 
 
 
 
Pregnancy test for WOCP15 
X 
X 
 
X 
 
X 
 
X 
X 
Vital signs16 and body weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
8 Samples for these lab assessments will be obtained at the beginning of each study visit (8am), after overnight fast (nothing to eat since the previous midnight), and before the subject has taken any 
morning dose of glucocorticoid medication. If a morning dose of study drug is added, samples for these lab assessments will be obtained before the morning dose of study drug for that day (where 
applicable). 
9 Clinical laboratory assessments include hematology, clinical chemistry, fasting glucose, lipid panel, thyroid panel, urinalysis, LH, FSH, inhibin B, SHBG, renin, aldosterone, and, for females only, 
estradiol, prolactin, and progesterone. 
10 ACTH, 17-OHP, androstenedione, testosterone, and background glucocorticoid levels (cortisol/prednisolone/dexamethasone, depending on what the subject is taking) will be measured from blood 
samples. 17-OHP will also be measured from a saliva sample. 
11 A single blood sample will be drawn for measurement of exploratory adrenal hormones at each specified visit. 
12 A single blood sample will be drawn for PK measurement at each specified visit. The PK blood sample does not need to be obtained from SPR001-naïve subjects at screening. 
13 These screening assessments will be performed for SPR001-naïve subjects and for subjects who completed the final follow-up visit in Study SPR001-201 >3 months before the screening visit for this 
study. 
14 eGFR for screening will be calculated from blood creatinine measured as part of clinical chemistry during screening. 
15 A serum pregnancy test will be performed at screening for WOCP who are SPR001-naïve and for WOCP who completed the final follow-up visit in Study SPR001-201 >3 months before the screening 
visit for this study. All other pregnancy tests will be urine pregnancy tests. 
16 Systolic and diastolic blood pressure, pulse rate, body temperature, and respiration rate. 
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Screening Period 
Treatment Period 
Follow-up/ET 
VISIT NUMBER 
11 
Screening 
2 
Baseline 
3 
4 
5 
6 
7 
8 
9 
STUDY WEEK 
 
0 
2 
4 
6 
8 
10 
12 
16 
STUDY DAY2 
≤30 days before Day 
1 
1 
15 
29 
43 
57 
71 
85 
Last dose  
+30 days 
Site Visits3 
X 
X 
 
X 
 
X 
 
X 
X 
Home Visits4 
 
 
X 
 
X 
 
X 
 
 
Physical examination17  
X 
X 
 
X 
 
X 
 
X 
X 
Scrotal ultrasound for males 
X18 
X 
 
 
 
 
 
X 
 
Optional semen sample for males19 
 
X 
 
 
 
 
 
X 
 
12-lead ECG 
X 
X 
 
X 
 
X 
 
X 
 
MINI Version 7.0.213 
X 
 
 
 
 
 
 
 
 
C-SSRS 
X 
X 
 
X 
 
X 
 
X 
 
HADS 
X 
X 
 
X 
 
X 
 
X 
X 
SF-3620 
 
X 
 
X 
 
X 
 
X 
X 
PGIC 
 
 
 
X 
 
X 
 
X 
X 
Bother score 
 
X 
 
X 
 
X 
 
X 
 
CAH signs and symptoms interview 
 
X 
 
X 
 
X 
 
X 
X 
Diary 
X 
 
 
 
 
 
 
 
 
Dispense study drug21 
 
X 
 
X 
 
X 
 
 
 
Study drug accountability 
 
 
X 
X 
X 
X 
X 
X 
 
Review adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
17 A full physical examination will be conducted at baseline (Day 1) and end of treatment (Week 12) for all subjects. A full physical examination will also be conducted at screening for SPR001-naïve 
subjects and subjects who completed the final follow-up visit in Study SPR001-201 >3 months before the screening visit for this study. The full physical examination may exclude rectal, genitourinary, 
and breast exams. An abbreviated physical examination will be conducted at Weeks 4 and 8 and final follow-up. Height needs to be collected at screening only. As part of the examination of the skin, 
acne will be evaluated for all subjects using an IGA score at baseline and Weeks 4, 8, and 12; hirsutism will be evaluated for female subjects using an mFG score at baseline and Week 12. Female 
subjects will be asked about their last menstrual period as part of both full and abbreviated physical exams. 
18 A scrotal ultrasound is required at screening only for SPR001-naïve male subjects. 
19 All male subjects should be encouraged (though not required) to provide a semen sample. Semen will be collected from male subjects for analysis of sperm count, morphology, and motility. 
20 The 4-week SF-36 will be administered. 
21 Subjects will be dispensed a 4-week supply of study drug each time. If a morning dose of study drug is added, subjects should hold off on taking their morning dose of study drug on the mornings of 
all study visits until after laboratory assessments have been completed. On all other days during the study, subjects should take their morning dose of study drug (if applicable) at the usual time. 
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5. 
PLANNED ANALYSES 
5.1.1. 
Changes to Protocol Specified Analyses 
Due to the low enrollment numbers for subjects enriched with acne and hirsutism at baseline 
(n=2), these endpoints will not be summarized.  
Due to no samples collected, analysis of semen will not be summarized. 
Due to the study short duration and lack of adequate baseline data, menstrual cyclicality will not 
be summarized. 
5.1.2. 
Revisions to Version 1.0 Statistical analysis plan 
The following changes are identified between version 1.0 and version 2.0 of the SAP 
Subject 004-004 was determined to be off treatment prior to the Week 4 (Day 28) visit starting at 
Day 21.  The following pharmacodynamic assessments were conducted and for the purposes of 
summary analysis will bet set to missing as this is an exploratory study with the primary intent to 
characterize on-treatment pharmacodynamic effects during the first 12 weeks of the study. 
Analysis Visit 
Parameter 
Value 
Summary Value 
Week 4 
17-OHP 
24746 
missing 
Week 4 
ACTH 
570.1 
missing 
Week 4 
A4 
1711 
missing 
Week 4 
TEST 
459.5 
missing 
5.1.3. 
Interim Analyses 
As this study is open-label, data cuts may be taken during study conduct to inform the future 
development plan for tildacerfont.  No formal statistical analyses are conducted in this SAP. 
5.1.4. 
Final Analysis 
The final analysis is planned once all enrolled subjects complete the Week 16 visit or discontinue 
prior to Week 16. 
 
 
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6. 
CONSIDERATIONS FOR DATA ANALYSES AND HANDLING 
All data from scheduled and unscheduled visits will be presented in the subject listings.  
However, unless noted otherwise, only data from scheduled/windowed visits will be included in 
the summaries, statistical analysis, and calculation of derived parameters. 
6.1. 
Summary Table and Individual Subject Data Listing Considerations 
Summary tables and listings (e.g., post text tables and individual subject data listings are 
prepared according to ICH Guideline E3) include a “footer” providing explanatory notes. 
6.2. 
Data Management 
Analyses and tabulations will generally be prepared using SAS, version 9.3 or later. 
Adverse Events 
Recorded adverse events will be mapped according to the MedDRA thesaurus with Theravance 
review and approval of the mappings.  MedDRA, version 21.0 will be used 
Medications 
Recorded prior and concomitant medication names will be mapped according to the World 
Health Organization Drug Dictionary (WHODD) for this study with Theravance review and 
approval of the mappings.  The 3Q2108 version of the WHODD will be used. 
Medical History 
Medical history will be mapped according to MedDRA version 21.0 and will be provided in 
listings.  
6.3. 
Data Presentation Conventions 
Table, Figure and Listing titles 
Table, figures and listing titles are denoted in underlined text in this SAP. For a complete list, see 
Appendix Section 11.3. 
Reporting Formats 
Appendix Section 11.1 lists the available reporting formats for summaries. 
Presenting Multiple Summaries on Same Table Summary 
In summary tables in which multiple single line frequency summaries are being presented, the “n 
line” can be suppressed in the individual summaries and presented at the top of the summary a 
single time. 
Ordering of Treatment Headers in Summary Tables 
In summary tables, treatment headers will be presented in the following order: 
• Tildacerfont 400 mg QD. 
 
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Rounding 
In general, the convention for rounding percentages is as follows: 
• Values greater than or equal to x.x5 are rounded up, 
• Values between 0 and less than x.x5 are rounded down, 
• Values between –x.x5 and 0 are rounded up, 
• Values less than or equal to −x.x5 are rounded down. 
Significant Digits 
Raw measurements will be reported the same as the data captured electronically or on the CRFs. 
Exceptions will be made for values reported with greater than 4 significant digits (round to 4 
significant digits using a similar criterion as for percentages with the 5 in the last digit)). 
The following significant digit convention will be used for the purposes of summarizing data in 
tables: 
• Mean, median: 2 significant digits, 
• Standard deviation: 3 significant digits, 
• Minimum, maximum: 2 significant digits, 
• Percentages: 1 decimal place. 
P-values 
P-values will be reported with 4 significant digits except when reporting p-values less than 
0.001, reported as < 0.001.  No p-values smaller than <0.001 will be reported.  
Colors/Symbols in Figures 
In figures that only contain the 3 treatment groups, the following colors will be used: 
• SPR001 400 mg QD (dodger blue- CX1E90FF / Square filled), 
6.4. 
Analysis Populations  
6.4.1. 
Screen Failures 
Subjects who give informed written consent but are not randomized are considered screen 
failures. Screen failure subjects and the main reason for screen fail will be captured in the EDC. 
6.4.2. 
Enrolled Population 
The Enrolled analysis set will include all subjects who were enrolled into the study. 
6.4.3. 
Safety Population 
The Safety analysis set will include all subjects who 
1. Were enrolled into the study, and, 
2. Received at least one dose of study drug.  
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The Safety analysis set is the primary analysis set for all analyses. 
6.4.4. 
Per-Protocol (PP) Population  
The Per-protocol analysis set included all subjects in the safety analysis set who meet the 
following criteria: 
1. No major analysis protocol deviations 
Treatment assignment will be based on actual treatment. 
Major Analysis Protocol Deviations 
Major analysis protocol deviations that could potentially affect the conclusions of the study will 
be identified prior to database lock.  Major analysis protocol deviations include: 
1. Study drug compliance defined as compliance < 80% or ≥ 120% over the interval from 
first to last dose for the treatment period, 
Subjects with major analysis protocol deviations will be identified before the database lock.  
6.4.5. 
Examination of Subgroups 
The following subgroups are pre-defined: 
1. Sex:  [a] male, [b] female  
2. Baseline hormone control:  [a] severe/moderate control issues, [b] mild control issues 
3. Baseline Glucocorticoid category: [a] Non-Dexamethasone [b] Dexamethasone 
Selected analysis will be conducted using the subgroup analysis sets.  
6.5. 
Baseline Definition 
The following table indicates the baseline to be used in the analysis. 
Table 2: 
Baseline Specifications for Specific Variables 
Parameter 
Day 1 pre-dose 
Laboratory (Chemistry, Hematology, Urinalysis) 
x 
Biomarkers 
x 
ECG 
x 
Vital signs 
x 
PROs  
x 
6.6. 
Derived and Transformed Data 
6.6.1. 
General Variable Definitions 
Baseline Age  
Subject’s age in years will be calculated based on date of informed consent date using the 
following formula: 
Age (year) = FLOOR ((date of informed consent – date of birth)/365.25*12) where FLOOR ( ) 
function returns the integer part of the result. 
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Study Day 
If the date of interest occurs on or after the first dose date, then study day will be calculated as 
(date of interest – date of first dose) + 1.  
If the date of interest occurs prior to the first dose date, then study day will be calculated as (date 
of interest – date of first dose).  
There is no study day 0. 
BMI 
BMI will be calculated and converted to metric units by the following: 
(
)
(
)
( )
2
2
/
.
weight kg
BMI kg m
height m
=
 
6.6.2. 
Safety Variable Definitions 
Compliance 
% Compliance = percentage of study drug actually taken compared to what was expected based 
on the planned dose in time period i (where subject is receiving a constant dose), calculated as 
follows: 
%𝐶𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒𝑖= 100 × (
# 𝐷𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑−# 𝑅𝑒𝑡𝑢𝑟𝑛𝑒𝑑
# 𝐷𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑−# 𝐸𝑥𝑝𝑒𝑐𝑡𝑒𝑑 𝑅𝑒𝑡𝑢𝑟𝑛𝑒𝑑)
𝑖
 
Treatment Emergent Adverse Events 
Adverse events (AEs) are recorded from signing of the informed consent form through the final 
follow-up assessment. 
Adverse events observed prior to first dose are non-treatment emergent. 
Treatment emergent adverse events are events with a start date/time after the first dose date/time 
until the last dose date/time plus the protocol defined follow-up period, 30 days.  
Adverse events observed after the last dose and after the follow-up period are non-treatment 
emergent. 
Only treatment-emergent AEs will be summarized in the tables.   
6.6.3. 
Efficacy Variable Definitions 
Baseline Hormone Control 
Severe: Baseline ACTH > 4x ULN and A4 > 2x ULN 
Moderate: Baseline ACTH > 2x ULN and A4 > 2x ULN 
Severe/Moderate: Baseline ACTH > 2x ULN and A4 > 2x ULN 
Mild: Baseline ACTH ≤ 2x ULN and A4 ≤ 2x ULN 
 
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Hormone Control Responder 
Week 12 ACTH < ULN and A4 < ULN 
Hydrocortisone equivalents 
Hydrocortisone equivalent (mg) = Corticosteroid (mg) ˟ Conversion Factor, using the following 
corticosteroid dosages equivalence table (reference is hydrocortisone 20 mg): 
Medication 
Equivalent Dose 
Conversion Factor 
Cortisone Acetate 
25 mg 
0.8 
Hydrocortisone 
20 mg 
1 
Prednisone/Prednisolone/ Methylprednisolone 
4 mg 
5 
Dexamethasone 
0.25 mg 
80 
Betamethasone 
0.6 mg 
33.33 
For example, if a subject receives 10 mg of prednisone, that is equivalent to 50 mg of 
hydrocortisone. 
Upper limit of Normal (ULN) 
The following are the upper limit of normal or targets based on the lab reference ranges.  
Hormone 
SEX 
ULN/Target 
Serum 17-OHP 
males 
< 1200 ng/dL 
Serum 17-OHP 
females 
< 1200 ng/dL 
ACTH 
males 
< 63.3 pg/mL 
ACTH 
females 
< 63.3 pg/mL 
A4 
males 
< 152 ng/dL 
A4 
females 
< 262 ng/dL 
6.6.4. 
Visit Windows 
All assessments will be summarized using analysis windows.  
The terminology of unscheduled will be applied to assessments that are outside an analysis 
window regardless, of the nominal label associated with the assessments in the EDC system. 
The following visit windows will be used in the summary of clinical data. 
Table 3: 
Analysis Visit Windows 
Nominal Period/Visit 
Start (days) 
Stop (days) 
Baseline 
1 
1 
Week 2 (Day 15) 
2 
21 
Week 4 (Day 29) 
22 
35 
Week 6 (Day 43) 
36 
49 
Week 8 (Day 57) 
50 
63 
Week 10 (Day 71) 
64 
77 
Week 12 (Day 85) 
78 
91 
Week 16 (Day 112) 
92 
120 
 
 
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Safety Endpoints 
The following windows summarize the definition of treatment-emergent. 
Table 4: 
Analysis Windows for Safety Endpoints 
Window 
Start 
Stop 
Adverse events 
Sign of ICF 
30 days post last dose 
Treatment-emergent Adverse 
events, ECGs and Labs 
Post first dose 
Last dose + 30 days 
Prior Medications 
Prior to first dose 
First dose 
Concomitant Medications 
Post first dose 
Last dose + 24 hours 
Post Medications 
Post last dose + 24 hours 
NA 
6.6.5. 
Multiple Assessments 
In general, if multiple, valid, non-missing observations exist at a visit or collection time point 
then records will be chosen based on the following rules.  
The record closest to the nominal time point in question. 
If 2 records are equidistant: later record if the two visits.  
If 2 records with same date/time: average (generally applies to assessments done in triplicate). 
6.7. 
Handling of Missing Data 
6.7.1. 
Missing Efficacy Endpoints 
Missing data will not be imputed for continuous efficacy endpoints in primary or secondary 
analyses.   
A sensitivity analysis will impute missing hormone data using last observation carried forward. 
For binary efficacy endpoints, missing data will be assumed as a failure (subject did not meet the 
efficacy endpoint). 
6.7.2. 
Adverse Events Severity 
For graded adverse event summaries, AEs with no grade reported will be graded as severe. 
 
 
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6.7.3. 
Missing Start and Stop Dates for Adverse Events 
Missing start date and times will be handled as follows: 
• AE onset date completely missing: 
− If AE is not ongoing and AE onset date missing and AE end date missing, then 
impute AE onset as date/time of first dose. 
− Else if AE is not ongoing and AE onset date missing and AE end date not missing 
and date/time of first dose <= AE end date, then impute AE onset as date/time of 
first dose of study drug. 
− Else if AE is not ongoing and AE onset date missing and AE end date not missing 
and AE end date is BEFORE first dose of study drug, then impute AE onset as 
AE end date YEAR and MONTH with 01 as the day and 00:00 as time. 
− Else if AE IS ongoing and AE onset date missing, then impute AE onset as 
date/time of first study drug dose. 
• AE onset date has year and month only: 
− If AE onset date has year and month only and they are the year and month of first 
dose of study drug, then impute AE onset as date/time of first dose: 
− Else if AE onset date has year and month only and date/time of first dose is not 
missing, then impute AE onset as AE onset year and month with 01 as the date 
and 00:00 as the time. 
• AE onset date has year only: 
− If AE onset date has year only and it is year of first dose of study drug, then 
impute AE onset as date/time of first dose of study drug. 
− Else if AE onset date has year only and date of first study drug dose is not missing 
and year of AE onset is NOT the year of first dose of study drug, then impute AE 
onset as Jan. 1 of the AE onset year and 00:00 as the time. 
• AE onset missing (where it was not handled by the above cases): 
− If AE onset date is missing, then impute AE onset as date/time of first study drug 
dose. 
• AE onset has complete date but missing time: 
− If AE onset date is a date only and is same as date of first study drug dose, then 
impute AE onset as date/time of first study drug dose. 
− Else if AE onset date is a date only and is NOT = date of first study drug dose, 
then impute AE onset as AE onset date with 00:00 as the time. 
 
 
 
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Missing end date and times will be handled as follows: 
• AE end date - completely missing:  
− If AE if not ongoing and both AE onset and AE end dates are missing, then 
impute AE end date as date/time of last study drug dose. 
− Else if AE is not ongoing and AE onset date not missing and AE end date missing 
AND AE onset date <= date/time of last dose, then impute AE end date as 
date/time of last study drug dose. 
− Else if AE is not ongoing and AE onset date is not missing and AE end date is 
missing and date of last dose is not missing and AE onset is AFTER date of last 
dose, then impute AE end date as the last day of the month of AE onset date, with 
23:59 as time.  
• AE end date = year and month only: 
− If AE is NOT ongoing and AE end date consists of year and month only, then 
impute AE end date as the last day of the month of AE end date month and year, 
with 23:59 as time.  
• AE end date = year only: 
− If AE is NOT ongoing and AE end date consists of a year only, and year = year of 
AE onset and AE onset date <= date of last study drug dose, then impute AE end 
date as the date of last study drug dose. 
− Else if AE is NOT ongoing and AE end date consists of a year only, and year = 
year of AE onset and AE onset date > date of last study drug dose, then impute 
AE end date as the year and month of AE onset, with the last day of the month as 
the day, and 23:59 as the time. 
• AE end date = complete date but no time: 
− If AE is NOT ongoing and AE end date consists of a complete date but no time, 
then impute AE end date = trim (AE end date) || "T23:59".  
 
 
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6.7.4. 
Missing Start and Stop Dates for Medications 
To determine whether medications were used prior to initiation of dosing and whether they were 
used after initiation of dosing, missing or partial dates for medications will be imputed according 
to the following rule: 
Missing medication start date/time: 
• If only have a YEAR, impute as Jan. 1, at one minute after midnight. 
• Else if only have YEAR and MONTH, impute as Day 1 of month, at one minute after 
midnight. 
• Else if have a complete date, impute TIME as one minute after midnight. 
• Else if completely missing, and ((end date is present and >=date of first dose) or (end 
date is missing and is marked as “ONGOING”)), impute as date and time of first 
dose. If missing and end date/time is present and prior to date of first dose then leave 
as missing. 
Missing medication end date/time: 
• If only have a YEAR and it is same as year of study completion, impute as date of 
study completion with time of 23:59. 
• Else if only have a YEAR, impute as December 31 with time of 23:59. 
• Else if only have YEAR and MONTH, then impute to last day of the month, with 
time of 23:59. 
• Else if have a complete date but no time, impute time of 23:59 
• Else if end date/time completely missing and not flagged as Ongoing, impute as date 
of study completion with time of 23:59. 
Otherwise missing, no imputation.  
6.7.5. 
Laboratory Data 
For non-efficacy laboratory data, a missing baseline value will be replaced with the last available 
assessment, generally the screening assessment.  A retest value will be used if the first test is 
invalidated, e.g., specimen hemolyzed.   
Laboratory data that are continuous in nature but are less than the lower limit of 
quantitation/limit of detection (LOD) will be, in general, imputed as follows: 
• A value that is 1 unit less than the LOD will be used for calculation of descriptive 
statistics if the data are reported in the form of “< x” (x is considered as the LOD).  
More specifically, x−1 is used for data summarization if the data are reported in the 
form of “< x”; and x.e where e = d−1, will be used for analysis if the data are reported 
in the form of “< x.d”; 
• The LOD will be used for calculation of descriptive statistics if the data is reported in 
the form of “≤x” or “≥x. 
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7. 
STUDY POPULATION 
7.1. 
Enrollment by Investigator 
Enrollment by investigator will summarize the number of subjects enrolled by investigator by 
treatment group and total, sorted by highest enroller first. 
The randomized analysis set is used to for this summary. 
7.2. 
Subjects Disposition 
Subject disposition information will be summarized for all subjects by dose.  Summaries will 
include: 
Label 
Reporting Format 
Subject Enrolled 
F 
Subjects Enrolled and Treated with Study Drug 
F 
Subjects Enrolled and NOT Treated with Study Drug 
F 
Subjects Completing Study  
F 
Subjects Not Completing Study 
MF; Adverse event, 
Lost of follow-up, 
Non-compliance 
with study drug, 
Physician Decision, 
Pregnancy,  
Protocol Violation, 
Study terminated by 
Sponsor,  
Other 
A listing of subject disposition will include the ITT analysis set status, the date of informed 
consent signed, the date of first dose and last dose of study drug, primary reason for subject 
discontinuation of study medication, the date of last visit, study completion status, primary 
reason for study termination, and the date of last contact. 
The randomized analysis set is used to for this summary. 
7.3. 
Protocol Deviations 
A summary of protocol deviation identified prior to database lock by site will be provided. 
In addition, 2 listings will be provided, a listing of protocol deviation identified prior to database 
lock and a listing of protocol deviation identified post database lock.  The second listing will 
compose any new protocols derivations identified during site close out visits. 
In addition, a listing of all major analysis protocol deviations will be provided. 
The randomized analysis set is used to for this summary. 
 
 
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7.4. 
Demographic and Baseline Characteristics 
Demographics and baseline characteristics will be summarized. 
Label 
Reporting Format 
Subject Age 
C 
Sex 
MF;  
Male,  
Female,  
Missing 
Ethnicity 
MF;  
Hispanic or Latino,  
Not Hispanic or 
Latino,  
Not Reported, 
Unknown, Missing 
Race 
MF;  
White, Black or 
African American, 
Asian,  
American Indian or 
Alaska Native,  
Native Hawaiian or 
Other Pacific 
Islander,  
Other,  
Multiple Race, 
Missing 
Baseline Weight (kg) 
C  
Baseline Height (cm) 
C 
BMI (kg/m^2) 
C 
A listing will also be provided. 
7.5. 
Listing of Subject Inclusion and Exclusion Criteria 
A listing of Inclusion and Exclusion criteria will be provided.  
7.6. 
Medical History and Medical Conditions Present at Entry 
Medical history will be summarized by treatment group, system Organ class and preferred term. 
7.7. 
Prior Medication History and Medications Present at Entry 
Prior Medications will be listed and summarized separately.  
Summaries will be provided for glucocorticoid medications and prior medications summarizing 
medication name by the number and proportions of subjects with use.  
Coding logic for each group is in Appendix Section 11.2. 
 
 
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7.8. 
Baseline Clinical Characteristics 
A summary of Baseline Hormones will be provided: 
Label 
Reporting Format 
Baseline Serum 17-OHP 
GM 
Baseline ACTH 
GM 
Baseline Androstedione (A4) 
GM 
7.9. 
Mini International Neuropsychiatric Interview 
The number and percent of subjects answering affirmatively (i.e., “yes”) to the questions in the 
Mini International Neuropsychiatric Interview (MINI) (version 7.0.2) questionnaire will be 
tabulated by individual cohort and overall.  
The topics of the questionnaire include past and current instances of Major Depressive Episode, 
Suicidality, Manic/Hypomanic Episodes, Bipolar I and II Disorders, and Psychotic Disorders 
(including Major Depressive Episodes or Bipolar Episodes with Psychotic Features). 
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8. 
SAFETY AND TOLERABILITY 
The analysis of safety and tolerability data includes an overall summary of tolerability, adverse 
event preferred terms by body/organ system, drug exposure (duration of treatment), dosing 
information/compliance, concomitant medications, clinical laboratory results, vital signs and 
ECGs.  Tables summarizing the adverse events reported by subjects who died, experienced non-
fatal serious adverse events (SAE), or prematurely discontinued the study due to adverse event 
(AEs) will be prepared.  Summaries of potentially clinically notable laboratory results and vital 
sign abnormalities are presented.   
In general, inferential statistical tests are not performed for adverse event incidence rates. 
For all safety analyses, the safety analysis population will be used. 
8.1. 
Adverse Event Preferred Term and Body/Organ System Summary 
Tables 
Adverse events will be coded to the preferred terms of the Medical Dictionary for Regulatory 
Activities (MedDRA®). Summaries will present by system organ class (SOC), preferred term 
(PT) and severity and/or relatedness, the frequency and percentage of subjects reporting each 
observed event. 
A treatment-emergent adverse event (TEAE) will be defined as any AE that begins on or after 
the date of first dose of study drug up to the date of last dose of study drug plus the number of 
days in the follow-up period.  AEs observed during the period from obtaining informed consent 
to the start of administration of study drug will be regarded separately from TEAEs. 
All AEs and all TEAEs will be listed by subject.   
Subjects who experienced treatment-limiting AEs will be listed.  Treatment-limiting AEs are 
defined as any event that leads to permanent or temporary discontinuation from treatment, or a 
reduction in the treatment dose. 
Summary of adverse events will be dependent on adverse events observed.  If no adverse events 
meeting a specific table are observed, the summary table will not be completed. Blank summary 
tables will not be utilized.   
The following is the list of adverse event tables: 
Overall: 
• Overall Summary of Adverse Events 
Label 
Reporting Format 
Adverse Event 
F 
Moderate or Severe Adverse Event 
F 
Adverse Event Related to Study Drug 
F 
Moderate or Severe Adverse Event Related to Study Drug 
F 
Serious Adverse Event 
F 
Serious Adverse Event Related to Study Drug 
F 
Adverse Events Leading to Permanent Study Drug Discontinuation 
F 
Adverse Events Leading to Temporary Interruption of Study Drug 
F 
Death During Study 
F 
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By preferred term: 
• Treatment-emergent Adverse Events by PT 
• Treatment-emergent Adverse Events by SOC and PT 
By severity: 
• Treatment-emergent Adverse Events by SOC, PT and Severity 
• Serious Adverse Events 
• Deaths during Study 
By relatedness: 
• Drug-Related Treatment-emergent Adverse Events by SOC and PT 
• Drug-Related Treatment-emergent Adverse Events by SOC, PT and Severity 
• Drug-related Serious Adverse Events 
Other: 
• Adverse events leading to premature study drug discontinuation 
8.2. 
Total Duration of Therapy and Compliance 
Study drug exposure (Number of doses) will be summarized using the 8-point descriptive 
summary.  The source for exposure data is the drug accountability data domain. 
Study drug compliance will be assessed using the following categories using the same source as 
the drug exposure data: 
Label 
Reporting Format 
≥100%; 
F 
95%; 
F 
90%; 
F 
80%; 
F 
Study drug administration (date/time and study day) will be provided in a data listing.  The 
source for study drug administration is the diary data domain. 
8.3. 
Concomitant and Other Medications 
Concomitant medications, prescribed and over the counter, that the subject takes or continues to 
take after the baseline visit will be summarized according to the following rules.   
Medications with a start date before the date of the first dose of study medication will also 
appear in the prior medication summary table.  The same summary format applies here as it was 
described for the medication history and medications present at study entry tables with respect to 
major drug class, minor drug class, and generic name.  The data will be presented by treatment 
group and for all treated subjects.  The same subject counting procedures will also apply (e.g., 
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major class frequencies will represent subjects only once even though the same subject can be 
counted for multiple minor sub-classes and generic names). 
The supportive individual subject data listing should be organized as the medication history 
listings with trade and generic drug names, start and stop dates, days relative to the start of 
therapy, dose, frequency, route, and indication(s). 
8.4. 
Routine Laboratory Data 
Laboratory data, hematology, serum chemistry and urinalysis, will be summarized in terms of 
observed values, changes from baseline for each period.  In addition, changes from baseline for 
each period relative to normal ranges (e.g., shifts from normal to abnormal high/low) will be 
summarized in hematology: shift from baseline, serum chemistry: shift from baseline and 
urinalysis: shift from baseline.   
Listings will flag laboratory values that are outside of normal range. 
A listing of all abnormal lab values will be provided. 
8.5. 
Vital Signs 
For each nominal time point, vital signs will be summarized in terms of observed values and 
changes from Baseline.  Outlier values of vital signs will be flagged in the listing. 
Table 5: 
Vital Signs Outlier Thresholds 
Heart Rate 
(bpm) 
Systolic Blood Pressure 
(mmHg) 
Diastolic Blood Pressure 
(mmHg) 
<40 
>110 
<85 
>160 
<45 
>100 
8.6. 
ECGs 
A summary of ECG parameters, parameters reported separately QTcF, PR interval, QT interval, 
QRS duration, RR, and HR, will be summarized in terms of observed values and change from 
baseline.  
Subjects without post-baseline measurement for a given treatment period will be excluded from 
the summary statistic (e.g., denominator of the summary statistic) for that time point.   
All recorded values by central reader at ECG core lab for the standard 12-lead electrocardiogram 
parameters will be presented in a by-subject listing.   
Outlier Analysis 
The number of subjects with absolute ECG values and change from baseline in the ranges shown 
in Table 6 will be presented in Electrocardiogram Outlier Summary by Visit and Time Point. 
In addition in the same summary, QTcF will also be summarized by the following categories, 
Normal (males <430, females ≤450), Borderline (males (>430, ≤450); females (>450, ≤470)) and 
Prolonged (males >450, females >470). 
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Individual ECG data collected during the study will be presented in a listing. A separate listing 
of subjects with values of QTcF > 500 msec or an increase > 60 msec will be provided, as 
necessary. 
Figures 
Cumulative distribution plots will be provided for maximum change in QTcF at Week 12. 
Investigator Assessment of ECG Readings 
The investigators’ assessment of ECGs as normal, abnormal and clinically significant, or 
abnormal but not clinically significant will be summarized for baseline and for each visit. 
Table 6: 
ECG Outlier Thresholds 
Heart Rate 
(bpm) 
Heart Rate 
Change 
from 
Baseline 
(bpm) 
PR 
 Interval 
(msec) 
PR 
Percentage 
Change 
from 
Baseline (%) 
QRS 
 Interval 
(msec) 
QTcF (msec) 
QTcF change 
from 
Baseline 
(msec) 
>120 
>20 
> 200 
> 15 
> 120 
Males: 
≤ 30 
>130 
>30 
> 220 
> 25 
 
≤ 430 
>30, ≤ 60 
 
 
 
 
 
> 430 
> 60 
 
 
 
 
 
> 450 
 
 
 
 
 
 
> 470 
 
 
 
 
 
 
> 480 
 
 
 
 
 
 
> 500 
 
 
 
 
 
 
Females: 
 
 
 
 
 
 
≤ 450 
 
 
 
 
 
 
> 450 
 
 
 
 
 
 
> 470 
 
 
 
 
 
 
> 480 
 
 
 
 
 
 
> 500 
 
8.7. 
Hospital Anxiety and Depression Scale 
Hospital Anxiety and Depression Scale is a 14-question scale. Seven questions compose the 
anxiety domain with scores of 0 to 3 with 3 representing a maximum response and 0 representing 
a minimal response. Seven questions compose the depression domain with scores of 0 to 3 with 3 
representing a minimal response and 0 representing a maximal response.  
The summary will summarize the anxiety, depression and total scores at each time point using a 
continuous reporting format. 
8.8. 
Suicidal Risk Monitoring 
Baseline and treatment-emergent suicidal ideation and behavior will be assessed during the study 
using the C-SSRS which will be administered at each in-clinic visit. This scale consists of a 
baseline evaluation that assesses the lifetime experience of the subject with suicidal ideation and 
behavior, and a post-baseline evaluation that focuses on suicidality since the last study visit. The 
C-SSRS includes “yes” or “no” responses for assessment of suicidal ideation and behavior as 
well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being the most 
severe).  
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Tables will include results from the Suicidal Ideation and Suicidal Behavior sections of the C-
SSRS. Frequencies and percent of subjects with a response of “Yes” at any point on the Suicidal 
Ideation and Suicidal Behavior items will be summarized by overall subjects. Screening (lifetime 
and past 6 months), baseline (“pre-treatment”), and post-baseline (“post-treatment”) results will 
be presented. 
Suicidality data collected on the C-SSRS will be listed for all subjects. 
8.9. 
Testicular Ultrasound 
A testicular ultrasound will be performed before first dose and at Week 12 in selected male 
subjects. If there are testicular adrenal rest tumors (TART) lesions present at baseline, a change 
in tumor size (i.e., sum of the size of all tumors) after treatment will be summarized by cohort 
and overall male subjects with TARTs at baseline in the FAS. Additionally, change in the 
number of TARTs from baseline to postbaseline will be summarized. In this context, baseline is 
the value before first dose. 
If historical TART data exist, they will be presented in a listing along with the ultrasound 
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9. 
EFFICACY  
9.1. 
General Considerations 
For all efficacy data analyses, the safety analysis set will be used unless otherwise specified.  
For all endpoints, nominal p-values will be provided.  
9.2. 
Statement of the Null and Alternate Hypotheses for the Hormone 
Endpoints 
The estimate of interest, change from baseline [17-OHP; ACTH; A4; Testosterone], is used to 
evaluate the effectiveness of SPR001 therapy in CAH subjects.  
The following hypothesis testing schema will be employed to assess each endpoint:   
The null hypothesis for the comparison will be that there is no difference between the baseline 
and the Week 12 mean response for [17-OHP; ACTH; A4; Testosterone].   
The alternative hypothesis will be that there is a difference.   
9.3. 
Subgroup Analyses 
Subgroup analyses will characterize the consistency of the treatment effect across select subject 
subgroups. Subgroups analyses using the pre-specified subgroups in Section 6.4.5 will repeated 
for select analyses as specified in subsequent SAP sections.   
9.4. 
Multiple Comparisons and Multiplicity 
No control for multiplicity is planned given the hypothesis generating nature of this study. 
9.5. 
Analysis of Secondary Efficacy Endpoints 
Analysis of hormone data will be conducted only on subgroups.   
9.5.1. 
Efficacy Analysis of Hormones 
Hormones [17-OHP; ACTH; A4; Testosterone] will be summarized using geometric means and 
geometric means ratios to assess change and percentage change. 
A summary of [17-OHP; ACTH; A4; Testosterone] by Visit will include the observed parameter 
(using GM reporting format).  
Figures 
A serial figure with week as the x-axis and % change as the y-axis will be provided.   
Separate serial figures will be provided for each hormone. 
 
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9.5.2. 
Efficacy Analysis of Hormones by Subgroups 
To characterize the consistency of the treatment effect for the primary endpoint, each hormone 
will be summarized using a combination of subgroups 
A summary of [17-OHP; ACTH; A4; Testosterone] by Visit: [subgroup] will be provided.  The 
following subgroups will be summarized in separate summaries: 
• Non-Dexamethasone subjects 
• Non-Dexamethasone subjects with severe/moderate control issues 
• Non-Dexamethasone subjects with mild control issues 
Figures 
A serial figure with week as the x-axis and % change as the y-axis will be provided.   
Separate serial figures will be provided for each hormone. 
9.6. 
Analysis of the Exploratory Efficacy Endpoints 
9.6.1. 
Patient Reported Outcomes 
Data for the SF-36 (individual domain scores and summary scores), and total score for the CAH 
signs and symptoms interview will be summarized using descriptive statistics and presented by 
visit.   
Data for PGIC will be summarized using counts and percentages for each SPR001 dose level. 
9.6.2. 
Changes in Lipid Profile 
The following parameters will be repeated from the standard lab output and as a standalone 
summary, changes in lipid profile summary by visit: 
• Cholesterol 
• HDL Cholesterol 
• LDL Cholesterol 
• Triglycerides 
9.6.3. 
Changes in Insulin profile 
 The following parameters will be repeated from the standard lab output and as a standalone 
summary, changes in insulin profile summary by visit: 
• Hemoglobin A1C  
• Glucose 
 
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9.6.4. 
Changes in Body Weight 
 The following parameters will be repeated from the demog summary by visit as a standalone 
summary, changes in body weight profile summary by visit: 
• Body weight  
• BMI 
9.6.5. 
Bother Score 
Subjects scored their most bothersome symptom (symptom was not collected) on a scale of 1 
(not bothersome) to 7  (most bothersome; bothersome all the time). A summary of the magnitude 
of bothersome symptoms will summarize the score and change from baseline in the score using 
the C reporting format. 
 
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10. 
REFERENCES 
No references. 
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11. 
APPENDICES 
11.1. 
Reporting Formats 
C: Continuous endpoints will be presented with an 8-point summary using the following 
reporting structure, unless otherwise noted, 
N 
x 
Mean (SD) 
x.xx (x.xxx) 
Median 
x 
Q1, Q3 
xx.x, xx.x 
Minimum, Maximum 
xx.x, xx.x 
GM: Continuous endpoints reported in log scale with a Geometric mean 
n 
x 
Geometric Mean (CV) 
x.xx (x.xxx) 
95 CI for Geometric mean 
x.xx, x.xx 
95 CI for Geometric mean Ratio (GMR) 
x.xx 
95 CI for GMR 
x.xx, x.xx 
 
 
Percentage Change from Baseline 
0.xx 
95% CI for Percentage Change 
x.xx, x.xx 
F: Frequency endpoints will be presented by a 3-point summary using the following reporting 
structure, unless otherwise noted, 
Count (%) 
x (xx.x) 
MF Categorical variables (multiple frequency) will be presented by a 3-point summary using the 
following reporting structure, unless otherwise noted, where the sum of the category n’s is the 
total n 
n 
x 
Category 1 count (%) 
x (x.x) 
Category 2 count (%) 
x (x.x) 
 
 
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11.2. 
Medication Logic 
 
Drug Class 
Drug Name/ Classification 
GLUCOCORTICOIDS 
ATCtext4 = GLUCOCORTICOIDS 
 
 
 
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11.3. 
 Tables, Figures and Listings 
This index may be updated post finalization of the SAP. 
Tables 
Number 
Title 
Analysis Set 
14.1.1.1.1 
Enrollment by Investigator 
Randomized 
14.1.1.3 
Analysis Sets  
Randomized 
14.1.1.4 
Subject Disposition 
Randomized 
14.1.1.5.1 
Summary of Protocol Deviation Identified Prior To Database Lock by Site 
Randomized 
14.1.1.5.2 
Summary of Protocol Deviation Identified Prior To Database Lock by Treatment Group 
Randomized 
14.1.1.6 
I/E Table 
Randomized 
14.1.2.1.1 
Demographic and Baseline Characteristics 
Safety 
14.1.2.2.1 
Summary of Baseline Hormones 
Safety 
14.1.2.3.1 
Mini International Neuropsychiatric Interview 
Safety 
14.1.3.1 
Medical History by System Organ Class and Preferred Term  
Safety 
14.1.3.2 
Prior Medications 
Safety 
14.1.3.3 
Prior Glucocorticoid Therapy  
Safety 
14.2.1.1 
Summary of 17-OHP by Visit: Dexamethasone Subjects 
Safety 
14.2.1.2 
Summary of 17-OHP by Visit: Non-Dexamethasone Severe/moderate Control Issues 
Safety 
14.2.1.3 
Summary of 17-OHP by Visit: Non-Dexamethasone Severe/moderate Control Issues- LOCF 
Safety 
14.2.1.4 
Summary of 17-OHP by Visit: Non-Dexamethasone Mild Control Issues 
Safety 
14.2.2.1  
Summary of ACTH by Visit: Dexamethasone Subjects 
Safety 
14.2.2.2 
Summary of ACTH by Visit: Non-Dexamethasone Severe/moderate Control Issues 
Safety 
14.2.2.3 
Summary of ACTH by Visit: Non-Dexamethasone Severe/moderate Control Issues- LOCF 
Safety 
14.2.2.4 
Summary of ACTH by Visit: Non-Dexamethasone Mild Control Issues 
Safety 
14.2.3.1  
Summary of Androstenedione by Visit: Dexamethasone Subjects 
Safety 
14.2.3.2 
Summary of Androstenedione by Visit: Non-Dexamethasone Severe/moderate Control Issues 
Safety 
14.2.3.3 
Summary of Androstenedione by Visit: Non-Dexamethasone Severe/moderate Control Issues- LOCF 
Safety 
14.2.3.4 
Summary of Androstenedione by Visit: Non-Dexamethasone Mild Control Issues 
Safety 
14.2.4.1 
Summary of Testosterone by Visit 
Safety 
14.2.4.2 
Summary of Testosterone by Visit: Males 
Safety 
14.2.4.3 
Summary of Testosterone by Visit: Females  
Safety 
14.2.5 
Summary of SF-36 by Visit 
Safety 
14.2.6 
Summary of CAH Signs and Symptoms 
Safety 
14.2.7 
Summary of Patient Global Impression of Change 
Safety 
14.2.8 
Changes in Lipid Profile Summary by Visit 
Safety 
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Number 
Title 
Analysis Set 
14.2.9 
Changes in Insulin Profile Summary by Visit 
Safety 
14.2.10 
Changes in Body weight Summary by Visit 
Safety 
14.2.11 
Summary of the Magnitude of Bothersome Symptoms 
Safety 
14.3.1.1 
Study Drug Exposure 
Safety 
14.3.1.2 
Study Drug Compliance   
Safety 
14.3.3.1.1 
Treatment-Emergent Adverse Events Overall Summary 
Safety 
14.3.3.1.2 
Treatment-Emergent Adverse Events by Preferred Team 
Safety 
14.3.3.1.3 
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
Safety 
14.3.3.2 
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term and Severity 
Safety 
14.3.3.3.1 
Drug-Related Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
Safety 
14.3.3.3.2 
Drug-Related Treatment-Emergent Adverse Events by System Organ Class and Preferred Term and 
Severity   
Safety 
14.3.3.4.1 
Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
Safety 
14.3.3.4.2 
Drug-Related Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred Term  
Safety 
14.3.3.5.1 
Treatment-Emergent Adverse Events Resulting On-Study Deaths  
Safety 
14.3.3.5.2 
Deaths Within 28 Days  
Safety 
14.3.3.6.1 
Treatment-Emergent Adverse Events Leading to Premature Study Drug Discontinuation 
Safety 
14.3.4.1.1.1 
Hematology 
Safety 
14.3.4.1.1.2 
Hematology: Shift from Baseline 
Safety 
14.3.4.1.2.1 
Serum Chemistry 
Safety 
14.3.4.1.2.2 
Serum Chemistry: Shift from Baseline 
Safety 
14.3.4.1.3 
Urinalysis 
Safety 
14.3.5.1.1 
Vital Signs: Diastolic Blood Pressure 
Safety 
14.3.5.1.2 
Vital Signs: Systolic Blood Pressure 
Safety 
14.3.5.1.3 
Vital Signs: Heart Rate 
Safety 
14.3.6.1 
Concomitant Medications   
Safety 
14.3.7.1.1 
Electrocardiogram Summary: HR 
Safety 
14.3.7.1.2 
Electrocardiogram Summary: PR 
Safety 
14.3.7.1.3 
Electrocardiogram Summary: QRS 
Safety 
14.3.7.1.4 
Electrocardiogram Summary: QT 
Safety 
14.3.7.1.6 
Electrocardiogram Summary: QTcF 
Safety 
14.3.7.2 
Electrocardiogram Threshold Summary 
Safety 
14.3.7.3 
Electrocardiogram Outlier Summary by Visit and Time Point 
Safety 
14.3.8.1 
Hospital Anxiety and Depression Scale by Visit 
Safety 
14.3.8.2 
Suicidal Ideation and Suicidal Behavior (C-SSRS) by Visit 
Safety 
 
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Spruce Biosciences 
 
 
 
Tildacerfont (SPR001) 
Statistical Analysis Plan- Study 202 
 
 
 
 
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Listings 
Number 
Title 
Analysis Set 
16.2.1.1 
Study Disposition 
Randomized 
16.2.1.2 
Discontinuations 
Randomized 
16.2.1.3 
Inclusion And Exclusion Criteria 
Randomized 
16.2.1.4 
Analysis Sets 
Randomized 
16.2.1.5.1 
Randomization 
Randomized 
16.2.1.5.2 
Subjects Receiving Incorrect Treatment 
Randomized 
16.2.1.7 
Medical History 
Randomized 
16.2.2.1.1 
Protocol Deviation Identified Prior To Database Lock By Site 
Randomized 
16.2.2.1.2 
Protocol Deviation Identified Post Database Lock 
Randomized 
16.2.2.1.3 
Major Analysis Protocol Deviations 
Randomized 
16.2.3.1 
Subjects Excluded From Efficacy Analyses 
Randomized 
16.2.4.2.1 
Baseline Demographics 
Randomized 
16.2.4.2.7 
Baseline Hormones 
Randomized 
16.2.5.1.1 
Study Drug Accountability 
Safety 
16.2.5.1.2 
Study Drug Administration - Ediary Data  
Safety 
16.2.5.1.3 
Study Drug Overdoses 
Safety 
16.2.6.1 
Post Baseline Hormones 
Safety 
16.2.6.2 
SF-36 
Safety 
16.2.6.3 
HADS 
Safety 
16.2.6.4 
PGIC 
Safety 
16.2.6.5 
C-SSRS 
Safety 
16.2.7.1 
Treatment Emergent Adverse Events 
Safety 
16.2.7.2 
Adverse Events Leading To Premature Study Drug Discontinuation 
Safety 
16.2.7.3 
Serious Adverse Events 
Safety 
16.2.7.4 
Deaths 
Safety 
16.2.7.5 
Non-Treatment-Emergent Adverse Events 
Safety 
16.2.8.1.1.1 
Laboratory Test – Hematology (Part 1 Of 9) 
Safety 
16.2.8.1.1.2 
Laboratory Test – Hematology (Part 2 Of 9) 
Safety 
16.2.8.1.1.3 
Laboratory Test – Hematology (Part 3 Of 9) 
Safety 
16.2.8.1.1.4 
Laboratory Test – Hematology (Part 4 Of 9) 
Safety 
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Spruce Biosciences 
 
 
 
Tildacerfont (SPR001) 
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Number 
Title 
Analysis Set 
16.2.8.1.1.5 
Laboratory Test – Hematology (Part 5 Of 9) 
Safety 
16.2.8.1.1.6 
Laboratory Test – Hematology (Part 6 Of 9) 
Safety 
16.2.8.1.1.7 
Laboratory Test – Hematology (Part 7 Of 9) 
Safety 
16.2.8.1.1.8 
Laboratory Test – Hematology (Part 8 Of 9) 
Safety 
16.2.8.1.1.9 
Laboratory Test – Hematology (Part 9 Of 9) 
Safety 
16.2.8.1.2.1 
Laboratory Test – Chemistry (Part 1 Of 4) 
Safety 
16.2.8.1.2.2 
Laboratory Test – Chemistry (Part 2 Of 4) 
Safety 
16.2.8.1.2.3 
Laboratory Test – Chemistry (Part 3 Of 4) 
Safety 
16.2.8.1.2.4 
Laboratory Test – Chemistry (Part 4 Of 4) 
Safety 
16.2.8.2.1 
Abnormal Laboratory Findings- Chemistry 
Safety 
16.2.8.2.2 
Abnormal Laboratory Findings- Hematology 
Safety 
16.2.9.1 
Vital Signs 
Safety 
16.2.10.1.1 
Concomitant Medications 
Safety 
16.2.10.2.1 
Prior Medications  
Safety 
16.2.10.3 
Post-Treatment Medications 
Safety 
16.2.11.1 
Electrocardiogram 
Safety 
16.2.11.2 
Electrocardiogram QTcF >500 Msec 
Safety 
16.2.11.3 
Electrocardiogram QTcF Change >60 Msec 
Safety 
Figures 
Number 
Title 
Analysis Set 
Type 
15.2.1.1  
Summary of 17-OHP by Visit: Dexamethasone Subjects 
Safety 
Serial 
15.2.1.2 
Summary of 17-OHP by Visit: Non-Dexamethasone Severe/moderate Control Issues 
Safety 
Serial 
15.2.1.3 
Summary of 17-OHP by Visit: Non-Dexamethasone Severe/moderate Control Issues- LOCF 
Safety 
Serial 
15.2.1.4 
Summary of 17-OHP by Visit: Non-Dexamethasone Mild Control Issues 
Safety 
Serial 
15.2.2.1  
Summary of ACTH by Visit: Dexamethasone Subjects 
Safety 
Serial 
15.2.2.2 
Summary of ACTH by Visit: Non-Dexamethasone Severe/moderate Control Issues 
Safety 
Serial 
15.2.2.3 
Summary of ACTH by Visit: Non-Dexamethasone Severe/moderate Control Issues- LOCF 
Safety 
Serial 
15.2.2.4 
Summary of ACTH by Visit: Non-Dexamethasone Mild Control Issues 
Safety 
Serial 
15.2.3.1  
Summary of Androstenedione by Visit: Dexamethasone Subjects 
Safety 
Serial 
15.2.3.2 
Summary of Androstenedione by Visit: Non-Dexamethasone Severe/moderate Control Issues 
Safety 
Serial 
15.2.3.5 
Summary of Androstenedione by Visit: Non-Dexamethasone Severe/moderate Control Issues- LOCF 
Safety 
Serial 
15.2.3.6 
Summary of Androstenedione by Visit: Non-Dexamethasone Mild Control Issues 
Safety 
Serial 
15.2.4.1 
Summary of Testosterone by Visit 
Safety 
Serial 
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Spruce Biosciences 
 
 
 
Tildacerfont (SPR001) 
Statistical Analysis Plan- Study 202 
 
 
 
 
JUL 18, 2019 
 
 
47 
 
 
  
 
Number 
Title 
Analysis Set 
Type 
15.2.4.2 
Summary of Testosterone by Visit: Males 
Safety 
Serial 
15.2.4.3 
Summary of Testosterone by Visit: Females 
Safety 
Serial 
 
Page 48 of 49