Clinical trial NCT04308590
Conditions: Hypercortisolism
Keywords: Cushing syndrome Cushing Hypercortisolemia Type 2 Diabetes Impaired Glucose Intolerance Hypertension Adrenocorticotropic hormone Primary Pigmented Nodular Adrenal Disease Macronodular adrenal hyperplasia Adrenal Adenoma Adrenal Autonomy Cortisol Autonomous cortisol secretion
Sponsor: Corcept Therapeutics
Start date: 2020-07-27; Completion date: 2024-10-11
Enrollment: 137 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 3, randomized, double-blind, placebo-controlled study to assess the efficacy, and safety of relacorilant to treat hypercortisolism in patients with cortisol-secreting adrenal adenoma or hyperplasia associated with diabetes mellitus/ impaired glucose tolerance (DM/IGT) and/or uncontrolled systolic hypertension (HTN).

Detailed description:
The primary outcome measures of the study are 1) to assess the efficacy of relacorilant based on blood pressure control at Week 22 compared with placebo, and 2) to assess the safety of relacorilant based on adverse events. Patients will be randomized in a 1:1 ratio to treatment with relacorilant (active drug) or placebo. Patients will receive relacorilant or placebo for 22 weeks. Patients who complete the study may also be eligible to roll over into an extension study.

Arms: arm 1: Patients will receive relacorilant increased sequentially from 100 mg once daily to a maximum dose of 400 mg once daily. arm 2: Patients will receive placebo matched to study drug once daily.
Interventions: intervention 1: Relacorilant intervention 2: Placebo
Intervention descriptions: intervention 1: Relacorilant is supplied as blister-packed capsules for oral dosing. Relacorilant 400 mg dose consists of 4 relacorilant 100-mg capsules. Relacorilant 100-mg, 200-mg, and 300-mg doses are each given as a combination of 4 capsules containing relacorilant 100-mg and placebo as per the assigned dose. intervention 2: Placebo is supplied as blister-packed capsules for oral dosing. Each dose consists of 4 capsules containing placebo.

Protocol documents:
Prot_000.pdf: 
Title: Glucocorticoid Receptor Antagonism in the Treatment of Hypercortisolism in Patients with 
Cortisol-Secreting Adrenal Adenomas or Hyperplasia (GRADIENT): A Phase 3, Randomized, 
Double-Blind, Placebo-Controlled Study of the Efficacy and Safety of Relacorilant 
 
 
NCT Number: NCT04308590 
 
Date: 11 October 2024 
 
























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CONTENTS 
CLINICAL STUDY PROTOCOL CORT125134-456 .................................................................. 1 
SPONSOR SIGNATURE PAGE ................................................................................................... 2 
SYNOPSIS ...................................................................................................................................... 3 
CONTENTS .................................................................................................................................. 12 
LIST OF TABLES ........................................................................................................................ 18 
LIST OF FIGURES ...................................................................................................................... 18 
LIST OF ABBREVIATIONS AND DEFINITIONS ................................................................... 19 
1 
INTRODUCTION: BACKGROUND INFORMATION AND 
SCIENTIFIC RATIONALE ............................................................................................. 22 
1.1 
Therapeutic Area ............................................................................................................... 22 
1.2 
Relacorilant ....................................................................................................................... 24 
1.3 
Clinical Summary ............................................................................................................. 24 
1.3.1 Phase 1 Studies ..................................................................................................... 25 
1.3.2 Phase 2 Study ........................................................................................................ 25 
1.4 
Rationale for Study Design and Dose Regimen ............................................................... 27 
1.4.1 Design Considerations .......................................................................................... 27 
1.4.2 Rationale for Dose Selection and Regimen .......................................................... 27 
1.5 
Risk/Benefit Assessment .................................................................................................. 28 
2 
STUDY OBJECTIVES ..................................................................................................... 32 
2.1 
Primary Objectives............................................................................................................ 32 
2.2 
Secondary Objective ......................................................................................................... 32 
2.3 
Exploratory Objectives ..................................................................................................... 32 
3 
STUDY DESIGN.............................................................................................................. 33 
3.1 
Overall Design .................................................................................................................. 33 
3.2 
Study Endpoints ................................................................................................................ 33 
3.2.1 Primary Endpoints ................................................................................................ 33 
3.2.2 Secondary Endpoints (from Baseline to Week 22/ET, compared between 
relacorilant and placebo) ....................................................................................... 33 
3.2.3 Exploratory Efficacy Endpoints ............................................................................ 34 
3.3 
Number of Patients and Study Duration ........................................................................... 35 


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3.3.1 Number of Patients ............................................................................................... 35 
3.3.2 Study Duration ...................................................................................................... 35 
3.3.3 Discontinuation of Study Sites.............................................................................. 35 
3.4 
Definitions......................................................................................................................... 35 
3.4.1 Enrollment............................................................................................................. 35 
3.4.2 End of Treatment .................................................................................................. 35 
3.4.3 Patient Study Completion ..................................................................................... 35 
3.4.4 End of Study ......................................................................................................... 35 
3.5 
Treatment Continuation .................................................................................................... 36 
3.6 
Study Termination by Sponsor ......................................................................................... 36 
4 
STUDY POPULATION ................................................................................................... 37 
4.1 
Inclusion Criteria .............................................................................................................. 37 
4.2 
Exclusion Criteria ............................................................................................................. 37 
4.3 
Screen Failures .................................................................................................................. 38 
4.4 
Early Patient Discontinuation or Withdrawal ................................................................... 39 
4.5 
Replacement of Patients .................................................................................................... 40 
4.6 
Restrictions During Study ................................................................................................. 40 
4.6.1 Dietary Restrictions .............................................................................................. 40 
4.6.2 Contraception ........................................................................................................ 40 
4.6.3 Surgery during the Study ...................................................................................... 40 
5 
STUDY TREATMENTS AND MANAGEMENT .......................................................... 41 
5.1 
Study Drug and Placebo.................................................................................................... 41 
5.2 
Non-Investigational Medicinal Agent............................................................................... 42 
5.3 
Dose-Escalation Process ................................................................................................... 42 
5.4 
Dose Modifications ........................................................................................................... 43 
5.4.1 Dose Interruption and/or Discontinuation: Special Safety Events ....................... 43 
5.4.2 Pharmacokinetic Criteria for Dose Adjustment or Discontinuation ..................... 45 
5.5 
Concomitant Medications ................................................................................................. 45 
5.5.1 Rules for Use of Antidiabetic and Antihypertensive Concomitant Medications .. 46 
5.5.1.1 Decrease or Discontinuation of Concomitant Medications ................... 46 


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5.5.1.2 Increase or Initiation of Concomitant Medication ................................. 47 
5.6 
Prohibited Medications ..................................................................................................... 48 
5.7 
Method of Treatment Assignment and Randomization .................................................... 49 
5.8 
Blinding/Unblinding ......................................................................................................... 49 
5.9 
Dosing Diary ..................................................................................................................... 50 
5.10 
Product Accountability and Treatment Adherence ........................................................... 50 
5.11 
Continued Access to Study Treatment .............................................................................. 50 
5.12 
External Data Review Committee .................................................................................... 51 
5.12.1 Independent Data-Monitoring Committee to Monitor Patient Safety .................. 51 
5.13 
Monitoring of and Treatment for Electrolyte Abnormalities and Edema ......................... 51 
6 
DESCRIPTION OF STUDY ASSESSMENTS AND PROCEDURES ........................... 52 
6.1 
Informed Consent and Screening ...................................................................................... 52 
6.1.1 Dexamethasone Suppression Test......................................................................... 52 
6.1.2 Adrenal-Imaging History ...................................................................................... 52 
6.1.3 History Cushing-6\QGURPH௅0HGLFDWLRQ :DVKRXW ............................................... 52 
6.1.4 Demographics and Baseline Disease Characteristics ........................................... 53 
6.1.5 Medical and Medication History .......................................................................... 53 
6.2 
Safety Assessments ........................................................................................................... 53 
6.2.1 Physical Examination............................................................................................ 53 
6.2.2 Vital Signs ............................................................................................................. 53 
6.2.3 Height, Weight, and Waist Circumference ........................................................... 54 
6.2.4 Electrocardiogram ................................................................................................. 54 
6.2.5 Adverse Events ..................................................................................................... 54 
6.2.6 Concomitant Medications ..................................................................................... 55 
6.2.7 Clinical Laboratory Assessments .......................................................................... 55 
6.2.7.1 Laboratory Parameters ........................................................................... 55 
6.2.7.2 Sample Collection, Preparation, and Shipping ...................................... 56 
6.2.7.3 Blood-Volume Summary ....................................................................... 57 
6.3 
Pregnancy Test .................................................................................................................. 57 
6.4 
Efficacy Assessments........................................................................................................ 57 
6.4.1 Glucose Tolerance ................................................................................................ 58 


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6.4.2 Ambulatory Blood Pressure Monitoring (ABPM) ................................................ 58 
6.4.3 Glycated Hemoglobin (HbA1c) ............................................................................ 59 
6.4.4 Hypothalamic-Pituitary-Adrenal Axis Parameters ............................................... 59 
6.4.4.1 Plasma ACTH ........................................................................................ 59 
6.4.4.2 Plasma DHEA-S .................................................................................... 59 
6.4.4.3 Fasting Serum Cortisol .......................................................................... 59 
6.4.5 Sit-to-Stand Test ................................................................................................... 59 
6.4.6 Trail-Making Test ................................................................................................. 59 
6.4.7 Biochemical Markers of Bone Remodeling .......................................................... 60 
6.4.8 DXA Scans............................................................................................................ 60 
6.5 
Pharmacodynamic Assessments ....................................................................................... 60 
6.5.1 Urinary Free Cortisol (UFC) ................................................................................. 60 
6.5.2 Late-Night Salivary Cortisol ................................................................................. 60 
6.5.3 Early-Morning Salivary Cortisol .......................................................................... 61 
6.6 
Patient-Reported Outcomes .............................................................................................. 61 
6.6.1 Cushing QoL Questionnaire ................................................................................. 61 
6.6.2 Beck Depression Inventory-II ............................................................................... 61 
6.7 
Pharmacokinetic (PK) Assessments ................................................................................. 61 
6.8 
Pharmacodynamic/Biomarker Assessments ..................................................................... 62 
6.9 
Appropriateness of the Measures ...................................................................................... 62 
6.10 
Blood Storage.................................................................................................................... 62 
7 
STUDY ASSESSMENTS AND PROCEDURES BY STUDY VISIT ............................ 63 
7.1 
Scheduled Visits................................................................................................................ 63 
7.1.1 6FUHHQLQJ 9LVLW í WR í GD\ ............................................................................ 64 
7.1.2 Baseline Visit (Day 1) ........................................................................................... 65 
7.1.3 Week 2 (±7 days) .................................................................................................. 66 
7.1.4 Week 6 (±7 days) .................................................................................................. 67 
7.1.5 Week 10 (±7 days) ................................................................................................ 68 
7.1.6 Week 14 (±7 days) ................................................................................................ 68 
7.1.7 Week 18 (±7 days) ................................................................................................ 69 
7.1.8 Week 22 (-14/+7 days) ......................................................................................... 70 


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7.1.9 Early-Termination Visit (+14 days) ...................................................................... 71 
7.1.10 Follow-Up Visit (±7 days) .................................................................................... 72 
7.2 
Unscheduled Visits ........................................................................................................... 72 
8 
SAFETY EVENT DOCUMENTATION AND REPORTING ........................................ 73 
8.1 
Investigator’s Responsibilities .......................................................................................... 73 
8.2 
Definition of an Adverse Event ........................................................................................ 73 
8.3 
Definition of a Serious Adverse Event ............................................................................. 73 
8.4 
Expectedness ..................................................................................................................... 74 
8.5 
Clinical-Laboratory Adverse Events ................................................................................. 74 
8.6 
Documentation of Adverse Events ................................................................................... 74 
8.7 
Adverse Event Classification ............................................................................................ 75 
8.7.1 Intensity Grades of Adverse Events ...................................................................... 75 
8.7.2 Relationship of Adverse Event to Study Drug or Procedure ................................ 75 
8.8 
Procedures for Reporting a Serious Adverse Event .......................................................... 76 
8.9 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs or SAEs
........................................................................................................................................... 76 
8.10 
Adverse Event Follow-Up ................................................................................................ 76 
8.11 
Pregnancy .......................................................................................................................... 76 
8.11.1 Maternal Exposure ................................................................................................ 76 
8.11.2 Paternal Exposure ................................................................................................. 77 
8.12 
Treatment of Overdose ..................................................................................................... 77 
8.13 
Emergency Sponsor Contact ............................................................................................. 77 
9 
STATISTICAL METHODS ............................................................................................. 78 
9.1 
Analysis Populations ......................................................................................................... 78 
9.2 
General Statistical Considerations .................................................................................... 78 
9.3 
Hypothesis Testing............................................................................................................ 78 
9.4 
Sample-Size Calculation ................................................................................................... 79 
9.5 
Analysis Plan .................................................................................................................... 80 
9.5.1 Patient Disposition ................................................................................................ 80 
9.5.2 Demographic and Baseline Characteristics Data .................................................. 80 
9.5.3 Prior and Concomitant Medications ..................................................................... 80 


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9.5.4 Analysis of Efficacy Endpoints ............................................................................ 80 
9.5.4.1 Analysis of Primary Efficacy Endpoint ................................................. 80 
9.5.4.2 Analysis of Secondary Efficacy Endpoints............................................ 81 
9.5.4.3 Analysis of Exploratory Endpoints ........................................................ 81 
9.5.5 Safety Analyses ..................................................................................................... 81 
9.5.6 PK Analysis .......................................................................................................... 82 
9.5.7 PD Analysis .......................................................................................................... 82 
9.5.8 Biomarker/Pharmacogenetic Analysis .................................................................. 82 
9.5.9 Interim Analysis .................................................................................................... 82 
10 
ETHICAL AND LEGAL CONSIDERATIONS .............................................................. 83 
10.1 
Compliance with IRB/IEC Regulations ............................................................................ 83 
10.2 
Ethical Conduct of the Study ............................................................................................ 83 
10.3 
Protection of Human Patients ........................................................................................... 83 
10.3.1 Compliance with Informed-Consent Regulations ................................................. 83 
10.3.2 Patient Confidentiality .......................................................................................... 84 
10.3.3 Patient Privacy ...................................................................................................... 84 
11 
ADMINISTRATIVE CONSIDERATIONS ..................................................................... 85 
11.1 
Study Monitoring .............................................................................................................. 85 
11.2 
Quality Management ......................................................................................................... 85 
11.3 
Documentation .................................................................................................................. 86 
11.3.1 Case Report Forms and Study Records ................................................................ 86 
11.3.2 Access to Source Documentation ......................................................................... 86 
11.3.3 Source Documents ................................................................................................ 86 
11.3.4 Study Files and Retention of Study Records ........................................................ 86 
11.4 
Sample Collection, Preparation, and Shipping ................................................................. 87 
11.5 
Long-Term Retention of Biological Samples ................................................................... 87 
11.6 
Clinical Supplies ............................................................................................................... 88 
11.6.1 Inventory, Reconciliation, Return, and Disposition of Clinical Supplies ............. 88 
11.6.2 Clinical-Supply Inventory ..................................................................................... 88 
11.6.3 Return or Disposal of Study Drug and/or Supplies .............................................. 88 
11.7 
Drug Accountability.......................................................................................................... 88 


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11.8 
Post-Trial Care .................................................................................................................. 89 
11.9 
Protocol Noncompliance ................................................................................................... 89 
11.10 Financial Disclosure.......................................................................................................... 89 
11.11 Publication and Disclosure Policy .................................................................................... 89 
12 
REFERENCES ................................................................................................................. 91 
APPENDICES .............................................................................................................................. 94 
Appendix A: Schedule(s) of Activities ......................................................................................... 95 
Appendix B: Summary of Changes ............................................................................................ 100 
 
LIST OF TABLES 
Table 1 
Study Drug and Placebo: Description, Administration, Packaging, and Storage ..41 
Table 2 
Criteria for Dose Modification or Discontinuation Due to Special Safety Events 44 
Table 3 
Permitted Concomitant Medications ......................................................................46 
Table 4 
Clinical Laboratory Variables Evaluated During the Study ..................................56 
Table 5 
List of Efficacy Assessments .................................................................................57 
Table 6 
Time Window for Collection of 2-hour oGTT Blood Samples .............................58 
Table 7 
Time Windows for Collection of Pharmacokinetic Samples .................................61 
Table 8 
AE Grades Based on the Common Terminology Criteria for Adverse Events .....75 
Table 9 
Causal Attribution Guidance for AEs ....................................................................76 
Table 10 
Definitions of Analysis Populations ......................................................................78 
Table 11 
Schedule of Clinical Assessments and Procedures ................................................95 
Table 12 
Summary of Changes in Protocol CORT125134-456 Amendment 3 .................101 
LIST OF FIGURES 
Figure 1 
CORT125134-456 Study Design ...........................................................................33 
Figure 2 
Sequential Gatekeeping Hierarchy ........................................................................79 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS 
Abbreviation 
Definition 
ABPM 
ambulatory blood pressure monitoring 
ACTH 
adrenocorticotropic hormone 
AE 
adverse event 
ALT 
alanine aminotransferase (SGPT) 
AST 
aspartate aminotransferase (SGOT) 
AUC 
area under the concentration-time curve 
AUC0–24h 
AUC values from time 0 to 24 hours postdose 
AUCglucose 
area under the concentration-time curve for glucose  
AUCinf 
AUC values from time 0 extrapolated to infinity 
AUClast 
AUC values from time 0 to time of last measurable concentration 
BDI-II 
Beck Depression Inventory®-II 
BP 
blood pressure 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cmax 
maximum concentration 
Cmin 
minimum concentration within a dose interval 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DBP 
diastolic blood pressure 
DHEA-S 
dehydroepiandrosterone sulfate 
DM 
diabetes mellitus 
DRB 
Data Review Board 
DST 
dexamethasone suppression test 
DXA 
dual-energy X-ray absorptiometry 
ECG 
electrocardiogram 
EC 
Ethics Committee 
EMA 
European Medicines Agency 
eCRF 
electronic case report form 
ET 
early termination 
FDA 
(United States) Food and Drug Administration 
FKBP5 
FK506-binding protein 5 


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Abbreviation 
Definition 
FU 
follow-up 
GAPDH 
glyceraldehyde 3-phosphate dehydrogenase 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
GR 
glucocorticoid receptor 
HbA1c 
hemoglobin A1c 
Hgb 
hemoglobin 
HOMA IR 
homeostatic-model assessment of insulin resistance 
HPA 
hypothalamic-pituitary-adrenal 
ICF 
informed consent form 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IGT 
impaired glucose tolerance 
IHC 
immunohistochemistry 
IND 
Investigational New Drug  
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
Ki 
inhibition constant 
m-RNA 
messenger RNA 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
MR 
mineralocorticoid receptor 
oGTT 
oral glucose tolerance test 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PR 
progesterone receptor 
PTT 
partial thromboplastin time 
QoL 
quality-of-life 
QTc 
corrected QT interval 
QTcF 
QT interval corrected for heart rate using Fridericia’s equation: QTcF=QT/(RRѿ) 
REB 
Research Ethics Board 


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Abbreviation 
Definition 
SAE 
serious adverse event 
SBP 
systolic blood pressure 
SD 
standard deviation 
SE 
standard error  
SEM 
standard error of the mean 
SOA 
schedule of activities 
SOC 
system organ class 
t1/2 
apparent terminal elimination half-life 
TAT 
tyrosine aminotransferase; thrombin antithrombin 
TEAE 
treatment-emergent adverse event 
UFC 
urinary free cortisol 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cell (count) 
 


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1 
INTRODUCTION: BACKGROUND INFORMATION AND 
SCIENTIFIC RATIONALE 
1.1 
Therapeutic Area 
Hypercortisolism, often referred to as Cushing syndrome, is caused by excessive activity of the 
hormone cortisol. Endogenous Cushing syndrome is a rare endocrine disease associated with 
prolonged exposure to abnormally high levels of cortisol. Clinical manifestations vary, but most 
patients experience one or more of the following: hyperglycemia, hypertension, central obesity, 
facial plethora, abnormal fat distribution (supraclavicular fat pads and “buffalo hump”), proximal 
muscle weakness, skin thinning, and easy bruising. Irritability, anxiety, depression, sleep, and 
cognitive disturbances are also common. 
Establishing the diagnosis of Cushing syndrome is often difficult because few of the symptoms 
or signs are pathognomonic of the syndrome in isolation. There is a large variation in disease 
severity, depending on duration and intensity of excess cortisol production. Furthermore, some 
disease manifestations (e.g., as hypertension, obesity, and glucose intolerance) are common in 
individuals who do not have cortisol excess. The diagnosis of Cushing syndrome involves three 
steps: 1) suspecting it based on the patient’s signs and symptoms, 2) documenting the presence 
of hypercortisolism, and 3) determining the cause of hypercortisolism.  
Determination of the cause of hypercortisolism requires an understanding of the 
pathophysiology of the different types of Cushing syndrome. Cushing syndrome may be 
either adrenocorticotropic hormone (ACTH) dependent or ACTH independent. The most 
common cause of overt Cushing syndrome is ACTH-secreting pituitary tumors, followed by 
cortisol-secreting adrenal tumors or hyperplasia. Ectopic Cushing syndrome, which can produce 
severe manifestations of excessive cortisol activity, is a rare form of Cushing syndrome 
secondary to nonpituitary, ACTH-secreting tumors (benign or malignant). For patients with overt 
endogenous Cushing syndrome, there is consensus about the need for treatment, with surgical 
resection of the ACTH-or cortisol-secreting tumor as the first-line treatment. In cases in which 
surgery has failed, or is not an option, medical therapy targeting cortisol synthesis or cortisol 
activity is used.  
Management of patients with milder forms of Cushing syndrome, in particular those with 
cortisol-secreting adrenal adenomas or hyperplasia, is more challenging. Although these patients 
lack many of the more specific signs of ‘overt’ Cushing syndrome (Cushingoid appearance, 
proximal muscle weakness, easy bruising, and striae), they frequently have one or more of the 
less-specific comorbidities associated with elevated cortisol, including hypertension, diabetes 
mellitus (DM)/impaired glucose tolerance (IGT), central obesity, dyslipidemia and osteoporosis 
(Fassnacht et al. 2016).  
Several surgical series in patients with cortisol-secreting adrenal masses have failed to 
consistently demonstrate a causal relationship between hypercortisolism and comorbidities 
common in the general population (e.g., hyperglycemia, hypertension, dyslipidemia, and 
obesity). In some reports, a significant proportion of patients undergoing surgery experienced 
improvement of cortisol-excess-related comorbidities (e.g., hypertension, DM/IGT, obesity) 
(Toniato et al. 2009, Bancos et al. 2016). For example, Toniato, et al reported that post 
adrenalectomy and normalization of cortisol and ACTH levels, approximately half of 


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patients experienced normalization of obesity, and approximately 40% and 80% of patients 
had normalization/improvement of hyperglycemia and hypertension, respectively (Toniato et al. 
2009). Similar to Toniato’s study, several other surgical series showed that clinical improvement 
is often observed with adrenalectomy, but not in every case (Fassnacht et al. 2016). 
The European Endocrine Society recommends considering the risk of malignancy in helping 
determine whether surgery is the proper course for the management of adrenal incidentalomas 
(Fassnacht et al. 2016). For patients with bilateral adrenal tumors, unilateral adrenalectomy can 
significantly improve the disease (Bancos et al. 2016). However, due to continuous growth of the 
contralateral gland, relapse is common. Resection of the second adrenal gland, or bilateral 
adrenalectomy as a first-line therapy, is associated with primary adrenal insufficiency, which 
requires lifelong treatment with glucocorticoid and mineralocorticoid analogues and significant 
morbidity.  
If hypercortisolism in the presence of an adrenal adenoma or hyperplasia is suspected, abnormal 
cortisol secretion is demonstrated using the 1mg overnight dexamethasone suppression test 
(DST). Historically, the cortisol cut-off following the DST to make a diagnosis has been a source 
of debate in the endocrine community. But in 2015, the European endocrine guidelines for 
adrenal incidentalomas agreed to interpret the results of this test using a continuous variable 
rather than a categorical one (i.e., using a numerical value instead of Yes/No) (Fassnacht et al. 
2016). By these guidelines, a value  ȝJG/ (50 nmol/L) is considered ‘normal’. This cut-off 
value is supported by studies demonstrating that patients with post-dexamethasone cortisol 
YDOXHV ! ȝJG/ have increased morbidity or mortality. For patients with post-DST serum 
cortisol of 1.9௅ ȝJG/ 51௅138 nmol/L), and without overt Cushing syndrome, the committee 
proposed the term ‘possible autonomous cortisol secretion’. For patients with higher values, the 
term ‘autonomous cortisol secretion’ was proposed (Fassnacht et al. 2016).  
Although surgery is usually recommended in patients who have a DST >5 ȝJ/dL and the 
presence of 2 or more comorbidities (at least one of which is poorly controlled by medical 
treatment), there remains a lack of consensus on the optimal treatment approach (i.e., surgery vs. 
symptomatic treatment of comorbidities) for patients with adrenal adenoma and post-DST serum 
cortisol between 1.9௅ ȝJG/. 
Although patients with cortisol-secreting adrenal lesions do not often progress into overt Cushing 
syndrome, they may develop comorbidities, including hypertension, DM/IGT, and dyslipidemia, 
and currently it is not possible to predict which patients might benefit from adrenalectomy 
(Zografos et al. 2014, Elhassan et al. 2019, Fassnacht et al. 2016).  
Recent retrospective studies have demonstrated an association between hypercortisolism and 
cardiovascular and bone abnormalities (Debono et al. 2014, Debono et al. 2013), and it has been 
reported that patients with milder forms of Cushing syndrome do not receive specific treatment 
for their hypercortisolism and instead receive symptomatic treatment of their metabolic and 
cardiovascular symptoms (Zografos et al. 2014). Although there is accumulating evidence to 
support the role of cortisol in the disease profile of these patients, direct management of the 
underlying hypercortisolism is not standard clinical practice (Fassnacht et al. 2016, Chiodini et 
al. 2019, Morelli et al. 2016, Zografos et al. 2014). 


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Other treatment options for hypercortisolism have limitations in the setting of adrenal adenoma 
or hyperplasia. Agents targeting ACTH secretion (pasireotide) are not beneficial for 
ACTH-independent hypercortisolism. For cortisol-synthesis inhibitors (e.g., ketoconazole, 
metyrapone, and mitotane), the normalization of urinary free cortisol (UFC) is used to monitor 
titration to avoid overtreatment and ensuing adrenal insufficiency. Patients with cortisol-
secreting adrenal adenomas, however, do not usually present with elevated UFC levels. 
Glucocorticoid receptor (GR) antagonists, which are titrated via clinical efficacy and tolerability 
and not UFC measurements, could play a useful role in the management of hypercortisolism due 
to adrenal adenoma/hyperplasia. The concept of using GR antagonists for the management of 
hypercortisolism due to adrenal adenoma is similar to the use of aldosterone-receptor antagonists 
for the treatment of primary aldosteronism. 
Mifepristone, the first GR antagonist to become available for the treatment of patients with 
Cushing syndrome in the US, was approved following an open-label study demonstrating clinical 
improvement in glucose control. In the pivotal trial with mifepristone, all patients had overt 
Cushing syndrome; there were no patients with benign adrenal tumors. Case reports and small 
case series in patients with autonomous cortisol secretion treated with mifepristone demonstrated 
improvement in hyperglycemia and weight loss similar to the surgical series (Belokovskaya et al. 
2019, Debono et al. 2013). However, a smaller effect on hypertension was seen. The lack of as 
strong an effect on hypertension is likely due to the significant increase in ACTH levels 
following treatment with mifepristone, which stimulates secretion of additional cortisol from the 
adrenal adenoma and normal cortisol-secreting cells of the adrenal cortex, which, in turn, 
stimulates the mineralocorticoid receptor (MR).  
Relacorilant (CORT125134) is a next-generation GR antagonist being developed for the 
treatment of Cushing syndrome and other conditions that was designed to overcome adverse 
effects of mifepristone. 
1.2 
Relacorilant 
Relacorilant is a selective, high-affinity antagonist of the GR (inhibition constant <1 nM in a 
human GR binding assay and <10 nM in a human functional assay) and it has considerably 
greater selectivity for GR over the progesterone receptor (PR), producing only 7% displacement 
of labelled progesterone at a concentration of 1 M (relacorilant Ki >10 M, mifepristone 
Ki=1.2 nM) in a PR ligand binding assay (Cerep Report 100011862). Given this selective and 
potent GR antagonism, relacorilant has the potential advantage compared with mifepristone of 
not having any antiprogesterone effects, including endometrial hypertrophy and the potential for 
irregular vaginal bleeding. The effect of relacorilant on the pituitary also appears to be smaller 
compared with mifepristone—ACTH levels appear to be less affected in both patients with 
ACTH-dependent and adrenal Cushing syndrome (CSR CORT125134-451), which offers a 
potential advantage of relacorilant over mifepristone in the treatment of patients with 
hypercortisolism due to adrenal adenoma or hyperplasia.  
1.3 
Clinical Summary 
A brief summary of relacorilant clinical studies is presented (Sections 1.3.1 and 1.3.2). Further 
details on pharmacology, absorption, distribution, metabolism, and elimination (ADME), and 
toxicology of relacorilant are presented in the Investigator’s Brochure.  


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1.3.1 Phase 1 Studies 
In a single-ascending dose/multiple-ascending dose study (Study CORT125134-120; 
NCT03508635), 84 healthy subjects received single doses of up to 500 mg or repeated doses of 
up to 250 mg daily of the ‘clinical-pharmacology’ formulation (an earlier formulation with a 
higher bioavailability than the current ‘clinical-trial formulation’). In this study, a single dose of 
500 mg or multiple doses of 250 mg of relacorilant along with a high dose of prednisone in 
healthy subjects showed prevention of the changes induced by prednisone alone in several 
glucocorticoid-induced biomarkers, including osteocalcin, lymphocytes, eosinophils, and FKBP5 
mRNA levels. Single doses of relacorilant up to 500 mg daily were well tolerated. During the 
repeated-dose parts of Study CORT125134-120, there was a dose-related trend in subjects who 
reported at least 1 treatment-emergent adverse event (TEAE): 44.4% (50 mg), 66.7% (150 mg), 
and 85.7% (250 mg), compared with 50% of placebo-treated subjects. The most commonly 
reported TEAEs were within the system organ class (SOC) musculoskeletal and connective 
tissue disorders.  
Two additional studies in healthy volunteers (Study CORT125134-453, Study CORT125134-
126), with multiple doses of relacorilant have been completed. In Study CORT125134-453, in 
which multiple doses of 150 mg, 250 mg, and 350 mg relacorilant daily, the most commonly 
reported TEAEs were musculoskeletal, connective tissue, GI, and nervous system related. The 
most commonly reported TEAE were headache, for which a dose-related trend was reported 
(12.5%, 25.0%, and 37.5% of subjects following dosing with 150 mg, 250 mg, and 350 mg 
relacorilant daily, respectively), and back pain, which was reported at the 350 mg dose level 
only, in 50% of subjects. Similar safety results were observed in Study CORT125134-126. 
In the drug-drug interaction Study CORT125134-126, relacorilant exhibited no relevant effect on 
exposure to probe substrates for CYP2D6, CYP2C8, CYP2C9, or CYP2C19. However, 
relacorilant was shown to be a strong CYP3A inhibitor of the probe substrate midazolam, 
resulting in AUC extrapolated to infinity (AUCinf) and Cmax of 8.8-fold and 3.3-fold higher, 
respectively, relative to midazolam alone.  
Study CORT125134-129 was conducted with relacorilant 400 mg (4 × 100 mg 
 capsule; 
clinical-trial formulation that is also considered the “to-be-marketed” formulation). Following 
administration of relacorilant under fed conditions with a low-fat meal, relacorilant Cmax and 
AUCinf increased approximately 69% and 2.0-fold, respectively, relative to relacorilant 
administered under fasting conditions. Following administration of relacorilant under fed 
conditions with a high-fat meal, relacorilant Cmax and AUCinf increased approximately 92% and 
2.4-fold, respectively, relative to relacorilant administered under fasting conditions. 
1.3.2 Phase 2 Study 
A total of 35 patients were included in the Safety Population of this Phase 2, open-label, 
multicenter, dose-escalation study in patients with endogenous Cushing syndrome (Study 
CORT125134-451; NCT02804750). Group 1 (n=17) had a two-step dose escalation (monthly) of 
once-daily relacorilant (dose range, 100–200 mg, clinical-trial formulation; total treatment 
period, 12 weeks), and Group 2 (n=18) had a three-step dose escalation (monthly) of once-daily 
relacorilant (dose range, 250–400 mg, clinical-trial formulation; total treatment period, 


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16 weeks). Relacorilant exposure remained well below the 40 g•h/mL cap (exposure limit 
guided by results of the toxicology studies) at all doses.  
Overall, 94.3% of patients experienced TEAEs. In Group 1, 15/17 (88.2%) patients experienced 
a total of 101 TEAEs. The most common  TEAEs in Group 1 were back pain, diarrhea, 
headache, and pain in extremity (23.5% each). In Group 2, all 18 patients (100%) experienced a 
total of 228 TEAEs. The most common  TEAEs in Group 2 were back pain (38.9%), 
headache and nausea (27.8% each), and abdominal pain, arthralgia, dizziness, dyspepsia, 
myalgia, and pain in extremity (22.2% each).  
There were no TEAEs resulting in death during the study. Four (11.4%) patients experienced 
treatment-emergent SAEs (TESAEs); no TESAEs were reported in Group 1 and 5 TESAEs (in 
4 patients) were reported in Group 2. All TESAEs were Grade 3 in severity. Three (8.6%) 
patients had TESAEs (polyneuropathy, myopathy, and acute myocardial infarction) that were 
considered possibly related to study drug by the Investigator and led to study-drug 
discontinuation. These TESAEs were considered not related to the study drug by the Sponsor.  
Because relacorilant affects cortisol action and not cortisol secretion, measuring cortisol levels is 
not a suitable method to monitor the treatment effect. Therefore, the efficacy of relacorilant in 
this study was measured based on improvement of cortisol-excess-related comorbidities (e.g., 
hyperglycemia and hypertension).  
For patients with DM at Baseline D GHFUHDVH LQ +E$F E\  IURP %DVHOLQH WR WKH ODVW YLVLW
normalization of the 2-KRXU R*77 JOXFRVH  PJG/GHFUHDVH E\  PJG/ IURP %DVHOLQH
WR ODVW YLVLW RU GHFUHDVH LQ WRWDO GDLO\ LQVXOLQ GRVH E\  ZLWK +E$F XQFKDQJHG RU
decreased compared with Baseline) was considered a clinically meaningful response. For 
patients with IGT at Baseline, normalization of the 2-hour oGTT glucose was considered a 
response. In the mPP Population (IGT/diabetes subgroup), 2 of 13 (15.38%) patients (95% CI 
lower bound 1.92%) in Group 1 and 6 of 12 (50%) patients (95% CI lower bound 21.09%) in 
Group 2 met at least one of the above response criteria. 
For patients with uncontrolled hypertension at Baseline D GHFUHDVH RI  PP +J GHFUHDVH LQ
mean systolic BP (SBP) and/or diastolic BP (DBP) from Baseline to last visit, without worsening 
of either, based on 24-hour ambulatory BP monitoring (ABPM), was considered a response. 
Among patients with hypertension, 41.7% of patients in Group 1, and 63.6% of patients in 
Group 2 responded.  
In summary, this Phase 2 study of relacorilant (Study CORT125134-451), demonstrated clinical 
improvement in glucose control and in hypertension in patients with Cushing syndrome. There 
was also improvement in several comorbidities associated with cortisol excess, including 
improvement in quality of life and other comorbidities including CNS manifestations (e.g., 
depression and cognitive impairment), bone metabolism, coagulation parameters, and liver 
function tests. 


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1.4 
Rationale for Study Design and Dose Regimen  
1.4.1 Design Considerations 
This will be a Phase 3, randomized, double-blind, placebo-controlled study conducted in the US, 
Europe, and Israel at approximately 60 sites. Approximately 130 patients will be randomized 1:1 
to relacorilant or placebo.  
The study proposed here specifically targets patients with hypercortisolism due to cortisol-
secreting adrenal adenomas or hyperplasia. These patients may or may not present the classic 
clinical manifestations of overt Cushing syndrome (i.e., facial appearance, buffalo hump, striae, 
etc.). Although adrenal tumors are frequently detected incidentally during abdominal imaging 
studies (incidentalomas), especially in older patients, up to 29% of these tumors secrete cortisol 
(Fassnacht et al. 2016).  
Because of the mechanism of action of relacorilant, a GR antagonist that does not affect cortisol 
levels, efficacy will be assessed by monitoring clinical manifestations frequently associated with 
cortisol excess—hyperglycemia (DM/IGT) and hypertension. Two robust and validated clinical 
measures of blood glucose control and blood pressure (BP) control, will be used. For patients 
with hyperglycemia, glucose metabolism and insulin resistance will be evaluated with the oGTT. 
The secondary endpoint of the mean change in the AUCglucose was chosen because it reflects 
glucose control in patients with diabetes as well as those with IGT, for whom neither HbA1c nor 
fasting glucose are reliable measures of glucose control. The primary endpoint of mean change 
in SBP was chosen because adrenal adenomas are usually diagnosed in older patients for whom 
systolic hypertension is most frequently observed (diastolic hypertension is more frequently 
observed in younger patients). This endpoint uses 24-hour ambulatory blood pressure monitoring 
(ABPM), which is considered the gold-standard measurement.  
To examine the many manifestations of cortisol excess in the study patients, several other 
efficacy assessments will be used to assess clinical benefit, including assessment of Quality-of-
Life, bone microarchitecture, weight, whole-body fat composition, coagulation markers, and 
lipid profile.  
1.4.2 Rationale for Dose Selection and Regimen 
Dose selection for this study was based on PK and safety results from Phase 1 studies in healthy 
subjects and safety, efficacy, and PK results in a Phase 2 study in patients with Cushing 
syndrome (CORT125134-451) (see Section 1.3.2). Across all studies, exposure to relacorilant (as 
AUC0-24h) at steady-state was well below the toxicology threshold and was consistent between 
healthy subjects and patients with Cushing syndrome. The PK of relacorilant support once-daily 
dosing. 
In the Phase 2, open-label, multicenter Study CORT125134-451, 35 patients with endogenous 
Cushing syndrome received daily relacorilant in escalating doses ranging from 100௅200 mg 
(Group 1, 12 weeks) or from 250௅400 mg (Group 2, 16 weeks).  
Efficacy results indicate that treatment with relacorilant in patients with endogenous Cushing 
syndrome leads to improved glycemic and hypertension control. In Group 1, clinically 
significant changes in DM/IGT and hypertension control were generally observed starting with 


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the 200-mg dose. In Group 2, most responders start achieving clinical benefit at the starting dose 
of 250 mg daily, although some patients required doses up to 400 mg daily for optimal benefit.  
There was, however, a difference in the TEAEs between the two groups. In Group 1, treatment 
was generally well tolerated. In Group 2, patients experienced TEAEs (especially 
musculoskeletal symptoms) at a higher frequency and with greater intensity compared with 
patients in Group 1. Although the maximum dose of relacorilant in Group 1 (200 mg) was very 
well tolerated, every patient in Group 2 experienced TEAEs at the starting dose of relacorilant of 
250 mg daily, despite the fact that the levels of relacorilant at the highest dose of Group 1 (i.e., 
200 mg) were similar to the levels achieved with the starting dose of relacorilant in Group 2 
(250 mg). The frequency of TEAEs in Group 2 decreased with continuous therapy with 
relacorilant at the same or higher dose indicating that most of those TEAEs were consistent with 
cortisol-withdrawal symptoms, commonly seen in patients starting on an effective dose of a 
Cushing syndrome medication without preceding titration. Therefore, the approach in this study 
is to titrate the relacorilant dose from a starting dose of 100 mg, which was well tolerated in the 
Phase 2 study, to higher potentially more efficacious doses. 
1.5 
Risk/Benefit Assessment 
The United States (US) Food and Drug Administration (FDA), as well as the European 
Medicines Agency (EMA), acknowledge the impact of coronavirus disease 2019 (COVID-19) on 
the health system and broader society, and recognize the impact it could have on trials and trial 
participants (FDA 2021, EMA 2022). Both agencies underscore that safety of trial participants is 
paramount.  
In addition to the risks/potential benefits to trial participation, the added challenges of conducting 
a clinical trial during the time of the public health emergency related to COVID-19 require the 
Sponsor to perform initial and ongoing risk assessment to determine its potential impact on the 
safety and confidentiality/privacy of the trial participant, integrity of the trial, and the benefit of 
the trial for participants and society. 
With regard to Protocol CORT125134-456, Corcept has been working with clinical investigators 
and Institutional Review Boards (IRBs)/Ethics Committees (Ecs) on a continuing basis to ensure 
that the patient’s safety, welfare, and rights are best served by participating in this trial. Corcept 
will continue to communicate guidance and provide support to clinical study sites during the 
COVID-19 pandemic. 
x Corcept recognizes that the protocol may require modification to ensure integrity of the 
trial and appropriate safety monitoring are implemented for all enrolled trial participants. 
This may involve alternative methods for safety and study assessments (i.e., phone 
contact, virtual study visits, use of alternative locations for assessment, including local 
labs or imaging centers, etc.). New processes or modifying protocol-described processes 
may be required, depending on the specific situation.  
x Corcept also recognizes that, depending on the specific situation, treatment with the 
investigational product may be ended or paused.  


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x Lastly, Corcept recognizes that if the study cannot be properly conducted under the 
existing protocol, it could be necessary to amend the protocol, stop recruitment, and/or 
withdraw trial participants. 
All decisions will be properly documented. Risk assessment will be made on an ongoing basis.  
As required, information pertaining to protocol modifications (including study visits, remote 
study monitoring, investigational drug supply distribution, etc.) as a result of COVID-19 will be 
recorded and submitted to Regulatory Agencies and/or IRBs/Ecs in accordance with COVID-19 
guidances issued at country level and/or by IRB/EC, unless otherwise requested/required by 
these entities. 
As described in the EMA guideline, “It is expected that the sponsor performs a risk assessment 
of each individual ongoing trial and the investigator of each individual trial participant and 
implement measures, which prioritize trial participant safety and data validity. In case these two 
conflict, trial participant safety always prevails.” 
The following risk assessments and aspects of trial conduct will be considered by Corcept on an 
ongoing basis in conjunction with clinical investigators and IRBs/IECs, as applicable, to ensure 
that the safety of trial participants can be maintained:  
x Whether the limitations imposed by the COVID-19 public health emergency on protocol 
implementation pose new safety risks to trial participants, and whether it is feasible to 
mitigate these risks by amending study processes and/or procedures. 
x Whether there will be continued availability of the clinical investigator/sub-investigators 
to provide oversight of the trial, and properly assess and manage safety issues that 
may emerge. 
x Whether there will be sufficient trial support staff given the evolving COVID-19 
situation, and that staff are appropriately trained and could be available to handle the 
expected tasks, and that they have adequate equipment and materials. 
x Whether clinical investigator sites will remain open to trial participants for required 
in-person assessments or whether the clinical investigator has the ability to provide 
required in-person assessments at an acceptable alternate location(s), or whether such 
protocol-specified in-person assessments can instead be conducted virtually. 
x Whether there is continued supply of the investigational product and/or trial supplies 
essential to maintaining appropriate safety monitoring or other key trial procedures for 
trial participants. 
x Whether there is continued availability of, and support for, information technology 
systems and any other technological tools needed to support the trial. 
x Whether there will be continued operations of, and adequate communications with, 
IRB/EC, if applicable, to support trial needs. 
x Whether it is feasible to conduct the trial in light of any COVID-19 public health 
measures implemented by Federal/Government, state, and/or local authorities to control 
the virus. 
 


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Depending on the specific situation, additional assessments may be added. Study participants 
will be informed of changes to the study and monitoring plans that could affect them. Processes 
for remote monitoring will include the protection of trial participant data privacy and 
confidentiality. Study participants may choose not to participate in this study or may leave this 
study at any time, without having to give a reason. Study participants will still receive care for 
their condition and will not be penalized or lose any benefits to which they are otherwise 
entitled. They will not lose any rights they are entitled to as a study participant. 
Patients with endogenous Cushing syndrome are immunocompromised due to a direct 
suppressive effect of high cortisol on the bone marrow and immune cells, as well as due to an 
effect on the immune system of the cortisol-H[FHVV௅UHODWHG FRPRUELGLWLHV HJ GLabetes, 
hypertension, obesity). Patients with Cushing syndrome who remain untreated are at high risk 
for infections from common and uncommon pathogens. Infection is the second most common 
cause of death among patients with overt Cushing syndrome (Dekkers et al. 2013) and in 
patients with milder forms of hypercortisolism due to cortisol-secreting adrenal adenomas 
(Debono et al. 2014). In Study CORT125134-451, in which patients with endogenous Cushing 
syndrome were treated with relacorilant, in the high-dose group, we observed an overall increase 
in the number of lymphocytes (which is often suppressed in this patient population).  
In addition, should a patient in the study become infected with COVID-19, the Investigator 
should consult the Medical Monitor regarding any possible interactions of relacorilant with the 
various treatment options for COVID-19. 
COVID-19 measures cited in this protocol amendment are temporary and will be repealed 
back to previous state when the situation (governmental rules, benefit/risk assessment for the 
trial) allows. 
Glucocorticoid receptor antagonism is a proven mechanism of action for the treatment of the 
DM/IGT secondary to hypercortisolism in adult patients with Cushing syndrome (Fleseriu et al. 
2012). Relacorilant antagonizes the GR similar to mifepristone, but has no effect on the PR. 
Relacorilant is therefore expected to effectively treat hypercortisolism, without the drawbacks of 
PR antagonism that may result in untoward reproductive effects, which may lead to interruption 
of therapy. 
In the Phase 2 study (Study CORT125134-451) in patients with endogenous Cushing syndrome, 
relacorilant showed evidence of clinical benefit based on improvement of cortisol-H[FHVV௅UHODWHG
comorbidities. The drug was well tolerated, with the most common side effects observed at 
higher doses. Compared with the predecessor drug mifepristone, relacorilant offers two key 
safety advantages—lack of affinity for the PR, and lack of significant cortisol rise (which is 
mostly responsible for the hypokalemia and worsening hypertension observed with 
mifepristone).  
Based on the mechanism of action of relacorilant, there is a theoretical risk of excessive 
GR antagonism, which could manifest by weakness, tiredness, dizziness, nausea, vomiting, and 
muscle aches. Since relacorilant does not affect the MR, it is unlikely that hypotension would 
occur in the absence of antihypertensive medication. Because plasma glucocorticoid levels are 
not decreased with relacorilant administration, a single laboratory test of excessive GR 
antagonism is not possible; diagnosis must rely on clinical assessment. In cases of suspected 


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excess GR antagonism, study drug will be interrupted for 3 days and supplemental 
glucocorticoid may be given to overcome the GR antagonism (see Section 5.4.1).  
The safety profile of relacorilant in study patients will be monitored by physical examinations, 
measurement of vital signs, blood tests for analysis of clinical chemistry and hematology 
parameters, 12-lead electrocardiograms (ECGs), and AEs.  
Patients receiving placebo cannot expect a meaningful improvement of the manifestations of 
their hypercortisolism. However, these tumors progress very slowly, and rarely progress into 
overt Cushing syndrome (Fassnacht et al. 2016). Thus, no significant worsening of the clinical 
manifestations of hypercortisolism is expected in the placebo group during the study.  
Relacorilant is metabolized by multiple CYP enzymes, including CYP3A and CYP2C8, and by 
carbonyl reductases. Relacorilant is a strong inhibitor of CYP3A. If a concomitant medication is 
required to treat an AE, the Investigator must consider the risk of drug-drug interaction. 
Study procedures include venous blood sampling and noninvasive procedures, including ECG 
recording, imaging, and vital-sign measurement. During cannulation, more than 1 attempt may 
be needed to insert the cannula in a vein of a patient, and it is possible that bruising and/or 
inflammation may be experienced at the site of cannulation. Because dual-energy X-ray 
absorptiometry (DXA) scans use X-ray energy, there is risk due to exposure radiation. The total 
volume of blood collected will not exceed 505 mL, unless the Investigator or designee considers 
additional unplanned collection(s) are required for safety laboratory tests.  
Because the study is placebo controlled, measures are in place (Section 5.5) to allow patients to 
receive treatment for comorbid conditions as necessary.  
More information on the risks and benefits of relacorilant is provided in the Investigator’s 
Brochure. 
 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
x To assess the efficacy of relacorilant for the treatment of hypercortisolism in patients 
with cortisol-secreting adrenal adenomas or hyperplasia, based on blood pressure (BP) 
control at Week 22 compared with placebo 
x 
To assess the safety of relacorilant for the treatment of hypercortisolism 
2.2 
Secondary Objective 
x To assess changes in cortisol excess-related comorbidities (e.g., body weight and 
glycemic control) in patients with hypercortisolism due to cortisol-secreting adrenal 
adenomas/hyperplasia 
2.3 
Exploratory Objectives 
x To explore changes in cortisol excess-related comorbidities including assessments of 
glucose, insulin resistance indices, coagulation markers, GR activity biomarkers, HPA 
axis, and bone turnover markers, depression and quality of life questionaries in patients 
with cortisol-secreting adrenal adenomas or hyperplasia 
x To assess the pharmacokinetics of relacorilant in patients with hypercortisolism due to 
cortisol-secreting adrenal adenomas/hyperplasia 


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3 
STUDY DESIGN 
3.1 
Overall Design 
This is a Phase 3, double-blind, placebo-controlled study to assess the efficacy, and safety of 
relacorilant to treat hypercortisolism in patients with cortisol-secreting adrenal adenoma or 
hyperplasia associated with DM/IGT and/or uncontrolled systolic hypertension. Two 
subgroups—DM/IGT and hypertension—will be analyzed.  
Figure 1 
CORT125134-456 Study Design 
 
3.2 
Study Endpoints 
3.2.1 Primary Endpoints  
In patients with systolic hypertension, the mean change in 24-hour average SBP based on 
24-hour ABPM, from Baseline to Week 22 as compared between relacorilant and placebo arms.  
In all patients, assessment of safety based on TEAEs. 
3.2.2 Secondary Endpoints (from Baseline to Week 22/ET, compared between 
relacorilant and placebo) 
Endpoints for Hypertension 
1. In patients with systolic hypertension at Baseline, mean change in average DBP and HR 
(based on 24-hour ABPM). 
2. In patients with systolic hypertension at Baseline, mean change in daytime average SBP, 
DBP, and HR (based on 24-hour ABPM). 
3. In patients with systolic hypertension at Baseline, mean change in nighttime average 
SBP, DBP, and HR (based on 24-hour ABPM). 
4. In patients with systolic hypertension at Baseline, proportion of patients with any dose 
increase in antihypertensive medications due to worsening hypertension. 
5. In patients with systolic hypertension at Baseline, proportion of patients with a reduction 
in 24-hour average SBP by 5 mm Hg (based on 24-hour ABPM). 
6. In patients with systolic hypertension at Baseline, proportion of patients with any dose 
decrease in antihypertensive medication due to improved blood pressure. 


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7. In patients with systolic hypertension at Baseline, proportion of patients with 
normalization of the average SBP (<130 mm Hg, based on 24-hour ABPM). 
Endpoints for Hyperglycemia 
1. In patients with DM/IGT at Baseline, the mean change in AUCglucose, from Baseline to 
Week 22 as compared between relacorilant and placebo arms. 
2. In patients with DM (HbA1c at BaselinH  WKH PHDQ FKDQJH LQ +E$F 
3. ,Q SDWLHQWV ZLWK '0,*7 +E$F DW %DVHOLQH  WKH PHDQ FKDQJH LQ +E$F 
4. 3URSRUWLRQ RI SDWLHQWV ZLWK +E$F % at Baseline who achieved HbA1c <6.5%. 
5. In patients with DM at Baseline, proportion of patients who achieved 2-hour oGTT 
glucose <140 mg/dL. 
6. In patients with IGT at Baseline, proportion of patients who achieved 2-hour oGTT 
glucose <140 mg/dL. 
7. In patients with DM/IGT at Baseline, proportion of patients with any dose decrease of 
diabetes medication due to improved glucose control. 
8. In patients with DM/IGT at Baseline, proportion of patients with any dose increase of 
diabetes medications due to worsening hyperglycemia. 
9. In patients with DM/IGT in the ITT population, the proportion of patients who achieved 
decrease of AUCglucose RI    DQG DQ\ GHFUHDVH from Baseline to Week 22. 
10. In patients with DM/IGT in the ITT population, the mean change in 2-hour oGTT 2-hour 
timepoint from Baseline to Week 22. 
11. In patients with DM/IGT in the ITT population, the mean change in 2-hour oGTT 
predrink timepoint from Baseline to Week 22. 
Other Secondary Endpoint 
1. In all patients, the mean change in body weight and waist circumference. 
3.2.3 Exploratory Efficacy Endpoints 
The mean change from Baseline to Week 22/ET in serum osteocalcin; in trabecular bone 
score, bone mineral density, and body composition from DXA scans; the Beck Depression 
Inventory®-II (BDI-II) score; sit-to-stand test score; trail making test scores; coagulation 
markers (Factor VIII, von Willebrand factor, protein S, protein C, TAT, platelets, and PTT); 
biomarkers related to GR activity (such as FKBP5); DHEA-S concentrations; ACTH 
concentrations; lipids (total cholesterol, LDL cholesterol, triglycerides, and very-low-density 
lipoprotein cholesterol); HPA-axis; difference between morning and late-night salivary cortisol; 
AUCglucose; fasting glucose in patients with DM; insulin resistance indices and 
hyperglucagonemia (AUCinsulin, Matsuda Index, homeostatic model assessment of insulin 
resistance [HOMA IR], and at selected visits AUCglucagon), and Cushing Quality-of-Life (Cushing 
QoL) score. 
Intensive pharmacokinetic blood sampling will be conducted in all patients at the Week 18 visit. 
The plasma concentrations of relacorilant and/or its metabolites will be examined.  


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3.3 
Number of Patients and Study Duration 
3.3.1 Number of Patients 
Approximately 130 patients will be randomized. 
3.3.2 Study Duration 
The maximum expected duration of a patient’s participation is 32 weeks, including up to 6 weeks 
for Screening, 22 weeks of double-blind treatment, and a follow-up visit 28 days after the last 
dose of study drug. 
3.3.3 Discontinuation of Study Sites 
Participation of a study site may be discontinued if the Sponsor, its designee, the Investigator, 
or the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) determines it 
necessary for medical, safety, regulatory, or other reasons consistent with applicable laws, 
regulations, and guidelines. 
3.4 
Definitions 
3.4.1 Enrollment 
Patients are considered enrolled in the study when they have signed the ICF, been screened, and 
their eligibility has been verified.  
3.4.2 End of Treatment 
The end of treatment is defined as the date on which the patient received his or her last treatment, 
which may be the end of the Treatment Period if the patient completed all treatments or may be 
earlier if the patient discontinued study treatment before the designated stopping point at 
Week 22. 
3.4.3 Patient Study Completion 
Patients who complete 22 weeks of the double-blind, placebo-controlled phase and return for the 
follow-up visit 28 days after the last dose of study drug will be considered to have completed the 
study. The follow-up visit will serve as the last study visit. 
Patients who complete 22 weeks of the double-blind, placebo-controlled phase, and enter an 
extension study without interruption will also be considered to have completed the study; in that 
case the follow-up visit will not be required, and Week 22 will serve as the last study visit.  
3.4.4 End of Study 
The end of study is defined as the date of last contact (visit, telephone, e-mail) with the last 
patient in the study. The Sponsor will ensure that the Institutional Review Board (IRB)/ 
Independent Ethics Committee (IEC) and the regulatory authority(ies) are notified that the 
study has finished according to Corcept’s standard operating procedures and/or local or 
national regulations. 


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3.5 
Treatment Continuation 
Patients who complete the study will be permitted to continue relacorilant treatment in an 
extension study provided that they have at least 80% adherence with scheduled dosing (by 
capsule counts). Patients who continue on to the extension study within 28 days of the last dose 
of study drug will not be required to complete the follow-up visit. The last study visit for these 
patients will be the Week 22 visit.  
Patients who complete the Week 22 visit and do not wish to enter an extension safety study will 
be instructed to discontinue study drug. Patients should not discontinue study drug before all 
the Week 22 assessments are performed and the unblinded medical monitors confirm all the 
data required for the analysis of the primary endpoint have been collected and reported. The 
follow-up visit will be conducted 28 days after the last dose of study drug and will serve as the 
last study visit. 
3.6 
Study Termination by Sponsor 
If the Sponsor/CRO, Investigator, Study Monitor, or regulatory officials discover conditions 
arising during the study that indicate that the study should be halted or that the study site’s 
participation should be terminated, this action may be taken after appropriate consultation 
between the Sponsor and Investigator. Conditions that may warrant termination of the study 
include, but are not limited to, the following: 
x Discovery of an unexpected, serious, or unacceptable risk to the patients enrolled in the 
study. 
x Decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of the product. 
Study termination (if required) and follow-up will be performed in compliance with applicable 
regulations and guidelines. 


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4 
STUDY POPULATION 
This study includes patients with cortisol-secreting adrenal adenomas or hyperplasia associated 
with DM/IGT and/or uncontrolled systolic hypertension.  
The following eligibility criteria are designed to select patients for whom treatment with 
relacorilant is considered appropriate. All relevant medical and nonmedical conditions will be 
taken into consideration when deciding whether treatment with relacorilant is suitable for a 
particular patient.  
4.1 
Inclusion Criteria 
Each patient must meet all of the following criteria to be enrolled in the study: 
1. Male or female, 18 to 80 years of age, inclusive. 
2. Lack of cortisol suppression (>1.8 ȝJG/ VHUXP FRUWLVRO ZLWK DGHTXDWH GH[DPHWKDVRQH
levels) on either 1-mg overnight or 2-mg 48-hour DST during Screening. 
3. Suppressed or low (15 pg/mL) early-morning ACTH levels on at least 2 occasions 
during Screening. 
4. A radiologically confirmed benign adrenal lesion (single adenoma, multiple adenomas, 
hyperplasia [3 times the size of the normal adrenal gland]) within 3 years prior to 
Screening. 
5. Has at least 1 of the following at Baseline: 
 DM (fasting plasma glucose t126 mg/dL and/or 2-hour oGTT plasma glucose 
t200 mg/dL at 2 hours, RU +E$F  RU ,*7 SODVPD JOXFRVH  mg/dL and 
<200 mg/dL on a 2-hour oGTT) (American Diabetes Association 2020). 
 Systolic hypertension (average 6%3 0 WR  mm Hg) based on 24-hour ABPM 
(Parati et al. 2014). 
6. If receiving medical treatment for DM/IGT or hypertension, there has been no increase in 
medication dosage for at least 4 weeks prior to Baseline assessment. 
7. For women of childbearing potential, has a negative serum pregnancy test at Screening 
and negative urine pregnancy test at Baseline. 
4.2 
Exclusion Criteria 
Patients who meet any of the following criteria will not be permitted entry to the study: 
1. Has severe, uncontrolled hypertension (average SBP >170 mm Hg or average 
DBP >110 mm Hg at Screening), based on 24-hour ABPM. 
2. Has poorly controlled DM (HbA1c >12% at Screening). 
3. Has DM Type 1. 
4. Has abnormal liver test results (total bilirubin >1.5×ULN or elevated alanine 
aminotransferase or aspartate aminotransferase >3×ULN at Baseline). 
5. +DV VHYHUH UHQDO LQVXIILFLHQF\ JORPHUXODU ILOWUDWLRQ UDWH  mL/min/1.73 m2 at 
Baseline). 
6. Has uncontrolled, clinically significant hypothyroidism or hyperthyroidism. 


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7. Has prolonged QT interval corrected for heart rate using Fridericia’s equation (QTcF) 
(>450 ms for men and >470 ms for women) with normal QRS interval (<120 ms) or 
QTcF interval >500 ms with wide QRS interval (t120 ms). 
8. Has persistent atrial fibrillation. 
9. Has used or plans to use any treatments for Cushing syndrome within 12 weeks 
prior to Screening and throughout the study, including mifepristone, metyrapone, 
osilodrostat, ketoconazole, fluconazole, or any investigational drug for treatment 
of Cushing syndrome. 
10. Patients who require inhaled glucocorticoids and have no alternative option if their 
condition deteriorates during the study. 
11. Has adrenocortical carcinoma.  
12. Has pseudo-Cushing syndrome. Patients with known or suspected pseudo-Cushing 
syndrome based on medical history (such as patients with severe obesity, major 
depression, or a history of alcoholism) should undergo a dexamethasone-CRH/DDAVP 
stimulation test (Yanovski et al.1993, Giraldi et al. 2007, Yanovski et al. 1998) to rule-in 
or rule-out this possibility. 
13. Has a history of cyclic Cushing syndrome with fluctuating clinical manifestations. 
14. Has autonomous cosecretion of aldosterone. 
15. Has plans for adrenalectomy or nodulectomy during the study, including follow-up. 
16. Has taken any non-Cushing syndrome investigational drug within 4 weeks prior to 
Baseline, or within less than 5 times the drug’s half-life, whichever is longer. 
17. Ongoing use of antidiabetic, antihypertensive, antidepressant or lipid-lowering 
medications that are highly dependent on CYP3A for clearance and that cannot undergo 
dose modification upon coadministration with strong CYP3A inhibitors.  
18. Ongoing use of any strong CYP3A4 inducer or any other prohibited medications (see 
Section 5.6). 
19. Is pregnant or lactating. 
20. Is a female patient of childbearing potential who cannot use a highly effective method of 
contraception (including all women <50 years old, women whose surgical sterilization 
was performed <6 months ago, and women who have had a menstrual period in the last 2 
years); see Section 4.6.2.  
21. Has an acute or unstable medical problem that could be aggravated by treatment with the 
investigational study drug. 
22. Has a history of severe reaction to the study drug, to a similar class of drug, or to the 
study drug’s excipient. 
23. In the Investigator’s opinion, should not participate in the study or may not be capable of 
following the study schedule. 
24. Has known HIV, hepatitis B, or hepatitis C infection and is taking medication for 
treatment of HIV, hepatitis B, or hepatitis C infection. 
25. Has used mitotane prior to Baseline. 
4.3 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study but did not 
meet the eligibility criteria for the study and were not enrolled.  


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Patients who fail screening due to a laboratory result may be retested within the screening period 
without prior Sponsor approval. Other laboratory tests not directly affecting patient eligibility 
may be repeated at the Investigator’s discretion during Screening. The 24-hour ABPM may be 
repeated if there is a technical problem with the test.  
If a patient is rescreened, they must sign a new informed consent form (ICF) and be assigned a 
new screening ID each time. 
4.4 
Early Patient Discontinuation or Withdrawal  
Patients may withdraw their consent to participate in the study at any time for any reason without 
prejudice. The Investigator should make reasonable attempts to retain the patient in the trial and 
to document the specific reason why consent is withdrawn.  
x Patient must be discontinued from the study if the patient becomes pregnant (see 
Section 8.11). 
Patients should be discontinued from the study if the patient requires or starts a prohibited 
medication(s), or is not adhering to protocol procedures. 
The Investigator can also withdraw patients from the study.  
Reasons may include, but are not limited to: 
x The Investigator decides it is in the patient’s best interest to discontinue study drug and/or 
participation in the study. 
x The patient experiences an AE or any of the special safety events outlined in Table 2, 
Section 5.4.1 that the Investigator believes requires withdrawal from the study. 
x Patient is lost to follow-up. Before a patient is determined to be lost to follow-up, 
reasonable efforts will be made to contact the patient and complete study termination 
procedures. 
If a patient discontinues early from the study, the patient will complete an early termination (ET) 
visit at the time of last dose of study drug or within 2 weeks. They will be instructed to return to 
the site for the Week 22 visit per their original dosing schedule, and for the follow-up visit 28 
days after the last dose of study drug. Depending on the timing of the patient’s discontinuation, 
the visits may happen out of sequence, and either visit may serve as the patient’s last study visit. 
Patients who discontinue study drug early should be encouraged to complete the end of treatment 
and follow-up assessments and to report any AEs, including SAEs, for 28 days after the last 
administration of study drug. The date when the patient discontinues study drug and the reason 
for discontinuation must be recorded on the electronic case report form (eCRF).  
For patients who withdraw consent to participate in the study, every effort should be made to 
determine whether the withdrawal of consent was related to an AE or a specific aspect of the 
study. If a patient wishes to withdraw consent to further participation in the study entirely—
including Follow-up, this should be clearly documented (1) in the patient’s medical record and 
signed by the Investigator and (2) in the eCRF. 
Before a patient is determined to be lost to follow-up, reasonable efforts (i.e., 3 documented 
attempts) will be made to contact the patient and complete study termination procedures. 


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For guidelines about temporary interruption of study drug or study drug modifications, see 
Section 5.4. 
A patient may be withdrawn early from the study if the study is terminated early by the Sponsor 
or regulatory authority.  
4.5 
Replacement of Patients 
Patients who withdraw from study early will not be replaced. 
4.6 
Restrictions During Study 
4.6.1 Dietary Restrictions 
The assigned dose will be administered orally once daily in the morning or at bedtime, with no 
food for 4 hours before and 1 hour after dosing. Any other medication(s) that the patient is 
taking should be taken 30 minutes after the dose of study drug. Each dose should be taken 
with 240 mL water. 
4.6.2 Contraception 
All female patients of childbearing potential (including all women <50 years old, women whose 
surgical sterilization was performed <6 months ago, and women who have had a menstrual 
period in the last 2 years) will take pregnancy tests at every visit from Screening through 
Follow-up. The Screening pregnancy test will be a blood test. All subsequent pregnancy tests 
will be urine tests. 
Female patients of childbearing potential are required to use a highly effective method of 
contraception from 30 days prior to Day 1 to 30 days following the last dose of study-drug 
administration. Male patients with female partners are required to use to use 2 forms of 
contraception, one of which is a barrier method, from Day 1 (prior to study drug administration) 
until 30 days following the last dose of study drug administration.  
Highly effective forms of contraception include:  
x Abstinence 
x Surgical sterilization  
x Intrauterine device or intrauterine system  
x Oral contraception plus a barrier method  
x Double-barrier method (e.g., male condom or a diaphragm plus a vaginal spermicidal 
cream) 
If a patient is usually not sexually active but becomes active, they, with their partner, must 
comply with the contraceptive requirements detailed above. In addition, male patients should not 
donate sperm until 30 days after the last dose of study drug.  
4.6.3 Surgery during the Study 
Patients may not undergo unilateral or bilateral adrenalectomy or nodulectomy from Screening 
through the follow-up visit. 


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5 
STUDY TREATMENTS AND MANAGEMENT 
5.1 
Study Drug and Placebo 
Study drug is defined as relacorilant or placebo equivalent. 
Relacorilant and placebo equivalent, including dose and regimen, formulation, packaging, and 
storage, are described in Table 1.  
Table 1 
Study Drug and Placebo: Description, Administration, Packaging, 
and Storage 
 
Study Drug and Placebo 
Specifications 
Relacorilant 
Placebo 
Description  
For each capsule, relacorilant is prepared 
as a
 
 
  
The placebo for relacorilant capsule is designed 
to match the study drug in appearance. Each 
placebo capsule contains a formulation of 
 
 
Supplied 
Capsules, 28-count in child-resistant, 
blister-packaged cards and labeled per 
country requirement. 
Capsules, 28-count in child-resistant, 
blister-packaged cards and labeled per 
country requirement. 
Appearance 
Yellow, oblong, 
 capsules 
Yellow, oblong 
 capsules 
Unit dose 
strength 
100 mg relacorilant/capsule 
Placebo equivalent 
Dose levels 
100, 200, 300, or 400 mg 
Placebo equivalent 
Administration  
Orally, with 240 mL of water under fasted 
conditions 
Orally, with 240 mL of water under fasted 
conditions 
Regimen 
4 capsules, once daily a 
4 capsules, once daily a 
Restrictions 
Refer to Section 4.6.1 
Refer to Section 4.6.1 
Dispensing 
study drug 
Dispense to patients at the visits specified 
in Appendix A  
Dispense to patients at the visits specified in 
Appendix A  
Storage 
Store as follows:  
x In a secure location 
x At 
 Excursions 
permitted, 
  
x Out of reach and sight of children 
Store as follows:  
x In a secure location 
x At 
 Excursions 
permitted, 
  
x Out of reach and sight of children 
Note: Procedures for inventory, reconciliation, and destruction or return of study drug are provided in Section 11.6. 
a. No matter which arm patients are randomized, every patient will take 4 capsules at each dose every day. The study 
drug is provided in a blister pack containing 28 capsules divided into 7 rows (Days 1 to 7). For patients 
randomized to relacorilant, each row will contain either a mix of relacorilant capsules and placebo capsules to 
ensure the patient gets the correct dose (i.e., for 300 mg of relacorilant, each row contains 3 relacorilant capsules 
and 1 placebo capsule), or the row will contain 4 relacorilant capsules (i.e., for 400 mg of relacorilant). For 
patients randomized to placebo, all 28 capsules in the blister pack contain placebo capsules. Patients must take all 
4 capsules to ensure they get the full dose. 


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5.2 
Non-Investigational Medicinal Agent 
Not applicable.  
5.3 
Dose-Escalation Process 
During dose escalation, all patients will be escalated in a stepwise manner from 100 mg to 
400 mg once daily, based on tolerability and improvement in hyperglycemia and/or 
hypertension. The starting dose at Baseline will be 100 mg relacorilant or matching placebo 
once daily for 2 weeks, after which the dose will be increased to 200 mg. Then the dose will 
increase in 100 mg increments every 4 weeks. Dose titrations after Week 18 are not permitted. 
Dose escalation will be performed based on tolerability assessed by the unblinded Medical 
Monitor considering the following factors (only in patients whose current dose is well tolerated). 
In patients with DM/IGT only, the 2-hour glucose based on oGTT: 
x is 140 mg/dL or 
x is <140 mg/dL and KDV QRW GHFUHDVHG E\  PJG/ IURP %DVHOLQH 
In patients with systolic hypertension only, the average 24-hour systolic BP (based on 
ABPM): 
x is 130 mm Hg or 
x is <130 mm Hg and KDV QRW GHFUHDVHG E\  PP Hg from Baseline 
In patients with both DM/IGT and systolic hypertension: 
x The 2-hour glucose of the oGTT: 
x is 140 mg/dL or 
x is <140 mg/dL and KDV QRW GHFUHDVHG E\  PJG/ IURP %DVHOLQH 
OR 
The average 24-hour systolic BP (based on ABPM): 
x is 130 mm Hg or 
x 
is <130 mm Hg and has not decreased by 5 mm Hg from Baseline 
Dose escalation may be held if the patient cannot safely tolerate escalation to the next dose.  
If access of patients to the study site is restricted due to the COVID-19 pandemic, dose 
escalation up to 200 mg may occur remotely if necessary. Subsequent dose escalations, however, 
are permitted only after completion of safety assessments. 
Dose escalations start the day after the visit at which they are approved by the Investigator.  
Results of 2-hour oGTT, ABPM, and safety laboratory results will be reviewed by an unblinded 
Medical Monitor to monitor patient safety and allow dose escalation. The unblinded Medical 
Monitor will be unblinded to results of study assessments but is blinded to the treatment 
assignment. The Sponsor or designee, the Investigator, the blinded Medical Monitor, study-site 
personnel, and the patient will be blinded to treatment assignment (see Section 5.8).  


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5.4 
Dose Modifications 
Every effort should be made to administer study drug on the planned dose and schedule. 
However, if in the opinion of the Investigator a relacorilant dose is not tolerated, a dose 
interruption or dose reduction is permitted. Re-escalation after a dose reduction is permitted, 
with the approval of the Medical Monitor. 
Dose reductions to manage excessive GR antagonism are detailed in Section 5.4.2. 
Dose interruption or dose reduction to a previous dose may occur at any time.  
During study-drug interruptions, patients will continue on the same visit schedule.  
5.4.1 Dose Interruption and/or Discontinuation: Special Safety Events 
Based on the mechanism of action of relacorilant, there is a theoretical risk of excessive GR 
antagonism, which could manifest with findings such as weakness, tiredness, dizziness, weight 
loss, nausea, vomiting, or muscle aches. Because relacorilant does not affect the MR, it is 
unlikely that hypotension would occur in the absence of antihypertensive medication. 
The actions outlined in Table 2 should be taken if a patient: 
x Exhibits signs and symptoms of excessive GR antagonism 
x Experiences significant trauma, surgery, or medical illness occurring at any time during 
the study (through 2 weeks after last dose) 
At study enrollment, all patients will be given a card to carry with them that identifies their 
potential risk for excessive GR antagonism. The card will contain the following information: 
x Mention use of relacorilant (“glucocorticoid receptor antagonist”) 
x Potential need for glucocorticoid use in setting of shock, surgery, serious illness, or injury 
x Recommended dose of replacement steroids (4௅10 mg dexamethasone intramuscularly or 
intravenously for 2–3 days as needed) 
x Investigator contact information.  
 


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Table 2 
Criteria for Dose Modification or Discontinuation Due to Special Safety 
Events 
 
Criteria for Interrupting and Restarting or Modifying 
Study Drug and Patient Management 
Criteria for Stopping Study 
Treatment 
Excessive GR 
antagonism 
Criteria: Signs and symptoms of excessive GR antagonism 
Management:  
Immediately interrupt relacorilant treatment for at least 3 days 
and start standard supportive care, including fluid 
resuscitation, as indicated. 
If appropriate, administer supplemental glucocorticoids given 
in high doses to overcome the GR antagonism produced by 
relacorilant. Initially, consider parenteral dexamethasone  
(4௅10 mg), followed by additional parenteral or oral doses 
once or twice daily for 1௅3 days and tapered thereafter, 
depending on clinical response. In some cases, higher doses of 
dexamethasone for longer periods of time may be required. 
If the patient has been receiving treatment with a MR 
antagonist, consider discontinuing it or adjusting the dose, 
particularly in the presence of hypotension.  
Restart relacorilant treatment only if the potential benefits 
outweigh the risks and after a discussion with the Medical 
Monitor.  
Restart relacorilant at the highest dose previously tolerated by 
the patient.  
After 2 weeks, resume the current dose or increase by 100 mg 
with the approval of the Medical Monitor.  
A combination of at least 2 of 
the following Grade 3 or 
higher events can lead to 
stopping/reducing dose: 
fatigue, anorexia, nausea/ 
vomiting a (associated with 
decreased oral intake), or 
abdominal pain, seen either at 
the 200-mg dose level or at 
other dose levels for which 
the Investigator deems dose 
reduction is not an option. 
Significant trauma, 
surgery, or medical 
illness at any time 
during the study 
(through 2 weeks 
after last dose) 
Management: 
As medically indicated, interrupt relacorilant treatment and 
provide supplemental glucocorticoids to offset the 
glucocorticoid receptor antagonism even in patients not 
experiencing signs and symptoms of excessive antagonism.  
After resolution of the physiological stress associated with the 
event and if still within the Treatment Period, resume 
relacorilant at the last dose level the patient was receiving 
before interruption. 
 
GR, glucocorticoid receptor; MR, mineralocorticoid receptor. 
a. For the purpose of this assessment, nausea and vomiting are considered 1 criterion. 


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5.4.2 Pharmacokinetic Criteria for Dose Adjustment or Discontinuation 
Not applicable. 
5.5 
Concomitant Medications 
Concomitant medications are defined as any prescription or over-the-counter medication, herbal 
preparations, and vitamin and/or mineral supplements that the patient began or continued in the 
period starting with the first dose of study drug on Day 1 and ending at the follow-up visit. 
Medications that the patient started and ended before the first dose of study drug will be noted as 
prior medications.  
At Screening, a list of current medications will be obtained, including start date, dosage, and 
route of administration, along with any medications taken in the 3 months before Screening to 
treat Cushing syndrome, diabetes, and/or hypertension. 
Antidiabetic, antihypertensive, antidepressant and/or lipid-lowering medications that are highly 
dependent on CYP3A for clearance and cannot undergo dose modifications on coadministration 
with strong CYP3A inhibitors are prohibited. Strong CYP3A4 inducers are also prohibited. 
For example, the FDA provides a current list of Substrates and Inducers of CYP3A at the 
following website.  
https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteracti
onslabeling/ucm093664.htm#table4-1 
The list may not be inclusive of all currently available substrates and inducers of CYP3A 
worldwide. The Investigator should contact the Medical Monitor with any questions.  
Patients on such medications at Screening will need to have their dose adjusted or be switched to 
an alternative medication. For patients switched to an alternative antidiabetic or antihypertensive 
medication, there must have been no increase in medication dosage for at least 4 weeks prior to 
first dose of study medication (see Table 3). 
Information about concomitant medications will be collected from all patients at each visit from 
Screening through the Follow-up Visit. If access of patients to the study site is restricted due to 
the COVID-19 pandemic, a review of concomitant medications may involve alternative methods 
(e.g., phone contact or virtual study visits). Any changes in medications since the last visit will 
be captured and recorded.  
Efficacy assessments include the total daily dose of insulin for patients with DM/IGT and 
antihypertensive medications for patients with uncontrolled hypertension. 
Permitted concomitant medications are listed in Table 3. 


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Table 3 
Permitted Concomitant Medications 
Medication 
Use and/or Restriction 
Mineralocorticoid receptor 
antagonists and other potassium-
sparing diuretics 
Do not initiate or increase dose without prior consultation with the 
Medical Monitor. 
Potassium supplements 
To treat hypokalemia 
Insulin and oral antidiabetic 
medication 
Do not take before the oGTT on the day of the procedure; can be taken 
with food after oGTT is completed 
Dose can be decreased during study-drug dosing to prevent 
hypoglycemia; upward titration should be avoided and may occur only 
after consultation with the Medical Monitor. 
Long-acting insulin 
Can take the night before the oGTT. 
Antihypertensive medication 
Dose can be decreased during the study-drug dosing to prevent 
hypotension or orthostatic symptoms.  
Do not increase dose or add new antihypertensive medications without 
prior consultation with the Medical Monitor. 
Lipid-lowering drug 
No increases in current dose allowed from 4 weeks before Baseline 
through the follow-up visit.  
oGTT, oral glucose tolerance test.  
5.5.1 Rules for Use of Antidiabetic and Antihypertensive Concomitant Medications 
x Patients should not take antidiabetic medications before the oGTT on the day of the 
procedure; antidiabetic medications may be taken with food after the oGTT is completed. 
Long-acting insulin may be taken the prior evening. 
x If any modification of existing diabetes medications or initiation of new diabetes 
medication is being considered during dosing, a 2-hour oGTT glucose should be obtained 
prior to modification of medications. 
x Unblinding of fasting or postprandial glucose from the 2-hour oGTT or unblinding of 
ABPM results will not result in the unblinding of study treatment. 
x If any modification of existing antihypertensive medication or initiation of new 
antihypertensive medication is being considered during dosing, an ABPM should be 
performed prior to modification of medications. 
5.5.1.1 
Decrease or Discontinuation of Concomitant Medications 
In patients with DM/IGT at Baseline 
Reduction or discontinuation of insulin and insulin secretagogues should be considered only if:  
x Fasting or postprandial blood glucose <70 mg/dL on at least 2 home measurements, 
or 1 serum glucose measurement associated with symptoms of hypoglycemia 
 For basal and prandial insulin, consider decreasing dosage by 20%. 


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 For insulin secretagogues, consider decreasing dosage by 50%; discontinue 
if recurrent. 
 Reductions of insulin and/or insulin secretagogues can be adjusted depending on the 
degree of hypoglycemia and the current total dose of insulin. 
x In patients with hypoglycemia unawareness, changes in insulin and insulin secretagogues 
should be considered if fasting or postprandial glucose is <70 mg/dL on at least 2 home 
measurements or 1 serum glucose measurement.  
Every effort should be made to obtain an oGTT prior to a reduction in anti-diabetic medication 
(if patient’s condition allows it).  
The unblinded Medical Monitor will notify the site of the pre-challenge fasting or 2-hour glucose 
from the oGTT decreases below 70 mg/dL.  
Unblinding of pre-challenge fasting or the 2-hour glucose of the oGTT will not result in the 
unblinding of study treatment. 
In patients with uncontrolled systolic hypertension at Baseline 
Reduction or discontinuation of antihypertensive medications should be considered only if: 
x Blood pressure decreases below 100 mm Hg systolic or 60 mm Hg diastolic by office 
measurement on at least two measurements obtained 15 min apart with symptoms of 
orthostatic hypotension.  
x Symptoms of hypotension (including orthostatic hypotension) occur. 
Every attempt should be made to obtain an ABPM prior to any decrease of BP medication (if 
patient’s condition allows it). 
The unblinded Medical Monitor will notify the site if BP decreases below 100 mm Hg average 
SBP or 60 mm Hg mean diastolic by ABPM. 
Unblinding of ABPM results will not result in the unblinding of study treatment. 
5.5.1.2 
Increase or Initiation of Concomitant Medication 
In patients with DM/IGT at Baseline 
Increases in, or initiation of, antidiabetic medications used as rescue medication are allowed if 
patients meet one of the following criteria:  
Local laboratory based on standard of care assessments (serum glucose and/or HbA1c):  
x Morning fasting glucose >300 mg/dL on 2 consecutive days  
x HbA1c >12% 
Central laboratory study related assessments (serum glucose, HbA1c and/or 2-hour oGTT):  
Results will be reviewed by an unblinded Medical Monitor to monitor patient safety. If a patient 
meets at least 1 of the following criteria, the results will be communicated to the study site, and 
rescue medication may be initiated or increased.  


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x Morning OR pre-challenge fasting glucose from the 2-hour oGTT >300 mg/dL 
x HbA1c >12% 
x Pre-challenge fasting glucose increases by 50 mg/dL AND the 2-hour oGTT glucose 
increases by 100 mg/dL from Baseline 
If antidiabetic medication dose is increased or medication is initiated during the study, oGTT and 
HbA1c tests will be performed per the protocol schedule. 
In patients with uncontrolled systolic hypertension at Baseline: 
Increases in, or initiation of, antihypertensive medications used as rescue medication are allowed 
if patients meet one of the following criteria (based on standard-of-care measurements):  
x Mean office SBP >170 mm Hg or DBP >110 mm Hg on  PHDVXUHPHQWV REWDLQHG
15 minutes apart  
x Average SBP >170 mm Hg or DBP >110 mm Hg based on standard of care ABPM  
Study ABPM results will be reviewed by an unblinded Medical Monitor to monitor patient 
safety. If a patient meets the following criterion, the results will be communicated to the study 
site, and rescue medication may be initiated or increased:  
x Average SBP >170 mm Hg or DBP >110 mm Hg 
Unblinding of ABPM results will not result in the unblinding of study treatment.  
If antihypertensive medication dose is increased or medication is initiated during the study, 
ABPM tests will be performed per regular schedule.  
5.6 
Prohibited Medications 
Relacorilant is a strong inhibitor of CYP3A. Medications that are highly dependent on CYP3A 
for clearance for which elevated plasma concentrations are associated with SAEs and for which 
dose modification is not an option with strong CYP3A ‘inhibitors’ should be avoided (consult 
the prescribing information of the respective concomitant medications for further details). 
Additionally, the following medications used in the treatment of Cushing syndrome are 
prohibited during treatment with study drug in this study: 
x Adrenostatic medications: metyrapone, osilodrostat, ketoconazole, fluconazole, 
aminoglutethimide, mitotane, or etomidate. 
x Mifepristone. 
x Strong CYP3A4 inducers.  
x Antidiabetic, antihypertensive, antidepressant, and/or lipid-lowering medications that are 
highly dependent on CYP3A for clearance and cannot undergo dose modifications upon 
coadministration with strong CYP3A inhibitors.  
x Systemic glucocorticoids (with the exception of temporary use for treatment of excessive 
GR antagonism), potent (group III) topical corticosteroids in extended body surface 


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areas, and intra-articular corticosteroids unless other treatment options 
fail/contraindicated. 
x Other investigational agents. 
5.7 
Method of Treatment Assignment and Randomization 
Eligible patients will be randomized 1:1 to relacorilant or placebo and stratified by one factor 
(disease at Baseline) with 3 levels:  
x DM/IGT only at Baseline  
x Systolic hypertension only at Baseline  
x DM/IGT and systolic hypertension at Baseline 
Randomization will be centrally assigned using 
. The log-in 
information and directions for the 
 will be provided to each site. 
Study drug will be dispensed at the study visits summarized in Appendix A. Returned study drug 
should not be re-dispensed to the patients. 
Statisticians involved in generation of randomization codes, or who have access to the 
randomization code will not be involved in the analyses of the study. 
5.8 
Blinding/Unblinding 
The Sponsor or designee, the Investigator, the blinded Medical Monitor, study-site personnel, 
and the patient will be blinded to treatment assignment. Selected study-assessment and 
laboratory results (as described in Section 6) that could potentially reveal the treatment 
assignment in some patients will remain blinded until after database lock.  
To maintain the overall quality and blinding of the clinical trial, unblinding of treatment 
assignment should occur only in exceptional circumstances. If unblinding treatment assignment 
is deemed necessary, the Investigator should complete the unblinding process through the 
, 
or, if the 
 is unavailable, contact the emergency unblinding toll-free number, which can be 
found in the study manual. The Investigator should notify the Sponsor of any unblinding 
occurrences. 
 
 
 
 
 
 
 
 
 


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Investigators wishing to discuss potential unblinding should contact the Medical Monitor for 
further discussion.  
If unblinding of either central laboratory or ABPM data is required, the site should refer to the 
respective manual for the unblinding process.  
Note: Even if laboratory values or ABPM values are unblinded, the treatment assignment will 
remain blinded.  
The Investigator is encouraged to maintain the blind as far as possible. The patient’s treatment 
assignment must not be disclosed to the patient and/or other study staff. There should not be any 
written or verbal statements of the patients’ treatment assignment in any patient documents.  
If any accidental unblinding occurs for treatment assignment or blinded laboratory/ABPM 
values, the Investigator should promptly document the occurrence and notify the Sponsor.  
5.9 
Dosing Diary 
A dosing diary will be dispensed at the time points specified in Appendix A for patients to record 
each self-administered dose of study drug and any concomitant medications. Entries should 
include the number of capsules as well as the date and time of study drug administration. Time 
and dose administered should be documented in the clinic charts. 
Patients will be instructed to return all unused study drug and the dosing diary at the patient 
visits. 
5.10 
Product Accountability and Treatment Adherence  
The Investigator is responsible for the accountability of all used and unused study drug. All 
investigational materials should be kept in a secure area inaccessible to unauthorized individuals. 
Drug accountability records must be maintained at the site and be available for monitoring by the 
Sponsor or its representatives. At a minimum, records will be maintained to document receipt of 
supplies, dispensing of supplies to specific patients, and return of unused product by patients.  
After study drug accountability monitoring has occurred, opened and unopened cartons of study 
drug must be returned to the Sponsor or its designee at the end of the study or destroyed onsite 
upon approval from Sponsor, in accordance with local requirements. 
Under no circumstances will the Investigator allow the study drug to be used other than as 
directed by the protocol. 
Adherence to the study drug regimen will be determined by review of the dosing diary and 
counting the number of capsules taken and returned at each study visit. 
5.11 
Continued Access to Study Treatment 
All patients completing the study will be eligible to enter an extension study provided that they 
have at least 80% adherence with scheduled dosing (by capsule counts). 


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5.12 
External Data Review Committee 
5.12.1 Independent Data-Monitoring Committee to Monitor Patient Safety 
An Independent Data Monitoring Committee (IDMC) will be established to conduct periodic 
reviews of data to ensure the safety of patients. The IDMC will be composed of at least 3 voting 
members: two physicians and one statistician. The IDMC will meet at least quarterly. Further 
details describing the IDMC composition, contents of data reports, responsibilities, and 
decision rules will be described in the IDMC Charter and actions taken will be documented 
in meeting minutes. 
5.13 
Monitoring of and Treatment for Electrolyte Abnormalities and Edema 
Monitoring for electrolyte abnormalities occurs at every visit and any clinically significant 
abnormality should be treated per standard of care. 
Monitoring for edema occurs at every visit during a physical examination and should be treated 
per standard of care.  


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6 
DESCRIPTION OF STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in Appendix A. Protocol waivers or 
exemptions are not allowed.  
The Investigator and Sponsor will conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and local regulations. Adherence to the study-design requirements is essential 
and required for study conduct, and the Investigator must ensure that trial procedures are 
performed as described in the protocol. During the study, procedures and observations will be 
monitored to confirm that study requirements are being followed as outlined in the SoA. 
In the event that a patient is unable to come to the clinic to participate in study-related visits or 
procedures due to the COVID-19 pandemic, Sponsor-approved alternative options may be 
provided to the Investigator sites based on the needs and safety of patients. This may include the 
provision of study drug dispensation and delivery outside of the clinic. 
6.1 
Informed Consent and Screening 
Written informed consent must be obtained before initiating any study-mandated procedures. 
If allowed by local regulatory authority, remote consenting will be permitted if access of 
patients to the study site is restricted due to the COVID-19 pandemic. IRB/EC guidelines 
should be followed. 
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria.  
6.1.1 Dexamethasone Suppression Test 
The dexamethasone suppression test (DST) will be performed at Screening. Dexamethasone will 
be administered either as a 1-mg (or higher) dose overnight or a 2-mg dose over 48 hours; a 
blood sample will be drawn and will be tested at a central laboratory. In special circumstances 
pre-approved by the Sponsor, a blood sample may be tested at a local laboratory. Dexamethasone 
levels should be measured concurrently. 
Estrogen preparations that affect significantly the cortisol binding globulin levels, including birth 
control and hormone replacement treatments, should be held for a duration of at least 5 half-lives 
of the estrogen analogue prior to DST.  
6.1.2 Adrenal-Imaging History 
Confirmation of a benign adrenal lesion can be made from the most recent imaging obtained as 
part of standard of care (within three years prior to Screening).  
If the imaging report or the actual imaging study is not available, an adrenal imaging study 
should be performed to confirm study eligibility before dosing with study drug. 
6.1.3 History Cushing-Syndrome௅Medication Washout 
Medications used in the treatment of hypercortisolism are prohibited and require washout of at 
least 12 weeks before Screening. Patients requiring washout of a medication for Cushing 


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syndrome must complete the Screening/Baseline oGTT, HbA1c, and 24-hour ABPM after 
washout and within 2 weeks before Day 1 dosing. 
6.1.4 Demographics and Baseline Disease Characteristics 
Patient demographic data, including age at time of informed consent, sex, and race/ethnicity, and 
baseline disease characteristics, such as years since diagnosis of hypercortisolism (e.g., primary 
pigmented nodular adrenocortical disease, primary macronodular adrenal hyperplasia, adrenal 
adenoma), will be documented.  
6.1.5 Medical and Medication History 
Relevant patient medical history, including the diagnosis, etiology, and treatment history of 
hypercortisolism (including dexamethasone suppression test failure where appropriate), 
diagnosis of DM/IGT and/or hypertension, as well as other illnesses and allergies, date(s) of 
onset, and whether conditions are currently ongoing will be recorded at Screening and Baseline 
(Appendix A). Adrenal surgical history will include date and type.  
A menstrual history will be obtained for all female patients at Screening. 
At Screening, a list of current medications will be obtained, including start date, dosage, and 
route of administration, along with any medications to treat hypercortisolism, diabetes, and/or 
hypertension taken in the 3 months prior to Day 1. 
6.2 
Safety Assessments 
Safety will be determined from evaluation of AEs, physical examinations, clinical laboratory 
tests, vital signs, and ECGs.  
6.2.1 Physical Examination  
A comprehensive physical examination will be performed. If clinically significant abnormalities 
are observed during Screening, they should be reported in the patient’s medical history; if 
observed any time after the first dose of study drug (Day 1), they will be considered treatment-
emergent AEs.  
Investigators will assess the general physical appearance of patients during the examination. 
6.2.2 Vital Signs 
Vital signs, including BP, heart rate, respiratory rate, and body temperature, will be obtained at 
the time points specified in Appendix A. Blood pressure will be measured in both arms at 
Screening and the arm with the higher reading will be recorded and used for all subsequent 
measurements. Blood pressure and heart rate will be taken after the patient has rested in a sitting 
position for approximately 15 minutes and 30 minutes after smoking or caffeine intake. 
Automated BP machines can be used to standardize measurements. 
Unscheduled assessments of vital signs can be performed as necessary.  
To determine whether an increase in or initiation of antihypertensive medication is needed for 
patients with hypertension, office blood pressure measurements may be collected. At least three 


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blood pressure measurements separated by an interval of 15 minutes in the designated arm are 
required. If 2 sequential readings differ by >5 mm Hg (systolic or diastolic), repeat the 
measurement until consecutive readings are within 5 mm Hg of each other.  
In addition to the safety vital signs collected, a 24-hour ABPM will also be done by all patients 
at Screening and by patients with hypertension (Section 6.4.2) during treatment at the time points 
specified in Appendix A. 
6.2.3 Height, Weight, and Waist Circumference 
Body weight and waist circumference will be measured for all patients at the time points 
specified in Appendix A. Weight will be measured without overcoat and shoes and with only 
light clothing. Clinical sites will be provided with tape measures to ensure consistency of waist 
circumference measurements. Waist-circumference measurements should be obtained to the 
nearest 0.5 cm (1/4 inch) following removal of clothing from the waistline. Detailed instructions 
for measurement of waist circumference will be provided in the study manual. 
Body weight, measured without overcoat and shoes and with only light clothing, will be 
measured at every visit.  
Height will be measured only at Screening (Appendix A).  
6.2.4 Electrocardiogram 
Twelve-lead ECG tracings will be obtained from all patients in duplicate at the visits noted in 
Appendix A. Patients should lie down for 10 minutes before each ECG evaluation.  
On days when study drug is administered, the ECG should be performed 2 hours (±30 minutes) 
after study-drug dosing. A Sponsor-approved alternative option for ECGs (i.e., use of alternative 
locations for assessment) is permitted in the event of site closures due to the COVID-19 
pandemic. 
The Investigator or designee will indicate in the source documents whether the ECG was normal, 
abnormal but not clinically significant, or abnormal and clinically significant. Any new or 
worsened abnormality noted as clinically significant will be reported as an AE. 
In patients with an abnormal QTc interval at Screening, in which no concomitant drugs known 
to prolong QTc and no electrolyte abnormalities are present, duplicate ECG recordings should be 
obtained. The final decision to exclude a patient should be based on the average QTcF interval 
across the recordings. If an electrolyte abnormality is present, it should be corrected before the 
ECG is repeated. If the patient is taking a concomitant medication known to cause QT 
prolongation, an alternative medication may be considered, and the ECG repeated after an 
appropriate washout period.  
Electrocardiogram data will be submitted to a central reviewer; instruction will be provided in 
the study manual. 
6.2.5 Adverse Events 
Details on definitions and reporting of AEs are provided in Section 8. 


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All AEs will be recorded from the time of signing of the ICF until 28 days after the last dose of 
study drug. Patients should be monitored for AEs consistent with the current Investigator’s 
Brochure for relacorilant.  
6.2.6 Concomitant Medications 
Review usage and dosage of antidiabetic and antihypertensive medications. See Section 5.4 and 
Section 5.5 for rules for use of antidiabetic and antihypertensive concomitant medications and 
the procedures to accompany any changes. 
6.2.7 Clinical Laboratory Assessments 
6.2.7.1 
Laboratory Parameters 
Fasting blood samples will be collected for the analysis of safety at the time points specified in 
Appendix A. Laboratory samples will be analyzed at 1 or more central laboratories; instructions 
will be provided in the laboratory manual.  
During Screening, the Investigator will review laboratory reports evaluate the results, and 
sign/date the report.  
During dosing, all laboratory assessments will remain blinded. The unblinded Medical Monitor 
will review laboratory values and notify the Investigator and study-site staff of any significant 
out-of-range laboratory values. Critical lab values will be reported directly by the central lab to 
the Investigator. The unblinded Medical Monitor will follow up with the site to discuss critical 
laboratory values. To maintain the blind, investigators should not repeat laboratory tests locally 
unless medically necessary.  
Any clinically significant laboratory value will be reported as an AE by the Investigator. Patients 
with a clinically significant out-of-range laboratory value will be followed until the laboratory 
value returns to normal or becomes medically stable. The Investigator will treat the patient, as 
medically required, at appropriate intervals until this occurs. 
Laboratory tests to be performed are listed in Table 4 and should be performed according to the 
schedule provided in Appendix A.  


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Table 4 
Clinical Laboratory Variables Evaluated During the Study 
Hematology 
Red blood cell count  
Hemoglobin  
Hematocrit  
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin volume 
Mean corpuscular volume  
Platelet count 
Mean platelet volume 
Red-blood-cell distribution and width 
White-blood-cell count  
Neutrophils (percent and absolute) 
Lymphocytes (percent and absolute) 
Monocytes (percent and absolute) 
Eosinophils (percent and absolute) 
Basophils (percent and absolute) 
Serum Chemistry 
Sodium  
Potassium  
Calcium  
Chloride  
Phosphorus  
Magnesium  
Creatinine 
Creatine kinase 
Bilirubin (total and direct) 
Albumin  
Alkaline phosphatase 
Lactate dehydrogenase 
Aspartate aminotransferase  
Alanine aminotransferase 
Fasting glucose  
Fasting insulin 
Blood urea nitrogen 
Uric acid  
Bicarbonate  
Total protein  
Glucocorticoid-Receptor 
Activity 
Potential biomarkers of GR 
activity 
Pregnancy 
Serum/urine pregnancy test 
Thyroid Function 
Thyroid-stimulating hormone  
Total T3 Reflex 
Free T4 Reflex 
Glucose Control 
2-hour oGTT b  
HbA1c 
Biochemical Markers for Bone 
Remodeling 
Serum osteocalcin 
Pharmacokinetic 
Relacorilant 
Coagulation panel a 
Factor VIII 
von Willebrand factor 
Protein S 
Protein C 
Thrombin antithrombin (TAT) 
Partial thromboplastin time 
(PTT) 
Pharmacodynamic 
DST with dexamethasone levels 
Urinary free cortisol (UFC) 
Salivary cortisol 
Hypothalamic-pituitary-adrenal 
(HPA)-axis parameters: 
Plasma ACTH 
Serum DHEA-S 
Fasting serum cortisol 
Lipid-Metabolism Panel a 
Total cholesterol 
Low-density lipoprotein-cholesterol 
High-density lipoprotein-cholesterol 
Very low-density lipoprotein 
cholesterol 
Triglycerides 
ACTH, adrenocorticotropic hormone; DHEA-S, dehydroepiandrosterone sulfate; DST, dexamethasone 
suppression test; GR, glucocorticoid receptor; HbA1c, hemoglobin A1c; oGTT, oral glucose tolerance test; 
T3, triiodothyronine; T4, thyroxine.  
a. Lipid-metabolism panel and coagulation panels should be performed either before or  Kours after DST. 
b. 2-Hour oGTT includes glucose, insulin, and glucagon (at selected visits). 
6.2.7.2 
Sample Collection, Preparation, and Shipping 
Instructions for collection, preparation, and shipping of all laboratory samples will be provided 
in the study laboratory manual.  
Shipping instructions for samples collected for PK analysis and GR activity biomarkers will also 
be provided. Long-term retention of biological samples is described in Section 11.5.  


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6.2.7.3 
Blood-Volume Summary 
Blood samples will be used for analysis of safety laboratory, efficacy, PK, PD, biomarker, and 
pharmacogenetic parameters. The total volume of blood to be collected from each patient will be 
no more than 505 mL for his/her entire study participation. 
6.3 
Pregnancy Test 
All female patients of childbearing potential (including all women <50 years old, women whose 
surgical sterilization was performed <6 months ago, and women who have had a menstrual 
period in the last 2 years) will undergo pregnancy tests at every visit from Screening through 
Follow-up. The Screening pregnancy test will be a blood test; all subsequent pregnancy tests will 
be urine tests, as specified in Appendix A. 
6.4 
Efficacy Assessments 
The key efficacy assessments in this study are effects on glucose tolerance in the impaired 
glucose tolerance/diabetes subgroup and the effects on BP in the hypertensive subgroup. All 
other effects assessments are considered exploratory. Table 5 lists all efficacy assessments. 
Details are provided below.  
Table 5 
List of Efficacy Assessments 
AUCglucose 
Reduction in concomitant medications for DM or 
hypertension 
Glycated hemoglobin (HbA1c) concentration 
Systolic blood pressure (based on ABPM) 
Fasting glucose 
Diastolic blood pressure (Based on ABPM) 
Fasting insulin 
Hormonal and menstrual cycle 
2-hour oGTT 
 
glucose, insulin, and glucagon (glucagon at select 
timepoints) 
Serum osteocalcin 
Plasma ACTH 
Bone density 
Serum DHEA-S 
Trabecular bone score 
Fasting serum cortisol 
Body composition 
Late-night salivary cortisol 
Factor VIII 
Early-morning salivary cortisol 
von Willebrand factor 
Beck Depression Inventory 
Protein S 
Cushing QoL questionnaire 
Protein C 
Sit-to-stand test 
Thrombin antithrombin (TAT) 
Trail-making test 
Partial thromboplastin time (PTT) 
 


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6.4.1 Glucose Tolerance 
A 2-hour oGTT will be used to assess the effect of study drug on glucose tolerance, insulin 
resistance indices, and hyperglucagonemia (AUCinsulin, Matsuda Index, HOMA IR, and at 
selected visits AUCglucagon) following an 8-hour fast at the time points specified in Table 11.  
In general, patients should not take antidiabetic oral medication or insulin the morning of their 
visit, however, long-acting insulin can be taken the night before. Oral antidiabetes medications 
and insulin preparations can be taken with food after completion of the oGTT. 
During the 2-hour oGTT, blood samples for plasma glucose, insulin, and glucagon will be 
collected before the glucose drink and 0.5, 1.0, 1.5, and 2.0 hours after the glucose drink (see 
Table 6).  
In patients with an increase to their DM medications before or during Screening, oGTT should 
EH SHUIRUPHG  ZHHNV DIWHU WKH LQFUHDVH LQ WKH GLDEHWHV PHGLFDWLRQ and within 2 weeks prior to 
the Baseline Visit R*77 GXULQJ 6FUHHQLQJ VKRXOG EH SHUIRUPHG HLWKHU EHIRUH RU  Kours after, 
the DST test. 
Table 6 
Time Window for Collection of 2-hour oGTT Blood Samples  
Nominal Time 
Reporting Standards 
0.5, 1.0, 1.5, and 2.0 hours post glucose drink 
±10 minutes 
6.4.2 Ambulatory Blood Pressure Monitoring (ABPM) 
The 24-hour ABPM will be assessed for patients with an increase to their anti-hypertension 
medications either before or during Screening, ABPM VKRXOG EH SHUIRUPHG  ZHHNV DIWHU WKH
increase and within 2 weeks prior to the Baseline Visit. ABPM during Screening should be 
SHUIRUPHG HLWKHU EHIRUH RU  Kours after, the DST test. At least 2 attempts should be made to 
obtain an accurate ABPM in all patients enrolled in the study. 
Average 24-hour systolic and diastolic ambulatory BP will be obtained by the patient at home 
using an ambulatory BP monitor provided and initiated at the study site (or under the condition 
of a Sponsor-approved alternative option in the event a patient is unable to come to the study site 
due to the COVID-19 pandemic) at the time points specified in Appendix A. The patient should 
use the monitor during a time when a full 24-hour recording can be completed. The patient 
should perform the ABPM under consistent conditions throughout the study. In cases where the 
ABPM fails QC and needs to be repeated, initiation of the ABPM at home will be allowed. The 
monitor should be worn on the non-dominant arm. Please see the vendor manual for additional 
details. 
The patient will bring the monitor to each study visit or will send it to the study site in advance 
of the next study visit. ABPM should be initiated at the end of the visit after collection of blood 
samples at each study visit with the exception of the Week 22 Visit where the ABPM should be 
performed within 7 days prior to the visit. If more than 2 consecutive hours, or 5 hours over the 
entire period are missing, then the data are considered missing, and test should be repeated. The 
results of 24-hour ABPM will remain blinded.  
Standard-of-care ABPM may be performed as needed in the opinion of the Investigator.  


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6.4.3 Glycated Hemoglobin (HbA1c) 
Blood samples will be collected to measure HbA1c, a glycoprotein whose concentration reflects 
the amount of glucose bound to hemoglobin. In patients who have an increase to their DM 
PHGLFDWLRQV EHIRUH RU GXULQJ 6FUHHQLQJ +E$F VKRXOG EH SHUIRUPHG  weeks after the 
increase in diabetes medication and within 2 weeks prior to the Baseline Visit.  
6.4.4 Hypothalamic-Pituitary-Adrenal Axis Parameters 
Blood samples will be obtained for analysis of plasma ACTH, dehydroepiandrosterone sulfate 
(DHEA-S), and serum cortisol at the time points specified in Appendix A.  
6.4.4.1 
Plasma ACTH 
Plasma ACTH should be measured at least twice during Screening. ACTH should be measured 
either before, or at least 24 hours after, the DST test. 
6.4.4.2 
Plasma DHEA-S 
Plasma DHEA-S should be measured either before, or at least 24 hours after, the DST test. 
6.4.4.3 
Fasting Serum Cortisol 
Serum fasting cortisol should be measured along with ACTH either before, or at least 24 hours 
after, the DST test. 
6.4.5 Sit-to-Stand Test 
The sit-to-stand test will be performed at the time points specified in Appendix A. The sit-to-
stand test evaluates the ability of patients to go from standing to sitting in a chair and then getting 
up again with/without the use of their arms or other aids. Patients seated in a chair will be asked 
to fold their arms across their chests and to stand up from the seated position once. If they are 
able to successfully rise from the chair, they will be asked to sit down again and then stand up 
and sit down 5 times as quickly as possible.  
The chair should be of standard height so that the patient’s legs are in flexion of approximately 
90 degrees about the knee when the feet are flat on the floor. Patients should be advised not to 
place their feet far beneath chair and not to offset the feet in the horizontal plane (i.e., asked to 
place their feet under the front of the chair, not too far forward [in front of the chair] or too far 
back [under the chair seat]). The same or similar chair should be used for all measurements. 
The study staff will use a stopwatch to measure the total time it takes for the patient to stand up 
and sit down 5 consecutive times; start time is in the seated position and stop time is in the final 
standing position. The total time of the test is measured. Patients with gait or balance disorders 
are not required to complete the sit-to-stand test. 
6.4.6 Trail-Making Test 
The trail-making test will be performed at the time points specified in Appendix A. The 
trail-making test is a neuropsychological test of visual attention and task switching that consists 
of 2 parts in which the patient is instructed to connect a set of 25 dots as quickly as possible 


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while maintaining accuracy. It can provide information about visual search speed, scanning, 
processing speed, and mental flexibility, as well as executive functioning.  
The total time of the test is measured, with a maximum of 300 seconds. 
6.4.7 Biochemical Markers of Bone Remodeling 
Blood samples for analysis of serum osteocalcin will be obtained from all patients at the time 
points specified in Appendix A.  
6.4.8 DXA Scans 
Trabecular bone score, bone mineral density, and body composition (change in the percent and 
absolute amounts of total body and regional fat and lean tissue [whole body, trunk, and leg)] will 
be determined from the DXA scans (Shepherd et al. 2017, Athimulam et al. 2019) for all 
patients, at the time points specified in Appendix A.  
6.5 
Pharmacodynamic Assessments 
Samples for pharmacodynamic (PD) assessments will be collected from all patients at the time 
points specified in Appendix A.  
6.5.1 Urinary Free Cortisol (UFC) 
The 24-hour UFC with creatinine test will be collected by the patient at home 2 times during 
Screening only. Each patient will be provided with instructions and supplies to collect all the 
urine produced during a 24-hour period. The 24-hour urine creatinine level and the total 24-hour 
urine volume will be obtained to confirm complete collection of the urine.  
Test must be performed either before or  KRXUV DIWHU '67 WHVW 
Patients should avoid drinking an unusual amount of fluids (5 L/day) during the 24-hour period. 
Patients should avoid use of any glucocorticoid preparations, including steroid-containing skin or 
hemorrhoid creams, during the collection period. Urinary free cortisol will be measured by 
tandem mass spectrometry. 
6.5.2 Late-Night Salivary Cortisol 
During Screening, two late-night salivary cortisol samples will be collected, one of which will be 
the night before the Day 1/Baseline Visit. Tests VKRXOG EH SHUIRUPHG HLWKHU EHIRUH RU  hours 
after, the DST test.  
During treatment with study drug, a late-night salivary-cortisol sample should be collected at the 
patient’s home at bedtime the night before the study visit. Patients should be instructed to avoid 
the chewing of licorice or tobacco 60 minutes prior to completing the test.  
Complete instructions will be provided to the patient and they will be given supplies for the 
collection of saliva. 


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6.5.3 Early-Morning Salivary Cortisol 
Early-morning salivary cortisol will be collected at the site if the patient arrives before 9 am (to 
avoid mix up with the late-night salivary cortisol samples collected by the patient). If the visit is 
scheduled after 9 am, the sample will be collected at home by the patient the morning of the visit. 
Early-morning salivary cortisol should be collected either on the same day as the late-night 
salivary cortisol is collected, or the morning after. 
6.6 
Patient-Reported Outcomes 
6.6.1 Cushing QoL Questionnaire 
The Cushing QoL patient questionnaire, which evaluates the health-related QoL in patients 
with Cushing syndrome (Webb et al. 2008), will be administered to all patients at the time points 
specified in Appendix A. It comprises 12 questions, each with 5 possible answers. The total 
VFRUH UDQJHV IURP ௅ 7KH &XVKLQJ 4R/ LQVWUXPHQW DGGUHVVHV NQRZQ SUREOHP DUHDV
associated with Cushing syndrome including trouble sleeping, wound healing/bruising, 
irritability/mood swings/anger, self-confidence, physical changes, ability to participate in 
activities, interactions with friends and family, memory issues, and future health concerns 
(Nelson et al. 2013). Lower values reflect lower quality of life.  
6.6.2 Beck Depression Inventory-II 
The Beck Depression Inventory-II (BDI-II), a 21-question self-report inventory that measures 
depression (Beck 1996), will be completed by all patients at the time points specified in 
Appendix A. Each answer is scored with values 0 to 3. The total score ranges from 0௅63. 
Scores of 0௅13 indicate minimal depression, 14௅19; mild depression; 20௅28; moderate 
depression; 29௅63; severe depression. 
6.7 
Pharmacokinetic (PK) Assessments 
Intensive PK sampling to assess the plasma concentrations of relacorilant and/or its metabolites 
will be conducted in all patients at the Week 18 visit (Appendix A).  
Pharmacokinetic sampling will take precedence over other procedures when more than 
1 procedure is scheduled for the same time point relative to dosing. 
PK sampling should be performed on the ongoing dose, prior to any dose escalation.  
Acceptable time windows for PK samples are shown in Table 7.  
Table 7 
Time Windows for Collection of Pharmacokinetic Samples 
Nominal Time 
Reporting Standards 
Predose 
Up to 60 minutes before dosing 
1, 2, 4, and 6 hours postdose 
±10 minutes 
 
Instructions for the collection and handling of the samples will detailed in the laboratory manual.  


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Drug concentration information that would unblind the study will not be reported to investigative 
sites or blinded personnel. 
6.8 
Pharmacodynamic/Biomarker Assessments 
Blood samples will be obtained from all patients for analysis of mRNA expression of 
glucocorticoid-modulated genes and proteins at the time points specified in Appendix A. Test 
PXVW EH SHUIRUPHG HLWKHU EHIRUH RU  KRXUV DIWHU '67 WHVW. The results of these assessments 
will remain blinded. 
6.9 
Appropriateness of the Measures 
The assessments to be used in this study are standard for evaluation of patients with Cushing 
syndrome and are generally recognized as reliable, accurate, and relevant.  
6.10 
Blood Storage 
A portion of the blood drawn predose at all visits (except the Screening Visit, Follow-up Visit, 
ET, and Unscheduled Visits) will be frozen and stored. For additional information on sample 
retention, see Section 11.5. These stored blood samples may be used by the Sponsor for retesting 
safety laboratory parameters, for measurement of study drug and/or concomitant drug levels in 
the blood, or for clinical laboratory testing to provide additional safety data. No human genetic 
testing will be performed without expressed consent of study patients. 


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7 
STUDY ASSESSMENTS AND PROCEDURES BY STUDY VISIT 
A Summary of Activities (SOA) is provided in Appendix A. Most assessments are for all 
patients; a few are performed only in patients in a specific subgroup (i.e., the impaired glucose 
tolerance/diabetes subgroup or the uncontrolled hypertension subgroup). 
In the event that a patient is unable to come to the clinic to participate in study-related visits or 
procedures, Sponsor-approved alternative options may be provided to the Investigator sites based 
on the needs and safety of patients. This may include the provision of study-drug dispensation 
and delivery outside of the clinic. 
Any deviation from protocol procedures will be noted in the patient’s clinical chart and eCRF 
and reported to the IRB/EC as applicable. In addition, the Sponsor will be promptly notified of 
any protocol deviations. Though alternative methods for safety and study assessments (i.e., 
phone contact, virtual study visits, use of alternative locations for assessment, including local 
labs or imaging centers, etc.) are permitted due to the COVID-19 pandemic, any modified 
protocol-described processes should be recorded as protocol deviations. 
7.1 
Scheduled Visits 
The window for each study visit is relative to the Baseline Visit. The acceptable visit window is 
±7 days for all visits (except for the Week 22 and ET visits, in which case a 3-week visit window 
[2 weeks before the scheduled visit, 1 week after the scheduled visit] and 2-week [2 weeks after 
the scheduled visit] visit window, respectively, is permitted). 
Patients will remain on study treatment post Week 22 visit until it has been confirmed that all 
results for efficacy assessment have been received and no repeat assessments are required. The 
follow-up visit must occur 28 days after the last dose of study drug. 
With regard to sequence of tests and acceptable time windows: 
x Predose procedures must be completed before dosing and, where applicable, before 
breakfast. 
x Dosing will take place after completion of all predose procedures.  
x All clinical laboratory samples and the predose PK samples will be collected when the 
patient is fasting (at least 4 hours). 
x Measurement of vital signs and ECG recordings should be avoided within 15 minutes 
after venipuncture or cannulation and, therefore, will normally be performed before blood 
sampling.  
x At all visits beginning with Week 2, study drug should be taken in the clinic during the 
visit and after initial blood draws. 
x At every visit during dose escalation (Week 2+) and maintenance phase (Week 14+), 
blood chemistry including potassium concentrations are checked, blood pressure is 
measured, and physical examination (including checking for edema) is conducted. 
Investigators are required to report adverse events to the Sponsor promptly. 


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x Pharmacokinetic sampling (at Week 18) will take precedence over other procedures when 
more than 1 procedure is scheduled for the same time point relative to dosing. Acceptable 
time windows for PK samples are: 
Within 1 hour before dosing for the predose sample, and ±10 minutes for  
the 1-, 2-, 4-, and 6-hour postdose samples.  
x Ambulatory BP monitoring will be initiated in the clinic after all blood samples are 
obtained with the exception of the Week 22 Visit where the ABPM should be performed 
within 7 days prior to the visit. 
x Study-drug dosing should occur after completion of the 2-hour oGTT (except for 
Week 18, when oGTT may take place after dosing for logistical issues due to intensive 
PK sampling that would prolong patient stay).  
x Acceptable time windows for oGTT samples are: 
±10 minutes for the 0.5-, 1-, 1.5-, and 2-hour samples 
x Electrocardiogram recording should be performed 2 hours ±30 minutes after study-drug 
dosing. 
If a patient discontinues early from the study, the patient will complete an early termination (ET) 
visit at the time of last dose of study drug or within 2 weeks. They will be instructed to return to 
the site for the Week 22 visit per their original dosing schedule, and for the follow-up visit 28 
days after the last dose of study drug. Depending on the timing of the patient’s discontinuation, 
the visits may happen out of sequence, and either visit may serve as the patient’s last study visit.  
The Investigator may repeat tests in the event of a technical failure and/or if additional 
observations or samples of blood are needed to monitor patient safety; these will not be 
considered protocol deviations. 
The required procedures for each study visit are outlined in the study Schedule of Clinical 
Assessments and Procedures in Appendix A.  
7.1.1 6FUHHQLQJ 9LVLW í WR í GD\ 
The purpose of the Screening visit/period is to ensure that appropriate patients are entered into 
the study and that they remain stable during the pretreatment period.  
x Obtain written informed consent prior to performing any study procedures  
x Review inclusion/exclusion criteria 
x Complete medical history and review of medications 
x Collect demographic and baseline disease characteristics information, including 
confirmation of medication washout 
x Perform a complete physical examination, including height, weight, and waist 
circumference 
x 12-lead ECG (in duplicate) 


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x Measure vital signs 
x Review concomitant medications  
x Draw blood samples for laboratory tests 
 Serum pregnancy test (women of childbearing potential only). 
 Chemistry and hematology 
 GR-activity biomarker test 
 2-hour oGTT (after an 8-hour fast); VKRXOG EH FROOHFWHG  ZHHNV DIWHU an increase in 
diabetes medication must be performed within 2 weeks of the Baseline Visit and used 
as Baseline 
 HbA1c (should be collected  weeks after an increase in diabetes medication); must 
be performed within 2 weeks of the Baseline Visit and used as Baseline 
 HPA-axis parameters 
x Thyroid-function tests 
x 24-hour UFC with creatinine (collected by the patient at home twice during Screening).  
x DST with dexamethasone levels. 1-mg overnight or 2 day low-dose dexamethasone 
suppression test must be performed during Screening. Dexamethasone levels must be 
measured concurrently. Estrogen preparations, including birth control and hormone 
replacement treatments, should be held for a duration of at least 5 half-lives of the 
estrogen analogue prior to DST. 
x Late-night salivary cortisol (collected by the patient at home at least twice on different 
nights during Screening), one of which will be the night before the Day 1/Baseline Visit).  
x Early-morning salivary cortisol (collected at the site if the patient arrives before 9 am); 
should be collected either on the same day as the late-night salivary cortisol is collected, 
or the morning after. 
x ABPM (24-hour) test will be assessed for all patients during Screening. For patients with 
an increase to their anti-hypertension medications either before or during Screening, 
ABPM VKRXOG EH SHUIRUPHG  ZHHNV DIWHU WKH increase. During Screening, ABPM 
VKRXOG EH SHUIRUPHG HLWKHU EHIRUH RU  Kours after, the DST test; must be performed 
within 2 weeks of the Baseline Visit and used as Baseline. 
x Schedule next visit. 
Patients who fail Screening may be rescreened (see Section 4.3).  
7.1.2 Baseline Visit (Day 1) 
x Review inclusion/exclusion criteria 
x Complete medical history and review of medications 


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x Collect demographic and baseline disease characteristics information, including 
confirmation of medication washout 
x Perform a complete physical examination, including, weight, and waist circumference 
x Measure vital signs 
x Review concomitant medications  
x Urine pregnancy test (women of childbearing potential only) 
x Draw blood samples for laboratory tests 
 Chemistry and hematology 
 Lipid-metabolism panel (fasting) 
 Coagulation panel 
 Serum osteocalcin 
 2-hour oGTT, including measurement of glucagon levels (after an 8-hour fast and 
used as Baseline—unless performed within 2 weeks of the Baseline Visit; glucagon 
levels will be assessed only for patients with DM/IGT) 
 HbA1c (used for Baseline—unless collected within 2 weeks of the Baseline Visit) 
x Early-morning salivary cortisol (collected at the site if the patient arrives before 9 am) 
x Cushing QoL questionnaire 
x Beck Depression Inventory 
x Sit-to-stand test 
x Trail-making test 
x DXA scan (±2 weeks of the Baseline Visit); patients to get DXA scan before Baseline 
Visit only in the case they are already determined to qualify for the study 
x Dosing diary 
x Study-drug dispensing and/or adherence 
x Query for AEs 
x Schedule next visit  
7.1.3 Week 2 (±7 days) 
x Perform a complete physical examination, including, weight, and waist circumference 
x Measure vital signs 
x Query for AEs 
x Review concomitant medications 
x Urine pregnancy test (women of childbearing potential only) 


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x Draw blood samples for laboratory tests 
 Chemistry and hematology 
 2-hour oGTT (after an 8-hour fast; for DM/IGT patients only) 
x ABPM (24-hour) test (for hypertension patients only) 
x Dosing diary 
x Study-drug dispensing and/or adherence 
x Schedule next visit 
7.1.4 Week 6 (±7 days) 
x Perform a complete physical examination, including, weight, and waist circumference 
x Measure vital signs 
x Query for AEs 
x Review concomitant medications 
x Urine pregnancy test (women of childbearing potential only) 
x Draw blood samples for laboratory tests 
 Chemistry and hematology 
 GR-activity biomarker test 
 2-hour oGTT (after an 8-hour fast; for patients with DM/IGT at Baseline) 
 HPA-axis parameters  
x Late-night salivary cortisol (collected at the patient’s home at bedtime the night before 
the study visit) 
x Early-morning salivary cortisol (collected at the site if the patient arrives before 9 am) 
x ABPM (24-hour) test (for patients with systolic hypertension at Baseline) 
x Cushing QoL questionnaire 
x Beck Depression Inventory 
x Sit-to-stand test 
x Trail-making test 
x Dosing diary 
x Study-drug dispensing and/or adherence 
x Schedule next visit  


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7.1.5 Week 10 (±7 days) 
x Perform a complete physical examination, including, weight, and waist circumference 
x Measure vital signs 
x Query for AEs 
x Review concomitant medications 
x Urine pregnancy test (women of childbearing potential only) 
x Draw blood samples for laboratory tests 
 Chemistry and hematology 
 GR-activity biomarker test 
 2-hour oGTT, including measurement of glucagon levels (after an 8-hour fast; for all 
patients; glucagon levels will be assessed only for patients with DM/IGT) 
 HbA1c (for all patients) 
 HPA-axis parameters 
x Late-night salivary cortisol (collected at the patient’s home at bedtime the night before 
the study visit) 
x Early-morning salivary cortisol (collected at the site if the patient arrives before 9 am) 
x ABPM (24-hour) test (for all patients) 
x Cushing QoL questionnaire 
x Beck Depression Inventory 
x Sit-to-stand test 
x Trail-making test 
x Dosing diary 
x Study-drug dispensing and/or adherence 
x Schedule next visit  
7.1.6 Week 14 (±7 days) 
x Perform a complete physical examination, including, weight, and waist circumference 
x Measure vital signs 
x Query for AEs 
x Review concomitant medications 
x Urine pregnancy test (women of childbearing potential only) 
x 12-lead ECG (in duplicate) 


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x Draw blood samples for laboratory tests 
 Chemistry and hematology 
 Coagulation panel 
 GR-activity biomarker test 
 2-hour oGTT (after an 8-hour fast; for patients with DM/IGT at Baseline) 
 HPA-axis parameters  
x Late-night salivary cortisol (collected at the patient’s home at bedtime the night before 
the study visit) 
x Early-morning salivary cortisol (collected at the site if the patient arrives before 9 am) 
x ABPM (24-hour) test (for patients with systolic hypertension at Baseline). 
x Cushing QoL questionnaire 
x Beck Depression Inventory 
x Sit-to-stand test 
x Trail-making test 
x Dosing diary 
x Study-drug dispensing and/or adherence 
x Schedule next visit 
7.1.7 Week 18 (±7 days) 
x Perform a complete physical examination, including, weight, and waist circumference 
x Measure vital signs 
x Query for AEs 
x Review concomitant medications 
x Urine pregnancy test (women of childbearing potential only) 
x Draw blood samples for laboratory tests 
 Chemistry and hematology 
 2-hour oGTT (after an 8-hour fast; for patients with DM/IGT at Baseline) 
 Intensive PK sampling 
x Early-morning salivary cortisol (collected at the site if the patient arrives before 9 am) 
x ABPM (24-hour) test (for patients with systolic hypertension at Baseline) 
x Cushing QoL questionnaire 
x Beck Depression Inventory 


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x Sit-to-stand test 
x Trail-making test 
x Dosing diary 
x Study-drug dispensing and/or adherence 
x Schedule next visit 
7.1.8 Week 22 (-14/+7 days) 
x A 3-week visit window (2 weeks before the scheduled visit, 1 week after the scheduled 
visit) is permitted. 
x Perform a complete physical examination, including, weight, and waist circumference 
x Measure vital signs 
x Query for AEs 
x Review concomitant medications 
x 12-lead ECG (in duplicate) 
x Urine pregnancy test (women of childbearing potential only) 
x Draw blood samples for laboratory tests 
 Chemistry and hematology 
 Lipid-metabolism panel (fasting) 
 Coagulation panel 
 Serum osteocalcin 
 GR-activity biomarker test  
 2-hour oGTT, including measurement of glucagon levels (after an 8-hour fast; for all 
patients; glucagon levels will be assessed only for patients with DM/IGT) 
 HbA1c (for all patients) 
 HPA-axis parameters 
x Late-night salivary cortisol 
x Early-morning salivary cortisol (collected at the site if the patient arrives before 9 am) 
x ABPM (24-hour) test (for all patients), performed within 7 days prior to Week 22 Visit 
x Cushing QoL questionnaire 
x Beck Depression Inventory 
x Sit-to-stand test 
x Trail-making test 


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x DXA scan 
x Study-drug dispensing* and drug adherence 
x Schedule next visit  
* Patients will remain on study treatment until it has been confirmed that all results for efficacy 
assessment have been received and no repeat assessments are required. 
7.1.9 Early-Termination Visit (+14 days) 
If the patient discontinues study drug prior to Week 22, the patient will be encouraged to 
complete the following assessments at the time of last dose of study drug or within 2 weeks. 
They will be instructed to return to the site for the Week 22 visit per their original dosing 
schedule, and for the follow-up visit 28 days after the last dose of study drug. 
x Perform a complete physical examination, including, weight, and waist circumference 
x Measure vital signs 
x Query for AEs 
x Review concomitant medications 
x 12-lead ECG (in duplicate) 
x Urine pregnancy test (women of childbearing potential only) 
x Draw blood samples for laboratory tests 
 Chemistry and hematology 
 Lipid-metabolism panel (fasting) 
 Coagulation panel 
 Serum osteocalcin 
 GR-activity biomarker test 
 2-hour oGTT, including measurement of glucagon levels (after an 8-hour fast; for all 
patients; glucagon levels will be assessed only for patients with DM/IGT) 
 HbA1c (for all patients) 
 HPA-axis parameters 
x Late-night salivary cortisol 
x Early-morning salivary cortisol (collected at the site if the patient arrives before 9 am) 
x ABPM (24-hour) test (for all patients)  
x Cushing QoL questionnaire  
x Beck Depression Inventory 
x Sit-to-stand test 


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x Trail-making test 
x DXA scan (should not be repeated if it was already completed within 8 weeks prior to ET 
Visit; acceptable visit window is up to 3 months following ET Visit). 
x Study-drug adherence 
x Schedule next visit  
7.1.10 Follow-Up Visit (±7 days) 
x Perform a complete physical examination, including, weight, and waist circumference 
x Measure vital signs 
x Query for AEs 
x Review concomitant medications 
x Urine pregnancy test (women of childbearing potential only) 
x Draw blood samples for laboratory tests 
 Chemistry and hematology 
x Study-drug adherence 
7.2 
Unscheduled Visits 
As appropriate, assessments deemed clinically necessary by the Investigator may be done at 
unscheduled visits. 


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8 
SAFETY EVENT DOCUMENTATION AND REPORTING 
8.1 
Investigator’s Responsibilities 
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for providing appropriate medical care. By exercising appropriate healthcare options, the 
Investigator remains responsible for managing AEs. All SAEs must be reported to Sponsor 
within 24 hours from awareness of the event.  
The Investigator (or medically qualified designee) is responsible for determining whether an AE 
is clinically significant for the patient. Clinical significance will be documented in the patient’s 
medical records with the AE information. 
Safety results collected during the study (e.g., AEs, laboratory test results, physical findings) will 
be monitored on an ongoing basis by the Medical Monitor and Investigator. Sponsor or its 
designee will promptly evaluate all reported safety information against cumulative product 
experience to identify and expeditiously communicate possible new safety findings to 
Investigators and applicable regulatory authorities.  
8.2 
Definition of an Adverse Event 
An AE is any untoward medical occurrence in a study patient administered a pharmaceutical 
product that does not necessarily have to have a causal relationship with the treatment. An AE 
can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of any study drug that emerges 
or worsens relative to the patient’s pretreatment baseline, regardless of whether it is related to the 
study drug.  
8.3 
Definition of a Serious Adverse Event 
An SAE is any AE resulting in any of the following outcomes: 
x Death (i.e., the AE caused or led to the fatality) 
x Life-threatening AE (i.e., the AE refers to an event in which the patient was at risk of 
death at the time of the event; it does not refer to an event that hypothetically might have 
caused death if it were more severe) 
x Hospitalization or prolongation of existing hospitalization (i.e., hospitalizations for 
scheduled treatments and elective medical/surgical procedures are not SAEs by 
this criterion) 
x Persistent or significant disability/incapacity (i.e., the AE results in substantial reduction 
of the patient’s ability to perform activities of daily living) 
x Congenital anomaly or birth defect (i.e., an adverse finding in a child or fetus of a patient 
exposed to the study medication before conception or during pregnancy)  
x Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 


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medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse 
(21 CFR 312.32). 
8.4 
Expectedness 
A serious AE is considered unexpected if not reported in the Investigator’s Brochure or if the 
event is of greater severity or frequency than described in the Investigator’s Brochure, (i.e., not 
specified in the RSI section of the Investigator’s Brochure). 
8.5 
Clinical-Laboratory Adverse Events 
All out-of-range laboratory values will be determined to be clinically significant or not clinically 
significant by the Investigator. An abnormal laboratory value that meets any of the following 
criteria will be recorded as an AE on the eCRF:  
x Leads to a dose modification or patient withdrawal from the study. 
x Is accompanied by clinical symptoms. 
x Requires a change in concomitant medications.  
Other clinically significant laboratory values may be reported as AEs at the discretion of the 
Investigator.  
Patients with a clinically significant out-of-range laboratory value will be followed until the 
laboratory value returns to normal, the value becomes medically stable, or the patient is deemed 
by the Principal Investigator to be lost to follow-up. The Investigator will treat the patient as 
medically required at appropriate intervals until this occurs. 
8.6 
Documentation of Adverse Events 
Patients will be evaluated and questioned to identify AEs during the study.  
Collection of AEs will start immediately following signing of the ICF and will continue 
throughout the study. All AEs will be documented on the patient’s medical record and AEs for 
all the randomized patients will be documented in the eCRF. 
Illnesses present before the patient signs the informed consent form (ICF) are considered pre-
existing conditions and are documented on the medical history eCRF. Preexisting conditions that 
worsen during the study are entered on the AE eCRF. AEs that occur after start of study 
treatment and up to and including 28 days after administration of the last dose of study drug will 
be considered TEAEs. Any AEs reported more than 28 days after the last dose of study drug will 
be considered posttreatment AEs and do not need to be reported to Corcept, unless the event 
meets the definition of serious (see Section 8.3) and the relationship to the study drug is possibly 
related, probably related, or related (see Section 8.7.2). In such cases, these posttreatment SAEs 
need to be reported per the process in Section 8.8 and are not to be entered in eCRF. The 
Investigator will treat the patient as medically required until the AE either resolves or becomes 
medically stable. This treatment may extend beyond the duration of the study. The Investigator 
will record treatment and medications required for treatment on the appropriate eCRF(s). 


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In the event that a patient is withdrawn from the study because of an AE, the event must be 
recorded on the Termination eCRF as the reason for discontinuation. 
All AEs that are drug-related and unexpected (not specified in the RSI section of the 
Investigator’s Brochure) or if the event is of greater severity or frequency than that described in 
the Investigator’s Brochure) must be reported to the governing IRB/Independent Ethics 
Committee (IEC)/Health Authorities as required.  
8.7 
Adverse Event Classification 
8.7.1 Intensity Grades of Adverse Events 
Seriousness of an AE is not synonymous with severity. To describe the maximum severity of the 
AE on the AE eCRF, the Investigator will use the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0 (NCI-CTCAE 2017). For 
events not listed in the NCI-CTCAE, the definitions from the NCI-CTCAE provided in Table 8 
should be used to evaluate the grade of severity for the AE.  
Table 8 
AE Grades Based on the Common Terminology Criteria for Adverse Events 
Grade 
Description 
1 
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated 
2 
Moderate: minimal, local, or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living (e.g., preparing meals, shopping for groceries or clothes, using 
the telephone, and managing money) 
3 
Severe: severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living (e.g., 
bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden) 
4 
Life-threatening: Life-threatening consequences; urgent intervention indicated 
5 
Death: Death related to AE 
Source: National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 
(NCI-CTCAE 2017). 
8.7.2 Relationship of Adverse Event to Study Drug or Procedure 
The Investigator responsible for the patient’s care (or qualified designee) will assess causality of 
AEs and SAEs based on the causal attribution guidance in Table 9. The Investigator’s 
assessment of causality must be provided for all AEs (serious and nonserious).  


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Table 9 
Causal Attribution Guidance for AEs 
Not related to study drug  
An AE that is judged to be clearly due only to extraneous causes such as 
diseases, environment, and the like or for which it is temporally 
implausible to be related to use of the study drug. The cause must be noted 
on the AE eCRF. 
Possibly related to study drug 
An AE that might be due to the use of the drug. The relationship in time is 
reasonable; therefore, a causal relationship cannot be excluded. An 
alternative explanation is inconclusive, e.g., concomitant drug(s), 
concurrent disease(s). 
Probably related to study drug 
An AE that might be due to the use of the drug. The relationship in time is 
suggestive. An alternative explanation is less likely, e.g., concomitant 
drug(s) or concurrent disease(s). 
Related to study drug 
An AE that is due to the use of the drug.  
8.8 
Procedures for Reporting a Serious Adverse Event 
Any SAE occurring from the time of informed consent and for 28 days after the last dose of 
study drug must be reported immediately (latest within 24 hours) to the pharmacovigilance 
vendor by completing and submitting the SAE form to the contact specified on the SAE form. 
All patients with an SAE must be followed and the outcomes reported. The Investigator must 
supply the Sponsor and the IRB/IEC with any additional requested information.  
8.9 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
AEs or SAEs 
Not applicable.  
8.10 
Adverse Event Follow-Up 
All AEs considered to be related to study drug (see Section 8.7.2) and all SAEs will be followed 
until resolution, until deemed stable by the Investigator, or until the patient is deemed by the 
Principal Investigator to be lost to follow-up. 
8.11 
Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to the Sponsor during the study 
and within 28 days of the last dose of study treatment. 
8.11.1 Maternal Exposure 
If a patient becomes pregnant during the study, study treatment should be discontinued 
immediately. Pregnancy itself is not regarded as an AE.  
If any pregnancy occurs during the study or within 28 days of the final dose of the study drug, 
the Investigator or designee should inform the appropriate Sponsor representatives immediately 
but no later than 24 hours of when he or she becomes aware of it. 


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The Investigator or designee should ensure that all relevant information is provided to the 
responsible Clinical Safety Group. All outcomes of pregnancy must be reported by the 
Investigator within 24 hours after he or she becomes aware of it. 
Congenital abnormalities/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality) should be followed and documented even if the patient 
has discontinued the study. 
8.11.2 Paternal Exposure 
Pregnancy of the patient’s partner is not considered to be an AE; however, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth or 
congenital abnormality) will, if possible, be followed and documented. To capture information 
about a pregnancy from the partner of a male patient, the Investigator or designee must first 
obtain the consent of the male patient’s partner; the male patient should not be asked to provide 
this information. A consent form specific to this situation must be used. The outcome of any 
conception occurring from the date of the first dose until 28 days after dosing should be followed 
and documented. 
8.12 
Treatment of Overdose 
There is currently no experience with overdose of study drug. For monitoring symptoms of 
excessive GR antagonism, refer to Section 5.4.1. If clinically significant GR antagonism is 
suspected, dexamethasone may be administered. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the patient. 
8.13 
Emergency Sponsor Contact 
In a medical emergency (i.e., an event requiring immediate attention regarding the treatment of a 
patient, operation of the clinical study, and/or the use of study drug), study site personnel will 
apply appropriate medical intervention according to current standards of care and contact the 
Medical Monitor listed on the cover page. 


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9 
STATISTICAL METHODS 
9.1 
Analysis Populations 
The analysis populations are defined in Table 10.  
Table 10 
Definitions of Analysis Populations 
Population 
Description 
Safety 
All patients randomly assigned to study treatment and who take 1 dose of 
study treatment. Patients will be analyzed according to the treatment they 
actually received. 
Intent-to-treat (ITT) a 
The ITT population will include all patients who were randomized to receive 
relacorilant or placebo, even if they do not receive any study treatment. This 
population will be used for the analysis of the primary and secondary efficacy 
endpoints.  
Modified intent-to-treat (mITT)  
The mITT population will include all patients in WKH ,77 SRSXODWLRQ ZLWK 
post-randomization efficacy assessment for the primary and secondary 
efficacy endpoints of ABPM and/or AUCglucose. This population will be used 
for sensitivity analyses performed on the primary and secondary efficacy 
endpoints.  
PK 
The subset of the Safety population with adequate PK data. 
PD 
The subset of the Safety population with adequate PD data. 
a. Analyses of blood-pressure control measures will be performed on all patients in the ITT population with 
hypertension, regardless of whether they have DM/IGT at Baseline. Analyses of measures of glycemic control 
will be performed on all patients in the ITT population with DM/IGT, regardless of whether they have 
hypertension at Baseline. 
9.2 
General Statistical Considerations 
The statistical analysis will be conducted by the Sponsor and/or its designee. Statistical methods 
will be prespecified and documented in detail in a statistical analysis plan, to be finalized before 
study unblinding. 
All continuous variables will be summarized using descriptive statistics (number of patients, 
means, percentiles, standard deviations) and confidence intervals (CIs) for values measured at 
each visit, as well as changes from Baseline. For categorical variables, counts, percentages, and 
their 95% CIs will be presented for each visit. 
Predose measurements on Day 1 will be considered the baseline values. If a Day 1 predose value 
is not available, the Screening measurement may be used as the baseline value.  
9.3 
Hypothesis Testing 
For the testing of the primary and certain secondary efficacy endpoints, adjustment for 
multiplicity will be implemented to maintain a 2-sided 0.05 significance level for the Family-
Wise type I error rate.  
In order to provide strong control of the Type I error, certain secondary analyses will be tested 
using a gated testing approach at a 2-sided alpha level of 0.05. If the null hypothesis is rejected 




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Seventy-eight patients with hypertension (39 per treatment group) will ensure at least 90% power 
to detect a difference between placebo and treatment arms in average SBP of 7 mm Hg (based on 
ABPM). These calculations assume a common standard deviation of 8 mm Hg and a 0.025 
two-sided significance level two-sample t-test. Twenty-eight percent dropout rate from Baseline 
to Week 22 is assumed in this calculation. 
In summary, the expected randomization of 130 patients in the study will result in 78 patients 
within each of the DM/IGT and hypertension subgroups. This sample size will provide sufficient 
power to detect the target differences in the primary endpoint for each of the subgroups.  
9.5 
Analysis Plan 
9.5.1 Patient Disposition 
The numbers of patients who were enrolled, and who were randomized along with the reasons 
for withdrawal will be summarized by treatment group. 
9.5.2 Demographic and Baseline Characteristics Data 
Demographics and baseline characteristics will be summarized for the Safety Population, 
ITT, and mITT populations. The summaries will include frequencies and percentages for 
categorical variables, and mean, standard deviation, median, minimum, and maximum for 
continuous variables.  
These summaries will include patient medical history, including the diagnosis, etiology, and 
treatment history of adrenal adenomas/hyperplasia. 
9.5.3 Prior and Concomitant Medications 
A list of all medications for diabetes, hypertension, or Cushing-syndrome–related comorbidities 
used at Baseline and over the course of the study will be generated. 
9.5.4 Analysis of Efficacy Endpoints 
9.5.4.1 
Analysis of Primary Efficacy Endpoint 
The primary endpoint is defined in Section 3.2.1. 
For the hypertension subgroup of the ITT Population, the estimand of interest is the between-
treatment difference in change in average SBP based on 24-hour ABPM from Randomization to 
Week 22 (estimated using a MMRM model) regardless of treatment discontinuation and as if 
rescue medication was not available. For the primary analysis, missing values at Week 22 for 
patients who use rescue medication or discontinue treatment early, will be imputed using a 
placebo wash-out multiple imputation. For those patients who use rescue medication for 
hypertension after randomization and before Visit Week 22, the values collected after first use of 
rescue medication are irrelevant to the clinical question of interest and will not be used in the 
analysis. For patients who discontinue treatment early, all collected values (including retrieved 
drop-outs) will be used in the analysis. Additional details are provided in the SAP.The primary 
efficacy analysis for the primary endpoint of change in 24- hour average SBP from 
Randomization to Week 22 will be performed using a linear mixed-model-for-repeated-measures 


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(MMRM) using data with the imputation method described above. Restricted maximum 
likelihood (REML) estimation will be used. The MMRM model will include Baseline average 
SBP based on 24-hour ABPM as a covariate; treatment, visit, and treatment by visit interaction, 
and stratification factor as fixed effects; patients within treatment groups as random effects. In 
the hypertension subgroup, the stratification factor at randomization identifies patients with or 
without DM/IGT. An unstructured covariance structure will be used to model within-patient 
error, and the Kenward Roger approximation will be used to model denominator degrees of 
freedom. 
The primary analysis will determine whether there is a difference between treatment groups in 
terms of change in 24-hour average SBP from Randomization to Week 22. This will be 
accomplished by using appropriate linear contrasts of the parameters in the MMRM model 
described above. 
 Additional sensitivity and supplemental analyses for the primary endpoint, including subgroups 
of interest, will be specified in the SAP. 
9.5.4.2 
Analysis of Secondary Efficacy Endpoints 
The secondary efficacy endpoints are defined in Section 3.2.2. 
For continuous endpoints in the study, the analysis will be performed using a linear MMRM 
model. Restricted maximum likelihood (REML) estimation will be used. The MMRM model 
will include Baseline value (for the respective endpoint) as a covariate; treatment, visit, treatment 
by visit interaction, and stratification factor (at randomization) as fixed effects; and patients 
within treatment groups as random effects. An unstructured covariance structure will be used to 
model within-patient error, and the Kenward-Roger approximation will be used to model 
denominator degrees of freedom. 
The analysis for each of the endpoints will determine whether there is a difference between 
treatment groups in terms of change from Randomization to Week 22. This will be accomplished 
by using appropriate linear contrasts of the parameters in the MMRM model described above. 
Additional details will be described in the SAP. 
For endpoints described as proportions in the study, the point estimate and the 2-sided 95% CI 
will be calculated. A logistic model including effects for treatment, continuous baseline value, 
and stratification factor at randomization will be used to assess differences in proportions 
between treatment arms (Steingrimsson et al. 2017).  
9.5.4.3 
Analysis of Exploratory Endpoints 
The Exploratory Endpoints listed in Section 3.2.3 will be analyzed using methods similar to the 
analyses of primary and secondary endpoints if they are measured repeatedly over the course of 
the study. Detailed analysis methods will be described in SAP. 
9.5.5 Safety Analyses 
Safety variables will be analyzed for the Safety Population, defined as all patients who received 
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TEAEs will be summarized by treatment group. Serious AEs and TEAEs that lead to 
study-drug withdrawal or withdrawal from the study will be summarized by treatment 
group and listed by patient. 
TEAEs will be summarized by treatment, as applicable, and displayed using the Medical 
Dictionary for Regulatory Activities (MedDRA) system organ class and preferred term, as well 
as by intensity and relationship to the study drug.  
Clinical laboratory test results (chemistry and hematology), vital sign measurements, and 
ECG interval results will be summarized as changes from baseline by parameter and visit 
using descriptive statistics. Shift tables will describe changes from Baseline in clinical 
laboratory values. 
9.5.6 PK Analysis 
The details of the PK analysis will be outlined in a separate document. 
9.5.7 PD Analysis 
Analysis of PD endpoints will be described in a separate PD analysis plan finalized before study 
unblinding.  
9.5.8 Biomarker/Pharmacogenetic Analysis 
Biomarker and pharmacogenetic exploratory analyses will be described in the SAP finalized 
before study unblinding. 
9.5.9 Interim Analysis 
Not applicable.  


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10 
ETHICAL AND LEGAL CONSIDERATIONS 
10.1 
Compliance with IRB/IEC Regulations 
This study is to be conducted in accordance with IRB regulations (US 21 CFR Part 56.103), IEC 
regulations, or applicable local regulations. The protocol, informed consent form(s) (ICFs), 
recruitment materials, and all patient materials will be submitted to the IRB/IEC for review and 
approval. Approval of both the protocol and the consent form must be obtained before any 
patient is enrolled, and the Investigator must submit written approval to the Sponsor before 
enrolling any patient. The Investigator is responsible for informing the IRB/IEC of any 
amendment to the protocol in accordance with local requirements. The protocol must be re-
approved by the IRB/IEC on receipt of amendments and annually, as local regulations require. 
The investigators should not implement any deviation form, or changes to, the protocol without 
agreement by Corcept and documented approval from IRB/IEC, except where necessary to 
eliminate an immediate hazard(s) to trial subjects.  
All changes to the consent form must be approved by the IRB/IEC; a determination will be made 
regarding whether previously consented patients need to be re-consented.  
The Sponsor or their designee is to be notified immediately if the responsible IRB/IEC has been 
disqualified or if proceedings leading to disqualification have begun. Copies of all IRB/IEC 
correspondence with the Investigator should be provided to the Sponsor or their designee. 
Progress reports and notifications of serious adverse drug reactions will be provided to the 
IRB/IEC according to local regulations and guidelines. 
10.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP and applicable regulatory 
requirements. 
The Investigator will ensure that the study procedures outlined in this protocol will be conducted 
in accordance with applicable country and local regulations. 
10.3 
Protection of Human Patients 
10.3.1 Compliance with Informed-Consent Regulations  
Written informed consent is to be obtained from each patient and/or from the patient’s legally 
authorized representative prior to enrollment into the study or conducting any study procedures. 
The Investigator(s) at each center will ensure that each patient is given full and adequate oral and 
written information about the nature, purpose, possible risk, and benefit of the study. Patients 
must also be notified that they are free to discontinue from the study at any time. The patient 
should be given the opportunity to ask questions and allowed time to consider the information 
provided. The Informed Consent process discussion should be documented in patient’s record. 
The patient’s signed and dated ICF must be obtained before conducting any study procedures. 
The Principal Investigator(s) must maintain the original, signed ICF. A copy of the signed ICF 
must be given to the patient. 


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The ICF will contain all of the elements required by ICH guidelines for GCP and any additional 
elements required by local regulations. 
The ICF should include information about the possible retention of biological samples at the 
conclusion of this study. With the patient’s permission: 
x Samples, including blood, plasma, serum and tissue samples, may be retained for future 
analysis to help identify biomarkers of disease or relacorilant treatment.  
x Samples may be retained for future determination of active metabolite concentrations and 
possible biomarkers related to drug response. 
10.3.2 Patient Confidentiality 
To maintain patient privacy, all source documents, study reports, and communications will 
identify the patient by initials and the assigned patient number. The Investigator will grant 
monitor(s) and auditor(s) from the Sponsor or its designee and regulatory authority(ies) access to 
the patient’s original source records for data verification and to audit the data collection process. 
The patient’s confidentiality will be maintained and will not be made publicly available to the 
extent permitted by applicable laws and regulations. 
10.3.3 Patient Privacy 
The Investigator or designee must explain to each patient, before enrollment into the study, that 
for evaluation of study results, the patient’s protected health information obtained during the 
study may be shared with the Sponsor or its designee, regulatory agencies, and 
IRB/IEC/Research Ethics Board (REB). It is the Investigator’s (or designee’s) responsibility to 
obtain written permission to use protected health information per country-specific regulations 
from each patient or, if appropriate, the patient’s legally authorized representative. If permission 
to use protected health information is withdrawn, it is the Investigator’s responsibility to obtain a 
written request, to ensure no further data will be collected from the patient, and the patient will 
be removed from the study. 
Written authorization is to be obtained from each patient before enrollment into the study, and/or 
from the patient’s legally authorized representative in accordance with the applicable privacy 
requirements. 


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11 
ADMINISTRATIVE CONSIDERATIONS 
11.1 
Study Monitoring 
Monitoring of the study site (including, but not limited to, reviewing CRFs for accuracy and 
completeness, and assessing compliance with the protocol and adherence to regulatory and GCP 
requirements) will be performed by the Sponsor’s Clinical Monitor or designee.  
x Monitoring will be performed in accordance with applicable local and country 
regulations and guidance. 
x Monitoring will include regular site visits and communication with the Investigator and 
site staff as appropriate to discuss and answer study questions; ensure compliance with 
the protocol; and ensure quality and integrity of the data.  
x Monitors will ensure the site maintains an adequate supply of study drugs; any necessary 
supplies and ensure that appropriate storage conditions are maintained. 
x Monitoring visits will be conducted according to the US CFR Title 21 parts 50, 56, and 
312; and International Council on Harmonisation (ICH) Guideline for GCP.  
Monitoring methods, responsibilities, and requirements will be outlined in the study 
monitoring plan. 
11.2 
Quality Management 
As part of quality management based on a risk-based approach per ICH E6(R2): 
Risk reduction activities may be incorporated in protocol design and implementation, 
monitoring plans, agreements between parties defining roles and responsibilities, systematic 
safeguards to ensure adherence to standard operating procedures, and training in processes 
and procedures.  
Predefined quality tolerance limits should be established, taking into consideration the 
medical and statistical characteristics of the variables as well as the statistical design of the 
trial, to identify systematic issues that can impact subject safety or reliability of trial results. 
Detection of deviations from the predefined quality tolerance limits should trigger an 
evaluation to determine if action is needed.  
Study sites, the study database, and study documentation will be monitored regularly and may be 
subject to a quality assurance (QA) audit during the study by the Sponsor or its designee on 
behalf of the Sponsor. In addition, inspections may be conducted by regulatory agencies at their 
discretion.  
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution.  
Following written SOPs, the monitors will verify that the clinical study is conducted, data are 
generated, documented (recorded), and reported in compliance with the protocol, GCP, and the 
applicable regulatory requirements (e.g., Good Laboratory Practices, Good Manufacturing 
Practices).  


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The investigator site will provide direct access to all trial-related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the Sponsor, and inspection by local 
and regulatory authorities. 
11.3 
Documentation 
11.3.1 Case Report Forms and Study Records 
The Investigator must generate and maintain complete, adequate, accurate, reliable, and 
consistent records to enable full documentation of study conduct. Study data will be captured on 
CRFs. Investigators must retain all original source documents. The Sponsor or its designee will 
notify Investigators in writing when the trial-related records are no longer needed.  
11.3.2 Access to Source Documentation 
The Sponsor or its representative will be allowed to conduct site visits to the investigational 
facilities for the purpose of monitoring any aspect of the study. The Investigator agrees to allow 
the monitor to inspect the drug storage area, study-drug stocks, drug accountability records, 
patient charts and source documents, and other records relative to study conduct. 
By signing the protocol, the Principal Investigator agrees that, within local regulatory restrictions 
and institutional and ethical considerations, authorized representatives of the Sponsor, a 
regulatory authority, and/or an IRB/IEC may visit the site to perform audits or inspections, 
including the drug storage area, study-drug stocks, drug accountability records, patient charts and 
source documents, and other records relative to study conduct. The purpose of a Sponsor audit or 
inspection is to systematically and independently examine all study-related activities and 
documents (e.g., laboratory reports, x-rays, workbooks, patients’ medical records) to determine 
whether these activities were conducted, and data recorded, analyzed, and accurately reported 
according to the protocol, GCP guidelines of the ICH, and any applicable regulatory 
requirements.  
The Investigator should contact the Sponsor or their designee immediately if contacted by a 
regulatory agency regarding an inspection. 
11.3.3 Source Documents 
Source documents provide all original records of clinical findings, observations, or other 
information from a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to, a patient’s 
medical records, hospital charts, clinic charts, the Investigator’s patient study files, as well as the 
results of diagnostic tests such as x-rays, laboratory tests, and ECGs. All data entered into the 
CRFs must be substantiated by a source document. 
11.3.4 Study Files and Retention of Study Records 
The Investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified.  
Study documents should be retained for a minimum of 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 


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applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the study drug. These documents should be retained 
for a longer period, however, if required by local regulations. No records will be destroyed 
without the written consent of the Sponsor, if applicable. It is the responsibility of the Sponsor to 
inform the Investigator when these documents no longer need to be retained. 
Patient identification codes (patient names and corresponding study numbers) will be retained for 
this same period of time. These documents may be transferred to another responsible party, 
acceptable to the Sponsor, who agrees to abide by the retention policies. Written notification of 
transfer must be submitted to the Sponsor. The Investigator or designee must contact the Sponsor 
before disposing of any study records. 
11.4 
Sample Collection, Preparation, and Shipping 
Instructions for collection, preparation, and shipping of all laboratory samples will be provided 
in the study laboratory manual. 
11.5 
Long-Term Retention of Biological Samples 
All biological samples will be retained by Corcept or designee under the original informed 
consent of the patient and the IRB/IEC approval. Samples will be held for a period up to 20 years 
after acquisition. Corcept or the designee may store the patient’s sample(s) longer if required to 
address regulatory agency questions; in this event, the patient’s sample(s) will be destroyed after 
all questions are adequately answered.  
An individual patient can choose to withdraw consent to have his/her samples used for future 
research at any time without affecting their participation in the study or their care by the health 
provider. Upon receipt of a request for sample destruction, that patient’s sample(s) will then no 
longer be used for research purposes, and their sample(s) will be destroyed.  However, if there 
are ongoing regulatory questions, the patient’s sample(s) will be destroyed after all questions are 
adequately answered. 
The long-term retention samples will be coded to allow de-identification according to applicable 
regulatory guidelines. It is the responsibility of the trial site to ensure that samples are 
appropriately labelled in accordance with trial procedures to comply with all applicable laws, 
which may include but are not limited to European Directives 95/46/EC and 2002/58/EC and any 
legislation and/or regulation implementing or made pursuant to them, or which amends, replaces, 
re-enacts, or consolidates any of them, and all other applicable laws relating to processing of 
personal data and privacy that may exist in any relevant jurisdiction. Biological samples 
collected from participants as part of this trial will be transported, stored, accessed, and 
processed in accordance with all applicable laws relating to the use and storage of human tissue 
for research purposes and such activities shall at least meet the requirements as set out in the 
2004 Human Tissue Act and the 2006 Human Tissue (Scotland) Act. 


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11.6 
Clinical Supplies 
11.6.1 Inventory, Reconciliation, Return, and Disposition of Clinical Supplies 
All study drug and related materials should be stored, inventoried, reconciled, and destroyed or 
returned according to applicable state and federal regulations and study procedures. Relacorilant 
and placebo equivalent, including dose and regimen, formulation, packaging, and storage, are 
described in Table 1.  
11.6.2 Clinical-Supply Inventory 
A detailed inventory must be completed for all study drug. The study drug is to be used in 
accordance with the protocol by patients who are under the direct supervision of an Investigator. 
The study drug must be dispensed only by an appropriately qualified person to patients in 
the study.  
Unused study drug must be kept in a secure location for accountability and reconciliation by the 
study monitor. The Investigator or designee must provide an explanation for any destroyed or 
missing study drug or study materials. 
The Investigator or designee is responsible for maintaining accurate records (including dates and 
quantities) of study drug(s) received, patients to whom study drug is dispensed (patient-by-
patient dose specific accounting), and study drug lost or accidentally or deliberately destroyed. 
The Investigator or designee must retain all unused or expired study supplies until the study 
monitor (on-site CRA) has confirmed the accountability data and Sponsor has approved return 
or destruction. 
11.6.3 Return or Disposal of Study Drug and/or Supplies 
All clinical study drug and/or supplies will either be destroyed by the site per institutional policy, 
or be returned to the Sponsor or designee for destruction. 
Unused study drug may be destroyed on site, per the site’s SOPs, but only after Sponsor has 
granted approval for drug destruction. The study monitor must account for all study drug in a 
formal reconciliation process, before study-drug destruction. All study drug destroyed on site 
must be documented.  
Documentation must be provided to the Sponsor and retained in the Investigator study files. 
If a site is unable to destroy study drug appropriately, the site can return unused study drug to the 
Sponsor upon request. The return of study drug or study-drug materials must be accounted for on 
a Study-drug Return Form provided by the Sponsor. 
11.7 
Drug Accountability 
It is the responsibility of the Investigator to maintain drug accountability at the study site and 
ensure that a current record of study-drug disposition is maintained. It is the responsibility of the 
Investigator to ensure that the study drug is used only in accordance with the approved protocol. 
This includes acknowledgment of receipt of each shipment of study product (quantity and 
condition), patient dispensing records, and returned or destroyed study product.  


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Dispensing records will document quantities received from the Sponsor (or designee) and 
quantities dispensed to patients, including lot number, date dispensed, patient identifier number, 
patient initials, and the initials of the person dispensing the drug.  
At the end of the study, after final drug inventory reconciliation by the study monitor, the study 
site will dispose of and/or destroy all unused investigational medicinal product supplies, 
including empty containers, according to SOPs. 
11.8 
Post-Trial Care 
Patients who successfully complete the clinical study will be permitted to continue relacorilant 
treatment in an extension study provided they have at least 80% adherence with scheduled 
dosing (by capsule counts).  
Patients who enroll in an extension study without interruption will not be required to complete 
the follow-up visit. The last study visit for these patients will be the Week 22 visit. 
11.9 
Protocol Noncompliance 
Prospective approval of deviations from the inclusion and exclusion criteria, also known as 
protocol waivers or exemptions, is not permitted. 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or manual of 
procedures (MOP) requirements. The noncompliance may be either on the part of the patient, the 
Investigator, or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly. These practices are consistent with ICH E6.  
The Investigator should not implement any deviation from the protocol without prior review and 
agreement by the Sponsor in writing and in accordance with the IEC/IRB and local regulations, 
except when necessary to eliminate an immediate hazard to study patients. When a deviation 
from the protocol is deemed necessary for an individual patient, the Investigator must obtain 
approval in writing from the Sponsor. 
Such contact must be made as soon as possible to permit a review by the Sponsor to determine 
the impact of the deviation on the patient and/or the study. 
Any significant protocol deviations affecting patient eligibility and/or safety must be reviewed 
and/or approved by the IEC/IRB and regulatory authorities, as applicable, prior to 
implementation. 
11.10 Financial Disclosure 
Investigators will be required to disclose any financial equity interests in the Sponsor and any 
conflicts of interest, as defined by the Sponsor.  
11.11 Publication and Disclosure Policy 
Corcept, as the Sponsor, has a proprietary interest in this study.  
No individual publications will be allowed before publication of the multicenter results, except 
as agreed with Corcept. The Investigator agrees to submit all manuscripts or abstracts to Corcept 
for review before submission to the publisher. 


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Corcept will comply with the requirements for publication of study results and determination of 
authorship in accordance with standard editorial and ethical practice and with the International 
Committee of Medical Journal Editors (ICMJE) requirements. 


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12 
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Fassnacht M, Arlt W, Bancos I, Dralle H, Newell-Price J, Sahdev A, et al. 2016. Management of 
adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline 


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in collaboration with the European Network for the Study of Adrenal Tumors. Eur J 
Endocrinol. 175(2):G1௅G34. doi: 10.1530/EJE-16-0467. 
FDA (US Food and Drug Administration). 2017. Guidance for Industry: Multiple Endpoints in 
Clinical Trials. Draft Guidance. January. 
FDA (US Food and Drug Administration). 2021. Conduct of Clinical Trials of Medical Products 
during the COVID-19 Public Health Emergency. Guidance for Industry, Investigators, 
and Institutional Review Boards; updated on August 30, 2021. 
Fleseriu M, Biller BM, Findling JW, Molitch ME, Schteingart DE, Gross C, et al. 2012. 
Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic 
benefits in patients with Cushing's syndrome. J Clin Endocrinol Metab. 97(6):2039–2049. 
doi: 10.1210/jc.2011-3350. 
Giraldi FP, Pivonello R, Ambrogio AG, et al. 2007. The dexamethasone-suppressed 
corticotropin-releasing hormone stimulation test and the desmopressin test to distinguish 
Cushing’s syndrome from pseudo-Cushing’s states. Clin Endocrinol. 66:251–257. doi: 
10.1111/j.1365-2265.2006.02717.x. 
Hochberg Y. 1988. A sharper Bonferroni procedure for multiple tests of significance. 
Biometrika. 75:800–802.  
ICH E6, Guideline for good clinical practice E6(R2); 1 December 2016; principle 2.2.  
Morelli V, Eller-Vainicher C, Palmieri S, Cairoli E, Salcuni AS, Scillitani A, et al. 2016. 
Prediction of vertebral fractures in patients with monolateral adrenal incidentalomas. J 
Clin Endocrinol Metab. 101(7):2768-75. doi: 10.1210/jc.2016-1423.  
NCI (National Cancer Institute). 2017. Common Terminology Criteria for Adverse Events 
(CTCAE), version 5.0 published: November 27, 2017. US Department of Health and 
Human Services, National Institutes of Health, Accessed at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Q
uick_Reference_8.5x11.pdf 
Nelson LM, Forsythe A, McLeod L, et al. 2013. Psychometric evaluation of the Cushing's 
Quality-of-Life questionnaire. Patient. 6(2):113–124. doi: 10.1007/s40271-013-0012-5. 
Parati G, Stergiou G, O’Brien E, et al. 2014. European Society of Hypertension practice 
guidelines for ambulatory blood pressure monitoring. J Hypertens. 32:1359–66. doi: 
10.1097/HJH.0000000000000221. 
Shepherd JA, Ng BK, Sommer MJ, Heymsfield SB. 2017. Body composition by DXA. Bone. 
104:101–105. doi: 10.1016/j.bone.2017.06.010. 
Steingrimsson, Jon Arni et al. 2017. Improving precision by adjusting for prognostic baseline 
variables in randomized trials with binary outcomes, without regression model 
assumptions. Contemporary Clinical Trials. 54:18-24. 
Toniato A1, Merante-Boschin I, Opocher G, Pelizzo MR, Schiavi F, Ballotta E. 2009. Surgical 
versus conservative management for subclinical Cushing syndrome in adrenal 


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incidentalomas: a prospective randomized study. Ann Surg. 249(3):388–391. doi: 
10.1097/SLA.0b013e31819a47d2. 
Webb SM, Badia X, Barahona MJ, et al. 2008. Evaluation of health-related quality of life 
in patients with Cushing’s syndrome with a new questionnaire. Eur J Endocrinol. 
158:623–630. doi: 10.1530/EJE-07-0762. 
Yanovski JA, Cutler Jr GB, Chrousos GP, et al. 1993. Corticotropin-releasing hormone 
stimulation following low-dose dexamethasone administration: a new test to distinguish 
Cushing’s syndrome from pseudo-Cushing’s states. JAMA. 269(17):2232–2238. 
Yanovski JA, Cutler Jr GB, Chrousos GP, et al. 1998. The dexamethasone-suppressed 
corticotropin-releasing hormone stimulation test differentiates mild Cushing’s disease 
from normal physiology. J Clin Endocrinol Metab. 83(2):348–352. doi: 
10.1210/jcem.83.2.4568. 
Zografos GN, Perysinakis I, Vassilatou E. 2014. Subclinical Cushing's syndrome: current 
concepts and trends. Hormones (Athens). 2014. 13(3):323௅337. doi: 
10.14310/horm.2002.1506. 


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APPENDICES  
 


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Appendix A: Schedule(s) of Activities 
Table 11 
Schedule of Clinical Assessments and Procedures 
Study Procedure 
Screening a Baseline 
Double-Blind, Placebo-Controlled 
Weeks 1 to 22 
Early 
Termination 
Follow-up b 
Visit Name 
— 
— 
Week 2 
Week 6 
Week 10 Week 14 Week 18 Week 22 
ET 
— 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Visit Window (d) í WR í 
— 
±7d 
±7d 
±7d 
±7d 
±7d 
-14/+7d 
+14d 
±7d 
Informed consent 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Inclusion/exclusion criteria 
X 
X 
- 
- 
- 
- 
- 
- 
- 
- 
Medical and medication history c 
X 
X 
- 
- 
- 
- 
- 
- 
- 
- 
Demographics/baseline disease 
characteristics 
X 
X 
- 
- 
- 
- 
- 
- 
- 
- 
Physical examination d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height, weight, waist 
circumference e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events g 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG (in duplicate) 
X 
- 
- 
- 
- 
X 
- 
X 
X 
- 
Pregnancy test (women only) h 
X (s) 
X (u) 
X (u) 
X (u) 
X (u) 
X (u) 
X (u) 
X (u) 
X (u) 
X (u) 
Chemistry i, Hematology j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Study Procedure 
Screening a Baseline 
Double-Blind, Placebo-Controlled 
Weeks 1 to 22 
Early 
Termination 
Follow-up b 
Visit Name 
— 
— 
Week 2 
Week 6 
Week 10 Week 14 Week 18 Week 22 
ET 
— 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Visit Window (d) í WR í 
— 
±7d 
±7d 
±7d 
±7d 
±7d 
-14/+7d 
+14d 
±7d 
Lipid-metabolism panel (fasting) k 
- 
X 
- 
- 
- 
- 
- 
X 
X 
- 
Thyroid-function tests 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Coagulation panel l 
- 
X 
- 
- 
- 
X 
- 
X 
X 
- 
Serum osteocalcin 
- 
X 
- 
- 
- 
- 
- 
X 
X 
- 
GR activity biomarker tests 
X 
- 
- 
X 
X 
X 
- 
X 
X 
- 
2-hour oGTT m 
X 
X n 
X 
X 
X 
X 
X 
X 
X 
- 
HbA1c o 
X 
X n 
- 
- 
X 
- 
- 
X 
X 
- 
HPA-axis parameters p 
X 
- 
- 
X 
X 
X 
- 
X 
X 
- 
24-hour UFC with creatinine q 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
DST with dexamethasone levels r 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Late-night salivary cortisol s 
X 
- 
- 
X 
X 
X 
- 
X 
X 
- 
Early-morning salivary cortisol t 
X 
X 
- 
X 
X 
X 
X 
X 
X 
- 
ABPM (24-hour) test u 
X 
- 
X 
X 
X 
X 
X 
X v 
X 
- 
DXA scan w  
- 
X w 
- 
- 
- 
- 
- 
X 
X w 
- 
Pharmacokinetics, intensive 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 


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Study Procedure 
Screening a Baseline 
Double-Blind, Placebo-Controlled 
Weeks 1 to 22 
Early 
Termination 
Follow-up b 
Visit Name 
— 
— 
Week 2 
Week 6 
Week 10 Week 14 Week 18 Week 22 
ET 
— 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Visit Window (d) í WR í 
— 
±7d 
±7d 
±7d 
±7d 
±7d 
-14/+7d 
+14d 
±7d 
Cushing QoL questionnaire  
- 
X 
- 
X 
X 
X 
X 
X 
X 
- 
Beck Depression Inventory  
- 
X 
- 
X 
X 
X 
X 
X 
X 
- 
Sit-to-stand test 
- 
X 
- 
X 
X 
X 
X 
X 
X 
- 
Trail-making test 
- 
X 
- 
X 
X 
X 
X 
X 
X 
- 
Dosing diary 
- 
X 
X 
X 
X 
X 
X 
- 
- 
- 
Study-drug dispensing and/or 
adherence x 
- 
X 
X 
X 
X 
X 
X 
X y 
X 
- 
ABPM, ambulatory blood pressure monitoring; BP, blood pressure; DST, dexamethasone suppression test; DXA, dual-energy X-ray absorptiometry, ECG, 
electrocardiogram; ET, early termination; GR, glucocorticoid receptor; HbA1c, hemoglobin A1c; HPA, hypothalamic-pituitary-adrenal; oGTT, oral glucose 
tolerance test; QoL, quality-of-life; (s), serum; (u), urine; UFC, urinary free cortisol. 
 
a. 
All assessments done during Screening can be used as Baseline with the exception of oGTT, HbA1c, and 24-hour ABPM, which must be performed within 
2 weeks of the Baseline Visit and used as Baseline. Medications used in the treatment of Cushing syndrome are prohibited and require washout of at least 
12 weeks before Screening. 
b. For patients who do not enroll in an extension study, the Follow-up visit will occur 28 days after the last dose of study drug. 
c. 
For any medication used to treat hypercortisolism, hypertension, and/or diabetes 3 months prior to Day 1. 
d. General physical appearance of patients during the examination will be assessed.  
e. 
Height is measured at Screening only. Body weight and circumference will be measured at all visits. 
f. 
Vital signs: BP, heart rate, respiratory rate, and body temperature. 
g. Adverse events will be collected after the informed consent form is signed. Events ongoing at study entry are considered medical history.  
h. Pregnancy tests: for women of childbearing potential: (s)=serum pregnancy test at Screening; (u)=urine pregnancy test at other time points. 


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i. 
Chemistry parameters: full chemistry profile that includes albumin, alkaline phosphatase, ALT, AST, bicarbonate, blood urea nitrogen, calcium, chloride, 
cholesterol, creatinine, fasting glucose, fasting insulin, lactate dehydrogenase, magnesium, phosphorus, potassium, sodium, creatine kinase, total and direct 
ELOLUXELQ WRWDO SURWHLQ XULF DFLG 6KRXOG EH SHUIRUPHG HLWKHU EHIRUH RU  Kours after, the DST test. 
j. 
+HPDWRORJ\ SDUDPHWHUV D FRPSOHWH EORRG FRXQW DQG GLIIHUHQWLDO 6KRXOG EH SHUIRUPHG HLWKHU EHIRUH RU  Kours after, the DST test. 
k. Lipid-metabolism panel: total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, very low-density lipoprotein-cholesterol, 
DQG WULJO\FHULGHV 6KRXOG EH SHUIRUPHG HLWKHU EHIRUH RU  Kours after, the DST test. 
l. 
Coagulation panel: Factor VIII, von Willebrand factor, protein S, protein C, thrombin antithrombin (TAT), and partial thromboplastin time (PTT). Should be 
SHUIRUPHG HLWKHU EHIRUH RU  Kours after, the DST test. 
m. oGTT, including measurement of glucagon levels at selected visits (i.e., Baseline Visit, Week 10, Week 22, and ET Visit [if applicable]; for patients with 
DM/IGT at Baseline): The 2-hour oGTT will be performed on all patients during Screening. During Screening, oGTT should be performed either before, or 
 hours after, the DST test. In patients with an increase to their '0 PHGLFDWLRQV EHIRUH RU GXULQJ 6FUHHQLQJ R*77 VKRXOG EH SHUIRUPHG  ZHHNV DIWHU
the increase. The Screening 2-hour oGTT must be performed within 2 weeks of the Baseline Visit and used as Baseline. During treatment with study drug, a 
2-hour oGTT will be performed only in patients with DM/IGT except at the Baseline Visit, Week 10, Week 22 and ET Visit (if applicable), when the 2-hour 
oGTT will be performed for all patients.  
n. oGTT and HbA1c will only be performed at Baseline if the prior assessment was not performed within 2 weeks. 
o. HbA1c: The HbA1c test will be performed on all patients during Screening. In patients who have an increase to their DM medications before or during 
6FUHHQLQJ +E$F VKRXOG EH SHUIRUPHG  ZHHNV DIWHU the increase in the diabetes medication. The Screening HbA1c test must be performed within 2 weeks 
of the Baseline Visit and used as Baseline. During treatment with study drug, HbA1c will be performed only in patients with DM/IGT except at the Baseline 
Visit, Week 10, Week 22 and ET Visit (if applicable), when the HbA1c test will be performed for all patients. 
p. HPA-axis: Early-morning plasma ACTH, fasting serum cortisol, and DHEA-S. HPA-D[LV WHVWV VKRXOG EH SHUIRUPHG HLWKHU EHIRUH RU  hours after, the 
DST test. ACTH should be measured at least twice during Screening. 
q. 24-hour UFC test samples will be collected by the patient at home twice during Screening. The average of the results will serve as Baseline. UFC collection 
VKRXOG EH SHUIRUPHG HLWKHU EHIRUH RU  hours after, the DST test. 
r. 
DST: 1-mg overnight or 2-mg 48-hour dexamethasone test must be performed during Screening. Dexamethasone levels should be measured concurrently. 
Estrogen preparations, including birth control and hormone replacement treatments, should be withheld for a duration of at least 5 half-lives of the estrogen 
analogue prior to DST. 
s. 
Two late-night salivary cortisol samples will be collected at Screening, one of which should be the night before the Day 1/Baseline Visit. During treatment 
with study drug, a late-night salivary-cortisol sample should be collected the night before the study visit. During Screening, salivary cortisol sample 
FROOHFWLRQ VKRXOG EH SHUIRUPHG HLWKHU EHIRUH RU  hours after, the DST test. 
t. 
Early-morning salivary cortisol will be collected at the site if the patient arrives before 9 am (to avoid mix up with the late-night salivary cortisol samples 
collected by the patient). If the visit is scheduled after 9 am, the sample will be collected at home by the patient the morning of the visit. Early-morning 
salivary cortisol should be collected either on the same day as the late-night salivary cortisol is collected, or the morning after.  
u. ABPM: The 24-hour ABPM will be assessed for all patients during Screening. During Screening, in patients with an increase to their anti-hypertension 
medications either before or during Screening, ABPM VKRXOG EH SHUIRUPHG  ZHHNV DIWHU WKH increase in anti-hypertension medications. During Screening, 
ABPM VKRXOG EH SHUIRUPHG HLWKHU EHIRUH RU  hours after, the DST test. ABPM must be performed within 2 weeks of the Baseline Visit and used as 
Baseline. During the study, ABPM measurements will be performed only for patients with systolic hypertension except at Week 10, Week 22, and ET Visit 
(if applicable), when ABPM will be performed for all patients.  
v. Week 22 visit ABPM should be performed within 7 days prior to the visit.  


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w. DXA scan should be performed within 2 weeks of the Baseline Visit. Patients to get DXA scan before Baseline Visit only in the case they are already 
determined to qualify for the study. At ET visit (if applicable), DXA scan should not be repeated if it was already completed within 8 weeks prior to ET 
Visit; acceptable visit window is up to 3 months following ET Visit. 
x. At ET visit, only study adherence needs to be performed; no study drug should be dispensed. Administration of study drug is the last procedure at applicable 
visits, other than the Week 18 visit, when it should be administered prior to blood draws for PK assessment. 
y. Patients will remain on study drug post Week 22 until it has been confirmed that all results for efficacy assessments are available and no repeated 
assessments are required. 
 
 


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Appendix B: Summary of Changes 
Significant changes in Amendment 3 of the protocol dated 11 October 2024 compared with 
Amendment 2 dated 21 June 2023 are summarized below with additional details in Table 12; 
deleted text is shown as a strikethrough and new text is shown in bold.  
Minor editorial or stylistic changes made for consistency are not summarized and may not be 
shown in the redline version of the amendment (e.g., punctuation, spelling, abbreviations). 
Throughout the document, sections, tables, and figures were renumbered as appropriate. Table of 
Contents, lists of tables or figures are updated without redline. 
Significant revisions to the protocol include the following: 
x Assessment of glycemic control was moved from a primary to secondary objective 
x Primary and secondary endpoints are updated to align with the revision to study 
objectives  
x Statistical analyses sections are updated to align with revisions to endpoints  
x Imputation methods for missing data related to the primary analysis are updated to use a 
placebo wash-out multiple imputation method 
x Endpoints for hyperglycemia are updated to include additional continuous endpoints   
x Statistical analyses sections are updated to reflect gated testing approach of certain 
secondary endpoints  


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Table 12 
Summary of Changes in Protocol CORT125134-456 Amendment 3  
Section 
Summary of Change 
Revisions 
Throughout the 
protocol 
Updated version and date of 
the protocol. 
Amendment 2 3 
21 June 202311 October 2024 
Title page 
Updated Sponsor address 
Corcept Therapeutics Incorporated 
149 Commonwealth Drive 
Menlo Park101 Redwood Shores Parkway 
Redwood City, California 9402594065 USA 
(650) 327-3270 
Synopsis 
Updated text in synopsis 
revised to align with changes 
in the protocol body. 
-- 
Throughout the 
protocol 
Updated text throughout to 
present hypertension before 
DM/IGT for consistency 
with revisions to endpoints 
-- 
2.1 Primary 
Objectives 
Updated to remove glycemic 
control as a primary 
objective 
To assess the efficacy of relacorilant for the treatment of 
hypercortisolism in patients with cortisol-secreting adrenal 
adenomas or hyperplasia, based on glycemic and blood 
pressure (BP) control at Week 22 compared with placebo 
2.2 Secondary 
Objectives 
Updated to include glycemic 
control as a secondary 
objective 
To assess changes in cortisol excess-related comorbidities 
(e.g., body weight and glycemic control) in patients with 
hypercortisolism due to cortisol-secreting adrenal 
adenomas/hyperplasia 
3.2.1 Primary 
Endpoints 
Updated to remove measure 
of AUCglucose (glycemic 
control) as a primary 
endpoint 
In patients with DM/IGT, the mean change in AUCglucose, 
from Baseline to Week 22 as compared between relacorilant 
and placebo arms. 
3.2.2 Secondary 
Endpoints  
Updated to include 
AUCglucose as a secondary 
endpoint for hyperglycemia 
1. In patients with DM/IGT at Baseline, the mean change 
in AUCglucose, from Baseline to Week 22 as compared 
between relacorilant and placebo arms. 
Added additional continuous 
endpoints for hyperglycemia 
9. In patients with DM/IGT in the ITT population, the 
proportion of patients who achieved decrease of 
AUCglucose RI    DQG DQ\ GHFUHDVH IURP
Baseline to Week 22. 
10. In patients with DM/IGT in the ITT population, the 
mean change in 2-hour oGTT 2-hour timepoint from 
Baseline to Week 22. 
7.11. In patients with DM/IGT in the ITT population, the 
mean change in 2-hour oGTT predrink timepoint from 
Baseline to Week 22. 
9.1 Analysis 
Populations 
Updated Table 10 to remove 
AUCglucose named as a 
primary endpoint  
The mITT population will include all patients in the ITT 
SRSXODWLRQ ZLWK  SRVW-randomization efficacy assessment 
the primary and secondary efficacy endpoints of ABPM 
and/or AUCglucoseor ABPM).. This population will be used 
for sensitivity analyses performed on the primary and 
secondary efficacy endpoints. The mITT population can 
vary for different efficacy endpoints. 


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Section
Summary of Change
Revisions
9.2 General 
Statistical 
Considerations
Revised timing for 
finalization of the statistical 
analysis plan
Statistical methods will be prespecified and documented in 
detail in a statistical analysis plan, to be finalized before 
database lockstudy unblinding.
9.3 Hypothesis 
Testing
Updated section to describe 
gated testing approach for
certain secondary endpoints
For the testing of the primary and certain secondary 
efficacy endpoints, adjustment for multiplicity will be 
implemented to maintain a 2-sided 0.05 significance level 
for the Family-Wise type I error rate. 
In order to provide strong control of the Type I error, 
certain secondary analyses will be tested using a gated 
testing approach at a 2-sided alpha level of 0.05. If the 
null hypothesis is rejected for the primary endpoint, 
certain secondary endpoints will be sequentially tested 
following the gatekeeping hierarchy (Figure 2). No 
adjustments for multiplicity will be made for other 
secondary or exploratory endpoints. 
Figure 2:
Sequential Gatekeeping Hierarchy  
Primary efficacy endpoints are defined in Section 3.2.13.2.1. 
The study will be considered to have a positive outcome if 
either of the 2 primary endpoints reaches statistical 
significance.
To adjust for multiplicity for the 2 primary efficacy 
endpoints, a Hochberg step up procedure (Hochberg 1988; 
FDA 2017) will be conducted as follows: 
1.
At the first step of the procedure, the larger 2-sided 
p-value of the 2 primary endpoints will be 
compared with the 0.05 significance level. 
2.
If the larger p-value is <0.05, responses with 
respect to both glycemic control and hypertension 
will be declared statistically significant.


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Section 
Summary of Change 
Revisions 
3. If the larger p-value is >0.05, the other primary 
endpoint will be declared statistically significant if 
the corresponding 2-sided p-value is <0.025.  
4. Otherwise, neither of the 2 primary endpoint results 
will be considered statistically significant. 
All statistical hypotheses for any other secondary endpoints 
and exploratory endpoints will be tested at a 2-sided 0.05 
significance level unless otherwise specified.  
9.5.4.1 Analysis 
of Primary 
Efficacy 
Endpoint 
Removed analysis of 
glycemic control 
(AUCglucose) from primary 
analysis and revised 
imputation methods for 
missing data related 
For the DM/IGT subgroup, the estimand of interest is the 
between-treatment difference in change in AUCglucose 
from Randomization to Week 22 (estimated using a mixed 
model for repeated measures [MMRM] model). All 
available values for AUCglucose will be used for analysis in 
the MMRM model, regardless of treatment adherence.  
If there are a sufficient number of retrieved dropouts (at least 
10 patients who discontinue treatment but still had an 
AUCglucose assessment at Week 22), imputation of missing 
data at Week 22 (for non-retrieved dropouts) will be 
performed based on known measurements from the retrieved 
dropouts with similar baseline characteristics for patients 
discontinuing the study without use of rescue medication, 
but placebo-mean imputation at visits after initiation of 
rescue medication for patients that use rescue medication.  
For patients who use rescue medication for hyperglycemia 
control before Week 22, the plasma 2-hours oGTT test 
values collected after first use of rescue medication will not 
be included in the primary analysis. Rather, patients who use 
rescue medication for hyperglycemia control are assumed to 
perform similarly to patients who received placebo. And, 
therefore, the missing AUCglucose values after initiation of 
rescue medication in patients treated with relacorilant that 
receive diabetes rescue medication are replaced with the 
estimated mean of the entire endpoint distribution of the 
placebo arm at visits after initiation of rescue medication 
(this is the placebo-based mean value at each visit). 
The primary efficacy analysis for the primary endpoint of 
change in AUCglucose from Randomization to Week 22 
will be performed using a linear mixed-model-for-repeated-
measures (MMRM) using data with the imputation method 
described above. Restricted maximum likelihood (REML) 
estimation will be used. The MMRM model will include 
Baseline AUCglucose as a covariate; treatment, visit, and 
treatment by visit interaction, and stratification factor as 
fixed effects; patients within treatment groups as random 
effects. In the DM/IGT subgroup, the stratification factor at 
randomization identifies patients with or without 
hypertension. An unstructured covariance structure will be 
used to model within-patient error, and the Kenward Roger 
approximation will be used to model denominator degrees of 
freedom. 
The primary analysis will determine whether there is a 
difference between treatment groups in terms of change in 


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Section 
Summary of Change 
Revisions 
AUCglucose from Randomization to Week 22. This will be 
accomplished by using appropriate linear contrasts of the 
parameters in the MMRM model described above. 
Multiple imputation will be implemented to allow additional 
source of variability in the imputed values. For each imputed 
dataset, the same MMRM model specified above will be 
used to estimate treatment effect on change in AUCglucose 
from Randomization to Week 22. The combination of 
individual estimates for treatment effect and the inference 
based on the combined estimate will be handled by SAS 
procedure MIANALYZE. Additional sensitivity analyses 
will be specified in the statistical analysis plan (SAP). 
For the hypertension subgroup of the ITT Population, the 
estimand of interest is the between-treatment difference in 
change in average SBP based on 24-hour ABPM from 
Randomization to Week 22 (estimated using a MMRM 
model). All available values for SBP will be used for 
analysis in the MMRM model, regardless of treatment 
adherence. 
If there are a sufficient number of retrieved dropouts (at least 
10 patients who discontinue treatment but still had an SBP 
assessment at Week 22), imputation of missing data at 
Week 22 (for non-retrieved dropouts) will be performed 
based on known measurements from the retrieved dropouts 
with similar baseline characteristics for patients 
discontinuing the study without use of rescue medication, 
but placebo-mean imputation at visits after initiation of 
rescue medication for patients that use rescue medication. 
For patients who use rescue medication or discontinue 
treatment early, a placebo wash-out multiple imputation 
will be used as the primary analysis. For those patients 
who use rescue medication for hypertension after 
randomization and before Visit Week 22, the values 
collected after first use of rescue medication are 
irrelevant to the clinical question of interest and will not 
be used in the analysis. For patients who discontinue 
treatment early, all collected values (including retrieved 
drop-outs) will be used in the analysis.For patients who 
use rescue medication for hypertension control before Week 
22, the average SBP based on 24-hour ABPM collected after 
first use of rescue medication will not be included in the 
primary analysis. Rather, patients who use rescue medication 
for hypertension control are assumed to perform similarly to 
patients who received placebo. And, therefore, the missing 
average SBP after initiation of rescue medication in patients 
treated with relacorilant that receive hypertension rescue 
medication are replaced with the estimated mean of the 
entire endpoint distribution of the placebo arm at visits after 
initiation of rescue medication (this is the placebo-based 
mean value at each visit).The ‘placebo wash-out’ analysis 
means the missing 24-hour average SBP at Visit Week 22 
data will be imputed by considering a wash-out of the 
effect of treatment using completers in the placebo arm. 


Protocol CORT125134-456 
Corcept Therapeutics Incorporated 
 Amendment 3  |  11 October 2024 
Confidential 
Page 105 of 105 
Section 
Summary of Change 
Revisions 
Specifically, 24-hour average SBP data for patients on 
the placebo arm without measurements at Week 22 will 
be imputed using a monotone regression model based on 
observed 24-hour average SBP data of completers on the 
placebo arm with intermediate measurements, Baseline 
value and stratification factor. For patients on the 
relacorilant arm with missing Week 22 data, the 
imputation model with only Baseline value and 
stratification factor will be used. 
… 
Additional sensitivity analyses of the primary endpoint, 
including subgroups of interest, will be specified in the 
SAP. 
Additional sensitivity analyses of the primary endpoints by 
subgroups of interest will be done. Details will be described 
in the SAP. 
9.5.7 PD 
Analysis 
Revised timing for 
finalization of the statistical 
analysis plan 
Analysis of PD endpoints will be described in a separate PD 
analysis plan finalized before database lockstudy 
unblinding. 
9.5.8 Biomarker/ 
Pharmacogenetic 
Analysis  
Revised timing for 
finalization of the statistical 
analysis plan 
Biomarker and pharmacogenetic exploratory analyses will 
be described in the SAP finalized before database lockstudy 
unblinding. 
 

SAP_001.pdf: 
Title: Glucocorticoid Receptor Antagonism in the Treatment of Hypercortisolism in Patients with 
Cortisol-Secreting Adrenal Adenomas or Hyperplasia (GRADIENT): A Phase 3, Randomized, 
Double-Blind, Placebo-Controlled Study of the Efficacy and Safety of Relacorilant 
 
NCT Number: NCT04308590 
 
 
Date: 11 October 2024 
 


Corcept Therapeutics Incorporated  
 Clinical Study Report 
16.1.9 Documentation of Statistical Methods 
 CORT125134-456 
Confidential 
 Page 1 
DOCUMENTATION OF STATISTICAL METHODS 
Document Title and Version 
Date 
Statistical Analysis Plan, Version 2.0 
11 October 2024 






 
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CONTENTS 
STATISTICAL ANALYSIS PLAN STUDY CORT125134-456 .................................................. 1 
APPROVAL SHEET ...................................................................................................................... 2 
CONTENTS .................................................................................................................................... 3 
List of Tables .................................................................................................................................. 6 
List of Figures ................................................................................................................................. 6 
LIST OF ABBREVIATIONS AND DEFINITIONS ..................................................................... 7 
1 
INTRODUCTION ............................................................................................................ 10 
2 
STUDY OVERVIEW ....................................................................................................... 11 
2.1 
Overall Design .................................................................................................................. 11 
3 
STUDY OBJECTIVES ..................................................................................................... 12 
3.1 
Primary Objectives............................................................................................................ 12 
3.2 
Secondary Objective ......................................................................................................... 12 
3.3 
Exploratory Objective ....................................................................................................... 12 
4 
STUDY ENDPOINTS ...................................................................................................... 13 
4.1 
Primary Efficacy Endpoint ............................................................................................... 13 
4.2 
Safety Endpoints ............................................................................................................... 13 
4.3 
Secondary Endpoints ........................................................................................................ 13 
4.4 
Exploratory Endpoints ...................................................................................................... 14 
5 
SAMPLE SIZE CONSIDERATION ................................................................................ 15 
6 
ANALYSIS POPULATION ............................................................................................. 17 
6.1 
Enrolled Population .......................................................................................................... 17 
6.2 
Safety Population .............................................................................................................. 17 
6.3 
Intent to Treat Population (ITT) ....................................................................................... 17 
6.4 
Modified Intent to Treat Population (mITT) .................................................................... 17 
6.5 
Per-Protocol Population (PP) ............................................................................................ 17 
6.6 
Key Subgroups .................................................................................................................. 17 
6.7 
Additional Subgroups ....................................................................................................... 18 
7 
DEFINITIONS, COMPUTATIONS, AND CONVENTIONS ........................................ 19 


 
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7.1 
Definitions......................................................................................................................... 19 
7.1.1 Definitions of Baseline ......................................................................................... 19 
7.1.2 Definition of Analysis Visit Windows .................................................................. 19 
7.2 
Reporting Conventions ..................................................................................................... 20 
7.3 
Summarization by Visit .................................................................................................... 21 
7.4 
Data Handling Rules ......................................................................................................... 22 
7.5 
Standard Calculations ....................................................................................................... 22 
7.6 
Handling Missing Data ..................................................................................................... 23 
7.6.1 Handling Missing Data for Primary Efficacy Endpoint ....................................... 23 
7.6.2 Handling Missing Data for Secondary Efficacy Endpoints .................................. 23 
7.6.2.1 Endpoints Summarized with Proportions .............................................. 23 
7.6.2.2 Continuous Secondary Efficacy Endpoints ........................................... 23 
7.6.3 Handling Missing Data for Exploratory Efficacy Endpoints ................................ 24 
7.6.4 Handling Incomplete or Missing Dates for Adverse Events and Concomitant 
Medications ........................................................................................................... 24 
7.6.5 Handling Incomplete or Missing Dates for Medical History ................................ 25 
8 
TIMING OF ANALYSES ................................................................................................ 26 
8.1 
Interim Analysis ................................................................................................................ 26 
8.2 
Final Analyses and Reporting ........................................................................................... 26 
9 
STATISTICAL METHODS ............................................................................................. 27 
9.1 
General Statistical Consideration ...................................................................................... 27 
9.2 
Patient Disposition ............................................................................................................ 27 
9.3 
Protocol Deviations ........................................................................................................... 27 
9.4 
Demographic Characteristics and Baseline Characteristics .............................................. 28 
9.5 
Medical History ................................................................................................................ 28 
9.6 
Prior and Concomitant Medications ................................................................................. 28 
9.7 
Extent of Exposure and Study Drug Compliance ............................................................. 30 
9.8 
Efficacy Analyses ............................................................................................................. 30 
9.8.1 Primary Efficacy Endpoint ................................................................................... 30 


 
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9.8.1.1 Primary Efficacy Endpoint for Patients with Uncontrolled Systolic 
Hypertension .......................................................................................... 30 
9.8.1.2 Multiplicity Adjustment for Analysis of Primary and Secondary Efficacy 
Endpoints ............................................................................................... 31 
9.8.1.3 Imputation for Primary Analysis ........................................................... 32 
9.8.2 Sensitivity Analysis for Primary Efficacy Endpoint ............................................. 33 
9.8.2.1 Analyses to Address Confounding by Rescue Medication and Early 
Discontinuation ...................................................................................... 33 
9.8.3 Secondary Efficacy Endpoints .............................................................................. 36 
9.8.3.1 Continuous Endpoints ............................................................................ 36 
9.8.3.2 Endpoints Summarized with Proportions .............................................. 39 
9.8.4 Exploratory Efficacy Endpoints ............................................................................ 42 
9.8.5 Multicenter Studies ............................................................................................... 47 
9.9 
Pharmacodynamic Analysis .............................................................................................. 47 
9.10 
Pharmacokinetic Analysis ................................................................................................. 47 
9.11 
Safety Analyses ................................................................................................................. 47 
9.11.1 Adverse Events ..................................................................................................... 47 
9.11.2 Special Safety Topics ............................................................................................ 50 
9.11.3 Deaths ................................................................................................................... 51 
9.11.4 Clinical Laboratory Tests ...................................................................................... 51 
9.11.5 Vital Signs ............................................................................................................. 52 
9.11.6 Electrocardiograms ............................................................................................... 52 
9.11.7 Physical Examination............................................................................................ 52 
9.11.8 Pregnancy Tests .................................................................................................... 53 
10 
CHANGES FROM PROTOCOL IN STUDY CONDUCT OR STATISTICAL 
ANALYSIS PLAN ........................................................................................................... 54 
11 
REFERENCES ................................................................................................................. 55 
12 
APPENDIX ....................................................................................................................... 57 
APPENDIX 1 ................................................................................................................................ 58 
APPENDIX 2 ................................................................................................................................ 59 
APPENDIX 3 ................................................................................................................................ 60 


 
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List of Tables 
Table 1 
Statistical Power for Single Primary Analysis of Change from Baseline in 24-hour 
Average Systolic Blood Pressure ...........................................................................15 
Table 2 
Analysis Visit Windows for Assessments .............................................................20 
Table 3 
Sensitivity Analyses for Primary Endpoint............................................................33 
Table 4 
Items in Subscales of the Cushing QoL .................................................................46 
List of Figures 
Figure 1 
CORT125134-456 Study Design ...........................................................................11 
Figure 2 
Sequential Gatekeeping Hierarchy ........................................................................32 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS 
Abbreviation 
Definition 
ABPM 
ambulatory blood pressure monitoring 
ACTH 
Adrenocorticotropic Hormone 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase  
ATC 
Anatomic Therapeutic Chemical 
AUC 
area under the concentration-time curve  
AUCglucose 
area under the concentration-time curve for glucose  
BDI-II 
Beck Depression Inventory®-II 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CMH 
Cochran-Mantel-Haenszel 
CI 
confidence interval 
CSR 
Clinical Study Report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events  
CV (%) 
coefficient of variation (%) 
DBP 
diastolic blood pressure 
DM 
diabetes mellitus 
DXA 
dual energy X-ray absorptiometry 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
ET 
early termination 
FDA 
Food and Drug Administration 
FKBP5 
FK506 binding protein 5 
GR 
glucocorticoid receptor 


 
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Abbreviation 
Definition 
HbA1c 
hemoglobin A1c 
HPA 
hypothalamic-pituitary-adrenal 
ICF 
informed consent form 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) 
IDMC 
Independent Data Monitoring Committee 
IGT 
impaired glucose tolerance 
IRT 
Interactive Response System 
ITT 
Intent-to-treat population 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat  
MMRM 
mixed model for repeated measures 
mRNA 
messenger RNA 
oGTT 
oral glucose-tolerance test 
OL 
open label 
PD 
Pharmacodynamic 
PK 
Pharmacokinetics 
PP 
Per Protocol Analysis Population  
QoL 
quality-of-life 
REML 
restricted maximum likelihood 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
systolic blood pressure 
SD 
Standard Deviation 
SE 
Standard Error 
SI 
Système International 


 
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Abbreviation 
Definition 
TEAE 
treatment-emergent adverse event 
UFC 
urinary free cortisol 
US 
United States 
vs. 
Versus 
WHO 
World Health Organization 


 
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1 
INTRODUCTION 
The purpose of the statistical analysis plan (SAP) is to provide a detailed description of the 
principal features of the analysis described in the protocol and to include detailed procedures for 
executing the statistical analysis of the primary and secondary endpoints and other data for 
Corcept Study CORT125134-456.  
This SAP contains definitions of analysis populations and endpoints, outlines the timing of 
statistical analyses, and provides a comprehensive description of statistical analyses to be 
implemented to assess the clinical efficacy and safety of treatment with relacorilant as per 
Protocol CORT125134-456: Glucocorticoid Receptor Antagonism in the Treatment of 
Hypercortisolism in Patients with Cortisol-Secreting Adrenal Adenomas or Hyperplasia 
(GRADIENT): A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy 
and Safety of Relacorilant. The statistical methods applied in the design and planned analyses of 
this study are consistent with the International Conference on Harmonization of Technical 
Requirements for Pharmaceuticals for Human Use, Guidance for Industry: E9 Statistical 
Principles for Clinical Trials (ICH E9 1998) and E9 (R1) Statistical Principles for Clinical 
Trials: Addendum: Estimands and Sensitivity Analysis in Clinical Trials (ICH E9[R1] 2021).  
This SAP will be finalized before study unblinding and prior to data analysis to provide full 
details of statistical analysis to be presented in the clinical study report (CSR). Any changes 
between the statistical methods provided in the clinical study protocol and this SAP will be 
explained herein; the methods described in the SAP take precedence over the protocol; any 
changes or deviations from this SAP relative to the final analysis will be fully documented in the 
CSR. Minor changes or deviations from the templates for tables, figures, and listings need not be 
documented in the CSR.  
 


 
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2 
STUDY OVERVIEW 
2.1 
Overall Design  
This is a Phase 3, double-blind, placebo-controlled study to assess the efficacy and safety of 
relacorilant to treat hypercortisolism in patients with cortisol-secreting adrenal adenoma or 
hyperplasia associated with DM/IGT and/or uncontrolled systolic hypertension. Two 
subgroups
DM/IGT and hypertension
will be analyzed (Figure 1). 
Figure 1 
CORT125134-456 Study Design 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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3 
STUDY OBJECTIVES 
3.1 
Primary Objectives 
 To assess the efficacy of relacorilant for the treatment of hypercortisolism in patients 
with cortisol secreting adrenal adenomas or hyperplasia, based on blood pressure (BP) 
control at Week 22 compared with placebo. 
 
To assess the safety of relacorilant for the treatment of hypercortisolism. 
3.2 
Secondary Objective 
 To assess changes in the cortisol excess-related comorbidities (e.g., body weight and 
glycemic control) in patients with hypercortisolism due to cortisol-secreting adrenal 
adenomas/hyperplasia. 
3.3 
Exploratory Objective 
 To explore changes in cortisol excess related comorbidities including assessments of 
glucose, insulin resistance indices, coagulation markers, GR activity biomarkers, HPA 
axis and bone turnover markers, depression, and quality of life questionaries in patients 
with cortisol secreting adrenal adenomas or hyperplasia. 
 To assess the pharmacokinetics of relacorilant in patients with hypercortisolism due to 
cortisol-secreting adrenal adenomas/hyperplasia. 
 
 
 
 
 


 
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4 
STUDY ENDPOINTS 
4.1 
Primary Efficacy Endpoint  
In patients with systolic hypertension, the mean change in 24-hour average systolic blood 
pressure (SBP) based on 24-hour ambulatory blood pressure monitoring (ABPM), from Baseline 
to Week 22 as compared between relacorilant and placebo arms.  
4.2 
Safety Endpoints 
In all patients, assessment of safety is based on TEAEs. 
4.3 
Secondary Endpoints  
Secondary endpoints will include data from Baseline to Week 22 to compare the treatment 
difference between relacorilant and placebo. 
Endpoints for Hypertension: 
1. In patients with systolic hypertension at Baseline, the mean change in 24-hour average 
diastolic blood pressure (DBP), and heart rate (HR, 
24-hour ABPM). 
2. In patients with systolic hypertension at Baseline, mean change in daytime average SBP, 
DBP, and HR (based on ABPM). 
3. In patients with systolic hypertension at Baseline, mean change in nighttime average 
SBP, DBP, and HR (based on ABPM). 
4. In patients with systolic hypertension at Baseline, proportion of patients with any dose 
increase in antihypertensive medications due to worsening hypertension. 
5. In patients with systolic hypertension at Baseline, proportion of patients with a reduction 
in 24-hour average SBP by 5 mm Hg (based on 24-hour ABPM).  
6. In patients with systolic hypertension at Baseline, proportion of patients with any dose 
decrease in antihypertensive medication due to improved blood pressure. 
7. In patients with systolic hypertension at Baseline, proportion of patients with 
normalization of the average SBP (< 130 mm Hg, based on 24 hour-ABPM). 
Endpoints for Hyperglycemia: 
1. In patients with DM/IGT at Baseline, the mean change in AUCglucose, from Baseline to 
Week 22 as compared between relacorilant and placebo arms.  
2. In patients with DM (HbA1c at Baseline  6.5%), the mean change in HbA1c. 
3. In patients with DM/IGT (HbA1c at Baseline  5.7%), the mean change in HbA1c. 
4. Proportion of patients with HbA1c  6.5% at Baseline who achieved HbA1c < 6.5%. 
5. In patients with DM at Baseline, proportion of patients who achieved 2-hour oGTT 
glucose < 
.  
6. In patients with IGT at Baseline, proportion of patients who achieved 2-hour oGTT 
glucose < 140 mg/dL. 
 
 
 
 
 
 


 
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7. In patients with DM/IGT at Baseline, proportion of patients with any dose decrease of 
diabetes medication due to improved glucose control. 
8. In patients with DM/IGT at Baseline, with any dose increase of diabetes medications due 
to worsening hyperglycemia. 
9. In patients with DM/IGT in the ITT population, the proportion of patients who achieved 
decrease of AUCglucose 
from Baseline to Week 22. 
10. In patients with DM/IGT in the ITT population, the mean change in 2-hour oGTT 2-hour 
timepoint from Baseline to Week 22.  
11. In patients with DM/IGT in the ITT population, the mean change in 2-hour oGTT 
predrink timepoint from Baseline to Week 22.  
Other Secondary Endpoint: 
1.  In all patients, the mean change in body weight and waist circumference. 
4.4 
Exploratory Endpoints 
The mean change from Baseline to Week 22/ET in serum osteocalcin; in trabecular bone score, 
bone mineral density, and body composition from DXA scans; the Beck Depression 
Inventory®-II (BDI-II) score; sit-to-stand test score; trail making test scores; coagulation markers 
(Factor VIII, von Willebrand factor, protein S, protein C, TAT, platelets, and PTT); DHEA-S 
concentrations; ACTH concentrations; lipids (total cholesterol, LDL cholesterol, triglycerides, 
and very-low-density lipoprotein cholesterol [VLDL]); HPA-axis; morning and late-night 
salivary cortisol; AUCglucose; fasting glucose in patients with DM; insulin resistance indices and 
hyperglucagonemia (AUCinsulin, Matsuda Index, homeostatic model assessment of insulin 
resistance [HOMA-IR], and at selected visits AUCglucagon); and Cushing Quality-of-Life 
(Cushing QoL) score and psychosocial and physical problem subscales.  
Intensive pharmacokinetic blood sampling will be conducted in all patients at the Week 18 visit. 
The plasma concentrations of relacorilant and/or its metabolites will be examined. The analysis 
of pharmacokinetic data will be included in a separate pharmacokinetic SAP. 
The analysis of biomarkers related to GR activity (such as FKBP5) will be included in a separate 
biomarker SAP.  
 
 
 
 
 
 


 
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5 
SAMPLE SIZE CONSIDERATION 
Approximately 130 patients are planned to be randomized into the study. 
Attainment of the randomization targets within the DM/IGT and hypertension subgroups in this 
study assumes that 40% of randomized patients will have DM/IGT only, 40% will have 
hypertension only, and 20% will have both DM/IGT and hypertension. This projected sample 
size will result in randomization of approximately 78 patients with DM/IGT (with or without 
hypertension) and 78 patients with hypertension (with or without DM/IGT). 
Seventy-eight patients with hypertension (39 per treatment group) will ensure at least 90% power 
to detect a difference between placebo and treatment arms of 7 mmHg in mean change from 
Baseline of the average SBP (based on ABPM). These calculations assume a common standard 
deviation of 8 mm Hg and a 0.025 two-sided significance level two-sample t-test. Twenty-eight 
percent dropout rate is assumed in this calculation.  
Seventy-eight patients with DM/IGT (39 patients per treatment group) will ensure at least 90% 
power to detect a difference of 3.1 h*mmol/L in mean changes in AUCglucose (based on the 
2-hour oGTT measurement) between placebo and treatment arm. This calculation assumes a 
common standard deviation of 3.7 h*mmol/L, and a 0.025 two-sided significance level 
two-sample t-test. Twenty percent dropout rate is assumed in this calculation. 
In summary, the expected randomization of 130 patients in the study will result in 78 patients 
within each of the DM/IGT and hypertension subgroups. This sample size will provide sufficient 
power to detect the target differences in the primary endpoint for each of the subgroups. 
Given the adjustment to a single primary endpoint of change from Baseline in the 24-hour 
average SBP (based on ABPM), Table 1 describes the power to detect a difference of 7 mmHg in 
mean change from Baseline of the average SBP with varying common standard deviations and a 
0.05 two-sided significance level two-sided t-test. 
Table 1 
Statistical Power for Single Primary Analysis of Change from Baseline in 
24-hour Average Systolic Blood Pressure 
Common Standard Deviation 
Power 
7.5 mmHg 
98.25% 
8.0 mmHg 
96.82% 
8.5 mmHg 
94.85% 
9.0 mmHg 
92.38% 
9.5 mmHg 
89.48% 
10.0 mmHg 
86.26% 


 
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Note: Given a sample size of 78 patients (39 patients per treatment group), an assumed 
difference of 7 mmHg in mean change from Baseline of the average SBP and the specified 
common standard deviation, the power to detect the difference is provided using a two group 
t-test with a 0.05 two-sided significance level. 


 
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6 
ANALYSIS POPULATION 
6.1 
Enrolled Population 
All patients who sign the informed consent form (ICF). 
6.2 
Safety Population 
All patients who receive relacorilant or placebo and who take  1 dose of study treatment. 
Patients will be analyzed according to the treatment they actually received. 
6.3 
Intent to Treat Population (ITT) 
The ITT population will include all patients who were randomized to receive relacorilant or 
placebo, even if they do not receive any study treatment. This population will be used for the 
analysis of the primary and secondary efficacy endpoints.  
6.4 
Modified Intent to Treat Population (mITT) 
The mITT population will include all patients in the ITT population with  1 post-randomization 
efficacy assessment for the primary and secondary efficacy endpoints of ABPM and/or 
AUCglucose. Specifically, for patients in the systolic hypertension only or systolic hypertension 
and DM/IGT subgroup, at least 1 post-randomization ABPM assessment is required. For patients 
in the DM/IGT only subgroup, at least 1 post-randomization AUCglucose is required. This 
population will be used for sensitivity analyses performed on the primary and secondary efficacy 
endpoints.  
6.5 
Per-Protocol Population (PP) 
The PP population will include all patients in the mITT population who had no important 
protocol deviations that might impact the validity of the primary efficacy analysis. Patients in the 
PP population who complete the study without an important deviation will be used in sensitivity 
analyses of the primary efficacy endpoint.  
6.6 
Key Subgroups  
Cushing Syndrome Comorbidity Type at Baseline based on CRF collected data: 
 Patients with systolic hypertension (average SBP  130 to  170 mm Hg) with or without 
DM/IGT 
 Patients with DM/IGT with or without systolic hypertension 
 Patients with DM/IGT only  
 Patients with systolic hypertension only 
 Patients with both DM/IGT and systolic hypertension   
 Patients with DM (fasting plasma glucose  126 mg/dL or /or 2-hour oGTT 
plasma glucose  200 mg/dL at 2 hours or HbA1c  6.5%) 
 Patient with impaired glucose tolerance (plasma glucose <126 mg/dL and < 200 mg/dL 
on a 2-hour oGTT at 2 hours and HbA1c < 6.5%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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6.7 
Additional Subgroups 
Patients with hypertension at Baseline: 
 Patients on vs. off diuretic treatment based on prior medication. 
 Patients treated with more than 3 prior antihypertensive medications, including a diuretic 
based on prior medication vs. less than or equal to 3 prior antihypertensive medications. 
 Patients with DST with serum cortisol concentrations between 1.8 and 5 ug/dl vs. 
> 5 ug/dl at screening/Baseline. 
Patients with DM/IGT at Baseline: 
 Treated with prior antidiabetic medications. 
 Not treated with prior antidiabetic medications. 
Other subgroups of interest: 
 Patient without prior long-acting insulin. 
 Biological sex assigned at birth. 
 Age: < 
< 65 vs.  65. 
 Race: White, African American, Other. 
 Ethnicity: Hispanic vs Non-Hispanic 
 Menopausal status: post-menopausal vs. pre-menopausal 
 Geographic location: North America vs Rest of the world. 
 BMI (kg/m2) (< 25, 25 29, 30 < 35, and  35) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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7 
DEFINITIONS, COMPUTATIONS, AND CONVENTIONS 
The statistical principles applied in the design and planned analyses of this study are consistent 
with Guidance for Industry FDA (US Food and Drug Administration) Guidance: E9 Statistical 
Principles for Clinical Trials (ICH E9 1998) and E9 (R1) Statistical Principles for Clinical 
Trials: Addendum: Estimands and Sensitivity Analysis in Clinical Trials (ICH E9[R1] 2021). 
All statistical analyses detailed in this SAP will be conducted using SAS version 9.4 or higher.  
All SAS programs that create tables, listings or figures and supporting analysis datasets will be 
validated per standard operating procedures. 
7.1 
Definitions 
Study day: Calculated in reference to the date of first dose of relacorilant or placebo (Study 
Day 1). For assessments conducted on or after the first dose date, study day is calculated as 
(assessment date  first dose date + 1). For assessments conducted before the first dose date, 
study day is calculated as (assessment date  first dose date). There is no Study Day 0.  
Treatment-emergent period: Is defined as the period of time from the date of the first dose of 
study drug through 28 days after the last dose of study drug. The treatment-emergent period will 
be used in the summaries of treatment-emergent adverse events (TEAEs). 
7.1.1 Definitions of Baseline  
The Baseline for oGTT plasma glucose will be defined for purposes of analyzing AUCglucose. 
Baseline oGTT plasma glucose is defined as the last non-missing oGTT measurement prior to 
first dose of study drug. Non-missing oGTT measurement will be defined as a measurement with 
sufficient data for derivation of AUCglucose (Section 7.6.1). Therefore, the Baseline for AUCglucose 
is defined at the same visit (unscheduled or scheduled) that the Baseline oGTT plasma glucose is 
defined.  
The Baseline for 24-hour UFC and late-night salivary cortisol is defined as the average of all 
measurements prior to first dose of study drug, including unscheduled visits. 
The Baseline for twelve-lead ECG interval parameters is defined as the average of the duplicate 
readings at Screening.  
The Baseline for all other efficacy and safety parameters not previously mentioned is defined as 
the last measurement prior to the first dose of study drug. The last visit prior to the first dose of 
study drug may be an unscheduled or scheduled visit.  
7.1.2 Definition of Analysis Visit Windows 
In analysis of data summarized by study visit, unscheduled and early termination visits will be 
reassigned an analysis visit where data is scheduled for collection based on the planned visit 
Study Day.  
The window for each study visit is relative to the Baseline visit. The protocol specified visit 
window is ±7 days for all visits (except for the Week 22 and ET visits, in which case a 3-week 


 
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visit window [2 weeks before the scheduled visit, 1 week after the scheduled visit] and 2-week [2 
weeks after the scheduled visit] visit window, respectively, is permitted). The analysis visit 
windows are defined to cover all study days for a participant in the trial. 
Patients will remain on study treatment post Week 22 visit until it has been confirmed that all 
results for efficacy assessment have been received and no repeat assessments are required. The 
follow-up visit must occur 28 days after the last dose of study drug. 
The randomization day is considered Study Day 1.  
Table 2 outlines the analysis visit windows.  
Table 2 
Analysis Visit Windows for Assessments  
Visit Name 
Start Day 
Target Day 
End Day 
Baseline 
 
1 
 
Week 2 
2 
15 
29 
Week 6 
30 
43 
57 
Week 10 
58 
71 
85 
Week 14 
86 
99 
113 
Week 18 
114 
126 
140 
Week 22 
141 
155 
176 
Follow-up 
Study day of last dose of 
study drug +21 
Study day of last dose of 
study drug +28 
Study day of last dose of 
study drug +35 
 
7.2 
Reporting Conventions  
Unless otherwise specified, the following conventions will be applied to all analyses: 
 Continuous variables will be summarized to indicate the population sample size (N), 
number of patients with available data (n), mean, standard deviation (SD), median, 
inter-quartile range (Q1, Q3), minimum, maximum and 95% confidence intervals (CI). 
 Categorical variables will be summarized by the population size (N), number of patients 
with available data (n), number of patients in each category, percentage of patients in 
each category and 95% CI. Unless otherwise noted, the denominator to determine the 
percentage of patients in each category will be based on the number of patients with 
available data (n).  
 Select ordinal data may be summarized using both descriptive statistics and counts and 
percentages of patients in each category, as appropriate. 
 Confidence intervals (CIs), when presented, will generally be constructed at the 95% 
level. For binomial variables, exact methods will be employed unless otherwise specified. 
 
 
 
 


 
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 Rounding conventions for presentation of summary statistics will be based on the 
precision of the variable of summarization, as it is collected in its rawest form (i.e., on the 
eCRF or as provided within an external file) and are outlined as follows: 
o The mean and median will be rounded to one more decimal place than the 
precision of the variable of summarization. 
o Measures of variability (e.g., SD, SE) will be rounded to two more decimal places 
than the precision of the variable of summarization; and 
o Minimum and maximum values will be presented using the same precision as the 
variable of summarization. 
o Non-zero percentages will be rounded to 1 decimal place. Number and percentage 
values will be presented as xx (xx.x%). 
 Analysis and summary tables will have the analysis population sample size (i.e., number 
of patients). 
 The descriptive summary for observed end of treatment visit will be included in all by 
visit summary table. 
 Laboratory data will be reported using standard international (SI) units and conventional 
unit; as central laboratories are used for this study, conversion factors from conventional 
units to SI units will be listed in the clinical study report. 
 1 inch = 2.54 cm.  
 For by-visit observed data analyses, percentages will be calculated based on the number 
of patients with non-missing data as the denominator unless otherwise specified. 
 P-values will be rounded to 4 decimal places. P-values that round to 0.0000 will be 
< 
-values that round to 1.000 will be presented as > 0.999
 
 Medical history and adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA version 26.0 or later). Adverse event severity will be 
evaluated using the National Cancer Institute Common Terminology Criteria for Adverse 
Events (CTCAE) v.5.0 (NCI-CTCAE 2017).  
 Prior therapies and concomitant medications will be coded using the World Health 
Organization (WHO) Drug Dictionary (version WHO Drug Global B3 March, 2023) and 
summarized by Anatomical Therapeutic Chemical (ATC) medication class and preferred 
names. 
 All statistical hypotheses will be tested at a two-sided 0.05 significance level unless 
otherwise specified.  
 Listings will be presented in the order of patient identifier, comorbidity type (DM/IGT or 
Hypertension), and visit (or date of procedure or event, when applicable), unless stated 
otherwise. 
 
 
 
 
 
 
 
 
 
 
 
   
  
  
  


 
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7.3 
Summarization by Visit 
Data collected at scheduled visits will be analyzed based on the nominal visit as reported in 
the database. If an unscheduled assessment is mapped to an analysis visit window that already 
has a non--missing assessment for the corresponding scheduled visit, the scheduled visit will be 
used in the analysis. Otherwise, if multiple assessments occur within a single visit window, then 
the closest assessment to the target day of the visit window will be used in the analysis. If 
distance to target visit date is the same for more than one assessment (e.g., one assessment is 
performed 2 days prior to the target visit date and one assessment is performed 2 days after the 
target visit date), the later assessment day that is still within the visit window will be used in the 
analysis.  
If there are repeated assessments of the same sample or procedure at a scheduled visit, the most 
recent value will be used for analysis. 
7.4 
Data Handling Rules  
Unless otherwise noted, values reported as greater than or less than limit of quantification (LOQ) 
(e.g., < 
ummary tables and figures, using 
the LOQ value instead. 
7.5 
Standard Calculations 
Conventions for calculations with dates are as follows: 
 Dates will be stored as numeric variables in the SAS analysis files and reported in 
DDMMMYYYY format (i.e., the Date9. datetime format in SAS). 
 Dates recorded in comment fields will not be imputed or reported in any specific format. 
 Age will be calculated in years as integer part of (DATE of ENROLLMENT - DATE of 
BIRTH + 1)/365.25. If both day and month fields are missing, impute missing day and 
month as July 1st. If the year field is missing, age will be set as missing. 
 Where appropriate, the calculated study day of each assessment or event will be 
presented with the assessment or event date on patient data listings, where study day is 
defined in Section 7.1. 
 Days: A duration between two dates expressed in days will be calculated using the 
following conventions: 
o (Later date  earlier date) + 1, if the earlier date is on or after the date of first dose 
of study drug; or 
o Later date  earlier date, if the earlier date is prior to the date of first dose of study 
drug. 
 Weeks: A duration expressed in Weeks will be calculated by dividing the duration in 
days by 7. 
 Months: A duration expressed in months will be calculated by dividing the duration in 
days by (30.4375=365.25 / 12). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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 Years: A duration expressed in years will be calculated by dividing the duration in days 
by 365.25. 
Detailed rules for imputation of missing/partially missing dates for adverse events and 
prior/concomitant medications/procedures are provided in Section 7.6.4. 
Conventions for calculations for other types of variables: 
 Change from Baseline: Change from Baseline will be calculated as the post-Baseline 
value minus the Baseline value. 
 Percentage Change from Baseline: Percentage change from Baseline will be calculated as 
the change from Baseline divided by the Baseline value, multiplied by 100. 
7.6 
Handling Missing Data 
The guidance on The Prevention and Treatment of Missing Data in Clinical Trials (National 
Research Council 2010) will be followed when these methods are applied.  
All efforts will be made to prevent missing data. To prevent bias caused by unavoidable missing 
data, different statistical approaches (described in Section 7.6.1 through Section 7.6.5) based on 
the nature of the endpoint will be used to handle missing data. For each endpoint, a summary of 
missing data at each of the visits will be presented by treatment arm and by visit. 
7.6.1 Handling Missing Data for Primary Efficacy Endpoint  
As described in the protocol, if a patient discontinues early from the study, the patient is 
instructed to return for Visit Week 2
. Retrieved 
dropouts are patients who discontinue study treatment prior to Visit Week 22 and return for the 
Visit Week 22 assessment as required by protocol. Missing data for patients who use rescue 
medication or discontinue treatment early will be imputed using a placebo wash-out multiple 
imputation. For patients who discontinue treatment early, all collected values (including 
retrieved drop-outs) will be used in the analysis. Further details are given in Section 9.8.1.3. 
7.6.2 Handling Missing Data for Secondary Efficacy Endpoints  
7.6.2.1 
Endpoints Summarized with Proportions 
For endpoints that are defined as response to certain criteria, patients with missing data at Visit 
Week 22 will be considered non-responders. 
7.6.2.2 
Continuous Secondary Efficacy Endpoints  
For calculations involving AUC based on plasma 2-hours oGTT test, the following rules for 
handling missing data will be applied: 
 If the pre-glucose drink time point or 30-minute post-glucose drink time point are 
missing, no AUC calculation will be performed. The AUC for that visit will be counted 
as missing.  
 
 
 
 
 
 
 
 
 
 
 


 
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 If more than one post-glucose drink time points are missing, no AUC calculation will 
be performed. 
 If only one post-glucose drink time point is missing, and it is not the 30-minute post-
glucose drink time point, then the AUC will be calculated using available data. For 
example, if the 90-minute time point is missing, a trapezoid will be constructed to 
connect the 60 minute and 120-minute time points.  
 If only the 120-minute post-glucose drink time point is missing, the AUC will be 
calculated using the available data and AUC, and that AUC pre-glucose drink to 
90minute post-glucose drink value will be used in the summary tables. 
 Otherwise, observed values only will be used.  
All other efficacy by-visit analyses will include summaries for the observed cases only, where no 
imputations will be used, except for the primary endpoint, 24-hour average SBP for which 
missing data handling rules are described above.  
7.6.3 Handling Missing Data for Exploratory Efficacy Endpoints 
For calculations involving exploratory efficacy endpoints, the same rules for handling missing 
data as described above for Secondary Efficacy Endpoints will be applied (i.e. observed cases 
only will be used in by-visit analyses and no imputations will be applied). 
7.6.4 Handling Incomplete or Missing Dates for Adverse Events and Concomitant 
Medications 
For safety analyses, incomplete date of last dose of study drug and incomplete start date of 
concomitant medications that are missing the day of the month, the 15th of the month will be 
used to impute the missing date. When imputing partial last dose dates, the last visit date will be 
taken into consideration. The imputed dates will be used to determine the treatment-emergent 
period. 
For adverse events with a partial date, available date parts (year, month, and day) of the partial 
date will be compared with the corresponding date components of the start date and end date of 
the treatment-emergent period to determine if the event is treatment emergent. The following 
rules will be applied to impute partial dates for adverse events. 
If start date of an adverse event is partially missing, following imputation rules will be applied: 
 If both Month and Day are missing and Year = Year of treatment start date, then set to 
treatment start date. 
 
January 1. 
 If Day is missing and Month and Year = Month and Year of treatment start date, then set 
to treatment start date. 
 
to first of the month. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 


 
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 If start date is completely missing, set to treatment start date as long as adverse event end 
date is not prior to treatment start date. 
If end date of an adverse event is partially missing, following imputation rules will be applied: 
 If both Month and Day are missing, then set to December 31. 
 If only Day is missing, then set to last day of the month. 
 If end date is completely missing, do not impute. 
When the start date or end date of a medication is partially missing, the date will be imputed to 
determine whether the medication is prior or concomitant (or both). The following rules will be 
applied to impute partial dates for medications: 
If start date of a medication is partially missing, following imputation rules will be applied: 
 If both Month and Day are missing, then set to January 1. 
 If only Day is missing, then set to the first day of the month. 
If end date of a medication is partially missing, following imputation rules will be applied: 
 If both Month and Day are missing, then set to December 31. 
 If only Day is missing, then set to last day of the month. 
If start date or end date of a medication is completely missing, no imputation is applied. 
7.6.5 Handling Incomplete or Missing Dates for Medical History  
If the diagnosis date of Cushing disease is incomplete, month will be imputed as the first month 
of the year, and day will be imputed as the first day of the month. Missing year will not be 
imputed. Same rules for handling missing diagnosis date of Cushing disease will be applied to 
other medical disease that patients have been diagnosed.  
 
 
 
 
 
 
 
 


 
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8 
TIMING OF ANALYSES  
8.1 
Interim Analysis  
No interim analyses are planned for purposes of early stopping of the study or modifying the 
study design. However, data may be reviewed periodically by the Sponsor, as needed. 
8.2 
Final Analyses and Reporting 
All planned analyses described in the SAP will be performed after the last patient has completed 
the study, all outstanding queries resolved, and the database has been locked and unblinded. The 
SAP must be signed off prior to study unblinding.  
 


 
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9 
STATISTICAL METHODS 
9.1 
General Statistical Consideration 
Statistical analyses will be reported with tables, figures, and listings, presented in rich text 
format, and using recommended ICH numbering. Output specifications for all tables, figures, and 
listings will be in conformance with guidelines specified by the ICH of the Electronic Common 
Technical Document Specification (ICH M2 eCTD 2003).  
9.2 
Patient Disposition 
Patient disposition will be summarized for the ITT population. Participant disposition will 
present the number of patients randomized, number treated with study drug, and among those 
number of patients who completed the study, discontinued from the study, number who 
discontinued from study treatment, reasons for study discontinuation and reasons for study drug 
discontinuation. Primary reason for discontinuation of treatment, including any of the following, 
will be summarized by treatment group: 
 Adverse Event 
 Lost to Follow-up 
 Pregnancy 
 Study Terminated by Sponsor 
 Withdrawal by Patient 
 Physician Decision 
 Death 
 Non-Compliance with study drug 
 Protocol Deviation 
 Other 
A listing of all patients who discontinued the study and their reason for discontinuation will be 
provided.  
If applicable, eligibility violations and occurrences of emergency and accidental treatment 
unblinding will be reported. 
Attendance at scheduled visits will be shown as the number of patients who completed each 
scheduled visit.  
9.3 
Protocol Deviations 
All important protocol deviations will be determined and appropriately categorized prior to 
database lock according to protocol deviation specification document. Protocol deviations will be 
listed study site, patient, and date of deviation, and will indicate if they are considered important. 
The number and percentage of patients with any important protocol deviations as well as the 
 
 
 
 
 
 
 
 
 
 


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number and percentage of patients with deviations by comorbidity type (DM/IGT or 
Hypertension), and overall, will be presented for the Safety Population. 
9.4 
Demographic Characteristics and Baseline Characteristics 
The following demographic characteristics will be presented in listings and summarized for the 
ITT and Safety Analysis Population, (by treatment arm and overall):  
Age  
Sex 
Fertility status 
Ethnicity 
Race  
Geographic region: North America and Rest of the World (Austria, Bulgaria, Germany, 
Israel, Italy, Poland, Romania, and Spain) 
Age will be summarized using descriptive statistics. Sex, ethnicity, race, fertility status, and 
geographic region will be summarized by the number and percentage of patients in each 
parameter category. 
Baseline characteristics including height, weight, body mass index (BMI), waist circumference, 
plasma ACTH, 24-hr UFC, late-night salivary cortisol, DHEA-S levels, oGTT plasma glucose, 
AUCglucose, HbA1c, osteocalcin, and 24-hour average systolic and diastolic BP from ambulatory 
BP monitoring (ABPM) will be summarized separately. BMI is calculated as: weight (kg) / 
[height (cm) / 100]2.  
Demographics and Baseline characteristics will be summarized by comorbidity subgroups in the 
ITT population. 
9.5 
Medical History 
Medical history will be presented in listings and summarized for all patients in the ITT 
population and presented by comorbidity type, and overall. Frequency counts and percentages 
will be presented to summarize patients reporting medical history by system organ class and 
preferred term (coded using MedDRA version 26.0 or higher). History of hypercortisolism will 
be presented separately including type of imaging, imaging results, benign vs. malignant, adrenal 
lesion history, and DST history.  
9.6 
Prior and Concomitant Medications  
Medications will be coded using the World Health Organization (WHODrug Global B3 March, 
2023) dictionary. Medications entered on the eCRF will be mapped to ATC drug class (level 4) 
and drug name. Prior and concomitant medications will be summarized for the Safety 
Population. 
 
 
 
 
 
 


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Prior and concomitant medications will be summarized separately. Whether or not the 
medication is prior and/or concomitant will be determined programmatically based on 
medication start and end dates. A prior medication is defined as any medication administered 
that started prior to the date of the first dose of study drug. A concomitant medication is defined 
as any medication administered on or after the date of the first dose of study drug. A medication 
may be defined as both prior and concomitant. Imputation of partial dates apply as described in 
Section 7.6.4.  
For the prior medications table summary, the number and percentage of patients receiving any 
medication will be summarized by comorbidity type, and all patients combined, as will the 
number and percentage receiving any medication by ATC drug class and generic drug name. For 
all concomitant medications table summaries, the number and percentage of patients receiving 
any medication will be summarized by treatment, comorbidity type, and all patients combined, as 
will the number and percentage receiving any medication by ATC drug class and generic drug 
name. Patients reporting use of more than one medication at each level of summarization (any 
medication received, ATC class, and generic drug name) will be counted only once. ATC class 
terms will be displayed alphabetically and by descending order of incidence for generic drug 
names within each ATC class. Whether or not the medication is prior and/or concomitant will be 
presented on the listing of prior and concomitant medications. 
Concomitant medications will also be summarized by the following: 
Medications used in greater than or equal to 20% of the patients in the Safety Population; 
and 
Medications used to treat diabetes or hypertension for patients in the Safety Population. 
The medication indication, e.g. antidiabetic, antihypertensive, and antidepressant, will be 
identified by the clinical team. Tables summarizing reduction in antidiabetic and 
antihypertensive concomitant medications will also be presented by comorbidity type (DM/IGT 
or Hypertension), and will include the number of patients taking the medication at Baseline,  
number of patients with a dose reduction,  the number of patients with any reduction in daily 
dose, the number of patients with any increase in daily dose, the number of patients with < 25% 
reduction in daily dose, 
 25% 
 50% reduction in daily dose, 
the number of patients with  50% reduction in daily dose, and the number of patients with 
complete discontinuation in daily dose. Antidiabetic and antihypertensive medications will be 
those that are entered as antidiabetic or antihypertensive on the eCRF, potassium sparing 
diuretics for antihypertensive medications, and any medications that were considered an 
antidiabetic or antihypertensive medication based on medical judgment. 
Prior and concomitant medications will be presented in a by-patient data listing by comorbidity 
type, ATC class and generic drug names, medication start date, and study drug dose level at time 
of medication start date. Concomitant medication will additionally be listed by comorbidity type, 
week on study, total daily dose and dose change from baseline.   
 
 
 
 
 
 
  
 
 




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patients that use rescue medication. Restricted maximum likelihood (REML) estimation will be 
used. 
The MMRM model will include Baseline 24-hour average SBP as a covariate; treatment, visit, 
and treatment by visit interaction, and stratification factor as fixed effects; patients within 
treatment groups as random effects. In the hypertension subgroup, the stratification factor at 
randomization identifies patients with or without DM/IGT. An unstructured covariance structure 
will be used to model within-patient error, and the Kenward Roger approximation will be used to 
model denominator degrees of freedom. 
The following covariance structures will be used until the convergence criteria is met, in this 
order: unstructured covariance, heterogeneous compound symmetry, compound symmetry.  
The primary analysis will determine whether there is a difference between treatment groups in 
terms of change from Baseline to Week 22 in 24-hour average SBP. This will be accomplished 
by using appropriate linear contrasts of the parameters in the MMRM model described above. 
SAS statement that implements PROC MIXED will be used and the sample SAS code is 
presented in Appendix 2 and can be modified as needed. Estimated least squares means and 95% 
CIs for change from Baseline in 24-hour average SBP will be plotted by treatment and over time 
(from Baseline to Week 22). 
The above-described analysis will be performed for mITT and PP populations as sensitivity 
analyses.  
A sensitivity analysis to address mis-stratification at randomization will be performed using an 
MMRM model that includes Baseline 24-hour average SBP as a covariate; treatment, visit, and 
treatment by visit interaction, and stratification factor derived per electronic data capture (EDC) 
as fixed effects; patients within treatment groups as random effects. An unstructured covariance 
structure will be used to model within-patient error, and the Kenward Roger approximation will 
be used to model denominator degrees of freedom. 
9.8.1.2 
Multiplicity Adjustment for Analysis of Primary and Secondary Efficacy 
Endpoints 
For the testing of the primary efficacy endpoints, adjustment for multiplicity will be 
implemented to maintain a two-sided 0.05 significance level for the Family-Wise type I error 
rate. 
In order to provide experiment-wise strong control of the Type I error, certain secondary 
analyses will be tested using a gated testing approach at a 2-sided alpha level of 0.05. If the null 
hypothesis is rejected for the primary endpoint, certain secondary endpoints will be sequentially 
tested following the gatekeeping hierarchy (Figure 2). No adjustments for multiplicity will be 
made for other secondary or exploratory endpoints.  




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missing Week 22 data, the imputation model with only Baseline value and stratification factor 
will be used. 
Missing data will be imputed by selecting random observations from a normal distribution 
centered at the value predicted by the regression model and with variance analogous to 
predicting a new observation. The imputation procedure will be iterated 100 times. 
One hundred datasets will be generated, and an MMRM model with the factors and covariates 
will be run on each dataset. The point estimates and standard errors are computed, and the results 
are combined to yield a multiple imputation point estimate and standard error. 
The analysis for the treatment difference will be based on an MMRM model with change from 
Baseline to Visit Week 22 as the dependent variable and the following covariate/factors:  
Treatment (with 2 levels, relacorilant and placebo). 
Visit (Scheduled), a categorical factor. 
Treatment-by-visit interaction. 
Baseline 24-hour average SBP, a continuous covariate. 
Stratification factor (with 2 levels, i.e., with or without DM/IGT). 
The MMRM model will include patients within treatment arms as random effects. An 
unstructured covariance matrix will be used to model within-patient error. In case of 
convergence issues, the following covariance structures will be used until the convergence 
criteria is met, in this order: unstructured covariance, heterogeneous compound symmetry, 
compound symmetry. The Kenward and Roger method for calculating the denominator degrees 
of freedom for tests of fixed effects will be used. 
This will constitute the data for the primary analyses. 
9.8.2 Sensitivity Analysis for Primary Efficacy Endpoint 
9.8.2.1 Analyses to Address Confounding by Rescue Medication and Early Discontinuation 
To demonstrate the robustness of the primary analysis and to address the confounding by early 
discontinuation of treatment, the following supplementary analyses (Table 3) will be performed 
on the ITT population:  
Table 3 
Sensitivity Analyses for Primary Endpoint 
 Sensitivity Analysis for Treatment Discontinuation and Rescue Medication 
1 
Placebo Wash-out Multiple Imputation Analysis (Section 9.8.2.1.1) 
Sensitivity Analysis for Treatment Discontinuation 
2 
Missing at Random (MAR) Analysis (Section 9.8.2.1.2) 
3 
Tipping Point Analysis (Section 9.8.2.1.3) 
 
 
 
 
 




 
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9.8.2.1.3 Tipping Point Analysis  
The assumption behind the tipping point analysis is that patients who drop out from the 
relacorilant arm would do worse after the drop-out and patients in the placebo arm would do 
better after drop-out than otherwise predicted by their observed outcomes and covariates. This 
pattern of missingness could be represented by a series of progressively more conservative shifts 
in the mean of missing values in each treatment arm (relacorilant and placebo) for 24-hour 
average SBP. The tipping point would correspond to the magnitude of the shift (denoted by 1R 
1P for relacorilant and placebo, respectively, in the description below) that reverses the 
study statistical conclusions from significant to nonsignificant. Combined with the clinical 
interpretation of the plausibility of the shifts, this approach would enable the assessment of the 
robustness of study conclusion to the differences between early discontinuations and completers. 
We will implement this approach as follows: 
 Impute missing values for Visit Week 22 using monotone regression-based multiple 
imputations with treatment and stratification factor included. This corresponds to the 
1R=0 
1P=0. A total of 100 
imputed datasets will be created. For each imputed dataset, the same MMRM model 
specified in Section 9.8.1.1 will be used to estimate treatment effect on change in 
SBP from Baseline to Week 22. The combination of individual estimates for 
treatment effect and the inference based on the combined estimate will be handled by 
SAS procedure MIANALYZE. 
 At the next step, for patients with imputed values in the relacorilant and placebo arms, 
a pre-
1R=2 mmHg 
1P=0 mmHg will be added to 24-hour 
average SBP. This will complete the generation of missing values at Visit Week 22 
for this shift value. 
 Steps 1-2 will be repeated for shift values in the range -6 to 6 mm Hg with increment 
of 2 mm Hg 
1R 
1P separately for one to consider as tipping points.  
 The magnitude of the shifts for 24-hour average SBP at the tipping point will be 
evaluated for clinical relevance in the context of their plausibility for the difference 
between completers and patients who discontinued. 
9.8.2.1.4 Multiple Imputation Analysis 
Multiple imputation will be implemented to allow additional source of variability in the imputed 
values. A total of 100 imputed datasets will be created. Impute missing values due to early 
discontinuation from treatment for all scheduled visits up to visit Week 22 using monotone 
regression-based multiple imputation by treatment arm. Missing data due to rescue medication 
will be imputed using a placebo wash-out multiple imputation for the Week 22 visit after 
initiation of rescue medication (Section 9.8.1.3). SAS code example is listed in the Appendix 2. 
For each imputed dataset, the same MMRM model specified in Section 9.8.1.1 will be used to 
estimate treatment effect on change in SBP from Baseline to Week 22. The final estimate of 
treatment difference will be the average of the estimates based on the individual imputed 
datasets. The final estimate of the variance will be the average of the estimated variances based 
  
  
 
 
 
  
  
  
 
  
 
  
  


 
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on the individual imputed datasets (within-imputation variance) plus the sample variance of the 
estimated treatment differences based on the individual imputed datasets (between-imputation 
variance). The combination of individual estimates for treatment effect and the inference based 
on the combined estimate will be handled by SAS procedure MIANALYZE.  
9.8.2.1.5 Sensitivity Analyses to Address Mis-stratification at Randomization 
The MMRM model described in Section 9.8.1.1 will be repeated with sfactor being the correct 
stratification factor per EDC (with 2 levels, with or without DM/IGT), instead of the stratification 
factor at randomization in IRT.  
9.8.2.1.6 Subgroup Analysis for Primary Efficacy Endpoints. 
The MMRM model as described above in Section 9.8.1.1 will be performed on observed values 
for subgroups to investigate the consistency of the results. All subgroup mentioned in Section 6.6 
and Section 6.7 will be performed for the primary endpoint if subgroup consists of 10 or more 
patients. A forest plot will be created including all the subgroup analysis results.   
9.8.3 Secondary Efficacy Endpoints 
9.8.3.1 
Continuous Endpoints 
Continuous secondary endpoints will be analyzed for the ITT population and mITT using a 
restricted maximum-
ed linear MMRM analysis. The model will use visit 
as a fixed effect, and patient as a random effect. A compound symmetry covariance structure will 
be used to model the within-patient errors unless otherwise specified. The Kenward-Roger 
approximation will be used to estimate denominator degrees of freedom. Least-squares means 
will be used to estimate the change from Baseline treatment effect at each visit, including Visit 
Week 22. The analysis using MMRM will be the main result. For endpoints collected only at the 
Week 22 or ET visit, ANCOVA model will be used for both Week 22 and last visit separately. In 
addition, the Wilcoxon signed-rank test (using observed data) will be used to evaluate if there is 
a significant change compared with Baseline at each visit in cases where departures from 
MMRM assumptions are noted.  
Sample SAS code for the PROC MIXED procedure is presented in Appendix 2 and can be 
modified as needed. 
9.8.3.1.1 Patients with DM/IGT: AUCglucose Based on oGTT Plasma Glucose 
AUCglucose will be calculated based on results of the plasma 2-hour oGTT tests taken at Baseline, 
Week 2, Week 6, Week 10, Week 14, Week 18, and Week 22 for those patients with DM/IGT at 
study entry. At each visit, plasma 2-hour oGTT test includes glucose measurements at every half 
hour time-interval (pre-glucose drink and 0.5, 1, 1.5, and 2 hours after the glucose drink). 
The AUC for such half hour time-interval will be calculated using the linear trapezoidal rule, as 
follows (where C1 and C2 are concentrations at times t1 and t2, respectively): 
 
 
 


 
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AUCglucose will be calculated as the sum of all-time intervals AUCs. Section 7.6.2.2 describes 
handling missing data for calculation of AUCglucose. 
For the DM/IGT subgroup of the ITT population, the estimand of interest is the between-
treatment difference in AUCglucose from Baseline to Week 22 (estimated using a mixed model for 
repeated measures [MMRM] model).  
The analysis for the primary endpoint of change in AUCglucose from Baseline to Visit Week 22 
will be performed using a MMRM model on the DM/IGT subgroup of the ITT population. 
Restricted maximum likelihood (REML) estimation will be used.  
The MMRM model will include Baseline AUCglucose as a covariate; treatment, visit, and 
treatment by visit interaction, and stratification factor as fixed effects; patients within treatment 
groups as random effects. In the DM/IGT subgroup, the stratification factor at randomization 
identifies patients with or without hypertension. An unstructured covariance structure will be 
used to model within-patient error, and the Kenward Roger approximation will be used to model 
denominator degrees of freedom. 
The following covariance structures will be used until the convergence criteria is met, in this 
order: unstructured covariance, heterogeneous compound symmetry, compound symmetry. The 
Kenward and Roger method for calculating the denominator degrees of freedom for tests of fixed 
effects will be used when applicable to the covariance structure. 
For this endpoint (change in AUCglucose), a negative difference (relacorilant minus placebo) 
represents greater improvement for relacorilant-treated compared with placebo-treated patients.  
In addition, AUCglucose will be summarized using descriptive statistics including two-sided 95% 
CI of the mean. 
The above-described analysis will be performed for mITT and PP populations.  
A sensitivity analysis to address mis-stratification at randomization will be performed using an 
MMRM model that includes Baseline AUCglucose as a covariate; treatment, visit, and treatment by 
visit interaction, and stratification factor derived per EDC as fixed effects; patients within 
treatment groups as random effects. An unstructured covariance structure will be used to model 
within-patient error, and the Kenward Roger approximation will be used to model denominator 
degrees of freedom. 
9.8.3.1.2 Subgroup Analysis for AUCglucose 
The analysis for change from baseline in AUCglucose as described above in Section 9.8.1.1 will be 
performed for subgroups to investigate the consistency of the results. All subgroup mentioned in 
Section 6.6 and Section 6.7 will be performed for AUCglucose endpoint if subgroup consists of 10 
or more patients. A forest plot will be created including all the subgroup analysis results. 


 
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9.8.3.1.3 Change in HbA1c from Baseline to Week 22 in Patients with DM/IGT 
For patients in the ITT population with DM/IGT, the mean change in HbA1c from Baseline to 
Week 22 will be analyzed using an MMRM analysis. Additionally, in patients with DM, patients 
with IGT
 6.5% at Baseline, and 
 5.7% at 
Baseline in the ITT population will be analyzed separately using an MMRM analysis.  
The MMRM model will include Baseline HbA1c value as a covariate; treatment, visit, treatment 
by visit interaction, and stratification factor (at randomization) as fixed effects; and patients 
within treatment groups as random effects. An unstructured covariance structure will be used to 
model within-patient error with parameters estimated by the REML estimation, and the 
Kenward-Roger approximation will be used to model denominator degrees of freedom. 
Estimated least squares means and 95% CIs for change in HbA1c will be plotted by treatment 
and over time (from Baseline to Week 22). 
The change from Baseline in HbA1c will also be analyzed by a Wilcoxon signed-rank test to 
evaluate if there is a significant change compared with Baseline at each visit up to Visit 
Week 22. 
9.8.3.1.4 Change in Ambulatory Blood Pressure Monitoring from Baseline to Week 22 in 
Patients with Systolic Hypertension 
Twenty-four-hour average SBP and DBP will be obtained by the patient at home using an 
ABPM. The mean change from Baseline to Week 22 in the 24-hour average SBP and DBP and 
HR will be analyzed using an MMRM analysis for systolic hypertension patients in the ITT 
population. Similarly, the mean change in the daytime and nighttime average SBP, DBP, and HR 
from Baseline to Week 22 will be analyzed using an MMRM analysis. The MMRM model will 
include Baseline value (for the respective endpoint) as a covariate; treatment, visit, treatment by 
visit interaction, and stratification factor (at randomization) as fixed effects; and patients within 
treatment groups as random effects. An unstructured covariance structure will be used to model 
within-patient error with parameters estimated by the REML estimation, and the Kenward-Roger 
approximation will be used to model denominator degrees of freedom. 
Estimated least squares means and 95% CIs for change in 24-hour average SBP and DBP will be 
presented and plotted by treatment and over time (from Baseline to Week 22). 
Two sets of Daytime and Nighttime windows will be applied: 
 Definition1: Daytime (defined as 06:00 21: 59) and Nighttime (defined as 22:00 
05:59). 
 Definition 2: Daytime (defined as 9:00 am to 9:00 pm) and Nighttime (defined as 1:00 
am to 6:00 am). 
For the subgroup of patients with systolic hypertension at Baseline in the ITT population, 
average ABPM measures will be summarized using descriptive statistics by visit, to include the 
change from Baseline. The change from Baseline will also be analyzed by a Wilcoxon signed-
 
 
 
 
 
  
 
 
  
 
 




 
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oGTT plasma glucose value, and stratification factor used at randomization (comorbidity status 
with 2 levels: DM/IGT only and both).  
Separately, for patients with DM/IGT at Baseline and patients with DM at Baseline in the ITT 
population, the number and percentage of patients who achieved 2-hour oGTT glucose 
< 140 mg/dL at Week 22 will be summarized including the 95% exact binomial two-sided CI 
(Clopper-Pearson). Similarly, risk differences between relacorilant and placebo will be evaluated 
using a logistic regression model including effects for treatment, Baseline 2-hour oGTT plasma 
glucose value and stratification factor used at randomization (comorbidity status with 2 levels: 
DM/IGT only and both).  
For analysis purposes, patients who discontinue treatment or take rescue medication will not be 
considered a responder. 
9.8.3.2.2 Proportion of Patients with Decrease in AUCglucose from Baseline to Week 22 
In patients with DM/IGT in the ITT population, the number and percentage of patients who 
achieved decrease of AUCglucose of  25%,  10%,  5% and any decrease will be summarized by 
visit including the 95% exact binomial two-sided CI (Clopper-Pearson). Risk differences 
between relacorilant and placebo will be evaluated using a logistic regression model including 
effects for treatment, Baseline AUCglucose value, and stratification factor used at randomization 
(comorbidity status with 2 levels: DM/IGT only and both).  
For analysis purposes, patients who discontinue treatment or take rescue medication will not be 
considered a responder. 
9.8.3.2.3 Change in HbA1c from Baseline to Week 22  
In patients with HbA1c  6.5% at Baseline, the proportion of patients who achieved HbA1c 
< 6.5% by visit will be compared between treatment arms. The risk differences will be assessed 
using a logistic regression model including effects for treatment, Baseline HbA1c value and 
stratification factor used at randomization (comorbidity status with 3 levels: DM/IGT only, 
hypertension only, and both) in the ITT population. The number and percentage of patients with 
HbA1c  6.5% at Baseline who achieved HbA1c < 6.5% by visit will be presented along with a 
95% exact binomial two-sided CI (Clopper-Pearson).  
For analysis purposes, patients who discontinue treatment or take rescue medication will not be 
considered a responder. 
9.8.3.2.4 Antidiabetic Medication and Antihypertensive medication  
In patients with systolic hypertension at Baseline in the ITT population, the number and 
proportion of patients whose dose of antihypertensive medication decreased, discontinued, 
stayed the same, or switched/increased from Baseline to Week 22 and last modification due to 
worsening hypertension will be summarized, among those patients taking such medications at 
Baseline.  
 
 
 
 
 


 
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Separately, the difference between treatment arms in the proportion of patients with any decrease 
in antihypertensive medication due to improved blood pressure will be assessed by a logistic 
regression model including effects for treatment, and stratification factor used at randomization 
(comorbidity status with 2 levels: hypertension only and both) and Baseline average SBP for 
patients in the ITT population with systolic hypertension at Baseline. The proportion of patients 
in the ITT population with systolic hypertension at Baseline, for whom there is any decrease in 
antihypertensive medication due to improved blood pressure, along with the 95% exact binomial 
two-sided CI (Clopper-Pearson) will be presented.  
Similarly, in patients with DM/IGT at Baseline in the ITT population, the number and proportion 
of patients whose dose of antidiabetic medication decreased, discontinued, stayed the same, or 
increased from Baseline to Week 22 and last modification due to worsening hyperglycemia will 
be summarized, among those patients taking such medications at Baseline.  
Separately, the risk differences by treatment arm for patients with any decrease in dose of 
antidiabetic medication due to improved glucose control will be assessed by logistic model 
including effects for treatment, and stratification factor used at randomization (comorbidity 
status with 2 levels: DM/IGT only and both) and Baseline 2-hour oGTT. The proportion of 
patients in the ITT population with DM/IGT at Baseline, for whom there is any decrease in dose 
of antidiabetic medication due to improved glucose control, along with the 95% exact binomial 
two-sided CI (Clopper-Pearson) will be presented.  
Differences in proportions between relacorilant and placebo will be evaluated using the stratified 
Cochran-Mantel-Haenszel (CMH) test and the estimated risk ratio and corresponding 95% CIs 
will be presented along with the 95% exact binomial two-sided CI (Clopper-Pearson). The 
stratification factor at randomization identifies hypertension patients with or without DM/IGT or 
DM/IGT patients with or without hypertension.   
For analysis purposes, patients who discontinue treatment or take rescue medication will not be 
considered a responder. Additionally, if a new medication is started post-Baseline, this will be 
considered an increase in antihypertensive or anti-diabetic medication, respectively. 
9.8.3.2.5 Change in Ambulatory Blood Pressure Monitoring from Baseline to Week 22  
The proportion of patients in the ITT population with a reduction in the mean change from 
Baseline to Week 22, in 24-hour average SBP by 5 mm Hg (based on 24-hour ABPM) will be 
summarized separately. The risk difference between the treatment arms will be evaluated using a 
logistic regression model including effects for treatment, Baseline average SBP, and 
stratification factor used at randomization (comorbidity status with 2 levels: hypertension only 
and both hypertension and DM/IGT). The proportion of patients along with the 95% exact 
binomial two-sided CI (Clopper-Pearson) will be presented. 
For analysis purposes, patients who discontinue treatment or take rescue medication will not be 
considered a responder. 


 
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9.8.3.2.6 Systolic Blood Pressure Normalization Analysis in Patients with Hypertension  
In patients with uncontrolled hypertension at Baseline in the ITT population, the proportion of 
patients whose systolic blood pressure is normalized will be calculated. Patients whose systolic 
blood pressure normalized are defined as those patients whose 24-hour average SBP is less than 
130 mm Hg at Week 22. The risk difference between the treatment arms will be evaluated using 
a logistic regression model including effects for treatment, Baseline 24-hour average SBP and 
stratification factor used at randomization (comorbidity status with 2 levels: hypertension only 
and both hypertension and DM/IGT). The number and percentage of patients in the ITT 
population with systolic hypertension at Baseline whose systolic blood pressure is normalized 
will be presented along with a 95% exact binomial two-sided CI (Clopper-Pearson).  
For analysis purposes, patients who discontinue treatment or take rescue medication will not be 
considered a responder. 
9.8.4 Exploratory Efficacy Endpoints  
9.8.4.1.1 Body-Fat Composition by DXA 
In all patients in the ITT population, changes in trabecular bone score, bone mineral density, and 
the percent and absolute amounts of total body and regional fat and lean tissue (whole body, 
trunk, and leg & arm) as measured by DXA scan will be summarized using descriptive statistics 
including two-sided 95% CI of the mean for Baseline, Week 22, last visit, as well as the change 
from Baseline. ANCOVA model will be used to evaluate the change in each parameter from 
Baseline to Week 22 and last visit separately. The ANCOVA model will include Baseline for the 
respective endpoint as a covariate; treatment, and stratification factor as fixed effects.  
9.8.4.1.2 Change in ACTH Levels from Baseline to Week 22 
For patients in the ITT population, the mean change in ACTH levels from Baseline to Week 22 
will be analyzed using an MMRM analysis using PROC MIXED in SAS. Restricted maximum 
likelihood (REML) estimation will be used. The MMRM model will include Baseline ACTH 
value as a covariate; treatment, visit, treatment by visit interaction, and stratification factor (at 
randomization) as fixed effects; and patients within treatment groups as random effects. An 
unstructured covariance structure will be used to model within-patient error, and the Kenward-
Roger approximation will be used to model denominator degrees of freedom. 
Estimated least squares means and 95% CIs for change in ACTH will be plotted by treatment 
and over time (from Baseline to Week 22). 
The change from Baseline in ACTH levels will also be analyzed by a Wilcoxon signed-rank test 
to evaluate if there is a significant change compared with Baseline at each visit up to Visit 
Week 22/ET. 


 
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9.8.4.1.3 Change in Cholesterol Levels and Triglycerides from Baseline to Week 22  
The change in total cholesterol, LDL cholesterol, VLDL cholesterol, and triglycerides from 
Baseline to Week 22 and Last visit will be analyzed separately using an ANCOVA Model for 
patients in the ITT population separately. The ANCOVA model will include Baseline value (for 
the respective endpoint) as a covariate; treatment, and stratification factor (at randomization) as 
fixed effects. 
Total cholesterol, LDL cholesterol, VLDL cholesterol, and triglycerides will be summarized 
using descriptive statistics for Baseline, Week 22 and Last visit, as well as the change from 
Baseline for patients in the ITT population. The change from Baseline in each parameter will 
also be analyzed by a Wilcoxon signed-rank test to evaluate if there is a significant change 
compared with Baseline at each visit up to Visit Week 22 and Last Visit separately. 
9.8.4.1.4 Change in Coagulation Markers from Baseline to Week 22  
For patients in the ITT population, the change in Factor VIII, von Willebrand factor, protein S, 
protein C, TAT, platelets, and PTT from Baseline to Week 22 will be analyzed separately using 
an MMRM analysis. The MMRM model will include Baseline value (for the respective 
endpoint) as a covariate; treatment, visit, treatment by visit interaction, and stratification factor 
(at randomization) as fixed effects; and patients within treatment groups as random effects. An 
unstructured covariance structure will be used to model within-patient error with parameters 
estimated by the REML estimation, and the Kenward-Roger approximation will be used to 
model denominator degrees of freedom. 
Estimated least squares means and 95% CIs for change in coagulation markers will be plotted by 
treatment and over time (from Baseline to Week 22). 
Factor VIII, von Willebrand factor, protein S, protein C, TAT, platelets, and PTT will be 
summarized using descriptive statistics by visit, to include the change from Baseline for patients 
in the ITT population. The change from Baseline in each parameter will also be analyzed by a 
Wilcoxon signed-rank test to evaluate if there is a significant change compared with Baseline at 
each visit up to Visit Week 22/ET. 
9.8.4.1.5 Change in DHEA-S from Baseline to Week 22  
In all patients, DHEA-S will be summarized using descriptive statistics by visit, to include the 
change from Baseline. The change in each parameter from Baseline to Week 22/ET will be 
analyzed separately using an MMRM analysis. The MMRM model will include Baseline value 
(for the respective endpoint) as a covariate; treatment, visit, treatment by visit interaction, and 
stratification factor (at randomization) as fixed effects; and patients within treatment groups as 
random effects. An unstructured covariance structure will be used to model within-patient error 
with parameters estimated by the REML estimation, and the Kenward-Roger approximation will 
be used to model denominator degrees of freedom. 




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and 
will be replaced with the mean of the observed data. 
AUCinsulin will be derived similar to AUCglucose (Section 9.8.1.1). 
9.8.4.1.8 Cushing QoL and the Beck Depression Inventory®-II (BDI-II) Score 
The Cushing QoL questionnaire is scored as a total score (ranging from 12 to 60), and is standardized 
to a scale from 0 (worst QoL) to 100 (best QoL) with the following formula:  
The standardized total score will be used for analysis purposes.  
be summed for a physical problems subscale and the scores for the remaining questions 
(questions 2, 5, 6, 7, 8, 9, 10, 11, and 12) will be summed for a psychosocial issues subscale 
(Table 4). The subscales of the Cushing QoL are standardized with the following formula: 
where X is the total score of the subscale of interest, L is the lowest possible score of the 
subscale, and H is the highest possible score for the subscale. This equation transforms scores to 
a 0-to-100 scale, with 100 indicating the best possible QoL. 
The mean change in Cushing QoL score, subscale in psychosocial issue, subscale in physical 
problems, and BDI-II score from Baseline to Week 22 will be analyzed separately using an 
MMRM analysis for patients in the ITT population. The MMRM model will include Baseline 
score for the respective endpoint as a covariate; treatment, visit, treatment by visit interaction, 
and stratification factor (at randomization) as fixed effects; and patients within treatment groups 
as random effects. An unstructured covariance structure will be used to model within-patient 
error with parameters estimated by the REML estimation, and the Kenward-Roger 
approximation will be used to model denominator degrees of freedom. 
  
    
    
    
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
  
 


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Table 4 
Items in Subscales of the Cushing QoL 
Physical Problems Subscale 
2. I have trouble sleeping
3. My wounds take a long time to heal
4. I bruise easily
Psychosocial Issues Subscale 
2. I have pain that keeps me from leading a normal life
5. I am more irritable. I have sudden mood swings and angry outbursts
6. I have less self-confidence. I feel more insecure
7. I am worried about the changes in my physical appearance due to my illness
8. I feel less like going out or seeing relatives or friends
9. I had to give up my social or leisure activities due to my illness
10. My illness affects my everyday activities such as working or studying
11. It is for me to remember things
12. I am worried about my health in the future
In ITT patients, Cushing QoL scores and BDI-II scores will be summarized separately using 
descriptive statistics including two-sided 95% CI of the mean by visit, to include the change 
from Baseline. Where appropriate, Cushing QoL assessments and BDI-II scores will also be 
analyzed by a Wilcoxon signed-rank test to evaluate if there is a significant change compared 
with Baseline at each visit up to Visit Week 22/ET. 
9.8.4.1.9 Other Continuous Exploratory Endpoints 
For all patients in the ITT population, exploratory endpoints of the mean change from Baseline 
to Week 22 in sit-to-stand test score; trail making test scores, HPA-axis, morning and late-night 
salivary cortisol, and AUCglucose will be analyzed separately using an MMRM analysis for 
patients in the ITT population. The MMRM model will include Baseline score for the respective 
endpoint as a covariate; treatment, visit, treatment by visit interaction, and stratification factor (at 
randomization) as fixed effects; and patients within treatment groups as random effects. An 
unstructured covariance structure will be used to model within-patient error with parameters 
estimated by the REML estimation, and the Kenward-Roger approximation will be used to 
model denominator degrees of freedom. 
For all patients in the ITT population, exploratory endpoints of the mean change from Baseline 
to Week 22 and last Visit in serum osteocalcin, will be analyzed using an ANCOVA model for 
patients in the ITT population separately (visit). The ANCOVA model will include Baseline 
value (for the respective endpoint) as a covariate; treatment, and stratification factor (at 
randomization) as fixed effects. 


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9.8.5 Multicenter Studies 
This is a multicenter study with sites across different regions expected to participate. A subgroup 
analysis is planned by region (United States vs. Rest of the World). The effect of study center on 
the efficacy analysis results may be explored post-hoc, as needed. 
9.9 
Pharmacodynamic Analysis  
Pharmacodynamic (PD) endpoints and analysis methods will be described in a separate 
PD Analysis Plan that will be finalized before the database lock. 
9.10 
Pharmacokinetic Analysis 
Intensive pharmacokinetic (PK) blood sampling will be conducted in all patients at the Week 18 
visit. The plasma concentrations of relacorilant and/or its metabolites will be examined. PK 
endpoints and analysis methods will be described in a separate PK Analysis Plan that will be 
finalized before the database lock. 
9.11 
Safety Analyses 
Safety variables will be analyzed for the Safety Population, defined as all patients who received 
at least 1 dose of study drug. All safety data will appear in by-patient data listings. 
9.11.1 Adverse Events 
Treatment-emergent adverse events (TEAEs) are defined as those AEs with onset after the first 
dose of study drug or existing events that worsened after the first dose during the study and up to 
28 days after the last dose of study drug. TEAEs will be summarized by treatment arm, and 
overall, unless otherwise specified.  
Events reported with a partial onset date (e.g., month and year are reported but the day is 
missing) will be considered treatment-emergent if it cannot be confirmed that the event onset 
was prior to the first dose of study drug based on the available date entries.  
Verbatim terms on case report forms will be mapped to preferred terms and system organ classes 
using MedDRA, version 26.0 or higher.  
The Exposure Adjusted Incidence Rate (EAIR) for a TEAE is defined as: 
The total patient-years-
treatment exposure period and is defined as: 
For patients with an event within the exposure period: 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 




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o
EAIR by SOC and PT
o
Crude risk difference by SOC and PT
o
By cumulative dose prior to the onset of the AE.
Summary of TEAEs related to study drug by investigator assessment: 
o
By SOC and PT
o
By decreasing incidence of PT
o
By SOC, PT, and maximum severity.
Summary of treatment-emergent serious adverse events: 
o
By decreasing incidence of PT
o
By SOC, PT, and maximum severity
o
EAIR by SOC and PT
o
Crude risk difference by SOC and PT
o
Related to study drug per investigator by SOC and PT
o
Related to study drug per investigator by decreasing frequency of PT
o
With action taken of permanent discontinuation of study drug by SOC and PT
o
With action taken of permanent discontinuation of study drug by SOC, PT, and
maximum severity
o
With action taken of permanent discontinuation of study drug by PT
o
With action taken of permanent discontinuation of study by SOC and PT
o
With action taken of permanent discontinuation of study by SOC, PT, and
maximum severity
o
With action taken of permanent discontinuation of study by PT
o
Leading to study drug dose change by SOC and PT (based on exposure CRF).
Summary of TEAEs with action taken of permanent discontinuation of study drug: 
o
By SOC and PT
o
By decreasing incidence of PT
o
By SOC, PT, and maximum severity.
Summary of TEAEs with action taken of permanent discontinuation of study: 
o
By SOC and PT
o
By decreasing incidence of PT
o
By SOC, PT, and maximum severity.
TEAEs by PT occurring in at least 10% of the Safety Population by treatment arm, 
overall and by comorbidity type. 
TEAEs by SOC, PT, and maximum severity occurring in at least 10% of the Safety 
Population by treatment arm, overall and by comorbidity type. 
TEAEs by PT for PT with  5% of difference between treatment arms. 
 
 
 
 
 
 
 
 


 
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 TEAEs with fatal outcome by SOC and PT by treatment arm and overall. 
 Grade 3 or higher TEAEs by SOC and PT. 
 Grade 3 or higher TEAEs related to study drug by investigator assessment, by SOC 
and PT. 
 TEAEs leading to dose reductions by SOC and PT by treatment arm and overall. 
 TEAEs leading to dose interruptions by SOC and PT by treatment arm and overall. 
 Summary of safety topics of interest listed in Section 9.11.2.  
At each level of summarization (e.g., any AE, SOC, and PT), patients experiencing more than 
one AE will be counted only once. In the summary of TEAEs by severity grade, patients will be 
counted once at the highest severity reported at each level of summarization; in the summary of 
TEAEs by relationship, patients will be counted once at the closest relationship to study drug.  
A subgroup analysis will be performed for overall TEAE table and TEAE by SOC and PT, and 
other key safety tables as applicable.   
A butterfly plot of patient incidence of TEAEs occurring in at least 10% of the population by 
CTCAE grade and MedDRA PT will be presented. 
Adverse event data will be presented in data listings. TEAEs, Serious TEAEs, TEAEs with 
action taken of permanent discontinuation of the study drug, TEAEs with action taken of 
permanent discontinuation of the study, TEAEs leading to dose reductions, TEAEs leading to 
dose interruptions, Grade 3 or higher TEAEs and TEAEs with fatal outcome will be presented in 
separate data listings. 
Adverse events that are associated with infections due to SARS-CoV-2, including adverse 
events reported as COVID-19, will be listed separately to assess the impact of the 2020 
pandemic on the results. 
9.11.2 Special Safety Topics 
A set of special safety topics were defined to identify and characterize events possibly associated 
with the use of relacorilant based on the mechanism of action, observed during the relacorilant 
pre-clinical and clinical development program, or are of clinical importance to the treated 
population. Summaries of these special safety topics will be produced to enhance the 
understanding of safety data.  
Each special safety topic is a grouped clinical term comprising a broad set of AEs that are related 
patho-physiologically. The search methods used to identify the AEs grouped within each topic 
vary and may utilize an algorithmic approach or include one or more of the following: 
standardized MedDRA queries (SMQs), keyword searches of MedDRA PTs, and predefined lists 
of relevant PTs/SOCs. The search strategies used in analyses are specified in Appendix 3.  
The special safety topics for this analysis include: 
 Excessive glucocorticoid receptor (GR) antagonism 
 Adrenal insufficiency 
 
 
 
 
 
 
 
 






 
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last post-Baseline visit within treatment arm using the average of the duplicate readings per 
patient per visit for ITT population.  Additionally, summaries of descriptive statistics will be 
provided separately by sex. The average of the triplicate readings at Screening will be used as 
Baseline. 
Twelve-
two-by-two contingency table will be presented to summarize the shift from the Baseline 
category to the worst post-Baseline category within the treatment period. Summary results will 
include the count and percentage of patients within each shift category. 
9.11.7 Physical Examination 
Results of the physical examination will be presented in by-patient listings including treatment, 
study visit, and body system. A listing of abnormal physical exam findings by visit and body 
system will be provided. The description of the abnormal finding and indication if the finding 
was clinically significant or not will be displayed. 
9.11.8 Pregnancy Tests 
Results of the pregnancy tests will be presented in by-patient listings including treatment and 
study visit.  
 
 
 
 
 
 
 
 
  
 
 
  


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10 
CHANGES FROM PROTOCOL IN STUDY CONDUCT OR STATISTICAL 
ANALYSIS PLAN 
The SAP supersedes the statistical methods described in the clinical study protocol. Analysis 
methods that summarize and evaluate study efficacy endpoints for statistical significance will be 
implemented as described in the SAP. 


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11 
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Health, Accessed August 14, 2020 at: 
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National Research Council (US) Panel on Handling Missing Data in Clinical Trials. 2010. The 
Prevention and Treatment of Missing Data in Clinical Trials. Washington (DC): National 
Academies Press (US). ISBN-13: 978-0-309-15814-5ISBN-10: 0-309-15814-1. 
Ulm K. A simple method to calculate the confidence interval of a standardized mortality ratio 
(SMR). Am J Epidemiol 1990;131 (2):373-5. 
Sahai H, Kurshid A. Statistics in epidemiology: methods techniques and applications. CRC Press 
1996. 


 
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12 
APPENDIX 
 


 
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APPENDIX 1 
Propensity score approach will be used to impute missing data of SBP at Week 22 for patients 
who do not take rescue medication. The step-by-step methods are described below:  
 Analysis will be performed for patients in the Hypertension subgroup of the ITT 
population. 
 Within the same treatment arm, obtain the set of propensity scores from a logistic 
Week 22 
assessment is regressed on observed Baseline characteristics including average 24-hour 
systolic and diastolic BP from ambulatory BP monitoring, comorbidity type (response to 
DM/IGT criteria, yes vs no), plasma ACTH, 24-hr UFC, late-night salivary cortisol, 
osteocalcin, age,  body mass index (BMI), waist circumference, height, weight. 
 Time on study treatment will also be a covariate in the model and will be in ahead of age 
and after osteocalcin for position of variable list included in the SAS model statement. 
 One-to-one or pair matching will be implemented, and patients will be matched with 
quartiles of the propensity score within the same treatment arm. 
 Impute missing values of average SBP at Visit Week 22 for patients who discontinue 
early, but do not come back for Week 22 measurement with the SBP values at Visit 
Week 22 from matched pair of patients.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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APPENDIX 2 
Example SAS code below will be used to conduct analyses described in Section 9.8.1.1. 
ods output tests3=tests3 estimates=dsestimates lsmeans=dslsmeans convergencestatus=cstatus  
                  FitStatistics=cfit modelinfo=cinfo; 
ods graphics on;  
proc mixed data=mixed method=reml; 
 class trt (ref= 0 ) visit (ref= BL ) sfactor usubjid; 
 model aucchg = trt visit trt*visit sfactor base_auc/ ddfm=kenwardroger; 
 repeated visit / type=un# subject=usubjid; 
 estimate "Trt diff at BL"      trt 1 -1  trt*visit 1  0  0  0  0  0  0  -1   0   0   0  0  0  0/ cl;  
 estimate "Trt diff at W22"   trt 1 -1  trt*visit 0  0  0  0  0  0  1  0   0   0   0  0  0  -1/ cl;  
lsmeans trt*visit / cl; 
run; 
# Go through the sequence of covariance structure as described in Section 9.8.1.1 if convergence 
 
Example of SAS code for monotone regression in Section 9.8.2.1.1:  
proc mi data=bpmi out=bpmi2 nimpute=100 seed=876453 minmaxiter=200; 
 
by trt01pn; 
            class patstype; 
 
var patstype base week_2 Week_6 Week_10 Week_14 Week_18 Week_22 ; 
 
monotone regression; 
run; 
  
 
 
 
 
 
 
 
 
 




 
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Topic 
Definition 
Search Methodology 
Search Strategy 
peripheral, Peripheral swelling, Fluid retention, Skin 
oedema, Swelling, Skin swelling 
Renal failure  
The inability of the kidneys to 
perform excretory function 
leading to retention of 
nitrogenous waste products 
from the blood 
MedDRA HLT 
(Predefined PT list) 
Renal failure and impairment (HLT) 
Arterial 
thromboembolisms  
Arterial occlusion from 
formation of localized blood 
clots or those that detach to 
occlude blood flow 
downstream. 
MedDRA SMQ 
Embolic and thrombotic events, arterial (SMQ) 
Venous 
thromboembolisms  
Venous occlusion from 
formation of localized blood 
clots or those that detach to 
occlude blood flow 
downstream. 
MedDRA SMQ 
Embolic and thrombotic events, venous (SMQ) 
Skin neoplasms  
Malignant and unspecified 
tumors and neoplasms related 
to the skin. 
MedDRA SMQ 
Skin malignant tumours (SMQ) (broad), Skin tumours of 
unspecified malignancy (SMQ) (broad) 
Neoplasms (all)  
Abnormal and excessive 
growth of cells in the body. 
MedDRA SOC 
(Predefined PT list) 
Neoplasms benign, malignant and unspecified (incl cysts 
and polyps) (SOC) 
Cardiotoxicity  
Toxicity that affects the heart 
(excluding 
thromboembolisms) 
MedDRA SOC 
(Predefined PT list) 
and Sponsor-defined 
PT list 
Cardiac disorders (SOC), or any PTs of: Ejection fraction 
decreased, Electrocardiogram abnormal, 
Electrocardiogram QT prolonged, Electrocardiogram QT 
interval abnormal 
Hepatotoxicity  
Toxicity that affects the liver 
MedDRA SOC 
(Predefined PT list) 
and Sponsor-defined 
PT list 
Hepatobiliary disorders (SOC), or any PTs of: Alanine 
aminotransferase increased, Aspartate aminotransferase 
increased, Blood bilirubin increased, Gamma-
glutamyltransferase increased, Hepatic enzyme increased, 


 
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Topic 
Definition 
Search Methodology 
Search Strategy 
Liver function test abnormal, Liver function test 
increased, Transaminases increased 
Anemia 
 
A reduction in hemoglobin or 
hematocrit or red blood cell 
count 
Sponsor-defined PT list Anaemia, Haematocrit decreased, Haemoglobin 
decreased, Red blood cell count decreased 
Thrombocytopenia  
A reduction in platelet count 
Sponsor-defined PT list Thrombocytopenia, Platelet count decreased, 
Thrombocytopenic purpura, Mean platelet volume 
decreased 
Hemorrhage  
Loss of blood from a damaged 
blood vessel 
MedDRA SMQ 
Haemorrhage terms (excl laboratory terms) (SMQ) 
Peripheral Neuropathy 
Impairment of the peripheral 
motor, sensory and autonomic 
nervous system 
MedDRA SMQ 
Peripheral neuropathy (SMQ) (broad) 
Hyperkalemia  
Serum or plasma potassium 
concentration of more than 5.0 
mEq/L caused by increased 
potassium intake, abnormal 
movement of potassium out of 
cells, or impaired potassium 
excretion. 
Sponsor-defined PT list Hyperkalaemia, Blood potassium increased 
Hypokalemia  
Serum or plasma potassium 
concentration of less than 3.0 
mEq/L caused by a deficit in 
total body potassium stores, 
abnormal movement of 
potassium into cells, or 
increased potassium loss. 
MedDRA SMQ 
Hypokalaemia (SMQ) (narrow) 
Hyperpigmentation  
A condition in which the skin, 
hair, or nails has become 
darker in color 
MedDRA HLT 
(Predefined PT list) 
and Sponsor-defined 
PT list 
Hyperpigmentation disorders (HLT), or any PTs of: 
Pigmentation disorder, Gingival discolouration, Mucosal 
discolouration, Nail discolouration, Nail pigmentation, 
Nail disorder, Hair colour changes 


 
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Topic 
Definition 
Search Methodology 
Search Strategy 
New onset or 
exacerbation of pre-
existing hypertension  
Clinically significant increase 
in arterial blood pressure  
MedDRA SMQ  
Hypertension (SMQ) (narrow)  
Acne 
An inflammatory skin 
condition in which the pores 
of the skin are blocked.  
Keyword search 
Any PT containing: %acne%, %folliculitis% 
Hyperandrogenism  
The presence of an excess 
amount of androgens in 
females 
Sponsor-defined PT list Adrenal androgen excess, Hyperandrogenism, Hirsutism, 
Blood testosterone increased, Androgens increased, Blood 
androstenedione increased, Dihydrotestosterone 
increased, Amenorrhoea, Hypomenorrhoea, Menstruation 
delayed, Menstruation irregular  
Hypogonadism 
Deficiency of androgens in 
males 
Sponsor-defined PT list Adrenal androgen deficiency, Androgen deficiency, 
Feminisation acquired, Hypogonadism male, Blood 
testosterone decreased, Androgens decreased, Blood 
androstenedione decreased, Dihydrotestosterone 
decreased