Conditions: Cushing's Syndrome
Keywords: Cushing's Syndrome Cushing's Disease Cushing's Hypercortisolemia Cushingoid Type 2 Diabetes Impaired Glucose Intolerance Hypertension Adrenal Corticotrophic Hormone (ACTH) Adrenocortical Carcinoma Primary Pigmented Nodular Adrenal Disease (PPNAD) Moon Facies Dorsocervical Fat Pad Adrenal Adenoma Adrenal Carcinoma Adrenal Autonomy Cortisol
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 35
Healthy volunteers: no

Brief summary:
Cushing's syndrome is a relatively rare disorder caused by prolonged exposure to high levels of the glucocorticoid hormone cortisol. Cushing's syndrome may result from elevated endogenous or exogenous sources of cortisol. Endogenous Cushing's syndrome resulting from cortisol overproduction by the adrenal glands is the subject of this protocol.

Patients with exogenous Cushing's syndrome, which develops as a side effect of chronic administration of high doses of glucocorticoids, were not eligible for enrollment in this study.

The purpose of this study was to evaluate the safety and efficacy of CORT125134 for treatment of endogenous Cushing's syndrome. The multicenter study was conducted in the United States and in Europe.

Detailed description:
This was a Phase 2, open-label study with two dose groups, each with a two-step dose escalation, designed to evaluate the safety and efficacy of CORT125134 for the treatment of endogenous Cushing's syndrome. CORT125134 was administered orally once daily for 16 weeks with dose escalations occurring every 4 weeks.

Pharmacokinetics (PK) profiles were generated at every dose level. A data review committee reviewed PK and safety data and recommended the final plan for dose escalation in Group 2.

Arms:
arm 1: 100 mg/day for 4 weeks in Period 1, then 150 mg/day for 4 weeks in Period 2, then 200 mg/day for 4 weeks in Period 3. There was no washout between treatment periods. Period 3 was followed by a 4-week follow-up period. Per-protocol, Group 1 did not participate in treatment Period 4. arm 2: 250 mg/day for 4 weeks in Period 1, then 300 mg/day for 4 weeks in Period 2, then 350 mg/day for 4 weeks in Period 3, then 400 mg/day for 4 weeks in Period 4. There was no washout between treatment periods. Period 4 was followed by a 4-week follow-up period.

Interventions: intervention 1: CORT125134
Intervention descriptions: intervention 1: None

Protocol document:
Prot_000.pdf: 
Title: Phase 2 Study of the Safety and Efficacy of CORT125134 in the Treatment 
of Endogenous Cushing’s Syndrome 
 
NCT number: NCT02804750 
 
Date: 15 January 2018 


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Version 7.0, 15 January 2018 
CLINICAL STUDY PROTOCOL CORT125134-451 
Protocol Title 
Phase 2 Study of the Safety and Efficacy of CORT125134 
in the Treatment of Endogenous Cushing’s Syndrome 
Study Phase 
2 
IND Number 
128625 
Investigational Product 
CORT125134 
International 
Nonproprietary Name 
Relacorilant 
Medical Monitor 
 
 
 
Clinical Trial Lead 
 
 
 
Sponsor 
Corcept Therapeutics Incorporated 
149 Commonwealth Drive 
Menlo Park, California 94025  US 
+1 (650) 327-3270 
Version  
7.0 
Date Final  
15 January 2018 
 
Good Clinical Practice Statement 
This study will be conducted in accordance with Good Clinical Practice (GCP) as defined in 
International Conference on Harmonisation (ICH) guidelines and US Code of Federal 
Regulations Title 21, Parts 11, 50, 54, 56, 312, and Title 45 Parts 46, 160 and 164; the ICH 
document “Guidance for Industry – E6 Good Clinical Practice: Consolidated Guidance”; the EU 
Directives 2001/20/EC and 2005/28/EC; the Declaration of Helsinki (version as currently 
endorsed by the European Medicines Evaluation Agency and the United States Food and Drug 
Administration [FDA], 1989); Institutional Review Board (IRB) Guidelines; and applicable 
local legal and regulatory requirements. 
Confidentiality Statement 
This document contains information which is the confidential and proprietary property of 
Corcept Therapeutics. Any use, distribution, or disclosure without the prior written consent of 
Corcept Therapeutics is strictly prohibited except to the extent required under applicable laws or 
regulations. Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 
 


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SPONSOR SIGNATURE PAGE 
Protocol Title 
Phase 2 Study of the Safety and Efficacy of CORT125134 in the 
Treatment of Endogenous Cushing’s Syndrome 
Protocol Number 
CORT125134-451  
Version  
7.0 
Date Final  
15 January 2018 
 
APPROVAL STATEMENT 
The undersigned have reviewed the format and content of the above protocol and approved 
for issuance.  
 
Signed:  
 
 
 
 
 
 
 
 
Date 
 


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INVESTIGATOR SIGNATURE PAGE 
Protocol Title 
Phase 2 Study of the Safety and Efficacy of CORT125134 in the 
Treatment of Endogenous Cushing’s Syndrome 
Protocol Number 
CORT125134-451  
Version  
7.0 
Date Final  
15 January 2018 
 
INVESTIGATOR AGREEMENT 
By my signature below, I attest to the following:  
1. I have read the attached protocol.  
2. I agree to conduct the study as outlined in the protocol and in accordance with all 
applicable regulations and guidelines, including the Declaration of Helsinki (version as 
currently endorsed by the European Medicines Evaluation Agency and the United States 
Food and Drug Administration [FDA]); the principles of Good Clinical Practice (GCP) as 
described in the United States Code of Federal Regulations (CFR) – 21 CFR parts 50, 54, 
56, and 312 and the ICH document “Guideline for Good Clinical Practice, E6 (R1)” dated 
10 June 1996. Further, I will conduct the study in keeping with local legal and regulatory 
requirements. 
3. I will initiate this study only with written and dated approval from the appropriate 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC). I understand 
that any changes in the protocol must be approved in writing by the Sponsor, the 
IRB/IEC, and, in certain cases the FDA or other applicable regulatory agencies, before 
they can be implemented. 
4. I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol. 
 
Signed:  
 
 
  
Signature 
 
 Date 
 
 
Name 
 Institution 
 


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PROTOCOL SYNOPSIS 
Name of Sponsor 
Corcept Therapeutics  
Name of Active 
Ingredient 
CORT125134 
Study Number 
CORT125134-451 
Title of Study:  
Phase 2 Study of the Safety and Efficacy of CORT125134 in the Treatment of Endogenous Cushing’s 
Syndrome 
Study centers: Multicenter (United States [US] and Europe) 
Study Period:  
Up to 38 weeks, including up to 6 weeks for 
screening, up to 28 weeks of treatment, and 4 weeks 
of follow-up 
Phase of Development:  
Phase 2 
Study Rationale:  
CORT125134 (relacorilant) is a potent, selective glucocorticoid receptor (GR) antagonist being 
developed for the treatment of Cushing’s syndrome. Glucocorticoid receptor antagonism is a proven 
mechanism of action for the treatment of the hyperglycemia secondary to hypercortisolism in adult 
patients with Cushing’s syndrome. Since its mechanism of action is similar to that of mifepristone, 
with the exception that it does not bind the progesterone receptor, CORT125134 may be a treatment of 
Cushing’s syndrome without the drawbacks of progesterone receptor antagonism. 
 
Objectives:  
The primary objective of the study is to assess the safety of CORT125134 in patients with endogenous 
Cushing’s syndrome. The secondary objective of the study is to assess the evidence of reduction in 
cortisol activity following treatment with CORT125134 in patients with endogenous Cushing’s 
syndrome based on improvement in blood glucose control and/or blood pressure (BP). 
 
Study Design and Methodology:  
This is a Phase 2, open-label study with two dose groups (15 patients/group), each with a two-step dose 
escalation. Because the study drug formulation has been updated (to enhance stability) for this protocol 
and has a different exposure/dose relationship than the formulation used in the initial Phase 1 Study 
CORT125134-120, full steady-state PK profiles will be generated at every dose level 2 weeks 
following the initial dose and each dose escalation. 
  
 
  
 
 
 
 
 
 


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• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment of new patients in Group 2 will be initiated once Group 1 (15 patients) has fully enrolled.  
Patient visits to the study site will be at screening, on Day 1 (baseline), Weeks 2, 4, 6, 8, 10, and 12, 
and after a 4-week follow-up period for Group 1. For Group 2, patient visits to the study site will be at 
screening, on Day 1 (baseline), Weeks 2, 4, 6, 8, 10, 12, 14, and 16, and after a 4-week follow-up 


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period. Patients from Group 1 who roll over to Group 2 will follow the visit schedule for Group 2 
without dose interruption. Patient dosing will be done at home, except on days of study visits. 
All patients will undergo at least a two-step dose escalation unless the Investigator and Medical 
Monitor agree it is not advised because of safety or tolerability issues, or the Medical Monitor does not 
approve dose escalation based on the most recent PK results. 
 
 
Number of Patients: 
Approximately 30 patients will be enrolled in the study. 
Patient Selection: 
Approximately 30 male and female adults with a confirmed diagnosis of endogenous Cushing’s 
syndrome and at least one of the following will be enrolled in this study: 
• 
Type 2 diabetes or impaired glucose tolerance (at least 6 patients in both Group 1 and 
Group 2)  
• 
Uncontrolled or untreated hypertension (at least 6 patients in both Group 1 and Group 2) 
Possible etiologies of Cushing’s syndrome include Cushing’s disease, ectopic adrenocorticotropic 
hormone (ACTH)-secreting tumors, ectopic corticotropin-releasing hormone-secreting tumors, adrenal 
cortisol-secreting adenomas, adrenocortical carcinoma, primary pigmented nodular adrenal disease 
(PPNAD), or primary macronodular adrenal hyperplasia (PMAH). 
Patients will be categorized in the impaired glucose tolerance/diabetes subgroup or the hypertension 
subgroup; a patient may be in both of these subgroups. 
 


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Inclusion Criteria: 
Patients must meet all of the following inclusion criteria before study entry to be eligible for 
enrollment into the study: 
1. Is a male or female adult, 18–80 years of age 
2. Has a diagnosis of endogenous Cushing’s syndrome confirmed by:  
At least two of the following test criteria (Nieman 2008): 
• 
Urinary free cortisol above the upper limit of normal (ULN) (50.0 μg/24 h) in at least 2, and 
up to 4, complete 24-hour collections within 3 weeks prior to Day 1 (baseline) 
• 
Late-night salivary cortisol above the ULN (at least 2, and up to 4, collections using a 
salivette) within 3 weeks prior to Day 1 (baseline)  
• 
Lack of cortisol suppression (>1.8 μg/dL serum cortisol) on either 1-mg overnight or 2-mg 
48-hour dexamethasone suppression testing during screening or within 12 weeks before the 
ICF is signed.  
And  
At least two of the following clinical signs and symptoms of Cushing’s syndrome: 
• 
Facial characteristics of a Cushingoid appearance (moon facies, dorsocervical fat pad, 
plethora) 
• 
Increased body weight or central obesity 
• 
Proximal muscle weakness 
• 
Low bone mass (dual energy X-ray absorptiometry [DXA] T < −1.0) 
• 
Psychiatric symptoms (including depression or psychosis) 
• 
Hirsutism and/or violaceous striae and/or acne 
• 
Easy bruising 
 
A patient with an adrenal lesion may alternatively qualify if there is autonomous cortisol secretion 
based on dexamethasone suppression testing (Fassnacht 2016) and supporting evidence of 
clinically significant cortisol excess. Such a patient must have: 
• 
Radiologically proven unilateral or bilateral adrenal disease (nodules, hyperplasia) 
• 
Lack of cortisol suppression (>5 µg/dL serum cortisol) on either 1-mg overnight or 2-mg 
48-hour dexamethasone suppression testing during screening 
• 
Low or suppressed ACTH (<10 pg/mL) to confirm ACTH-independency 
• 
Presence of at least two comorbidities potentially related to cortisol excess (eg, type 2 
diabetes, hypertension, obesity, osteoporosis), of which at least one is inadequately 
controlled by medical measures 
3. Requires medical treatment of hypercortisolemia (ie, those for whom surgery or radiation is 
contraindicated or has been refused)  
Examples include, but are not limited to, patients with Cushing’s disease who are post-surgery 
and/or post-radiation for whom additional surgery is not recommended; de novo patients with 
Cushing’s disease who are not eligible for surgery due to comorbidities; and patients with ectopic 
ACTH-dependent Cushing’s syndrome in which the tumor cannot be localized or completely 
removed. 
4. Meets at least one of the following criteria: 
• 
Has type 2 diabetes mellitus as confirmed at screening visit with a fasting glucose 
>126 mg/dL and a 2-hour oral glucose tolerance test (oGTT) result for plasma glucose 
≥200 mg/dL at 2 hours (Standards of Medical Care in Diabetes – 2015) 
• 
Has impaired glucose tolerance (2-hour oGTT result for plasma glucose in the range of 
≥140 mg/dL to <200 mg/dL) (Standards of Medical Care in Diabetes – 2015) 


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• 
Has hypertension (mean systolic BP of 130–170 mmHg and/or a mean diastolic BP of  
85–110 mmHg) based on 24-hour ambulatory BP measurement (O’Brien 2013) 
5. If taking antidiabetic medication, is on a stable dose (ie, cannot start new medication or change 
dose within 4 weeks prior to the first dose of study drug)  
6. If taking antihypertensive medication, is on a stable dose (ie, cannot start new medication or 
change dose within 4 weeks prior to the screening ambulatory BP measurement) 
7. Has potassium within the normal range (3.5–5.3 mEq/L) at screening or corrected to within the 
normal range by Day 1 
8. Female patients of childbearing potential must be willing to use a highly effective method of 
contraception from 30 days prior to Day 1 until 30 days after the last dose of study drug. Male 
patients with a female partner must agree to 2 forms of contraception, one of which must be a 
double-barrier method, from Day 1 until 30 days after the last dose of study drug. Highly effective 
methods of contraception include abstinence, oral contraceptives combined with a barrier method, 
diaphragm with vaginal spermicide, intrauterine device, condom and partner using vaginal 
spermicide, and surgical sterilization (6 months postsurgery).  
9. (Female patients): Has a negative serum pregnancy test at screening and a negative urine 
pregnancy test at baseline (Day 1) 
10. Has a life expectancy of at least 6 months 
11. Is able to participate in the study for up to 22 weeks in Group 1 and 26 weeks in Group 2, 
including returning to the investigative site to fulfill the safety and efficacy evaluations outlined in 
the protocol 
12. Is able to read and understand the consent form and communicate with the study staff 
13. Provides written consent to participate in the study prior to any study procedures and understands 
that he/she is free to withdraw from the study at any time 
 
Exclusion Criteria: 
Patients who meet any of the following exclusion criteria will not be eligible to participate in the study: 
1. 
Has a non-endogenous source of hypercortisolemia 
2. 
Has pseudo-Cushing’s syndrome. Patients with known or suspected pseudo-Cushing’s 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 1993, 
Giraldi 2007, Yanovski 1998) to rule-in or rule-out this possibility. 
3. 
Has uncontrolled, clinically significant hypothyroidism or hyperthyroidism 
4. 
Has poorly controlled hypertension, defined as systolic BP >170 mmHg or diastolic BP >110 
mmHg at screening 
5. 
Has Stage 4 renal failure (ie, glomerular filtration rate ≤29 mL/min) 
6. 
Has elevated total bilirubin >1.5×ULN or elevated alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) >3×ULN  
7. 
For patients with diabetes or abnormal oGTT at screening: has glycated hemoglobin (HbA1c) of 
>12% within 3 months of first dose of study drug 
8. 
Has a screening hemoglobin level of <9 g/dL 
9. 
Has a clinically significant electrocardiogram (ECG) abnormality at screening, which, in the 
opinion of the Investigator, will make the patient an unsuitable candidate for the study  


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10. 
Has a confirmed screening QTcF interval >450 ms for males and >470 ms for females (using 
Fridericia’s correction) in the presence of a normal QRS interval (QRS <120 ms) or a history of 
additional risk factors for torsades de pointes 
11. 
Is currently receiving chemotherapy for a tumor related to Cushing’s syndrome 
12. 
Had radiation therapy for Cushing’s syndrome-related tumor within 1 year of screening period 
13. 
Is planning surgery or radiation therapy for Cushing’s syndrome-related tumor during the study 
14. 
Has used or plans to use any of the following treatments for Cushing’s syndrome, as specified: 
• 
Adrenostatic medications: metyrapone, ketoconazole, fluconazole, aminoglutethimide, or 
etomidate from 4 weeks prior to baseline (Day 1) through the follow-up visit 
• 
Adrenolytic medications:  
– 
In Group 1, any patients taking mitotane 
– 
In Group 2 only, patients with adrenocortical carcinomas taking mitotane whose dose 
has not been stable for at least 2 months prior to baseline (Day 1) or in whom increases 
in the mitotane dosage are expected through the end of dosing 
• 
Neuromodulator drugs that act at the hypothalamic-pituitary level: serotonin antagonists 
(cyproheptadine, ketanserin, ritanserin), dopamine agonists (bromocriptine, cabergoline), 
gamma-aminobutyric acid agonists (sodium valproate), and somatostatin receptor ligands 
(octreotide long-acting release [LAR], pasireotide LAR, lanreotide) from 8 weeks before 
baseline (Day 1) through the follow-up visit. Use of short-acting somatostatin analogs 
(octreotide, pasireotide) from 4 weeks prior to baseline (Day 1) through the follow-up visit. 
• 
Mifepristone, from 6 weeks before baseline (Day 1) through the follow-up visit 
15. 
Has started or increased (or plans to start or increase) the dose of an antidepressant medication 
(eg, selective serotonin reuptake inhibitors or tricyclic compound) from 6 weeks before baseline 
(Day 1) through the end of the study dosing period 
16. 
Has started or increased (or plans to start or increase) the dose of a lipid-lowering drug from 
4 weeks before baseline (Day 1) through the follow-up visit 
17. 
Is lactating 
18. 
Has an acute or unstable medical problem that could be aggravated by treatment with the 
investigational study drug 
19. 
Has a history of hypersensitivity or severe reaction to the study drug, to a similar class of drug, 
or to the study drug’s excipients 
20. 
Has taken any investigational drug within 30 days before baseline (Day 1), or within a period of 
less than five times the drug’s half-life, whichever is longer 
21. 
In the Investigator’s opinion, should not participate in the study or may not be capable of 
following the study schedule 
22. 
Has known HIV or hepatitis B or C infection 
23. 
Is a family member of one of the Sponsor’s employees, the Investigator, or the site staff directly 
working on the study 
Test Product, Dose and Mode of Administration:  
CORT125134, administered to fasting patients orally as capsules containing 50 mg of CORT125134: 
Group 1: 100 mg/day for 4 weeks, then 150 mg/day for 4 weeks, then 200 mg/day for 4 weeks 
Group 2: 250 mg/day for 4 weeks, then 300 mg/day for 4 weeks, then 350 mg/day for 4 weeks, then 
400 mg/day for 4 weeks 
Duration of Treatment: Up to 28 weeks  


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Criteria for Evaluation:  
Key efficacy assessments  
• 
Oral glucose tolerance test (impaired glucose tolerance/diabetes subgroup only) 
• 
Ambulatory BP measurement (hypertension subgroup only) 
Exploratory efficacy assessments 
• 
Physician’s Global Assessment 
• 
HbA1c 
• 
Fructosamine 
• 
Adiponectin 
• 
24-hour urinary free cortisol (UFC) with creatinine 
• 
Late-night salivary cortisol 
• 
Body weight, waist circumference 
• 
Beck Depression Inventory (BDI-II), Trail Making Test, CushingQoL 
• 
Lipid panel 
• 
Sit-to-stand test 
• 
Sex hormone levels 
• 
Menstrual cycle characterization (premenopausal women not on hormonal birth control) 
• 
Coagulation tests 
• 
Glucocorticoid receptor (GR) biomarker tests 
• 
Bone markers (serum bone alkaline phosphatase, osteocalcin, urine N-telopeptides of type 1 
collagen [NTx], calcium from 24-hour UFC)  
• 
Hypothalamic-pituitary-adrenal (HPA) axis markers, including plasma ACTH and serum 
cortisol concentrations 
• 
ACTH precursors 
• 
High-sensitivity C-reactive protein concentrations 
• 
24-hour urine calcium and sodium 
• 
Insulin-like growth factor (IGF-1) 
• 
Thyroid function tests 
Pharmacokinetics 
Blood levels of CORT125134 and metabolites will be measured predose and at 1, 2, 4, 6, and 8 hours 
postdose at Weeks 2, 6, and 10, and predose only at Weeks 4, 8, and 12/early termination (ET) for 
patients in Group 1.  
For patients in Group 2, blood levels of CORT125134 and metabolites will be measured predose and at 
1, 2, 4, 6, and 8 hours postdose at Weeks 2, 6, 10, and 14 and predose only at Weeks 4, 8, 12, and 
16/early termination (ET). 
 
Safety 
Safety will be assessed by physical examination findings, vital signs, ECG results, pregnancy tests, 
clinical laboratory test results (hematology and chemistry panels), adverse events (AEs), and 
concomitant medications. 
 
Statistical Methods 
The sample size is not intended to support formal hypothesis testing. 
All summaries will be presented by starting dose group, regardless of the actual dose level at the time 
point associated with the data collection. In addition, data will be tabulated for all patients combined. 


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In general, continuous variables will be summarized by the number of patients with non-missing data, 
mean, standard deviation, median, minimum, and maximum values. Categorical variables will be 
summarized by the number and percentage of patients in each category. 
The analysis population for all efficacy and safety analyses will include all patients who received at 
least one dose of study drug. The PK analysis population will comprise all patients who have evaluable 
PK data. For all analyses, the patient will be included in the dose group to which he or she was 
assigned, regardless of actual dose level at the time point when the data were collected. 
Select efficacy endpoints will be analyzed by subgroup only:  
• 
Patients with impaired glucose tolerance/diabetes 
• 
Patients with hypertension.  
All enrolled patients will belong to at least one of these subgroups and an individual patient may be 
included in both. If a patient enters the study with hypertension but takes an additional 
antihypertensive medication or increases the dosage of a concurrent antihypertensive medication, that 
patient will be classified as a nonresponder. If a patient enters the study with diabetes/impaired glucose 
tolerance but takes an additional diabetes medication or increases the dosage of a concurrent diabetes 
medication, that patient will be classified as a nonresponder. 
 
Diabetes/Impaired Glucose Tolerance Subgroup  
The area under the concentration-time curve for glucose (AUCglucose) will be calculated based on results 
of the oGTTs from baseline to Week 12/ET for Group 1 and Week 16/ET for Group 2, for those 
patients with impaired glucose tolerance or diabetes at study entry. A responder will be defined as a 
patient who experiences at least a 25% decrease from baseline in AUCglucose. The number and 
percentage of patients who are responders will be presented by dose group and for all patients, along 
with the 95% binomial exact confidence interval. 
AUCglucose will be summarized by descriptive statistics by dose group and for all patients. In addition, 
plasma glucose, HbA1c, and adiponectin concentrations will be summarized using descriptive statistics 
by visit, time point, and dose group, to include the change from baseline. Plots of the mean plasma 
glucose values over time will be presented. 
The number and percentage of patients whose dose of medications that lower blood glucose decreased, 
stayed the same, or increased from baseline to Week 12/ET in Group 1 and Week 16/ET in Group 2 
will be summarized, among those patients taking such medications at baseline. 
 
Hypertension Subgroup  
Changes in the mean diastolic and mean systolic BP measured by 24-hour ambulatory BP monitoring 
will be analyzed for patients with hypertension at study entry. A responder will be defined as a patient 
who experiences at least a 5 mmHg decrease in diastolic or systolic BP from baseline to Week 12/ET 
in Group 1 and Week 16/ET in Group 2. The number and percentage of patients who are responders 
will be presented by dose group and for all patients, along with the 95% binomial exact confidence 
interval. 
Diastolic and systolic BP will be summarized using descriptive statistics by visit, time point, and 
dose group. 
The number and percentage of patients whose dose of antihypertensive medication decreased, stayed 
the same, or increased from baseline to Week 12/ET in Group 1 and Week 16/ET in Group 2 will be 
summarized, among those patients taking such medications at baseline. 
 
 


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Safety 
Adverse events will be mapped to system organ classes and preferred terms using the Medical 
Dictionary for Regulatory Activities (MedDRA). Treatment-emergent AEs (TEAEs) are defined as 
those that start or worsen after the start of study treatment and up to 28 days after the last dose of study 
treatment.  
Treatment-emergent AEs will be summarized overall and by dose group and displayed by system 
organ class and preferred term. Treatment-emergent AEs will be further summarized by severity and 
relationship to study treatment. At each level of summation, patients will be counted only once, under 
the greatest severity and strongest study-drug relationship (as reported by the Investigator).  
All AEs (whether TEAEs or not) will be listed by individual patient, including information regarding 
onset, duration, severity, and relationship to study drug. Serious AEs and AEs that led to withdrawal 
from the study will be listed by individual patient.  
Clinical laboratory test results (chemistry and hematology), vital sign measurements, and ECG interval 
results will be summarized overall and for each dose group by parameter, visit, and time point using 
descriptive statistics, to include the change from baseline values. Shift tables will be constructed that 
describe changes from baseline to the end of treatment in clinical laboratory values. 
 


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CONTENTS 
1 
INTRODUCTION ............................................................................................................ 22 
1.1 
Background ....................................................................................................................... 22 
1.1.1 Nonclinical Data ................................................................................................... 23 
1.1.2 Clinical Experience: Safety................................................................................... 25 
1.1.3 Clinical Experience: Pharmacokinetics ................................................................ 27 
1.1.4 Clinical Experience: Pharmacodynamics ............................................................. 28 
1.1.5 Adverse Events with Similar Drugs ...................................................................... 29 
1.2 
Rationale for the Current Study ........................................................................................ 30 
1.3 
 
 
 
2 
STUDY OBJECTIVES ..................................................................................................... 36 
3 
STUDY DESIGN.............................................................................................................. 37 
3.1 
Overview of Study Design ................................................................................................ 37 
3.2 
Data Review Committee ................................................................................................... 39 
4 
STUDY POPULATION ................................................................................................... 41 
4.1 
Inclusion Criteria .............................................................................................................. 41 
4.2 
Exclusion Criteria ............................................................................................................. 43 
4.3 
Screening Failures and Rescreening ................................................................................. 44 
4.4 
Patient Withdrawal............................................................................................................ 45 
5 
STUDY TREATMENT .................................................................................................... 46 
5.1 
Product Description .......................................................................................................... 46 
5.1.1 Study Drug ............................................................................................................ 46 
5.1.2 Reference Therapy ................................................................................................ 46 
5.1.3 Placebo .................................................................................................................. 46 
5.2 
Treatment Groups ............................................................................................................. 46 
5.3 
Blinding............................................................................................................................. 46 
5.4 
Treatment Administration ................................................................................................. 46 
5.4.1 Dosing Groups and Dose Escalation..................................................................... 46 


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5.4.2 Per-Protocol Dose Escalation ............................................................................... 47 
5.4.3 Dose Reductions ................................................................................................... 48 
5.4.4 Missed Doses ........................................................................................................ 49 
5.4.5 Study Drug Interruptions ...................................................................................... 49 
5.5 
Treatment Compliance ...................................................................................................... 49 
5.6 
Manufacturing, Packaging, and Labeling ......................................................................... 49 
5.7 
Storage and Accountability ............................................................................................... 49 
6 
PRIOR AND CONCOMITANT MEDICATIONS .......................................................... 51 
6.1 
Prohibited Medications/Treatments .................................................................................. 51 
6.2 
Potential Drug-Drug Interactions ...................................................................................... 51 
6.3 
Rules for Concomitant Medications ................................................................................. 51 
7 
STUDY ASSESSMENTS ................................................................................................ 53 
7.1 
Informed Consent.............................................................................................................. 53 
7.2 
Medication Washout ......................................................................................................... 53 
7.3 
Demographics and Baseline Disease Characteristics ....................................................... 53 
7.4 
Medical History and Medication History ......................................................................... 53 
7.5 
Pituitary Magnetic Resonance Imaging (MRI) Scans ...................................................... 53 
7.6 
Dexamethasone Suppression Test (DST) ......................................................................... 53 
7.7 
Study Enrollment .............................................................................................................. 54 
7.8 
Study Treatment Dispensing ............................................................................................. 54 
7.9 
Drug Compliance Assessment .......................................................................................... 54 
7.10 
Patient Diary ..................................................................................................................... 54 
7.11 
Efficacy Assessments........................................................................................................ 54 
7.11.1 Key Efficacy Assessment ..................................................................................... 54 
7.11.1.1 Effects on Glucose Tolerance ................................................................ 54 
7.11.1.2 Effects on Blood Pressure ...................................................................... 55 
7.11.2 Exploratory Efficacy Assessments ....................................................................... 55 
7.11.2.1 Physician’s Global Assessment ............................................................. 55 
7.11.2.2 Effects on Glucose Tolerance ................................................................ 55 
7.11.2.3 Effects on Cortisol Concentration .......................................................... 56 
7.11.2.4 Effects on Body Weight and Composition ............................................ 56 


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7.11.2.5 Central Nervous System/Psychiatric and Quality-of-Life Effects ......... 57 
7.11.2.6 Effects on Metabolism ........................................................................... 57 
7.11.2.7 Effects on Strength ................................................................................. 57 
7.11.2.8 Hormonal and Menstrual Cycle Effects ................................................. 58 
7.11.2.9 Coagulation Effects ................................................................................ 58 
7.11.2.10 Glucocorticoid Reception (GR) Activity Biomarkers ........................ 58 
7.11.2.11 Bone Effects ....................................................................................... 58 
7.11.2.12 HPA Axis Effects ............................................................................... 58 
7.11.2.13 ACTH Precursors ............................................................................... 59 
7.11.2.14 High-Sensitivity C-reactive Protein ................................................... 59 
7.11.2.15 24-Hour Urine Calcium and Sodium ................................................. 59 
7.11.2.16 Insulin-like Growth Factor (IGF)-1.................................................... 59 
7.11.2.17 Thyroid Function Tests ...................................................................... 59 
7.12 
Pharmacokinetic Assessments .......................................................................................... 59 
7.13 
Safety Assessments ........................................................................................................... 60 
7.13.1 Physical Examination............................................................................................ 60 
7.13.2 Vital Sign Measurements ...................................................................................... 60 
7.13.3 Electrocardiogram ................................................................................................. 61 
7.13.4 Pregnancy Tests and Contraception Methods ....................................................... 61 
7.13.5 Safety Clinical Laboratory Tests .......................................................................... 61 
7.13.5.1 Laboratory Parameters ........................................................................... 62 
7.13.5.2 Sample Collection, Storage, and Shipping ............................................ 62 
7.13.6 Safety Event Documentation and Reporting......................................................... 62 
7.13.6.1 Investigator’s Responsibilities ............................................................... 62 
7.13.6.2 Monitoring Safety Data During Study ................................................... 63 
7.13.6.3 Definition of an Adverse Event ............................................................. 63 
7.13.6.4 Definition of a Serious Adverse Event .................................................. 63 
7.13.6.5 Clinical Laboratory Adverse Events ...................................................... 64 
7.13.6.6 Documentation of Adverse Events ........................................................ 64 
7.13.6.7 Adverse Event Classification ................................................................. 64 
7.13.6.8 Procedures for Reporting a Serious Adverse Event ............................... 65 
7.13.6.9 Adverse Event Follow-Up ..................................................................... 66 
7.13.6.10 Emergency Sponsor Contact .............................................................. 66 


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7.14 
Pregnancy .......................................................................................................................... 67 
7.14.1 Maternal Exposure ................................................................................................ 67 
7.14.2 Paternal Exposure ................................................................................................. 67 
7.14.3 Prior and Concomitant Medications ..................................................................... 67 
7.14.4 Additional Assessments for Special Safety Events .............................................. 68 
7.14.4.1 Monitoring for Excessive Glucocorticoid Receptor Blockade .............. 68 
7.14.4.2 Monitoring for Hypokalemia ................................................................. 69 
7.14.4.3 Hypertension .......................................................................................... 69 
7.15 
Early Study Discontinuation ............................................................................................. 69 
7.16 
Removal of Patients from Treatment or Assessment ........................................................ 69 
8 
PROCEDURES................................................................................................................. 71 
8.1 
Screening (Day −42 to Day −1) ........................................................................................ 71 
8.2 
Baseline Visit (Day 1) ....................................................................................................... 72 
8.3 
Week 1: Study Day 7 (± 1 day) – Telephone or Email Contact ....................................... 73 
8.4 
Week 2: Study Day 14 (± 2 days) ..................................................................................... 73 
8.5 
Week 3: Study Day 21 (± 1 day) – Telephone or Email Contact ..................................... 74 
8.6 
Week 4: Study Day 28 (± 2 days) ..................................................................................... 74 
8.7 
Week 5: Study Day 35 (± 1 day) – Telephone or Email Contact ..................................... 75 
8.8 
Week 6: Study Day 42 (± 2 days) ..................................................................................... 75 
8.9 
Week 7: Study Day 49 (± 1 day) – Telephone or Email Contact ..................................... 76 
8.10 
Week 8: Study Day 56 (± 2 days) ..................................................................................... 76 
8.11 
Week 9: Study Day 63 (± 1 day) – Telephone or Email Contact ..................................... 77 
8.12 
Week 10: Study Day 70 (± 2 days) ................................................................................... 77 
8.13 
Week 11: Study Day 77 (±1 day) – Telephone or Email Contact .................................... 78 
8.14 
Group 1, Week 12: Study Day 84/Early Termination (± 2 days) ..................................... 78 
8.15 
Group 2, Week 12: Study Day 84 (± 2 days) .................................................................... 79 
8.16 
Group 2, Week 13: Study Day 91 (±1 day) – Telephone or Email Contact ..................... 80 
8.17 
Group 2, Week 14: Study Day 98 (± 2 days) .................................................................... 80 
8.18 
Group 2, Week 15: Study Day 105 (±1 day) – Telephone or Email Contact ................... 81 
8.19 
Group 2, Week 16: Study Day 112/Early Termination (± 2 days) ................................... 81 


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8.20 
Group 1, Follow-up Visit at Week 16: Study Day 112 (+7 days) and Group 2, Follow-up 
Visit at Week 20: Study Day 140 (+7 days) ..................................................................... 82 
9 
QUALITY CONTROL AND ASSURANCE .................................................................. 84 
10 
PLANNED STATISTICAL METHODS ......................................................................... 85 
10.1 
General Considerations ..................................................................................................... 85 
10.2 
Analysis Population .......................................................................................................... 85 
10.3 
Patient Disposition ............................................................................................................ 86 
10.4 
Demographic and Baseline Characteristics ...................................................................... 86 
10.5 
Concomitant Medications ................................................................................................. 86 
10.6 
Efficacy Analyses ............................................................................................................. 86 
10.6.1 Impaired Glucose Tolerance/Diabetes Subgroup ................................................. 86 
10.6.2 Hypertension Subgroup ........................................................................................ 87 
10.6.3 Other Measures of Efficacy .................................................................................. 87 
10.7 
Pharmacokinetic Analyses ................................................................................................ 87 
10.8 
Safety Analyses ................................................................................................................. 88 
10.9 
Determination of Sample Size .......................................................................................... 88 
11 
ADMINISTRATIVE CONSIDERATIONS ..................................................................... 89 
11.1 
Institutional Review Board/Independent Ethics Committee............................................. 89 
11.2 
Ethical Conduct of the Study ............................................................................................ 89 
11.3 
Patient Informed Consent ................................................................................................. 89 
11.4 
Patient Confidentiality ...................................................................................................... 90 
11.5 
Study Monitoring .............................................................................................................. 90 
11.6 
Case Report Forms and Study Records ............................................................................ 90 
11.7 
Access to Source Documentation ..................................................................................... 90 
11.8 
Protocol Deviations ........................................................................................................... 90 
11.9 
Records Retention ............................................................................................................. 91 
11.10 Financial Disclosure.......................................................................................................... 91 
11.11 Publication and Disclosure Policy .................................................................................... 91 
12 
REFERENCE LIST .......................................................................................................... 92 
13 
APPENDICES .................................................................................................................. 94 
13.1 
Schedule of Events for Group 1 ........................................................................................ 95 


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13.2 
Schedule of Events for Group 2 ........................................................................................ 98 
13.3 
Study Patient Identification Card .................................................................................... 101 
13.4 
Summary of Changes in Protocol CORT125134-451 Version 7.0................................. 102 
 


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LIST OF IN-TEXT TABLES 
Table 1 
Inhibition Constants (Ki) for CORT125134 and Mifepristone in a Human 
Glucocorticoid Receptor Fluorescence Polarization (FP) Binding Assay and 
in Human Glucocorticoid Receptor Activation (TAT) and Repression 
(TNF-α) Assays......................................................................................................23 
Table 5 
Adverse Event Grades Based on the Common Terminology Criteria for 
Adverse Events ......................................................................................................65 
Table 6 
Causal Attribution Guidance for Adverse Events ..................................................65 
Table 7 
Summary of Changes in Protocol CORT125134-451 Version 7.........................102 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Comparison of Day 13 AM Serum Cortisol Values (nmol/L) by Dose Level for 
50, 150, and 250 mg/day and Combined Placebos – Part 2 of the Phase 1 Study 
CORT125134-120..................................................................................................32 
Figure 2 
CORT125134-451 Study Design ...........................................................................39 
 


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LIST OF ABBREVIATIONS WITH DEFINITIONS 
ACTH 
adrenocorticotropic hormone 
AE 
adverse event 
ALT  
alanine aminotransferase  
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0–24h 
area under the concentration-time curve over 24 hours 
AUCglucose 
area under the concentration-time curve for glucose  
BDI-II 
Beck Depression Inventory 
BP 
blood pressure 
Ca 
calcium 
CFR 
Code of Federal Regulations 
Cmax 
maximum plasma concentration 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DHEA-S 
dehydroepiandrosterone sulfate 
DXA 
dual energy X-ray absorptiometry 
EAS 
ectopic ACTH secretion 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ET 
early termination 
FKBP5 
FK506 binding protein 5 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GR 
glucocorticoid receptor 
HbA1c 
glycated hemoglobin 
HEENT 
head, eyes, ears, nose, throat 
HPA 
hypothalamic-pituitary-adrenal 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IGF 
insulin-like growth factor 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
Ki 
inhibition constant 
LAR 
long-acting release 


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MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
Na 
sodium 
NCI 
National Cancer Institute  
NOAEL 
no-observed-adverse-effect-level 
NTx 
N-telopeptides of type 1 collagen 
oGTT 
oral glucose tolerance test 
PK 
pharmacokinetic 
PMAH 
primary macronodular adrenal hyperplasia 
PPNAD 
primary pigmented nodular adrenocortical disease 
RBC 
red blood cell 
SAE 
serious adverse event 
T3 
triiodothyronine 
T4 
thyroxine 
TAT 
tyrosine amino transferase 
TEAE 
treatment-emergent adverse event 
TNF-α 
tumor necrosis factor alpha  
UFC 
urinary free cortisol 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cell 


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1 
INTRODUCTION 
1.1 
Background 
In healthy individuals, cortisol is secreted from the cortical cells of the adrenal glands under the 
control of the pituitary hormone adrenocorticotropic hormone (ACTH). Endogenous Cushing’s 
syndrome is a rare multisystem disorder that results from overproduction of the glucocorticoid 
hormone cortisol. In both adults and children, Cushing’s syndrome is most commonly caused by 
an ACTH-secreting pituitary tumor (Cushing’s disease). Other forms of Cushing’s syndrome 
result from autonomous production of cortisol from adrenal cortical tumors or overproduction of 
ACTH from non-pituitary tumors (ectopic ACTH syndrome). 
The only curative treatment is resection of the tumor source of the excess cortisol. Depending on 
the nature of the underlying tumor (ie, benign versus malignant, localized versus metastatic), the 
selected treatment may be surgery, radiotherapy, medical therapy, or a combination of these. 
Pharmacological treatment is not curative in Cushing’s syndrome–only successful surgery is–but 
it serves to control the disease after unsuccessful surgery or recurrence (Nieman 2015). It may 
also be used to lower cortisol activity to improve a patient’s condition prior to surgery and is 
employed as interim therapy under specific circumstances, such as in patients waiting for 
radiotherapy to be effective (Cuevas-Ramos 2014).  
Currently, there are two United States (US) Food and Drug Administration (FDA)-approved 
medical therapies for endogenous Cushing’s syndrome. The first is mifepristone (Korlym®), 
which has been approved for the control of hyperglycemia secondary to hypercortisolism in adult 
patients with endogenous Cushing’s syndrome who have type 2 diabetes mellitus or glucose 
intolerance and have failed surgery or are not candidates for surgery. The second is pasireotide 
(Signifor®), a somatostatin receptor agonist, which has been approved for the treatment of adult 
patients with Cushing’s disease for whom pituitary surgery is not an option or has not been 
curative. 
In the US, drugs commonly used off-label in the medical therapy of Cushing’s syndrome either 
inhibit adrenal steroidogenesis (such as metyrapone, mitotane, or ketoconazole), or reduce 
ACTH release from the pituitary gland (such as the dopamine agonists bromocriptine and 
cabergoline; and the somatostatin receptor ligand octreotide). In general, the former agents show 
significant toxic effects and/or loss of efficacy over time, and the latter agents have not shown 
substantial efficacy. In Europe, drugs approved for the treatment of Cushing’s syndrome include 
aminoglutethimide (Orimeten®), ketoconazole (Nizoral®), metyrapone (Metopirone®), mitotane 
(Lysodren®), and pasireotide (Signifor) (Eckstein 2014). 
CORT125134 is a potent, selective glucocorticoid receptor (GR) antagonist being developed for 
the treatment of Cushing’s syndrome. The mechanism of action of CORT125134 is similar to 
that of mifepristone, with the exception that CORT125134 does not bind to the progesterone 
receptor. The potential advantage of CORT125134 compared with mifepristone is its selective 
and potent GR antagonism, without anti-progesterone effects, including endometrial hypertrophy 
and the potential for irregular vaginal bleeding.  
CORT125134 is a high-affinity antagonist of the GR (inhibition constant [Ki] <1 nM in a human 
GR binding assay and <10 nM in a human functional assay). Across a range of in vitro assays it 
is similar in both GR affinity and inhibition to mifepristone (an antagonist of both the 


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progesterone receptor and GR as measured in ligand binding assays), as summarized in Table 1. 
Functional antagonism is assessed by measuring the ability of CORT125134 and mifepristone to 
prevent dexamethasone-induced increase in the activity of tyrosine amino transferase (TAT). The 
expression of the TAT gene is regulated by GR, and a GR agonist such as dexamethasone 
increases gene expression, protein production, and enzyme activity. For routine screening, the 
human liver carcinoma cell line Hep-G2 and the rat hepatoma cell line H4-II-EC4 are used. 
Glucocorticoid receptor agonists also reduce the production of several inflammatory cytokines, 
including tumor necrosis factor alpha (TNF-α), in human peripheral blood mono-nuclear cells 
stimulated with lipopolysaccharide, by repressing gene transcription. Glucocorticoid receptor 
antagonists such as mifepristone and CORT125134 reverse the effects of the agonist 
dexamethasone.  
Table 1 
Inhibition Constants (Ki) for CORT125134 and Mifepristone in a Human 
Glucocorticoid Receptor Fluorescence Polarization (FP) Binding Assay and 
in Human Glucocorticoid Receptor Activation (TAT) and Repression 
(TNF-α) Assays 
Compound 
FP Binding Assay 
Ki (nM) 
Functional GR (TAT) 
Ki (nM) 
Functional GR (TNF-α) 
Ki (nM) 
Human HepG2 
Rat H4-II-EC4 
Human PBMC 
CORT125134 
0.15 
7.2 
1.2 
9.1 
Mifepristone 
0.09 
3.1 
2.2 
6.2 
CORT125201* 
0.20 
7.6 
Not tested 
Not tested 
*CORT125201 is a metabolite of CORT125134 
1.1.1 Nonclinical Data 
To characterize the nonclinical safety of CORT125134, preliminary ascending single-dose, 
repeat-dose, and Good Laboratory Practice (GLP) 14-day repeat-dose toxicology studies were 
conducted in rats and cynomologus monkeys. The results of the general toxicology studies 
indicated that CORT125134 produced many anticipated effects related to the antagonism of GR 
and compensatory perturbations of the hypothalamic-pituitary-adrenal (HPA) axis. In these 
studies, safety pharmacology assessments included cardiovascular effects in monkeys, 
respiratory function in rats, and neurobehavioral effects in rats. In general, there were no 
remarkable central nervous, respiratory, or cardiovascular system effects in rats or monkeys 
following single oral doses up to 200 mg/kg (highest dose tested). 
 
 
 
 


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CORT125134 was not genotoxic in in vitro bacterial and mammalian cell assays or in vivo in the 
rat micronucleus assay. 
CORT125134 is not a substrate for permeability glycoprotein (P-gp). It appears to be eliminated 
via multiple metabolic pathways including cytochrome P450 (CYP) 2C8, CYP3A4 and CYP3A5 
and a non-CYP pathway but not via renal elimination. This is reassuring with respect to the risk 
of drug-drug interactions affecting exposure to CORT125134. Based on in vitro studies, 
CORT125134 appears to be a potent inhibitor of CYP3A4 and CYP2C8 and a modest inhibitor 
of CYP2C9, CYP2C19, CYP2D6 and CYP3A5. No significant induction of CYP1A2, CYP2B6 
or CYP3A4 was noted in a study carried out in human hepatocytes. 
More information is provided in the Investigator’s Brochure 
1.1.2 Clinical Experience: Safety 
Clinical experience with CORT125134 is derived from three studies conducted in healthy 
subjects; Study CORT125134-120 which evaluated single ascending and multiple ascending 
doses of the earlier formulation in healthy subjects, Study CORT125134-122 which evaluated a 
single dose of 150 mg of the current formulation (modified to improve stability) in healthy 
subjects, and Study CORT125134-453 which evaluated multiple ascending doses of the current 
formulation in healthy subjects.  
Study CORT125134-120 consisted of Part 1 and Parts 2 and 3, which assessed the safety, 
tolerability, and pharmacokinetics (PK) of single and multiple ascending doses, respectively, in 
healthy volunteers. In total across all single-dose groups in Part 1, 69 subjects received 
CORT125134 and 12 received placebo (8 subjects received each of 5, 15, and 50 mg fasted; 
7 received 150 mg fasted; 6 received 300 mg fasted, and 24 received 500 mg fasted, and a further 
8 received 150 mg fed). Across all multiple-dose groups in Part 2, 25 subjects received up to 
14 days’ treatment with CORT125134 and 9 received placebo (9 subjects received each of 50 
and 150 mg, and 7 subjects received 250 mg once daily) after an overnight fast. Dosing in Part 3 
of the study, in which the safety, tolerability and PK of a higher multiple dose (500 mg) daily in 
healthy volunteers were assessed, was terminated prematurely due to lack of tolerability 
(principally musculoskeletal complaints). Safety follow-up for Part 3 subjects is completed (refer 
to accompanying Investigator Brochure). 
Overall, CORT125134 was safe and well tolerated following single doses up to 500 mg or 
repeated doses up to 250 mg once daily. The overall incidence of treatment-emergent adverse 
events (TEAEs) was low after administration of CORT125134, with no notable difference in the 
percentage of subjects reporting TEAEs after dosing with active drug compared with placebo.  


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In the multiple-ascending-dose study (Part 2), TEAEs in the musculoskeletal and connective 
tissue disorders system organ class were reported more frequently by subjects treated with 
CORT125134, and with increasing frequency with increasing dose. The proportions of subjects 
with reports of musculoskeletal and connective tissue disorder TEAEs by daily dose were 
Placebo:  0 subjects; 50 mg: 2 subjects (22.2%); 150 mg: 4 subjects (44.4%); and 250 mg: 4 
subjects (57.1%). The events reported were coded as back pain, pain in extremity, myalgia, 
arthralgia, musculoskeletal pain, spinal osteoarthritis, and tendon discomfort. However, back 
pain (0% [0/9] placebo, 22.2% [2/9] 50 mg, 11.1% [1/9] 150 mg, and 28.6% [2/7] 250 mg), pain 
in extremity (0% [0/9] placebo, 0% [0/9] 50 mg, 11.1% [1/9] 150 mg, and 28.6% [2/7] 250 mg), 
and myalgia (0% [0/9] placebo, 0% [0/9] 50 mg, 22.2% [2/9] 150 mg, and 0% [0/7] 250 mg) 
were the only TEAEs reported for at least 2 subjects in any of the three multiple ascending dose 
cohorts. There was also some evidence that gastrointestinal TEAEs, such as abdominal pain 
upper, epigastric pain, nausea, vomiting, and constipation were reported with increasing 
frequency with dose of CORT125134, with the majority assessed as treatment-related following 
both single and multiple doses. 
Most events were mild, but moderate abdominal pain and constipation in one subject treated with 
CORT125134, 250 mg daily, and severe pain in extremity in one subject treated with 
CORT125134, 150 mg daily, resulted in withdrawal of treatment.  
Findings in Part 3, the multiple-ascending-dose extension cohort, show that CORT125134 
500 mg once daily exceeds the maximum well-tolerated dose, with musculoskeletal symptoms 
and earache being the most frequently reported limiting symptoms. 
One serious adverse event (SAE) was reported in this Phase 1 study. A subject treated with 
CORT125134, 50 mg daily was admitted to the hospital overnight due to a head injury during 
the follow-up period. The subject declared this was due to an accidental fall; however, the 
hospital record states that the subject was assaulted. The event was considered unrelated to study 
treatment and the subject made a full recovery. 
There were no clinically significant findings in any laboratory assessments, vital signs, 12-lead 
ECGs, Holter electrocardiograms (ECGs), or body weight. Five CORT125134-treated subjects in 
the multiple-dose part of the study had substantial reductions in platelet count during the 
treatment period, with prompt recovery subsequently. The average of the absolute platelet counts 
decreased in the CORT125134-treated groups when compared with placebo. None of the 
individual decreases was considered clinically significant, and an independent review by an 
experienced hematologist did not consider these findings a safety concern. 
Study CORT125134-122 evaluated the safety, tolerability, and PK of a single 150 mg dose of the 
CORT125134 current formulation in 8 healthy male volunteers. No serious or severe adverse 
events were reported during the study, and no subjects withdrew from the study due to adverse 
events. A total of 1 treatment-emergent adverse event (mild dizziness) was reported by 1 of 8 
subjects (12.5%) during the study. 
 
 


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More information is provided in the Investigator’s Brochure. 
1.1.3 Clinical Experience: Pharmacokinetics 
Pharmacokinetic results from the Phase 1 study (Study CORT125134-120) in healthy subjects 
demonstrated that CORT125134 concentrations declined in a multiphasic manner. Plasma 
concentrations appeared to plateau by Day 7 with little accumulation from Day 7 to Day 14, 
indicating that concentrations were likely at or near steady-state by Day 7. Concentrations 
declined to unmeasurable levels prior to or by the last sampling time point, indicating that the 


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concentration-time profile was completely captured within the planned sampling time window 
and was limited only by the lower limit of the bioanalytical method.  
The half-life for CORT125134 in Part 2 after the last dose on Day 14 averaged 11.99, 19.09, and 
14.71 hours at 50, 150, and 250 mg/day, respectively. 
Based on the limited data available, an effect of food to reduce exposure to CORT125134 cannot 
be excluded. 
Dose proportionality analysis showed that for both maximum plasma concentration (Cmax) and 
area under the concentration-time curve (AUC), exposure increased in a greater than 
proportional manner with dose increment for both single and daily dosing. This effect was 
particularly noticeable at the lowest doses in the single ascending dose phase. Inter-subject 
variability in exposure was moderate. 
 
 
 
 
 
Metabolite (CORT125201) exposure was low compared with parent drug. At presumed steady-
state, metabolite AUC0-24h was less than 5% that of parent drug. 
In Study CORT125134-122, which evaluated the 150-mg dose of the updated, current capsule 
formulation in 8 healthy volunteers, CORT125134 was absorbed rapidly (median Tmax 1 hour, 
range 1-2 hours) to a mean Cmax of 200.5 ng/mL. Thereafter, elimination was rapid (median Tlast 
24 hours; mean t½ 7.7 hours), giving a mean AUCinf of 801 ng•h/mL. 
In comparison of the current capsule formulation with historical data for the earlier capsule 
formulation, exposure from the current formulation was substantially lower, with Cmax 
approximately 30 to 52% and AUCinf 22 to 36% of that of the earlier formulation 
. 
 
 
 
 
1.1.4 Clinical Experience: Pharmacodynamics 
The PD effects of CORT125134 were assessed in Study CORT125134-120 by evaluating the 
ability of CORT125134 to prevent selected effects of the GR agonist prednisone. This evaluation 
was conducted after the administration of a single dose of CORT125134 (500 mg) in Part 1 of 
the study, and 14 days repeat dosing of CORT125134 (250 mg/day) in Part 2 of the study. In Part 
1, a single dose of mifepristone (600 mg) was used as a comparator. 
Administration of a single dose of prednisone (25 mg) resulted in a rapid drop in eosinophils, 
lymphocytes, and osteocalcin, and an increase in neutrophils. After administration of 600 mg 
mifepristone with 25 mg prednisone, the effect of prednisone on these parameters was 
ameliorated to a large extent. Similarly, after administration of 500 mg CORT125134 the effect 


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of prednisone was also ameliorated. The 24-hour AUC on time point deltas for proof of 
pharmaceutical effect (PoPE) parameters for both mifepristone and CORT125134 were 
significantly different from those for prednisone alone on Day −19 (p <0.05) for eosinophils and 
neutrophils but not plasma osteocalcin. For lymphocyte 24-hour AUC, CORT125134 with 
prednisone (but not mifepristone with prednisone) was significantly different to prednisone 
alone. 
Administration of a single dose of prednisone 25 mg resulted in an abnormal glucose tolerance 
test. After administration of 500 mg of CORT125134 with 25 mg of prednisone, the effect of 
prednisone on glucose tolerance appeared to be ameliorated. Administration of 600 mg of 
mifepristone with 25 mg of prednisone was used as comparator.  
In Part 2 of the study, the 24-hour AUC on time point deltas for PoPE parameters for 
CORT125134 on Day 14 were significantly different from those for prednisone alone on Day −5 
(p <0.05) for eosinophils, neutrophils, and osteocalcin but not lymphocytes. Because there were 
only 3 placebo-treated subjects, no statistical comparison was done between placebo- and 
CORT125134-treated subjects. However, it was evident from plotting the data that active 
treatment on Day 14 resulted in an amelioration of the prednisone effect whereas placebo 
treatment did not. 
The administration of prednisone increased FK506 binding protein 5 (FKBP5) mRNA 
expression, and this increase was prevented by co-administration of either mifepristone (600 mg) 
or CORT125134 (500 mg) with the prednisone in Part 1 of the study. After dosing with 
CORT125134 (250 mg) for 14 days in Part 2 of the study, prednisone did not induce FKBP5 
mRNA expression. Administration of placebo for 14 days did not prevent prednisone-induced 
FKBP5 mRNA expression. 
Due to inhibition of the negative feedback mechanism, the administration of a GR antagonist 
causes an increase in morning serum plasma cortisol levels. After administration of 
CORT125134 for 14 days, there appeared to be a dose-related effect, with increased cortisol 
levels at the higher doses. A comparison between morning cortisol levels on Day 13 for 
CORT125134-treated subjects with placebo-treated subjects showed that 50 mg CORT125134 
did not have a statistically significant effect (p = 0.2634), whereas 150 mg and 250 mg 
CORT125134 did have a statistically significant effect (p = 0.0025 and 0.0006, respectively). 
Analysis of ECG safety data from the Phase 1 study showed that CORT125134 at doses up to 
500 mg, which resulted in plasma concentrations up to approximately 3 µg/mL, did not have a 
clinically relevant effect on ECG parameters (cardiac safety report, data on file). Based on the 
exposure-response analysis of the QT effect, the data demonstrated that CORT125134 does not 
have a clinically relevant effect on the QTc interval. An effect on ∆∆QTcF above 10 ms could 
clearly be excluded within the studied range of plasma concentrations up to approximately 
3 µg/mL, which corresponded to single doses up to 500 mg or repeated doses up to 250 mg 
once daily. 
1.1.5 Adverse Events with Similar Drugs 
Mifepristone is a potent antagonist of both progesterone via the progesterone receptor and 
cortisol via the GR receptor, and has weak antiandrogenic activity. In the pivotal, uncontrolled, 
open-label, multicenter study of mifepristone in 50 patients with Cushing’s syndrome, the 


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following adverse events (AEs), as reported in the Korlym prescribing information, were 
reported in ≥20% of patients: nausea, fatigue, headache, decreased blood potassium, arthralgia, 
vomiting, peripheral edema, hypertension, dizziness, decreased appetite, and endometrial 
hypertrophy. “Adrenal insufficiency” was reported in 2 patients (4%). The most common 
symptoms of adrenal insufficiency were nausea and decreased appetite. No hypotension or 
hypoglycemia was reported during the events. Adrenal insufficiency resolved in both cases with 
mifepristone interruption and/or dexamethasone administration. Adrenal insufficiency was 
reported in 5 of the 30 patients (16.7%) who participated in the extension study, in which 
patients received up to 1 year of treatment with mifepristone. 
Across five psychotic depression trials that evaluated 7-day dosing with mifepristone (up to 
1200-mg dose), AEs reported in ≥10% of patients who received mifepristone (N = 833) were 
nausea and headache. In these trials, the majority of reported treatment-emergent SAEs were 
psychiatric. The three most prevalent psychiatric disorder SAEs reported were worsened 
depression, worsened psychosis, and suicidal ideation. There were no reports of adrenal 
insufficiency. 
1.2 
Rationale for the Current Study 
This will be the first prospective clinical study to evaluate the safety of CORT125134, a selective 
GR antagonist, in patients with endogenous Cushing’s syndrome for whom the Investigator has 
determined that medical treatment of endogenous hypercortisolemia is indicated. The study will 
assess the effect of treatment on the signs and symptoms of hypercortisolemia.  
Glucocorticoid receptor antagonism is a proven mechanism of action for the treatment of the 
hyperglycemia secondary to hypercortisolism in adult patients with Cushing’s syndrome. Since 
its mechanism of action is similar to that of mifepristone, with the exception that it does not bind 
the progesterone receptor, CORT125134 may be a treatment of Cushing’s syndrome without the 
drawbacks of progesterone receptor antagonism that may result in untoward reproductive effects 
and/or interruption of therapy. 
The activity of CORT125134 has been demonstrated in various in vitro assays and CORT125134 
was shown to be well tolerated in a Phase 1 study that examined the clinical PK and safety of 
CORT125134 doses as high as 350 mg for 14 days. The combination of the preclinical and 
clinical assessments justifies the evaluation of CORT125134 in patients with Cushing’s 
syndrome. 
The study is intended to demonstrate safety and clinical effects of GR antagonism, with an 
emphasis on blood glucose control and blood pressure (BP) control, in patients with Cushing’s 
syndrome. The PK of CORT125134 will also be evaluated. In addition to blood glucose control 
and BP control, several other exploratory efficacy assessments will be used to assess clinical 
benefit. In patients with adrenal Cushing’s syndrome, changes of the HPA axis will be monitored 
in addition to clinical monitoring. Successful GR blockade at the hypothalamus and pituitary 
level will reverse the excessive negative cortisol feedback, as shown by ACTH increase, 
indicating recovery of the HPA axis. In addition, increased production of adrenal androgens 
(androstenedione and dehydroepiandrosterone sulfate [DHEA-S]), which are regulated by 
ACTH, would also signal recovery of the atrophic adrenal tissue. 


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Changes in serum cortisol, late-night salivary cortisol, and urinary free cortisol (UFC) will also 
be evaluated, as well as changes in body weight, waist circumference, body composition, lipid 
levels, and hormone levels; effects on strength and menstrual cycle (premenopausal female 
patients not taking hormonal birth control); a quality-of-life assessment (CushingQoL); the Beck 
Depression Inventory (BDI-II); and a Physician’s Global Assessment of the signs and symptoms 
of Cushing’s syndrome. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2 
STUDY OBJECTIVES 
The primary study objective is to assess the safety of CORT125134 in patients with endogenous 
Cushing’s syndrome.  
The secondary study objective is to assess the evidence of reduction in cortisol activity following 
treatment with CORT125134 in patients with endogenous Cushing’s syndrome, based on 
improvement in blood glucose control and/or BP. 


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3 
STUDY DESIGN 
3.1 
Overview of Study Design 
This is a Phase 2, open-label study to evaluate the safety and efficacy of two dose regimens of 
CORT125134 in patients with endogenous Cushing’s syndrome and type 2 diabetes or glucose 
intolerance and/or uncontrolled or untreated hypertension. Patients will be categorized in the 
impaired glucose tolerance/diabetes subgroup or the hypertension subgroup; a patient may be in 
both of these subgroups. The impaired glucose tolerance/diabetes subgroup will include at a least 
6 patients in both Group 1 and Group 2. The hypertension subgroup will include at least 
6 patients in both Group 1 and Group 2. 
Approximately 30 patients will be enrolled across clinical sites in the US and Europe. Two dose 
groups including 15 patients per group will be evaluated, each with a two-step dose escalation. 
The study will consist of 3 periods: a screening period (Days −42 to −1); a treatment period 
consisting of 4 weeks at the initial dose, immediately followed by 4 weeks at the next higher 
dose (ie, first dose escalation), immediately followed by an additional 4 weeks at the next higher 
dose (ie, second dose escalation); and a follow-up period of 4 weeks.  
Because the study drug formulation has been updated (to enhance stability) for this protocol, and 
has a different exposure/dose relationship than the formulation used in the initial Phase 1 Study 
CORT125134-120 
, full steady-state PK profiles will be generated at 
every dose level 2 weeks following the initial dose and each dose escalation. The Medical 
Monitor must approve all individual dose escalations and will review the patient’s safety profile 
and steady-state PK results, including AUC0–24h values. If the patient’s projected AUC0–24h value 
meets the dose-escalation rules outlined in Section 5.4.2, the patient’s dose will be escalated; 
otherwise, the patient’s dose will remain at the current level.  
An independent DRC will convene at least 4 times during the study to review safety and PK 
results, as listed below. 
Two dose groups will each enroll 15 patients sequentially, with enrollment of the second dose 
group occurring after the 15th patient has enrolled in the first dose group, as follows: 
• Patients enrolled into Group 1 will receive CORT125134 100 mg/day for 4 weeks, then 
CORT125134 150 mg/day for 4 weeks, then CORT125134 200 mg/day for 4 weeks. 
• After 6 patients have received CORT125134 through Week 10 (ie, 2 weeks following 
dose escalation to 200 mg/day), the DRC will review PK and safety data to confirm the 
appropriateness of the dose levels in Group 1. 
• After 12 patients have received CORT125134 through Week 10 (ie, 2 weeks following 
dose escalation to 200 mg/day), the DRC will review PK and safety data and recommend 
changes, if applicable, to the dose escalation in Group 2.  
• Group 2: CORT125134 250 mg/day for 4 weeks, then 300 mg/day for 4 weeks, then 
350 mg/day for 4 weeks, and then 400 mg for 4 weeks. Patients who discontinue prior to 
Week 10 may be replaced to ensure that at least 12 patients provide serial PK data 
through Week 10 in Group 1 and Group 2. 
• The DRC will also meet during Group 2, when steady-state PK data are available for 
6 patients who have reached their highest CORT125134 dose (ie, Week 10 if 350 mg and 
Week 14 if 400 mg) and at the end of the study. 


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• In the event that patients enrolled in Group 2 cannot tolerate the starting dose, they will 
be allowed to continue on study at a lower dose level (ie, 150 or 200 mg). 
• 
Patients who complete 12 weeks of dosing in Group 1 may, at the recommendation of the 
Investigator and with agreement of the Medical Monitor, roll over to Group 2 and follow 
the Group 2 dose escalation schedule. 
 
Enrollment of new patients in Group 2 will be initiated once Group 1 (15 patients) has fully 
enrolled.  
All patients will undergo at least a two-step dose escalation (Figure 2) unless the Investigator and 
Medical Monitor agree it is not advised because of safety or tolerability issues, or the Medical 
Monitor does not approve dose escalation based on the most recent PK results (see 
Section 5.4.2). Patient dosing will be done at home, except on days of study visits. 
Patient visits to the study site will be at screening, on Day 1 (baseline), Weeks 2, 4, 6, 8, 10, and 
12, and after a 4-week follow-up period for patients in Group 1 and Group 2 and additionally at 
Weeks 14 and 16 for patients in Group 2 who dose-escalate to 400 mg daily. Patients from 
Group 1 rolling over into Group 2 will continue the visit schedule for Group 2 without dose 
interruption; for these patients, Week 12 will be their baseline visit for Group 2 and they will not 
undergo the Group 1 4-week follow-up visit. The following safety measurements will be 
performed during each in-clinic visit: AE reporting, safety laboratories, physical exams, vital 
signs, ECGs, concomitant medications and pregnancy tests. Key efficacy parameters will also be 
measured including effects on: glucose tolerance, blood pressure, cortisol concentration, 
body/weight composition and metabolism. Predose and postdose samples for serial PK will be 
collected at Weeks 2, 6, and 10, and predose trough PK samples only will be collected at Weeks 
4, 8, and 12/early termination (ET) for patients in Group 1. For patients in Group 2 who dose-
escalate to 400 mg daily, predose and postdose samples for serial PK will also be collected at 
Week 14, and key efficacy parameters as well as predose trough PK samples will be collected at 
Week 16/ET. Between clinic visits, weekly contact with patients will occur via email or 
telephone to capture study drug compliance, AEs, and medication changes. 
 


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Figure 2 
CORT125134-451 Study Design 
 
3.2 
Data Review Committee  
An independent DRC consisting of at least one physician experienced in the evaluation and 
treatment of patients with Cushing’s syndrome, a clinical pharmacologist, and a statistician will 
review CORT125134 PK and safety data. Data will be reviewed in accordance with procedures 
detailed in a separate DRC Charter. The DRC meeting timelines and role are described below: 
The DRC will convene: 
• For oversight of Group 1: 
– When 6 evaluable patients have escalated to Dose 3 of Group 1 (200 mg), and steady-
state PK and safety data are available (to confirm the appropriateness of the Group 1 
dose levels) 
– When 12 evaluable patients have escalated to Dose 3 of Group 1, and steady-state PK 
and safety data are available  
• For oversight of Group 2: 
– When 6 evaluable patients have escalated to Dose 3 or 4 (whichever is the patient’s 
highest Group 2 dose) and PK and safety data are available 
– At end of study 


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• Overall, no less than every 6 months while the study is in progress 
The DRC will perform the following tasks:  
• Evaluate PK data from the study in concert with the results of updated PK modeling 
 
• Recommend changes, if applicable, to any planned dose levels 
  
The DRC’s evaluation of PK results for groups of patients and their review of the PK simulations 
and estimated exposures based on PK modeling will complement the Medical Monitor’s review 
of individual dose escalations.  
In the event that a decision is made by the Sponsor to reject a safety recommendation by the 
DRC, the decision and rationale will be communicated to the Food and Drug Administration 
(FDA) and site IRBs before enrolling additional patients.  


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4 
STUDY POPULATION 
The following eligibility criteria are designed to select patients for whom protocol treatment is 
considered appropriate. All relevant medical and nonmedical conditions will be taken into 
consideration when deciding whether this protocol is suitable for a particular patient.  
Approximately 30 patients with a confirmed diagnosis of endogenous Cushing’s syndrome and 
at least one of the following will be enrolled in this study:  
• Type 2 diabetes or impaired glucose tolerance (at least 6 patients in both Group 1 
and Group 2). 
• Uncontrolled or untreated hypertension (at least 6 patients in both Group 1 and Grou 2). 
Possible etiologies of Cushing’s syndrome include Cushing’s disease, ectopic ACTH-secreting 
tumors, ectopic corticotropin releasing hormone-secreting tumors, adrenal cortisol-secreting 
adenomas, adrenocortical carcinoma, primary pigmented nodular adrenal disease (PPNAD), or 
primary macronodular adrenal hyperplasia (PMAH). 
4.1 
Inclusion Criteria 
Patients must meet the following criteria in order to participate in the study: 
1. Is a male or female adult, 18–80 years of age 
2. Has a diagnosis of endogenous Cushing’s syndrome confirmed by:  
At least two of the following test criteria (Nieman 2008): 
• Urinary free cortisol above the upper limit of normal (50.0 μg/24 h) in at least 2, and 
up to 4, complete 24-hour collections within 3 weeks prior to Day 1 (baseline)  
• Late-night salivary cortisol above the upper limit of normal (at least 2, and up to 4, 
collections using a salivette) within 3 weeks prior to Day 1 (baseline)  
• Lack of cortisol suppression (>1.8 μg/dL serum cortisol) on either 1-mg overnight or 
2-mg 48-hour dexamethasone suppression testing (DST) during screening or within 
12 weeks before the ICF is signed. 
And 
At least two of the following clinical signs and symptoms of Cushing’s syndrome: 
• Facial characteristics of a Cushingoid appearance (moon facies, dorsocervical fat pad, 
plethora) 
• Increased body weight or central obesity 
• Proximal muscle weakness 
• Low bone mass (dual energy X-ray absorptiometry [DXA] T < −1.0) 
• Psychiatric symptoms (including depression or psychosis) 
• Hirsutism and/or violaceous striae and/or acne 
• Easy bruising  
 
A patient with an adrenal lesion may alternatively qualify if there is autonomous cortisol 
secretion based on dexamethasone suppression testing (Fassnacht 2016) and supporting evidence 
of clinically significant cortisol excess. Such a patient must have: 
• Radiologically proven unilateral or bilateral adrenal disease (nodules, hyperplasia) 


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• Lack of cortisol suppression (>5 µg/dL serum cortisol) on either 1-mg overnight or 
2-mg 48-hour dexamethasone suppression testing during screening 
• Low or suppressed ACTH (<10 pg/mL) to confirm ACTH-independency 
• Presence of at least two comorbidities potentially related to cortisol excess (e.g. type 
2 diabetes, hypertension, obesity, osteoporosis), of which at least one is inadequately 
controlled by medical measures  
 
3. Requires medical treatment of hypercortisolemia (ie, those for whom surgery or radiation 
is contraindicated or has been refused) 
 
Examples include, but are not limited to, patients with Cushing’s disease who are post-
surgery and/or post-radiation for whom additional surgery is not recommended; de novo 
patients with Cushing’s disease who are not eligible for surgery due to comorbidities; and 
patients with ectopic ACTH-dependent Cushing’s syndrome in which the tumor cannot 
be localized or completely removed. 
 
4. Meets at least one of the following criteria: 
• Has type 2 diabetes mellitus as confirmed at screening visit with a fasting glucose 
>126 mg/dL and 2-hour oral glucose tolerance test (oGTT) result for plasma glucose 
200 mg/dL at 2 hours (Standards of Medical Care in Diabetes – 2015) 
• Has impaired glucose tolerance (2-hour oGTT result for plasma glucose in the range 
of ≥140 mg/dL to <200 mg/dL) (Standards of Medical Care in Diabetes – 2015) 
• Has hypertension (mean systolic BP of 130–170 mmHg and/or a mean diastolic BP of 
85–110 mmHg) based on 24-hour ambulatory BP measurements (O’Brien 2013) 
5. If taking antidiabetic medication, is on a stable dose (ie, cannot start new medication or 
change dose within 4 weeks prior to the first dose of study drug) 
6. If taking antihypertensive medication, is on a stable dose (ie, cannot start new medication 
or change dose within 4 weeks prior to the screening ambulatory BP measurement) 
7. Has potassium within the normal range (3.5 to 5.3 mEq/L) at screening or corrected to 
within the normal range by Day 1 
8. Female patients of childbearing potential must be willing to use a highly effective method 
of contraception from 30 days prior to Day 1 until 30 days after the last dose of study 
drug. Male patients with a female partner must agree to 2 forms of contraception, one of 
which must be a double-barrier method, from Day 1 until 30 days after the last dose of 
study drug. Highly effective methods of contraception include abstinence, oral 
contraceptives plus barrier method, diaphragm with vaginal spermicide, intrauterine 
device, condom and partner using vaginal spermicide, and surgical sterilization 
(6 months post-surgery). 
9. (Female patients): Has a negative serum pregnancy test at screening and a negative urine 
pregnancy test at baseline (Day 1) 
10. Has a life expectancy of at least 6 months 
11. Is able to participate in the study for up to 22 weeks in Group 1 and 26 weeks in Group 2, 
including returning to the investigative site to fulfill the safety and efficacy evaluations 
outlined in the protocol 
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13. Provides written consent to participate in the study prior to any study procedures and 
understands that he/she is free to withdraw from the study at any time 
4.2 
Exclusion Criteria 
Patients who meet any of the following exclusion criteria will not be eligible to participate in the 
study:  
1. Has a non-endogenous source of hypercortisolemia 
2. Has pseudo-Cushing’s syndrome. Patients with known or suspected pseudo-Cushing’s 
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 1993, Giraldi 2007, Yanovski 1998) to rule-in or rule-out this 
possibility. 
3. Has uncontrolled, clinically significant hypothyroidism or hyperthyroidism 
4. Has poorly controlled hypertension, defined as systolic BP >170 mmHg or diastolic 
BP >110 mmHg at screening 
5. Has Stage 4 renal failure (ie, glomerular filtration rate ≤29 mL/min) 
6. Has elevated total bilirubin >1.5×ULN or elevated alanine aminotransferase (ALT) or 
aspartate aminotransferase (AST) >3×ULN  
7. For patients with diabetes or abnormal oGTT at screening: has glycated hemoglobin 
(HbA1c) of >12% within 3 months of first dose of study drug 
8. Has a screening hemoglobin level of <9 g/dL 
9. Has a clinically significant electrocardiogram (ECG) abnormality at screening, which, in 
the opinion of the Investigator, will make the patient an unsuitable candidate for the study 
10. Has a confirmed screening QTcF interval >450 ms for males and >470 ms for females 
(using Fridericia’s correction) in the presence of a normal QRS interval (QRS <120 ms) 
or a history of additional risk factors for torsades de pointes 
11. Is currently receiving chemotherapy for a tumor related to Cushing’s syndrome 
12. Had radiation therapy for Cushing’s syndrome-related tumor within 1 year of screening 
period 
13. Is planning surgery or radiation therapy for Cushing’s syndrome-related tumor during the 
study 
14. Has used or plans to use of any of the following treatments for Cushing’s syndrome, as 
specified: 
• Adrenostatic medications: metyrapone, ketoconazole, fluconazole, 
aminoglutethimide, or etomidate from 4 weeks prior to baseline (Day 1) through the 
follow-up visit  
• Adrenolytic medications:  
– In Group 1, any patients taking mitotane 
– In Group 2 only, patients with adrenocortical carcinomas taking mitotane whose 
dose has not been stable for at least 2 months prior to baseline (Day 1) or in 
whom increases in the mitotane dosage are expected through the end of dosing.  
• Neuromodulator drugs that act at the hypothalamic-pituitary level: serotonin 
antagonists (cyproheptadine, ketanserin, ritanserin), dopamine agonists 
(bromocriptine, cabergoline), gamma-aminobutyric acid agonists (sodium valproate), 
and somatostatin receptor ligands (octreotide long-acting release [LAR], pasireotide 


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LAR, lanreotide) from 8 weeks before baseline (Day 1) through the follow-up visit. 
Use of short-acting somatostatin analogs (octreotide, pasireotide) from 4 weeks prior 
to baseline (Day 1) through the follow-up visit.  
• Mifepristone, from 6 weeks before baseline (Day 1) through the follow-up visit. 
15. Has started or increased (or plans to start or increase) the dose of an antidepressant 
medication (eg, selective serotonin reuptake inhibitors or tricyclic compound) from 
6 weeks before baseline (Day 1) through the end of the study dosing period 
16. Has started or increased (or plans to start or increase) the dose of a lipid-lowering drug 
from 4 weeks before baseline (Day 1) through the follow-up visit 
17. Is lactating 
18. Has an acute or unstable medical problem that could be aggravated by treatment with the 
investigational study drug 
19. Has a history of hypersensitivity or severe reaction to the study drug, to a similar class of 
drug, or to the study drug’s excipients  
20. Has taken any investigational drug within 30 days before baseline (Day 1), or within a 
period of less than five times the drug’s half-life, whichever is longer 
21. In the Investigator’s opinion, should not participate in the study or may not be capable of 
following the study schedule 
22. Has known human immunodeficiency virus (HIV) or hepatitis B or C infection 
23. Is a family member of one of the Sponsor’s employees, the Investigator or the site staff 
directly working on the study. 
4.3 
Screening Failures and Rescreening 
Patients who fail screening due to a laboratory result may be retested within the screening period 
without prior Corcept approval. Screening UFC tests may be performed up to four times during 
the screening period. Salivary cortisol tests may also be performed up to four times during the 
screening period. The average of the results for each test will serve as the “baseline” for each 
test. Other laboratory tests during the screening period may be repeated at the Investigator’s 
discretion. The 24-hour ambulatory BP monitoring may be repeated if there is a technical 
problem with the test. 
Whenever patients are rescreened, they must sign an informed consent form each time and be 
assigned a new patient identification number. The only screening assessments that do not need to 
be repeated during rescreening are the oGTT and the dexamethasone suppression test.  
In patients with an abnormal QTc interval at screening in which no concomitant drugs known 
to prolong QTc and no electrolyte abnormalities are present, two repeat ECG recordings should 
be done. The final decision on excluding a patient should be based on the average QTcF interval 
across the 3 recordings. If an electrolyte abnormality is present, it should be corrected before the 
ECG is repeated. If the patient is on a concomitant medication known to cause QT prolongation, 
an alternative medication may be considered and the ECG repeated after an appropriate 
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4.4 
Patient Withdrawal 
Patients may withdraw their consent to participate in the study at any time for any reason without 
prejudice. The Investigator also has the right to withdraw patients from the study for the 
following reasons: 
• The patient withdraws consent. The Investigator should make a reasonable attempt to 
document the specific reason why consent is withdrawn. 
• The Investigator decides it is in the patient’s best interest to discontinue treatment and/or 
participation in the study. Reasons may include the following: 
• Patient requires or starts prohibited medication(s). 
• Patient is not adherent to protocol procedures. 
• The patient experiences an AE that requires withdrawal from the study. 
• Patient is pregnant. 
• 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. 
• The Sponsor terminates the study. 
When a patient withdraws, every effort should be made to complete the follow-up examinations. 


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5 
STUDY TREATMENT 
5.1 
Product Description 
5.1.1 Study Drug 
CORT125134 is a synthetically prepared small molecule with the following chemical name:  
(R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-1,4,5,6,7,8-hexahydro-4aH-
pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone. 
 
 
CORT125134 50-mg capsules are white, size 2, hard gelatin capsules. 
CORT125134 50-mg capsules will be provided in blister packs containing 7 capsules per strip. 
5.1.2 Reference Therapy 
No reference therapy will be used in this study. 
5.1.3 Placebo 
No placebo treatment will be used in this study. 
5.2 
Treatment Groups 
Patients will be enrolled sequentially into two groups. Fifteen patients enrolled in Group 1 will 
receive 100 mg/day for 4 weeks, then 150 mg/day for 4 weeks, then 200 mg/day for 4 weeks. 
After 6 patients have received CORT125134 through Week 10 (ie, 2 weeks following dose 
escalation to 200 mg/day), the Data Review Committee (DRC) will review pharmacokinetic 
(PK) and safety data to confirm appropriateness of dose levels in Group 1. 
After 10-week PK data are available from 12 patients in Group 1, the DRC will meet and 
evaluate PK and safety data  
Doses for patients enrolled in Group 2 will be 250 mg/day for 4 weeks, then 300 mg/day for 
4 weeks, then 350 mg/day for 4 weeks, and then 400 mg for 4 weeks. 
5.3 
Blinding 
In this open-label study, all study patients, Investigators, the Medical Monitor, Sponsor staff 
members, and other applicable personnel will be unblinded to study treatment. 
5.4 
Treatment Administration 
5.4.1 Dosing Groups and Dose Escalation 
Patients in Group 1 will receive CORT125134 100 mg/day for the first 4 weeks of treatment, 
then CORT125134 150 mg/day for the second 4 weeks of treatment, and then CORT125134 
200 mg/day for the third 4 weeks of treatment. After 6 patients have received CORT125134 
through Week 10 (ie, 2 weeks following dose escalation to 200 mg/day), the DRC will review 
PK and safety data to confirm the appropriateness of dose levels in Group 1. After 12 patients 


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have completed Week 10 (ie, 2 weeks following dose escalation in Group 1) in the study, the 
DRC will review PK and safety data and recommend changes, if applicable, to the dose 
escalation in Group 2. Patients who complete Group 1 may, at the Investigator’s 
recommendation, enter Group 2 and follow the Group 2 dose escalation schedule.  
Patients in Group 2 will receive CORT125134 250 mg/day for the first 4 weeks of treatment. 
Thereafter, the dose escalates to CORT125134 300 mg/day for the second 4 weeks of treatment, 
to CORT125134 350 mg/day for the third 4 weeks of treatment, and then to CORT125134 
400 mg/day for the fourth 4 weeks of treatment. Patients enrolled in Group 2 who cannot tolerate 
the starting dose selected for Group 2 will be allowed to continue on study at a lower dose level 
(eg, 200 or 150 mg). If the lower dose is well tolerated, the dose may be increased by 50 mg after 
at least 2 weeks of treatment at the lower dose and then escalated every 4 weeks according to the 
protocol schedule; all dose escalations must be approved by the Medical Monitor. 
 
Group 
First 4 Weeks  
of Treatment 
Second 4 Weeks  
of Treatment 
Third 4 Weeks  
of Treatment 
Fourth 4 Weeks  
of Treatment 
1 
100 mg  
(50-mg capsule  
× 2) 
150 mg 
(50-mg capsule  
× 3) 
200 mg  
(50-mg capsule  
× 4) 
Not applicable 
2 
250 mg 
(50-mg capsule  
× 5) 
300 mg 
(50-mg capsule  
× 6) 
350 mg  
(50-mg capsule  
× 7) 
400 mg 
(50-mg capsule  
× 8) 
 
The assigned dose will be administered orally once daily in the morning, 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.  
Patients will be instructed to take the appropriate number of 50-mg capsules to equal the 
prescribed daily dose (eg, 3 capsules for the 150-mg dose, 5 capsules for the 250-mg dose).  
5.4.2 Per-Protocol Dose Escalation 
After completing Weeks 4 and 8 of treatment, patients will escalate their doses 
 
 
  
 
 
 
 
 
 
  


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5.4.3 Dose Reductions 
Dose reductions may be performed according to the following rules: 
• The Investigator may reduce the dose of CORT125134 for AEs or tolerability issues to 
the next lower dose (eg, from 200 to 150 mg/day or from 350 to 300 mg/day). 
• With the approval of the Medical Monitor, the Investigator may subsequently increase 
the dose to the previous dose (eg, from 150 back to 200 mg/day or from 300 back to 
350 mg/day).  
• If the dose of CORT125134 is reduced, a subsequent dose increase should be avoided 
within 7 days of a Week 2, Week 6, or Week 10 PK evaluation. 
• Further dose escalations at Week 4 or Week 8 (as with all escalations) must be approved 
by the Medical Monitor. 
• Patients enrolled in Group 2 who cannot tolerate the starting dose selected for Group 2 
(ie, planned to be 250 mg) will be allowed to continue on-study at the next lower dose 
level (ie, 200 mg). Subsequent dose increases/escalations will follow the rules listed 
above.  
Dose reductions based on excessive GR blockade are outlined in Section 7.14.4.1. 


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5.4.4 Missed Doses 
Patients will be advised to take a missed dose on the same day of the missed dose, but not the 
following day; that is, no more than one dose on any day. Missed doses should be taken on an 
empty stomach, at least 4 hours after a meal, and no food should be consumed for 1 hour after 
the dose. The patient should inform the Investigator when a dose is not taken. Missed doses will 
be documented in the source documents. 
5.4.5 Study Drug Interruptions 
Study drug can be interrupted and restarted if the Investigator or Medical Monitor thinks that it is 
warranted in a particular patient. During study drug interruptions, patients will continue on the 
same visit schedule.  
Study drug interruptions due to excessive GR blockade are detailed in Section 7.14.4.1. 
5.5 
Treatment Compliance 
Patients will be provided with a diary card to record doses taken at home and will be instructed 
to bring used and unused packages of study drug to each study visit. Study staff will count and 
record the number of capsules taken and returned at each study visit to determine patient 
compliance. At each visit, the patients will be instructed on proper study drug administration. 
Adherence to the study protocol will be reinforced at each visit and during the weekly contact 
(telephone or email). 
Study staff will document dosing information on the source document. They will also count and 
record the number of capsules taken and returned at each study visit. 
5.6 
Manufacturing, Packaging, and Labeling 
The study drug will be manufactured and packaged under Good Manufacturing Practice (GMP) 
regulations. The capsules are provided in sealed, foil blister packs.  
At a minimum, the label on each package of study drug will contain the drug name, protocol 
number, storage conditions, statement on investigational use only, and Sponsor details. Labeling 
will meet country-specific requirements. 
5.7 
Storage and Accountability 
The investigational product CORT125134 should be stored at 25°C (77°F); excursions are 
permitted from 2–30°C (36–86°F). 
The Investigator is responsible for the accountability of all used and unused study medication. 
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.  
Opened and unopened packages of study drug must be returned to the Sponsor or its designee at 
the end of the study or destroyed onsite, after study drug accountability monitoring has occurred, 
in accordance with local requirements. 


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Under no circumstances will the Investigator allow the investigational drug to be used other than 
as directed by the protocol. 


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6 
PRIOR AND CONCOMITANT MEDICATIONS 
6.1 
Prohibited Medications/Treatments 
The following prior/concomitant medications are not allowed: 
• Medications used in the treatment of Cushing’s syndrome are prohibited and require 
washout (as applicable) during screening provided the intervals specified in Exclusion 
Criterion 14 fit within the screening window.  
– Adrenostatic medications: metyrapone, ketoconazole, fluconazole, 
aminoglutethimide, or etomidate 
– Neuromodulator drugs that act at the hypothalamic-pituitary level: serotonin 
antagonists (cyproheptadine, ketanserin, ritanserin), dopamine agonists 
(bromocriptine, cabergoline), gamma-aminobutyric acid agonists (sodium valproate), 
and somatostatin receptor ligands (octreotide long-acting release [LAR], pasireotide 
LAR, lanreotide) from 8 weeks before baseline (Day 1) through the follow-up visit. 
Use of short-acting somatostatin analogs (octreotide, pasireotide) from 4 weeks prior 
to baseline (Day 1) through the follow-up visit. 
– Mifepristone, from 6 weeks before baseline (Day 1) through the follow-up visit. 
• Group 1 only: Mitotane 
• Start of a new antidepressant medication (see Exclusion Criterion 15) 
• Strong CYP3A4 inhibitors (including grapefruit, grapefruit juice, or grapefruit-containing 
products) 
• Start of a new lipid-lowering drug (see Exclusion Criterion 16) 
• Other investigational agents 
• Corticosteroids: 
– Systemic corticosteroids 
– Potent (Group III) topical corticosteroids 
– Potent intra-articular corticosteroids 
6.2 
Potential Drug-Drug Interactions 
CORT125134 has been shown to inhibit the activity of CYP3A4 and CYP2C8 and may inhibit 
CYP3A5, CYP2C9, CYP2C19, and CYP2D6. Drugs metabolized by these isozymes, particularly 
drugs with a narrow therapeutic ratio, should be used with caution within 1 week prior to 
baseline (Day 1) through the follow-up visit, unless otherwise indicated. 
6.3 
Rules for Concomitant Medications 
• If hypokalemia ensues during therapy with CORT125134, patients may be given 
mineralocorticoid receptor antagonists, other potassium-sparing diuretics, and potassium 
supplements (see Section 7.14.4.2). 
• Patients in Group 2 receiving mitotane should not increase the mitotane dosage through 
the end of dosing (see Exclusion Criterion 14). Decreases in dose are allowed. 


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• The oGTT should be done fasting. In general, the patient should not take the antidiabetic 
oral medication in the morning of their visit. To avoid hypoglycemia, insulin cannot be 
taken prior to the oGTT. Long-acting insulin can be taken the night before the oGTT. 
Oral antidiabetes medications and insulin preparations can be taken with food after the 
completion of the oGTT 
• Insulin and other medications for diabetes can be decreased during the dosing period to 
prevent hypoglycemia, but upward titration should be avoided and occur only after 
consultation with the Medical Monitor. 
• Antihypertensive medication can be decreased during the dosing period to prevent 
hypotension or orthostatic symptoms. Increase of the dose of antihypertensive medication 
or addition of new antihypertensive medication should be avoided and occur only after 
consultation with the Medical Monitor. 
• An increase in dose of a current lipid-lowering drug is not allowed from 4 weeks before 
baseline (Day 1) through the follow-up visit (see Exclusion Criterion 16). 
• An increase in dose of a current antidepressant medication is not allowed from 6 weeks 
before baseline (Day 1) through the end of the study dosing period (see Exclusion 
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7 
STUDY ASSESSMENTS 
7.1 
Informed Consent 
Prior to performing any study-related procedures, the patient must sign and date an Institutional 
Review Board (IRB)-approved informed consent form (ICF). (See Section 11.3 for additional 
information about informed consent.) Health Insurance Portability and Accountability Act 
authorization, if applicable, will also be obtained. The informed consent process must be 
thoroughly documented in the patient’s record. Patients can be screened up to 42 days prior to 
the first dose of study drug on Day 1. 
7.2 
Medication Washout 
Medications used in the treatment of Cushing’s syndrome are prohibited and require washout (as 
applicable) during screening provided the intervals specified in Exclusion Criterion 14 fit within 
the screening window. Patients requiring washout of a medication for Cushing’s syndrome must 
complete the screening/baseline 24-hour UFC tests, salivary cortisol tests, oGTTs, and 24-hour 
ambulatory BP monitoring tests after washout and within 3 weeks before Day 1 dosing. 
7.3 
Demographics and Baseline Disease Characteristics 
Patient demographic data will be collected at screening. These include age, sex, race, and 
ethnicity. Baseline disease characteristics, such as years since diagnosis, and Cushing’s 
syndrome type (eg, EAS, PPNAD, PMAH), will also be documented. 
7.4 
Medical History and Medication History 
Patient medical history will be obtained at screening, including the diagnosis, etiology, and 
treatment history of Cushing’s syndrome (including dexamethasone suppression test failure 
where appropriate). Surgery and radiation history will include date and type. A menstrual history 
will be obtained for all female patients. 
7.5 
Pituitary Magnetic Resonance Imaging (MRI) Scans 
Pituitary MRI radiographic scans and assessments in patients with Cushing disease that are 
obtained up to 6 months before Day 1 and up to 1 month after last CORT125134 dose as 
standard of care will be collected if available. 
7.6 
Dexamethasone Suppression Test (DST) 
The dexamethasone suppression test (DST) should be performed at screening when an additional 
test is required to confirm endogenous Cushing’s syndrome (eg, if either the 24-hour UFC or late 
night salivary test results are within normal range and an additional test is required to confirm 
Cushing’s syndrome).  
In patients with adrenal incidentalomas, if the biochemical confirmation of cortisol excess cannot 
be made by late night salivary test and UFC, a 1-mg overnight or 2-mg 48-hour dexamethasone 
suppression test (DST) can be done. 


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7.7 
Study Enrollment 
Patients who meet all of the inclusion criteria and none of the exclusion criteria during the 
screening period and at baseline (Day 1) will be enrolled in the study. Refer to Section 5.2 for the 
method of assigning patients to dose groups. 
A screening log will be maintained and will include all patients who sign the ICF whether or not 
they are enrolled. Reasons for screen failure will be recorded. 
7.8 
Study Treatment Dispensing 
Study drug will be dispensed to each patient at baseline (Day 1) and, at a minimum, at Weeks 2, 
6, 8, and 10 for Group 1 and at Weeks 2, 6, 8, 12, and 14 for Group 2. Sufficient study drug will 
be provided for the period between visits. 
7.9 
Drug Compliance Assessment 
Patients will be instructed to bring used and unused packages of study drug to each study visit. 
At each visit, patients will be instructed on proper study drug administration. Adherence to the 
study protocol will be reinforced at each visit and during the weekly contact (telephone or 
email). 
At each visit starting with Day 1, study staff will document dosing information in the source 
document. They will also count and record the number of capsules taken and returned at each 
study visit. 
7.10 
Patient Diary 
Patient diary is dispensed to the patient at baseline and at Weeks 2, 4, 6, 8, and 10 for Group 1 
and at Weeks 2, 4, 6, 8, 10, 12, and 14 for Group 2. Diaries should be completed by the patient 
on a daily basis to capture whether study drug was taken per protocol. Diary cards should be 
returned and reviewed at Weeks 2, 4, 6, 8, 10, and 12 for Group 1 and at Weeks 2, 4, 6, 8, 10, 12, 
14, and 16 for Group 2.  
7.11 
Efficacy Assessments 
7.11.1 Key Efficacy Assessment 
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. 
7.11.1.1 
Effects on Glucose Tolerance 
A 2-hour oGTT will be administered to all patients at screening and to patients in the impaired 
glucose tolerance/diabetes subgroup at baseline (Day 1) and at Weeks 4, 8, and 12/early 
termination (ET) for Group 1 and at Weeks 4, 8, 12, and 16/ET for Group 2. 
During the 2-hour oGTT, blood samples for plasma glucose and insulin will be collected before 
the glucose drink and 0.5, 1, 1.5, and 2 hours after the glucose drink. 


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The oGTT should be performed after an 8-hour fast. In general, the patient should not take the 
antidiabetic oral medication in the morning of their visit. To avoid hypoglycemia, insulin cannot 
be taken prior to the oGTT. Long-acting insulin can be taken the night before the oGTT. Oral 
antidiabetes medications and insulin preparations can be taken with food after the completion of 
the oGTT.  
7.11.1.2 
Effects on Blood Pressure 
The 24-hour ambulatory BP will be assessed for all patients during the screening period. For the 
subgroup of patients who qualify for the hypertension subgroup, there must be a 24-hour 
ambulatory BP test done within 3 weeks before Day 1; this result will be used as “baseline”. (If 
the initial screening test was done within 3 weeks before Day 1, it does not need to be repeated.) 
The 24-hour ambulatory BP will also be measured in the hypertension subgroup at Weeks 2, 4, 
6, 8, 10, and 12/ET for Group 1 and at Weeks 2, 4, 6, 8, 10, 12, 14, and 16/ET for Group 2. 
Mean 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. The patient should use the 
monitor during a time when a full 24-hour recording can be made.  
An ambulatory BP monitor will be given to the patient at screening, and 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. 
7.11.2 Exploratory Efficacy Assessments 
7.11.2.1 
Physician’s Global Assessment 
At baseline, Weeks 2, 4, 6, 8, 10, 12/ET, and the follow-up visit for Group 1 and at baseline, 
Weeks 2, 4, 6, 8, 10, 12, 14, and 16/ET, and the follow-up visit for Group 2, the Investigator will 
consider all the patient’s signs and symptoms of Cushing’s syndrome and will rate the degree of 
illness on a scale of 1 to 9, where 1 = absent and 9 = incapacitating.  
7.11.2.2 
Effects on Glucose Tolerance 
7.11.2.2.1 Glycated Hemoglobin (HbA1c) Concentration 
HbA1c is a glycoprotein whose concentration reflects the amount of glucose bound to 
hemoglobin. It will be assayed in blood samples drawn at screening, baseline (Day 1), and Week 
12/ET for Group 1 and at screening, baseline, and Weeks 12 and 16/ET for Group 2. 
7.11.2.2.2 Fructosamine Concentration 
Fructosamine is a marker used to assess rapid changes in diabetes control and has an excellent 
correlation with HbA1c. Changes in fructosamine may be observed as early as 2 weeks after 
beginning dosing with study drug. Serum fructosamine will be assayed in blood samples drawn 
at baseline (Day 1) and at Weeks 2, 4, 6, 8, 10, and 12/ET for Group 1 and at Weeks 2, 4, 6, 8, 
10, 12, 14, and 16/ET for Group 2. 


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7.11.2.2.3 Adiponectin Concentration 
Adiponectin is a hormone secreted by adipose tissue that modulates glucose regulation and fatty 
acid metabolism. A blood sample will be collected at baseline (Day 1) and at Weeks 4, 8, and 
12/ET for Group 1 and at Weeks 4, 8, 12, and 16/ET for Group 2.  
7.11.2.3 
Effects on Cortisol Concentration 
The following tests will be performed in all patients in order to assess eligibility for the study 
and also to assess the changes in cortisol levels during the study period.  
7.11.2.3.1 24-Hour Urinary Free Cortisol (UFC) with Creatinine  
The 24-hour UFC with creatinine test will be measured by tandem mass spectrometry at least 
two times during each of the following: screening period, and within 7 days prior to the visits on 
Weeks 2, 4, 6, 8, 10, and 12/ET for Group 1 and also within 7 days prior to the visits on Weeks 
2, 4, 6, 8, 10, 12, 14, and 16/ET visits for Group 2.  
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. The patient 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.  
See Section 7.11.2.15 for urine calcium and sodium measurements from same samples. 
Complete instructions for the patient will be provided. 
7.11.2.3.2 Late-Night Salivary Cortisol Test 
This test will be performed at least two times during each of the following: screening period and 
within 7 days prior to the visits on Weeks 2, 4, 6, 8, 10, and 12/ET for Group 1 and also within 
7 days prior to the visits on Weeks 2, 4, 6, 8, 10, 12, 14 and 16/ET for Group 2.  
The patient will be given supplies for the collection of saliva at home prior to a clinic visit. 
Samples should be collected at bedtime.  
Complete instructions for the patient will be provided. 
7.11.2.4 
Effects on Body Weight and Composition 
The following assessments will be performed on all enrolled patients. 
7.11.2.4.1 Body Weight Measurement 
Body weight will be obtained at every visit.  
7.11.2.4.2 Waist Circumference Measurement 
Waist circumference will be measured at baseline (Day 1); at Weeks 4, 8, and 12/ET for Group 1 
and at Weeks 4, 8, 12, and 16/ET for Group 2; and at the follow-up visit. Clinical sites will be 
provided with tape measures to ensure consistency. 


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7.11.2.5 
Central Nervous System/Psychiatric and Quality-of-Life Effects 
The following assessments will be performed on all enrolled patients. 
7.11.2.5.1 Beck Depression Inventory 
The Beck Depression Inventory (BDI-II) is a 21-question self-report inventory that measures 
depression. Each answer is scored with values 0 to 3. Total scores are classified as minimal, 
mild, moderate, and severe depression, with larger scores indicating more severe depressive 
symptoms. Patients will complete the BDI-II at baseline (Day 1) and at Weeks 4, 8, and 12/ET 
for Group 1 and at Weeks 4, 8, 12, and 16/ET for Group 2.  
7.11.2.5.2 Trail Making Test 
The Trail Making Test is a neuropsychological test of visual attention and task switching. It 
consists of two parts in which the patient is instructed to connect a set of 25 dots as quickly as 
possible while still maintaining accuracy. It can provide information about visual search speed, 
scanning, processing speed, and mental flexibility, as well as executive functioning. The Trail 
Making Test will be administered at baseline (Day 1) and at Weeks 4, 8, and 12/ET for Group 1 
and at Weeks 4, 8, 12, and 16/ET for Group 2. 
7.11.2.5.3 CushingQoL 
The CushingQoL patient questionnaire evaluates the health-related quality of life in patients 
with Cushing’s syndrome (Webb 2008). It comprises 12 questions, each with 5 possible answers. 
The CushingQoL instrument addresses known problem areas associated with Cushing’s 
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. Lower values reflect lower quality of life. The 
CushingQoL questionnaire will be administered at baseline (Day 1), at Weeks 4, 8, and 12/ET 
for Group 1 and at Weeks 4, 8, 12, and 16/ET for Group 2, and at the follow-up visit. 
7.11.2.6 
Effects on Metabolism 
Lipid panel analysis, which will include total cholesterol, low-density lipoprotein-cholesterol, 
high-density lipoprotein-cholesterol, very low-density lipoprotein-cholesterol, and triglycerides, 
will be conducted. Blood will be collected from all enrolled patients at baseline (Day 1), at 
Weeks 4, 8, and 12/ET for Group 1 and Weeks 4, 8, 12, and 16/ET for Group 2, and at the 
follow-up visit for a lipid panel analysis.  
7.11.2.7 
Effects on Strength 
The sit-to-stand test will be performed by all enrolled patients. 
The sit-to-stand test measures the patient’s ability to go from standing to sitting in a chair and 
then getting up again with/without the use of their arms or other aids. The sit-to-stand test will be 
administered at baseline (Day 1), at Weeks 4, 8, and 12/ET for Group 1 and Weeks 4, 8, 12, and 
16/ET for Group 2, and at the follow-up visit. 
Patients seated in a chair will be asked to fold their arms across their chests and to stand up from 
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sit down again and then stand up and sit down five 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 (ie, 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 study staff will use a stopwatch to measure the total time it takes for the patient to 
stand up and sit down five times; start time is in the seated position and stop time is in the final 
standing position. Patients with gait or balance disorders are not required to complete the sit-to-
stand test. The same or similar chair should be used for all measurements. 
7.11.2.8 
Hormonal and Menstrual Cycle Effects 
Blood samples will be obtained from each patient for analysis of estradiol, total and free 
testosterone, sex hormone binding globulin, follicle-stimulating hormone, and luteinizing 
hormone at baseline (Day 1) and at the Week 12/ET visit for Group 1 and at baseline and the 
Week 16/ET visit for Group 2. 
Menstrual cycle information (eg, age at menarche, current pattern of menses, duration of vaginal 
bleed) will be recorded, along with any spotting occurrences, at every visit in premenopausal 
female patients not on hormonal birth control. 
7.11.2.9 
Coagulation Effects 
Blood samples will be obtained from all enrolled patients at baseline (Day 1) and at Weeks 4, 8, 
and 12/ET for coagulation tests for Group 1 and at baseline and Weeks 4, 8, 12, and 16/ET for 
Group 2. These include activated partial thromboplastin time, Factor VIII, Factor IX, Factor X, 
and von Willebrand factor, d-dimer, fibrinogen, and thrombin-antithrombin.  
7.11.2.10 Glucocorticoid Reception (GR) Activity Biomarkers 
A blood sample will be obtained from all patients for analysis of mRNA expression of 
glucocorticoid-modulated genes including FKBP5 and a panel of housekeeping genes. For 
Group 1, samples will be collected at baseline (Day 1) and Weeks 4, 8, and 12/ET; for Group 2, 
samples will be collected at baseline (Day 1) and Weeks 4, 8,12, and 16/ET. See the laboratory 
manual for details of preparation, storage, and shipping of these samples. 
7.11.2.11 Bone Effects 
Blood and urine samples for analysis of bone markers will be obtained from all patients at 
baseline (Day 1), and from Group 1 at Weeks 4, 8, and 12/ET and from Group 2 at Weeks 4, 8, 
12, and 16/ET. These will include urinary N-telopeptides of type 1 collagen (NTx), serum bone 
alkaline phosphatase, and serum osteocalcin.  
Urine calcium will be measured in the 24-hour UFC test (see Section 7.11.2.3.1). 
7.11.2.12 HPA Axis Effects 
Blood samples will be obtained at screening, baseline (Day 1), and at Weeks 2, 4, 6, 8, 10, and 
12/ET for analysis of plasma ACTH, serum cortisol, 17-OH-progesterone, 11-deoxycortisol, 
DHEA-S, and androstenedione for Group 1. For Group 2, samples will also be collected at 
screening, baseline, and Weeks 2, 4, 6, 8, 10, 12, and 16/ET. 


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7.11.2.13 ACTH Precursors 
ACTH precursors (proopiomelanocortin and pro-ACTH) will be measured at baseline (Day 1) 
and at Weeks 2, 4, 6, 8, 10, and 12/ET for Group 1. For Group 2, samples will be collected at 
baseline (Day 1) and Weeks 2, 4, 6, 8, 10, 12, 14, and 16/ET. 
7.11.2.14 High-Sensitivity C-reactive Protein 
High-sensitivity C-reactive protein is an endothelial inflammation marker. A blood sample will 
be collected for this assay at baseline (Day 1) and at Weeks 4, 8, and 12/ET for Group 1, and at 
baseline and Weeks 4, 8, 12, and 16/ET for Group 2.  
7.11.2.15 24-Hour Urine Calcium and Sodium 
Increased urinary calcium excretion is a major risk factor in the development of kidney stones in 
patients with Cushing’s syndrome. Increased sodium excretion in the urine reflects sodium 
consumption and is used during the investigation of hypertension as well as in the differential 
diagnosis of failure of antihypertensive medications or medications that target specific causes of 
hypertension. 
Using the urine samples collected for UFC, calcium and sodium levels will be measured in all 
patients at screening, baseline (Day 1), and for Group 1 at Weeks 2, 4, 6, 8, 10, and 12/ET and 
for Group 2 at Weeks 2, 4, 6, 8, 10, 12, 14, and 16/ET.  
7.11.2.16 Insulin-like Growth Factor (IGF)-1 
Insulin-like growth factor-1 is a hormone with a structure similar to that of insulin. A blood 
sample will be obtained from all patients for this determination at baseline (Day 1); at Weeks 4, 
8, and 12/ET for Group 1; and at Weeks 4, 8, 12, and 16/ET for Group 2.  
7.11.2.17 Thyroid Function Tests 
A blood sample will be obtained from all patients for thyroid function tests (free thyroxine [T4], 
free triiodothyronine [T3], reverse T3, thyroid stimulating hormone at screening, baseline (Day 
1), and at Weeks 2, 4, 6, 8, 10, and 12/ET for Group 1. For Group 2, samples will be collected at 
screening, baseline, and at Weeks 2, 4, 6, 8, 10, 12, 14, and 16/ET visits. 
7.12 
Pharmacokinetic Assessments 
For Group 1, blood levels of CORT125134 and metabolites will be measured predose and at 1, 2, 
4, 6, and 8 hours postdose at Weeks 2, 6, and 10, and predose only at Weeks 4, 8, and 12/ET. For 
Group 2, blood levels of CORT125134 and metabolites will be measured predose and at 1, 2, 4, 
6, and 8 hours postdose at Weeks 2, 6, 10, and 14, and predose only at Weeks 4, 8, 12, and 
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The time windows for collection of PK samples are listed below:  
Nominal Time 
Reporting Standards 
Predose 
Up to 60 minutes before dosing 
1 hour postdose 
±5 minutes 
2 hours postdose 
±10 minutes 
4, 6, and 8 hours postdose 
±15 minutes 
 
Dose escalations will proceed according to the procedures outlined in Section 5.4.2. For patients 
in Groups 1 and 2, the first planned escalation of dose will take place the day after the Week 4 
visit, and the second planned escalation of dose will take place the day after the Week 8 visit. For 
patients in Group 2, the third planned escalation of dose will take place the day after the Week 
12 visit.  
In case of a recent or pending dose interruption or dose reduction, the PK sampling day at Weeks 
2, 6, 10, or 14 may be adjusted (ie, made earlier or later) to try to capture at least 7 days of 
administration of the current dose of study drug before PK sampling. (Otherwise, all testing 
windows in the Schedule of Events [Sections 13.1 and 13.2] must be followed.) 
If a scheduled dose escalation is cancelled, the patient will provide subsequent blood samples for 
all trough CORT125134 levels only (ie, full PK profiles at Weeks 6, 10, or 14 will not be 
performed). 
If, as a result of a dose reduction, a Weeks 6, 10, or 14 full PK profile would be redundant 
(ie, a full PK profile was already successfully obtained at the patient’s current dose), it will not 
be repeated. 
7.13 
Safety Assessments 
7.13.1 Physical Examination 
A complete physical examination will be conducted at screening and baseline (Day 1); at Weeks 
2, 4, 6, 8, 10, and 12/ET for Group 1 and at Weeks 2, 4, 6, 8, 10, 12, 14, and 16/ET for Group 2; 
and at the follow-up visit. A complete physical examination will include evaluation of general 
appearance, HEENT (head, eyes, ears, nose, throat), as well as dermatologic, cardiovascular, 
respiratory, gastrointestinal, extremities/ musculoskeletal, and neurologic body systems.  
Height will be measured at the screening visit only.  
7.13.2 Vital Sign Measurements 
Vital signs include BP, heart rate, respiratory rate, and oral body temperature. Blood pressure 
and heart rates will be obtained in the dominant arm (writing arm), if possible, with the patient in 
a sitting position after resting for approximately 5 minutes. Automated BP machines can be used 
to standardize measurements. Vital signs will be collected in the clinic at screening and baseline 
(Day 1); at Weeks 2, 4, 6, 8, 10, and 12/ET for Group 1 and at Weeks 2, 4, 6, 8, 10, 12, 14, and 
16/ET for Group 2; and at the follow-up visit. In addition, unscheduled assessments of vital signs 
can be performed as necessary. 


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In addition to the safety vital signs collected, a 24-hour ambulatory BP test will also be done by 
all patients at screening and by patients in the hypertension subgroup at post-screening time 
points to assess the effect of CORT125134 on BP (see Section 7.11.1.2).  
7.13.3 Electrocardiogram 
Twelve-lead ECG tracings will be obtained in triplicate from all patients at screening and in 
duplicate at Weeks 2, 4, 6, 8, 10, and 12/ET for Group 1 and at Weeks 2, 4, 6, 8, 10, 12, 14, and 
16/ET for Group 2, and the follow-up visit. Patients should be lying down for at least 10 minutes 
prior to each ECG evaluation. A central reviewer will be used; instruction will be provided in the 
study manual.  
At Weeks 2, 4, 6, 8, 10, 12, 14, and ET, the ECG should be performed 2 hours (±30 minutes) 
after study drug dosing.  
The Investigator or designee will indicate on the site’s copy 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.  
7.13.4 Pregnancy Tests and Contraception Methods  
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 child bearing 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 double-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:  
• Abstinence 
• Surgical sterilization  
• Intrauterine device or intrauterine system  
• Oral contraception plus a barrier method  
• Double-barrier method (eg, 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, males should not donate 
sperm until 30 days after the last dose of study drug. 
7.13.5 Safety Clinical Laboratory Tests 
Complete instructions for sample processing and shipment will be provided in the Central 
Laboratory Manual. 


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7.13.5.1 
Laboratory Parameters 
Fasting blood samples will be collected for the analysis of safety in all patients at screening, 
baseline (Day 1); at Weeks 2, 4, 6, 8, 10, and 12/ET for Group 1 and at Weeks 2, 4, 6, 8, 10, 12, 
14, and 16/ET for Group 2; and the follow-up visit. Laboratory samples will be analyzed at one 
or more central laboratories. 
Laboratory values for an analyte that are outside of the normal range for that analyte per the 
applicable central laboratory will be identified and can be repeated at the Investigator’s 
discretion. The Investigator will determine if any out-of-range laboratory values that emerge 
during the study are clinically significant. An abnormal laboratory value that leads to a dose 
modification or patient withdrawal from the study will be recorded as an AE on the eCRF. 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, or becomes medically stable. The Investigator will 
treat the patient as medically required at appropriate intervals until this occurs. 
The Investigator will review all laboratory reports, evaluate the results, and sign/date the report.  
Safety laboratory measurements will include the following: 
Chemistry: 
• Full chemistry profile: albumin, alkaline phosphatase, ALT, AST, blood urea nitrogen, 
calcium, chloride, cholesterol, creatinine, glucose, lactate dehydrogenase, magnesium, 
phosphorus, potassium, sodium, total creatine kinase, total and direct bilirubin, total 
protein, uric acid 
Hematology: 
• Complete blood count: hematocrit, hemoglobin, mean corpuscular hemoglobin, mean 
corpuscular hemoglobin volume, mean corpuscular volume, mean platelet volume, 
platelet count, red blood cell distribution width, red blood cell (RBC) count, and 
WBC count 
• Differential: percent and absolute for the following: basophils, eosinophils, lymphocytes, 
monocytes, and neutrophils 
7.13.5.2 
Sample Collection, Storage, and Shipping 
Complete instructions for collection, preparation, and shipping of all laboratory samples will be 
provided by the central laboratory/ies in a laboratory manual. Shipping instructions for samples 
collected for PK analysis, ACTH precursors, and GR activity biomarkers will also be provided. 
The total volume of blood to be collected from each patient will be no more than 731 mL for 
Group 1 and 908 mL for Group 2 during the 12-week and 16-week treatment periods, 
respectively.  
7.13.6 Safety Event Documentation and Reporting 
7.13.6.1 
Investigator’s Responsibilities 
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for providing appropriate medical care. Investigators are required to report promptly to 


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Corcept Therapeutics or its designee any AE that may reasonably be regarded as caused by, or 
probably caused by, the study drug. If the adverse effect is alarming, the Investigator should 
report the adverse effect immediately. In addition, the Investigators are responsible for alerting 
Corcept Therapeutics or its designee to any event that seems unusual, even if the event may be 
considered an unanticipated benefit to the patient, and for reporting the event on the appropriate 
eCRF or safety report form. 
By exercising appropriate healthcare options, the Investigator remains responsible for managing 
AEs that are serious or that cause a patient to withdraw before completing the study. Frequency 
of follow-up of any particular AE is left to the discretion of the Investigator. Duration of follow-
up and requirements for immediate SAE reporting (within 24 hours of the event) are described 
below. 
7.13.6.2 
Monitoring Safety Data During Study 
Safety results collected during the study (eg, AEs, laboratory test results, physical findings) will 
be monitored on an ongoing basis by the Medical Monitor and Investigator. 
7.13.6.3 
Definition of an Adverse Event 
An AE is any untoward medical occurrence in a study patient administered a pharmaceutical 
product, which does not necessarily have to have a causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not related to the medicinal (investigational) product that emerges or 
worsens relative to the patient’s pretreatment baseline, whether or not it is considered to be 
related to the investigational product.  
Illnesses present before the patient signs the informed consent form (ICF) are considered 
pre-existing conditions and are documented on the medical history eCRF. Pre-existing conditions 
that worsen during the study are entered on the AE eCRF. 
7.13.6.4 
Definition of a Serious Adverse Event 
An SAE is any AE that meets any of the following criteria: 
• Results in death (ie, the AE caused or led to the fatality). 
• Is life-threatening (ie, 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 which hypothetically might have 
caused death if it were more severe). 
• Requires hospitalization or prolongation of existing hospitalization (ie, hospitalizations 
for scheduled treatments and elective medical/surgical procedures are not SAEs by this 
criterion). 
• Results in persistent or significant disability/incapacity (ie, the AE results in substantial 
reduction of the patient’s ability to perform activities of daily living). 
• Results in a congenital anomaly or birth defect (ie., an adverse finding in a child or fetus 
of a patient exposed to the study medication before conception or during pregnancy);  
• Involves other medically important conditions (ie, the AE does not meet any of the above 
serious criteria but based on appropriate medical judgment, may jeopardize the patient or 


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require medical or surgical intervention to prevent one of the serious outcomes listed in 
these criteria). 
7.13.6.5 
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 leads to a dose modification or 
patient withdrawal from the study will be recorded as an AE on the eCRF. Other clinically 
significant laboratory values may be reported as AEs at the discretion of the Investigator. 
7.13.6.6 
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. Illnesses present before the patient signs the informed consent form (ICF) 
are considered pre-existing conditions and are documented on the medical history eCRF. 
Pre-existing conditions that worsen during the study are entered on the AE eCRF. Adverse 
events 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. 
All AEs will be documented on the AE eCRF and in the patient’s medical record. The following 
attributes must be assigned: (1) description, (2) dates of onset and resolution, (3) severity (see 
Section 7.13.6.7.1), (4) relationship to the study medication (see Section 7.13.6.7.2), 
(5) “serious” criteria if applicable (see Section 7.13.6.4), and (6) action taken. The Investigator 
will actively solicit this information and assess the AEs in terms of severity and relationship to 
study drug. 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). 
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 considered to be related (see Section 7.13.6.7.2) to study drug and all SAEs will be 
followed until resolved or until a stable status has been achieved. 
All AEs that are drug-related and unexpected (not reported in 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) as required by the 
IRB/IEC, local regulations, and the governing health authorities.  
7.13.6.7 
Adverse Event Classification 
7.13.6.7.1 Severity Grades of Adverse Events 
The seriousness of an AE should not be confused with its 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 (CTCAE), version 4.03 (CTCAE 2010). For 


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events not listed in the CTCAE, the definitions from the CTCAE provided in Table 5 should be 
used to evaluate the grade of severity for the AE.  
Table 5 
Adverse Event 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 (eg, 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 (eg, 
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 4.03 
(CTCAE 2010). 
 
7.13.6.7.2 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 6. The Investigator’s 
assessment of causality must be provided for all AEs (serious and nonserious). 
Table 6 
Causal Attribution Guidance for Adverse Events 
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. 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, eg, 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, eg, concomitant 
drug(s) or concurrent disease(s). 
7.13.6.8 
Procedures for Reporting a Serious Adverse Event 
Any SAE occurring during the study period (beginning with informed consent) and for at least 
28 days after the last dose of study drug must be reported within 24 hours to the designated 
safety contact and recorded 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 (eg, autopsy reports and terminal medical reports). 


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SAE Reporting Contact Details: 
• US Toll Free Phone:  1-888-723-2445 
• US Fax: 1-888-726-8416 
• Ex-USA Fax: 00 800-529-34043 
• Global Email:  Global.SAEInbox@chiltern.com  
1. All SAEs occurring from the time of informed consent until 28 days following the last 
administration of study medication must be reported to Chiltern Pharmacovigilance 
within 24 hours of the knowledge of the occurrence 
2. Complete the SAE reporting form, including whether the event was or was not related to 
the investigational drug and send to Chiltern Pharmacovigilance. The clinical staff will 
obtain and maintain all pertinent medical records, information, and medical judgments 
from colleagues who assisted in the treatment and follow-up of the patient within the 
patient files. 
3. Promptly inform the governing IRB/IEC of all serious, unexpected, drug-related events 
that occur at his or her site or per the IRB/IEC regulations. It is the responsibility of each 
site to submit IND Safety Reports, as applicable, provided to them by the Sponsor to their 
IRB or IEC as required by the IRB/IEC, local regulations, and the governing health 
authorities. 
4. Fax or email additional follow-up information, if required or available, to Chiltern 
Pharmacovigilance within 24 hours of receipt. This information should be included on a 
follow-up SAE Form, placed with the original SAE Form, and kept with the appropriate 
section of the eCRF and/or study patient file. 
An AE, regardless of seriousness, 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. 
7.13.6.9 
Adverse Event Follow-Up 
All AEs will be followed until resolution, until deemed stable by the Principal Investigator, or 
until the patient is deemed by the Principal Investigator to be lost to follow-up. 
7.13.6.10 Emergency Sponsor Contact 
In a medical emergency (ie, an event that requires immediate attention regarding the treatment of 
a patient, operation of the clinical study, and/or the use of investigational product), study site 
personnel will apply appropriate medical intervention according to current standards of care and 
contact the Medical Monitor: 
 
Corcept Therapeutics Incorporated 
149 Commonwealth Drive 
Menlo Park, CA  94025 
 
 
 


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7.14 
Pregnancy 
All pregnancies with the estimated date of conception occurring during the study treatment or 
within 30 days of the last dose of study treatment should be reported immediately to the Sponsor 
or its designee.  The patient will be followed to determine the outcome of the pregnancy, and the 
outcome will be reported. 
7.14.1 Maternal Exposure 
If a patient becomes pregnant during the study, the study treatment should be discontinued 
immediately. Pregnancy itself is not regarded as an AE.  
If a pregnancy occurs during the study treatment or within 30 days of the last dose of study 
treatment, the Investigator or designee will inform the appropriate Sponsor representatives 
immediately but no later than 24 hours of when he or she becomes aware of it. The Investigator 
or designee will 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. 
7.14.2 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) should be followed and documented, if possible. 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. A consent form specific to this situation must be 
used. The outcome of any conception occurring from the date of the first dose of study drug until 
30 days after the last dose should be followed and documented. 
7.14.3 Prior and Concomitant 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’s syndrome, diabetes, or hypertension. 
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 medication 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.  
Information about concomitant medications will be collected from all patients at each visit from 
screening through the follow-up visit. Any changes in medications since the last visit will be 
captured and recorded.  


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7.14.4 Additional Assessments for Special Safety Events 
7.14.4.1 
Monitoring for Excessive Glucocorticoid Receptor Blockade 
Based on the mechanism of action of CORT125134, there is a theoretical risk of excessive GR 
blockade, which could manifest with findings such as weakness, tiredness, dizziness, 
hypoglycemia, dehydration, weight loss, nausea, vomiting, diarrhea and muscle aches. Since 
CORT125134 does not block the mineralocorticoid receptor, it is unlikely that hypotension 
would be seen in the absence of anti-hypertensive medication. 
At each study visit starting with the baseline visit, patients will be evaluated for signs and 
symptoms of excessive GR blockade, and for patients who experience symptoms, the following 
actions should be taken: 
• CORT125134 treatment should be immediately interrupted for at least 3 days and 
standard supportive care, including fluid resuscitation, as indicated, should be 
administered without delay.  
• Supplemental glucocorticoids may be given in high doses to overcome the GR blockade 
produced by CORT125134. Initially, parenteral dexamethasone 4 to 10 mg should be 
considered, followed by additional parenteral or oral doses once or twice daily for 1 to 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 mineralocorticoid receptor antagonist, 
consideration should be given to discontinuing it or adjusting the dose, particularly in the 
presence of hypotension.  
• Treatment with CORT125134 should be resumed only if the Investigator believes that the 
potential benefits outweigh the risks and after a discussion with the Medical Monitor. 
Dosing may be resumed at the lowest tolerable dose previously administered to the 
patients. For patients in Group 2 on 250 mg/day, the dose may be reduced to 200 mg/day 
or 150 mg/day, as deemed appropriate by the Investigator. After 2 weeks, the dose may 
be maintained at the current dose or may be increased by 50 mg with the approval of the 
Medical Monitor. (Subsequent dose escalations at Week 4 or Week 8 must also be 
approved by the Medical Monitor.) 
 
Note: In the event of significant trauma, surgery, or medical illness occurring at any time during 
the study (through 2 weeks after last dose), supplemental glucocorticoids may be needed to 
offset the GR blockade even in patients not experiencing signs and symptoms of excessive 
blockade. After resolution of the physiological stress associated with the event, CORT125134 
can be reinitiated at the last dose level the patient was receiving prior to interruption of dosing, if 
the dosing period of the study has not ended. 
At study enrollment, all patients will be given a card to carry with them that identifies their 
potential risk for excessive GR blockade. The card will contain the following information: 
• Mention of CORT125134 use (“glucocorticoid receptor antagonist”) 
• Potential need for glucocorticoid use in setting of shock, surgery, or serious illness or 
injury 


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• Recommended dose of replacement steroids (4–10 mg dexamethasone intramuscularly or 
intravenously) 
• Investigator contact information 
7.14.4.2 
Monitoring for Hypokalemia 
If a patient develops hypokalemia during the study, oral replacement of potassium (40-120 mEq 
per day) should be considered. Mineralocorticoid receptor antagonists, such as spironolactone or 
other potassium-sparing diuretics, may be initiated or increased to control persistent hypokalemia 
and associated elevated BP or edema. If daily oral potassium replacement, mineralocorticoid 
receptor antagonism, or other potassium-sparing diuretics are insufficient, the CORT125134 
dose can be decreased to the lower dose, if applicable, or study drug should be discontinued if 
the patient is on the lowest dose of CORT125134. If oral administration of potassium is not 
feasible or cardiac complications of hypokalemia exist, intravenous potassium replacement may 
be required and may necessitate cardiac telemetry.  
7.14.4.3 
Hypertension 
Patients who develop hypertension while on study drug should have the diagnosis confirmed by 
ambulatory BP monitoring. In addition, the patient should be examined for edema and potassium 
levels should be checked.  
7.15 
Early Study Discontinuation 
If a patient withdraws from the study before completing the Week 12 visit, he or she should be 
asked to return for an ET visit, at which all Week 12 assessments (Section 8.14) will be 
performed. 
The patient will be asked to also return for a follow-up visit 4 weeks after the ET visit has been 
completed. In both Group 1 and Group 2, patients who discontinue study early may be replaced 
to ensure that:  
• 12 patients per group provide steady-state PK data through Week 10  
• 15 patients provide safety and efficacy data through Week 10. 
 
The Medical Monitor should be notified of patient discontinuations from the study. 
7.16 
Removal of Patients from Treatment or Assessment 
Study drug treatment will be discontinued early if any of the following events occur:  
• Evidence of excessive GR blockade based on a combination of the following Grade 3 or 
higher events: fatigue, anorexia, nausea and vomiting (associated with decreased oral 
intake), and abdominal pain, seen either at the 100-mg dose level or at other dose levels 
for which the investigator deems dose reduction is not an option (refer to Section 7.14.4.1 
for monitoring for excessive glucocorticoid receptor blockade) 
• Uncontrolled hypertension, defined as systolic BP >170 mmHg or diastolic 
BP >110 mmHg (as confirmed by ambulatory blood pressure monitoring) despite the use 
of appropriate antihypertension medications. 


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• Severe (<2.5 mEq/L) hypokalemia and/or persistent hypokalemia that does not respond to 
replacement of potassium and MR antagonists or other potassium sparing diuretics. 
Confirmed QTcF >500 ms. If QTcF is >500 ms, another ECG should be repeated within 
24 hours and after any coexistent electrolyte abnormality is corrected. If a medication 
known to cause QTc prolongation has been started, it should be discontinued and the 
ECG should be repeated. If QTc prolongation persists, based on the average of at least 
2 ECGs, the patient should be discontinued. 
• 
 
 
 
 
 
 
THE DRC WILL BE NOTIFIED OF ALL  
SERIOUS ADVERSE EVENTS AND DISCONTINUATIONS 


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8 
PROCEDURES 
A schedule of events is provided in Appendix 13.1.  
Most assessments are for all patients; a few are performed only in patients in a specific subgroup. 
Note that a patient can be in the impaired glucose tolerance/diabetes subgroup, the hypertension 
subgroup, or both.  
For patients who roll over from Group 1 to Group 2: 
• There will not be a treatment completion visit in between Group 1 and Group 2 study 
visits. 
• The Week 12 visit will serve as the new baseline visit for the Group 2 treatment period 
• The safety follow-up visit for Group 1 (Week 16) is not necessary  
8.1 
Screening (Day −42 to Day −1)  
Note:  Patients requiring washout of a medication for Cushing’s syndrome must complete the 
screening/baseline 24-hour UFC tests, salivary cortisol tests, oGTTs, and 24-hour ambulatory BP 
monitoring tests after a minimum washout of 2 weeks for adrenostatic medications and short-
acting somatostatin analogs, 4 weeks for mifepristone and dopamine agonists, and 6 weeks for 
long-acting somatostatin ligands and within 3 weeks before Day 1 dosing. 
Patients rolling from Group 1 to Group 2 do not require these assessments, and the screening 
visit will not be repeated between participation in Group 1 and Group 2. 
• Informed consent  
• Demographics and baseline disease characteristics 
• Medical history and medication history 
• Height 
• Inclusion/exclusion criteria  
• DST (if warranted for study entry). A DST done within 12 weeks before the ICF is 
signed will be accepted. 
• Body weight  
• 24-hour UFC with creatinine (collected by the patient at home at least two times and up 
to four times during screening). The average of the results will serve as “baseline”. 
• Urinary calcium (Ca), sodium (Na) from 24-hour UFC 
• Salivary cortisol (collected by the patient at home at least two times and up to four times 
on different nights during screening). For screening, the average of the results will serve 
as “baseline”.  
• The 24-hour ambulatory BP will be assessed for all patients during the screening period. 
For the subgroup of patients who qualify for the hypertension subgroup, there must be a 
24-hour ambulatory BP test done within 3 weeks before Day 1; this result will be used as 
“baseline”. If the initial screening test was done within 3 weeks before Day 1, it does not 
need to be repeated. 
• Menstrual cycle information (premenopausal women not taking hormonal birth control) 
• Complete physical examination 
• Vital signs, including BP, heart rate, respiratory rate, and oral body temperature 
• 12-lead ECG 


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• AEs 
• Concomitant medications record 
• Blood samples for 
– 2-hour oGTT (after an 8-hour fast) 
– HbA1c (value within 3 months of Day 1 dose) 
– HPA axis tests (ACTH, serum cortisol, 17-OH-progesterone, 11-deoxycortisol, 
DHEA-S, and androstenedione) 
– Pregnancy test (female patients) 
– Chemistry, thyroid, and hematology tests 
 
Patients who fail screening may be rescreened (see Section 4.3). 
Pituitary MRI radiographic scans and assessments in patients with Cushing disease that are 
obtained up to 6 months before Day 1 as standard of care will be collected if available. 
8.2 
Baseline Visit (Day 1) 
Note: for patients rolling from Group 1 to Group 2, the Week 12 assessments in Group 1 equal 
the baseline visit assessments in Group 2. 
Predose assessments include:  
• Inclusion/exclusion criteria 
• Enrollment  
• Body weight 
• Waist circumference 
• BDI-II 
• Trail making test 
• CushingQoL questionnaire 
• Sit-to-stand test 
• Menstrual cycle information (premenopausal women not taking hormonal birth control) 
• Complete physical examination 
• Vital signs, including BP, heart rate, respiratory rate, and oral body temperature 
• AEs 
• Concomitant medications 
• Physician’s Global Assessment 
• Blood samples for  
– 2-hour oGTT (after an 8-hour fast; impaired glucose tolerance/diabetes 
subgroup only) 
– HbA1c  
– Fructosamine 
– Adiponectin  
– Lipid panel 
– Sex hormone levels 
– Coagulation panel 


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– GR activity biomarkers  
– HPA axis tests (ACTH, serum cortisol, 17-OH-progesterone, 11-deoxycortisol, 
DHEA-S, and androstenedione) 
– ACTH precursors  
– High-sensitivity C-reactive protein 
– IGF-1 
– Chemistry, thyroid, and hematology tests 
– Bone laboratory parameters 
• Urine samples for  
– Urine pregnancy test (female patients only) 
– Bone laboratory parameters 
• Administration of the Day 1 dose of study drug after completion of all baseline tests 
• Study drug dispensing (2-week supply of study drug) 
• Patient diary card dispensed  
 
8.3 
Week 1: Study Day 7 (± 1 day) – Telephone or Email Contact 
Study drug compliance, AEs, and concomitant medication changes will be captured. 
8.4 
Week 2: Study Day 14 (± 2 days) 
• Compliance check 
• 24-hour UFC with creatinine (collected by the patient two times at home within 1 week 
prior to the study visit) 
• Urinary Ca, Na from 24-hour UFC 
• Salivary cortisol (collected by the patient two times at home within 1 week prior to the 
study visit) 
• 24-hour ambulatory BP test (hypertension subgroup only; initiated in the clinic and 
completed by the patient at home) 
• Body weight 
• Menstrual cycle information (premenopausal women not taking hormonal birth control) 
• Complete physical examination 
• Vital signs, including BP, heart rate, respiratory rate, and oral body temperature 
• AEs 
• Concomitant medications 
• Physician’s Global Assessment 
• Blood samples for  
– Serial PK: predose and 1, 2, 4, 6, and 8 hours postdose 
– Fructosamine 
– HPA axis tests (ACTH, serum cortisol, 17-OH-progesterone, 11-deoxycortisol, 
DHEA-S, and androstenedione) 
– ACTH precursors 
– Chemistry, thyroid, and hematology tests 


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• Urine sample for  
– Urine pregnancy test (female patients only) 
• Administration of the daily dose of study drug 
• 12-lead ECG (2 hours ± 30 min after study drug dosing) 
• Study drug dispensing (2-week supply of study drug) 
• Patient diary collected, reviewed and a new diary card dispensed 
 
8.5 
Week 3: Study Day 21 (± 1 day) – Telephone or Email Contact 
Study drug compliance, AEs, and concomitant medication changes will be captured. 
8.6 
 Week 4: Study Day 28 (± 2 days) 
• Compliance check 
• 24-hour UFC with creatinine (collected by the patient two times at home within 1 week 
prior to the study visit) 
• Urinary Ca, Na from 24-hour UFC 
• Salivary cortisol (collected by the patient two times at home within 1 week prior to the 
study visit) 
• 24-hour ambulatory BP test (hypertension subgroup only initiated in the clinic and 
completed by the patient at home)  
• Body weight 
• Waist circumference 
• BDI-II 
• Trail making test 
• CushingQoL questionnaire 
• Sit-to-stand test 
• Menstrual cycle information (premenopausal women not taking hormonal birth control) 
• Complete physical examination 
• Vital signs, including BP, heart rate, respiratory rate, and oral body temperature 
• AEs 
• Concomitant medications 
• Physician’s Global Assessment 
• Blood samples for  
– 2-hour oGTT (after an 8-hour fast; impaired glucose tolerance/diabetes 
subgroup only) 
– Trough PK: predose only 
– Fructosamine 
– Adiponectin  
– Lipid panel 
– Coagulation panel 
– GR activity biomarkers  
– HPA axis tests (ACTH, serum cortisol, 17-OH-progesterone, 11-deoxycortisol, 
DHEA-S, and androstenedione) 


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– ACTH precursors  
– High-sensitivity C-reactive protein 
– IGF-1 
– Chemistry, thyroid, and hematology tests 
– Bone laboratory parameters 
• Urine samples for 
– Urine pregnancy test (female patients only) 
– Bone laboratory parameters 
• Administration of the daily dose of study drug 
• 12-lead ECG (2 hours ± 30 min after study drug dosing) 
• Study drug dispensing (2-week supply of study drug) 
• Patient diary collected, reviewed and a new diary card dispensed  
• Medical Monitor approves dose escalation 
• Dose escalation starts the day after the Week 4 visit 
 
8.7 
Week 5: Study Day 35 (± 1 day) – Telephone or Email Contact 
Study drug compliance, AEs, and concomitant medication changes will be captured. 
8.8 
Week 6: Study Day 42 (± 2 days) 
• Compliance check 
• 24-hour UFC with creatinine (collected by the patient two times at home within 1 week 
prior to the study visit) 
• Urinary Ca, Na from 24-hour UFC 
• Salivary cortisol (collected by the patient two times at home within 1 week prior to the 
study visit) 
• 24-hour ambulatory BP test (hypertension subgroup only; initiated in the clinic and 
completed by the patient at home) 
• Body weight 
• Menstrual cycle information (premenopausal women not taking hormonal birth control) 
• Complete physical examination 
• Vital signs, including BP, heart rate, respiratory rate, and oral body temperature 
• AEs 
• Concomitant medications 
• Physician’s Global Assessment 
• Blood samples for  
– Serial PK: predose and 1, 2, 4, 6, and 8 hours postdose 
– Fructosamine 
– HPA axis tests (ACTH, serum cortisol, 17-OH-progesterone, 11-deoxycortisol, 
DHEA-S, and androstenedione) 
– ACTH precursors  
– Chemistry, thyroid, and hematology tests 


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• Urine sample for 
– Urine pregnancy test (female patients only) 
• Administration of the daily dose of study drug 
• 12-lead ECG (2 hours ± 30 min after study drug dosing) 
• Study drug dispensing (2-week supply of study drug) 
• Patient diary collected, reviewed and a new diary card dispensed  
 
8.9 
Week 7: Study Day 49 (± 1 day) – Telephone or Email Contact 
Study drug compliance, AEs, and concomitant medication changes will be captured. 
8.10 
Week 8: Study Day 56 (± 2 days) 
• Compliance check 
• 24-hour UFC with creatinine (collected by the patient two times at home within 1 week 
prior to the study visit) 
• Urinary Ca, Na from 24-hour UFC  
• Salivary cortisol (collected by the patient two times at home within 1 week prior to the 
study visit) 
• 24-hour ambulatory BP test (hypertension subgroup only; initiated in the clinic and 
completed by the patient at home 
• Body weight 
• Waist circumference 
• BDI-II 
• Trail making test 
• CushingQoL questionnaire 
• Sit-to-stand test 
• Menstrual cycle information (premenopausal women not taking hormonal birth control) 
• Complete physical examination 
• Vital signs, including BP, heart rate, respiratory rate, and oral body temperature 
• AEs 
• Concomitant medications 
• Physician’s Global Assessment 
• Blood samples for 
– 2-hour oGTT (after an 8-hour fast; impaired glucose tolerance/diabetes 
subgroup only) 
– Trough PK: predose only 
– Fructosamine 
– Adiponectin  
– Lipid panel 
– Coagulation panel 
– GR activity biomarkers  
– HPA axis tests (ACTH, serum cortisol, 17-OH-progesterone, 11-deoxycortisol, 
DHEA-S, and androstenedione) 


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– ACTH precursors  
– High-sensitivity C-reactive protein 
– IGF-1 
– Chemistry, thyroid, and hematology tests 
– Bone laboratory parameters 
• Urine samples for 
– Urine pregnancy test (female patients only) 
– Bone laboratory parameters 
• Administration of the daily dose of study drug 
• 12-lead ECG (2 hours ± 30 min after study drug dosing) 
• Study drug dispensing (2-week supply of study drug) 
• Patient diary collected, reviewed and a new diary card dispensed  
• Medical Monitor approves dose escalation 
• Dose escalation starts the day after the Week 8 visit 
 
8.11 
Week 9: Study Day 63 (± 1 day) – Telephone or Email Contact 
Study drug compliance, AEs, and concomitant medication changes will be captured. 
8.12 
Week 10: Study Day 70 (± 2 days) 
• Compliance check 
• 24-hour UFC with creatinine (collected by the patient two times at home within 1 week 
prior to the study visit) 
• Urinary Ca, Na from 24-hour UFC 
• Salivary cortisol (collected by the patient two times at home within 1 week prior to the 
study visit) 
• 24-hour ambulatory BP test (hypertension subgroup only; initiated in the clinic and 
completed by the patient at home) 
• Body weight 
• Menstrual cycle information (premenopausal women not taking hormonal birth control) 
• Complete physical examination 
• Vital signs, including BP, heart rate, respiratory rate, and oral body temperature 
• AEs 
• Concomitant medications 
• Physician’s Global Assessment 
• Blood samples for  
– Serial PK: predose and 1, 2, 4, 6, and 8 hours postdose 
– Fructosamine 
– HPA axis tests (ACTH, serum cortisol, 17-OH-progesterone, 11-deoxycortisol, 
DHEA-S, and androstenedione) 
– ACTH precursors  
– Chemistry, thyroid, and hematology tests 


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• Urine sample for 
– Urine pregnancy test (female patients only) 
• Administration of the daily dose of study drug 
• 12-lead ECG (2 hours ± 30 min after study drug dosing) 
• Study drug dispensing (2-week supply of study drug) 
• Patient diary collected, reviewed and a new diary card dispensed  
 
8.13 
Week 11: Study Day 77 (±1 day) – Telephone or Email Contact 
Study drug compliance, AEs, and concomitant medication changes will be captured. 
8.14 
Group 1, Week 12: Study Day 84/Early Termination (± 2 days) 
If a patient discontinues from the study early (ET), all Week 12 assessments will be done at the 
time of termination or soon thereafter. For patients rolling over from Group 1 to Group 2, the 
Week 12 visit will serve as the baseline visit for their Group 2 treatment period.  
• Compliance check 
• 24-hour UFC with creatinine (collected by the patient at home within 1 week prior to the 
study visit) 
• Urinary Ca, Na from 24-hour UFC 
• Salivary cortisol (collected by the patient two times at home within 1 week prior to the 
study visit) 
• 24-hour ambulatory BP test (hypertension subgroup only; initiated in the clinic and 
completed by the patient at home) 
• Body weight 
• Waist circumference 
• BDI-II 
• Trail making test 
• CushingQoL questionnaire 
• Sit-to-stand test 
• Menstrual cycle information (premenopausal women not taking hormonal birth control) 
• Complete physical examination 
• Vital signs, including BP, heart rate, respiratory rate, and oral body temperature 
• AEs 
• Concomitant medications 
• Physician’s Global Assessment 
• Patient diary collected and reviewed  
• Blood samples for  
– 2-hour oGTT (after an 8-hour fast; impaired glucose tolerance/diabetes 
subgroup only) 
– Trough PK: predose only  
– HbA1c  
– Fructosamine 
– Adiponectin  


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– Lipid panel 
– Sex hormone levels 
– Coagulation panel 
– GR activity biomarkers  
– HPA axis tests (ACTH, serum cortisol, 17-OH-progesterone, 11-deoxycortisol, 
DHEA-S, and androstenedione) 
– ACTH precursors 
– High-sensitivity C-reactive protein 
– IGF-1 
– Chemistry, thyroid, and hematology tests 
– Bone laboratory parameters 
• Urine samples for  
– Urine pregnancy test (female patients only) 
– Bone laboratory parameters 
• Administration of final dose of study drug (Week 12 Visit only) 
• 12-lead ECG (this will be done 2 ± 30 mins hours after study drug dosing) 
 
8.15 
Group 2, Week 12: Study Day 84 (± 2 days) 
• Compliance check 
• 24-hour UFC with creatinine (collected by the patient two times at home within 1 week 
prior to the study visit) 
• Urinary Ca, Na from 24-hour UFC  
• Salivary cortisol (collected by the patient two times at home within 1 week prior to the 
study visit) 
• 24-hour ambulatory BP test (hypertension subgroup only; initiated in the clinic and 
completed by the patient at home 
• Body weight 
• Waist circumference 
• BDI-II 
• Trail making test 
• CushingQoL questionnaire 
• Sit-to-stand test 
• Menstrual cycle information (premenopausal women not taking hormonal birth control) 
• Complete physical examination 
• Vital signs, including BP, heart rate, respiratory rate, and oral body temperature 
• AEs 
• Concomitant medications 
• Physician’s Global Assessment 
• Blood samples for 
– 2-hour oGTT (after an 8-hour fast; impaired glucose tolerance/diabetes subgroup 
only) 
– Trough PK: predose only 


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– HbA1c 
– Fructosamine 
– Adiponectin  
– Lipid panel 
– Coagulation panel 
– GR activity biomarkers  
– HPA axis tests (ACTH, serum cortisol, 17-OH-progesterone, 11-deoxycortisol, 
DHEA-S, and androstenedione) 
– ACTH precursors  
– High-sensitivity C-reactive protein 
– IGF-1 
– Chemistry, thyroid, and hematology tests 
– Bone laboratory parameters 
• Urine samples for 
– Urine pregnancy test (female patients only) 
– Bone laboratory parameters 
• Administration of the daily dose of study drug 
• 12-lead ECG (2 hours ± 30 min after study drug dosing) 
• Study drug dispensing (2-week supply of study drug) 
• Patient diary collected, reviewed and a new diary card dispensed  
• Medical Monitor approves dose escalation 
• Dose escalation starts the day after the Week 12 visit 
 
8.16 
Group 2, Week 13: Study Day 91 (±1 day) – Telephone or Email Contact 
Study drug compliance, AEs, and concomitant medication changes will be captured. 
8.17 
Group 2, Week 14: Study Day 98 (± 2 days) 
• Compliance check 
• 24-hour UFC with creatinine (collected by the patient two times at home within 1 week 
prior to the study visit) 
• Urinary Ca, Na from 24-hour UFC 
• Salivary cortisol (collected by the patient two times at home within 1 week prior to the 
study visit) 
• 24-hour ambulatory BP test (hypertension subgroup only; initiated in the clinic and 
completed by the patient at home) 
• Body weight 
• Menstrual cycle information (premenopausal women not taking hormonal birth control) 
• Complete physical examination 
• Vital signs, including BP, heart rate, respiratory rate, and oral body temperature 
• AEs 
• Concomitant medications 
• Physician’s Global Assessment 


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• Blood samples for  
– Serial PK: predose and 1, 2, 4, 6, and 8 hours postdose 
– Fructosamine 
– HPA axis tests (ACTH, serum cortisol, 17-OH-progesterone, 11-deoxycortisol, 
DHEA-S, and androstenedione) 
– ACTH precursors  
– Chemistry, thyroid, and hematology tests 
• Urine sample for 
– Urine pregnancy test (female patients only) 
• Administration of the daily dose of study drug 
• 12-lead ECG (2 hours ± 30 min after study drug dosing) 
• Study drug dispensing (2-week supply of study drug) 
• Patient diary collected, reviewed and a new diary card dispensed  
 
8.18 
Group 2, Week 15: Study Day 105 (±1 day) – Telephone or Email Contact 
Study drug compliance, AEs, and concomitant medication changes will be captured. 
8.19 
Group 2, Week 16: Study Day 112/Early Termination (± 2 days) 
If a Group 2 patient discontinues from the study early (ET), all Week 16 assessments will be 
done at the time of termination or soon thereafter.  
• Compliance check 
• 24-hour UFC with creatinine (collected by the patient at home within 1 week prior to the 
study visit) 
• Urinary Ca, Na from 24-hour UFC 
• Salivary cortisol (collected by the patient two times at home within 1 week prior to the 
study visit) 
• 24-hour ambulatory BP test (hypertension subgroup only; initiated in the clinic and 
completed by the patient at home) 
• Body weight 
• Waist circumference 
• BDI-II 
• Trail making test 
• CushingQoL questionnaire 
• Sit-to-stand test 
• Menstrual cycle information (premenopausal women not taking hormonal birth control) 
• Complete physical examination 
• Vital signs, including BP, heart rate, respiratory rate, and oral body temperature 
• AEs 
• Concomitant medications 
• Physician’s Global Assessment 
• Patient diary collected and reviewed  
• Blood samples for  


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– 2-hour oGTT (after an 8-h fast; impaired glucose tolerance/diabetes subgroup only) 
– Trough PK: predose only  
– HbA1c  
– Fructosamine 
– Adiponectin  
– Lipid panel 
– Sex hormone levels 
– Coagulation panel 
– GR activity biomarkers  
– HPA axis tests (ACTH, serum cortisol, 17-OH-progesterone, 11-deoxycortisol, 
DHEA-S, and androstenedione) 
– ACTH precursors 
– High-sensitivity C-reactive protein 
– IGF-1 
– Chemistry, thyroid, and hematology tests 
– Bone laboratory parameters 
• Urine samples for  
– Urine pregnancy test (female patients only) 
– Bone laboratory parameters 
• Administration of final dose of study drug (Week 16 Visit only) 
• 12-lead ECG (this will be done 2 hours ± 30 min after study drug dosing) 
 
8.20 
Group 1, Follow-up Visit at Week 16: Study Day 112 (+7 days) and Group 2, 
Follow-up Visit at Week 20: Study Day 140 (+7 days) 
This visit is not necessary for patients who roll from Group 1 to Group 2. 
• Body weight 
• Waist circumference 
• CushingQoL questionnaire 
• Complete physical examination 
• Vital signs, including BP, heart rate, respiratory rate, and oral body temperature 
• 12-lead ECG 
• AEs 
• Concomitant medications 
• Physician’s Global Assessment 
• Blood samples for  
– Lipid panel 
– Chemistryand hematology tests 
• Urine sample for  
– Urine pregnancy test 


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Pituitary MRI radiographic scans and assessments in patients with Cushing disease that are 
obtained up to 1 month after last CORT125134 dose as standard of care will be collected 
if available. 


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9 
QUALITY CONTROL AND ASSURANCE 
This study will be performed and reported in compliance with Good Clinical Practice (GCP), the 
protocol, applicable standard operating procedures, and applicable regulations. To ensure 
compliance, the Sponsor may conduct a quality assurance audit. 
Prior to selection of the study site(s), a site evaluation visit(s) will be performed to review the 
adequacy of the facility (ies), personnel, and their ability to conduct research. A site initiation 
visit and/or Investigator’s meeting will be held prior to study start-up to train the Investigators 
and study coordinators on the protocol, source document and eCRF completion, safety, study 
drug handling, sample handling, and to review GCP. 
This study will use eCRFs designed to allow capture and recording of all protocol-required 
information for each patient. All eCRFs will be completed by the clinic staff, and all completed 
eCRFs will be reviewed by the Principal Investigator, as noted by his or her electronic signature, 
prior to review by the clinical monitor or designated representative. The clinical monitor or 
designated representative will review all source records on site and compare them to the data 
collected on the eCRF. 
Data will be entered into a clinical database as specified in the Sponsor’s/contract research 
organization’s data management plan. Quality control and data validation procedures will be 
applied to ensure the validity and accuracy of the clinical database. Data will be reviewed and 
checked for omissions, apparent errors, and values requiring further clarification using 
computerized and manual procedures. Data queries requiring clarification will be communicated 
to the investigational site for resolution. Only authorized personnel will make corrections to the 
clinical database, and all corrections will be documented in an audit trail. 
Assay of clinical safety laboratory samples and any other samples will be performed by certified 
laboratories using validated analytical methods. 


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10 
PLANNED STATISTICAL METHODS 
10.1 
General 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 prior 
to database lock. 
All summaries will be presented by starting dose group, regardless of the actual dose level at the 
time point associated with the data collection. In addition, data will be tabulated for all patients 
combined. All relevant data collected on the eCRF will be presented in by-patient data listings, 
to include the site identifier, patient number, and starting dose group. Listing presenting study 
data over time will include the dose level the patient received at the time of data collection. In 
addition to summary tables by dosing group and by-patient data listings, individual patient 
profiles will be generated to list and display graphically key study endpoints over time. 
In general, continuous variables will be summarized by the number of patients with non-missing 
data, mean, standard deviation, median, minimum, and maximum values. Categorical variables 
will be summarized by the number and percentage of patients in each category. 
Predose measurements on Day 1 will be considered the primary baseline values. If a Day 1 
predose value is not available, the screening measurement may be used as the baseline value. 
Select analyses may also assess changes from the last measurement prior to escalation to the 
current dose level received. Additionally, patients in Group 1 who continue treatment as part of 
Group 2 may have data collected while receiving Group 2 dosing summarized as a change 
relative to their last measurement collected prior to dosing as part of Group 1 (ie, the Group 1 
baseline value). 
10.2 
Analysis Population 
The analysis population for all efficacy and safety analyses will include all patients who received 
at least one dose of study drug. As defined in the PK analysis plan, the PK analysis population 
will comprise all patients who have evaluable PK data.  
For all analyses, the patient will be included in the dose group in which he or she was enrolled, 
regardless of actual dose level at the time point when the data were collected. 
Select efficacy endpoints will be analyzed by subgroup only:  
• Patients with impaired glucose tolerance/diabetes 
• Patients with hypertension  
All enrolled patients will belong to at least one of these subgroups and an individual patient may 
be included in both. If a patient enters the study with hypertension but takes an additional 
antihypertensive medication or increases the dosage of a concurrent antihypertensive medication, 
that patient will be classified as a nonresponder (see Section 10.6 for definition of response for 
each subgroup). If a patient enters the study with diabetes/impaired glucose tolerance but takes 
an additional diabetes medication or increases the dosage of a concurrent diabetes medication, 
that patient will be classified as a nonresponder. 


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10.3 
Patient Disposition 
Patient disposition information will be summarized by dose group and overall. Summaries will 
include the number of enrolled patients, the number of patients in each analysis population, the 
number of patients in each subgroup, the number of patients completing the study per protocol, 
and the number of patients terminating the study early by the primary reason for discontinuation. 
10.4 
Demographic and Baseline Characteristics 
Demographic variables will include age at the time of informed consent, sex, ethnicity and race. 
Other baseline characteristics will include relevant medical history and baseline disease 
characteristics (eg, time since diagnosis, Cushing’s syndrome type). Demographic and baseline 
characteristics will be summarized for all treated patients and presented separately by subgroup, 
by dose group, and overall. 
10.5 
Concomitant Medications 
Verbatim terms on eCRFs will be mapped to Anatomical/Therapeutic Chemical class and 
Generic Drug Names using the most current version of the World Health Organization Drug 
Dictionary. Concomitant medications will be summarized for all treatment patients by dose 
group and overall. 
10.6 
Efficacy Analyses 
The key efficacy assessments in this study are the evaluation of the glucose tolerance in the 
impaired glucose tolerance/diabetes subgroup and BP in the hypertensive subgroup. All other 
efficacy variables are considered exploratory.  
Responder endpoints for each subgroup as defined below will be summarized separately for the 
following patient analysis sets: 
• Group 1 patients, where responder status is determined based on the Group 1 baseline 
value; 
• Group 2 patients, where responder status is determined based on the Group 2 baseline 
value; 
• Group 2 patients, where responder status is determined based on the Group 1 baseline 
value for those patients who were also enrolled and treated in Group 1, and the Group 2 
baseline value for those patients who were not enrolled in Group 1; 
• Group 2 patients who were not enrolled and treated in Group 1, where responder status is 
determined based on the Group 2 baseline value; 
• Group 2 patients who were also enrolled and treated in Group 1, where responder status 
is determined based on the Group 2 baseline value. 
10.6.1 Impaired Glucose Tolerance/Diabetes Subgroup 
The area under the concentration-time curve for glucose (AUCglucose) will be calculated based on 
results of the oGTTs from baseline to Week 12/ET in Group 1 or Week 16/ET in Group 2, for 
those patients with impaired glucose tolerance or diabetes at study entry. A responder will be 
defined as a patient who experiences at least a 25% decrease from baseline in AUCglucose who has 
not taken an additional diabetes medication during the treatment period or increased the dosage 


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of a concurrent diabetes medication. The number and percentage of patients who are responders 
will be presented by dose group and for all patients, along with the 95% binomial exact 
confidence interval. 
AUCglucose will be summarized by descriptive statistics by dose group and for all patients. In 
addition, plasma glucose, HbA1c, fructosamine, and adiponectin concentrations will be 
summarized using descriptive statistics by visit, time point, and dose group, to include the 
change from baseline and change from the last measurement collected prior to escalation to the 
current dose level at each visit and time point. Plots of the mean plasma glucose values over time 
will be presented. 
The number and percentage of patients whose dose of medications that lower blood glucose 
decreased, stayed the same, or increased from baseline to Week 12/ET in Group 1 or Week 
16/ET in Group 2 will be summarized, among those patients taking such medications at baseline. 
10.6.2 Hypertension Subgroup 
Changes in mean diastolic BP and systolic BP measured by 24-hour ambulatory BP monitoring 
will be analyzed for patients with hypertension at study entry. A responder will be defined as a 
patient who experiences at least a 5 mmHg decrease in mean diastolic or systolic BP from 
baseline to Week 12/ET in Group 1 or Week 16/ET in Group 2 who has not taken an additional 
antihypertensive medication during the treatment period or increased the dosage of a concurrent 
antihypertensive medication. The number and percentage of patients who are responders will be 
presented by dose group and for all patients, along with the 95% binomial exact confidence 
interval. 
Diastolic and systolic BP will be summarized using descriptive statistics by visit, time point, and 
dose group, to include the change from baseline and change from the last measurement collected 
prior to escalation to the current dose level at each visit and time point.  
The number and percentage of patients whose dose of antihypertensive medication decreased, 
stayed the same, or increased from baseline to Week 12/ET in Group 1 or Week 16/ET in Group 
2 will be summarized, among those patients taking such medications at baseline. 
10.6.3 Other Measures of Efficacy 
Other measures of efficacy will be summarized for all patients receiving treatment, regardless of 
indication at study treatment, by dose group, and for all patients. 
Results for efficacy variables from data collection, including body weight and body composition 
by quality of life, 24-hour UFC, salivary cortisol, strength scores, lipid panel, coagulation, 
hormonal and menstrual cycle, bone laboratory parameters, and high-sensitivity C-reactive 
protein will be summarized using descriptive statistics by parameter, visit, and time point, to 
include the changes from baseline. 
10.7 
Pharmacokinetic Analyses 
The details of PK analysis will be outlined in a separate document. 


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10.8 
Safety Analyses 
Adverse events will be mapped to system organ classes and preferred terms using the Medical 
Dictionary for Regulatory Activities (MedDRA). Treatment-emergent AEs are defined as those 
that start or worsen after the start of study treatment and up to 28 days after the last dose of study 
treatment.  
Treatment-emergent AEs will be summarized overall and by dose group and displayed by system 
organ class and preferred term. Treatment-emergent AEs will be further summarized by severity 
and relationship to study treatment. At each level of summation, patients will be counted only 
once, under the greatest severity and strongest study-drug relationship (as reported by the 
Investigator).  
All AEs (whether TEAEs or not) will be listed by individual patient, including information 
regarding onset, duration, severity, and relationship to study drug. Serious AEs and AEs that led 
to withdrawal from the study will be listed by individual patient.  
Clinical laboratory test results (chemistry and hematology), vital sign measurements, and ECG 
interval results will be summarized overall and for each dose group by parameter, visit, and time 
point using descriptive statistics, to include the change from baseline values. Shift tables will be 
constructed that describe changes from baseline to the end of treatment in clinical laboratory 
values.  
10.9 
Determination of Sample Size 
The study is not powered for formal hypothesis testing. The Sponsor has deemed 30 patients 
(15 per dose group) as a sufficient number to evaluate efficacy and safety/tolerability and to 
establish point estimates for efficacy endpoints for future evaluation of the study drug. 


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11 
ADMINISTRATIVE CONSIDERATIONS 
11.1 
Institutional Review Board/Independent Ethics Committee 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB or IEC, as appropriate. The Investigator must submit 
written approval to the Sponsor, before he or she can enroll any patient into the study. 
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB or IEC must approve all 
advertising used to recruit patients for the study. The protocol must be re-approved by the IRB or 
IEC upon receipt of amendments and annually, as local regulations require. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
11.2 
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 Principal Investigator will ensure that the study procedures outlined in this protocol will be 
conducted in accordance with the US Code of Federal Regulations (CFR) governing Protection 
of Human Subjects (21 CFR 50), Financial Disclosure by Clinical Investigators (21 CFR 54), 
IRBs (21 CFR 56), Investigational New Drug Application (21 CFR 312), and Applications for 
Food and Drug Administration Approval to Market a New Drug (21 CFR 314), as appropriate. 
11.3 
Patient Informed Consent 
The Principal Investigator(s) at each center will ensure that the 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 ICF will contain all of the elements required by ICH guidelines for GCP and any additional 
elements required by local regulations. 
The ICF must include information about the possible retention of biological samples at the 
conclusion of this study; with the patient’s permission, samples may be retained for future 
determination of active metabolite concentrations and possible biomarkers related to drug 
response. 
The patient’s signed and dated informed consent 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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11.4 
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 study records for verification of data gathered on source documents 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. 
11.5 
Study Monitoring 
Monitoring of the study site (including, but not limited to, reviewing eCRFs 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. Monitoring will 
be performed in accordance with applicable federal regulations and guidance. Monitoring 
methods, responsibilities, and requirements will be outlined in a monitoring plan. 
11.6 
Case Report Forms and Study Records 
The Investigator must generate and maintain adequate and accurate records to enable full 
documentation of study conduct. Study data will be captured on eCRFs. Investigators must retain 
all original source documents. 
11.7 
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 (eg, 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 immediately if contacted by a regulatory agency 
regarding an inspection. 
11.8 
Protocol Deviations 
The Investigator should not implement any deviation from the protocol without prior review and 
agreement by the Sponsor 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 contact the Medical 


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Version 7.0, 15 January 2018 
Monitor. 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. 
11.9 
Records Retention 
The Principal Investigator must maintain all documentation relating to the study for a period of 
2 years after the last marketing application approval, or if not approved 2 years following the 
discontinuance of the test article for investigation. If it becomes necessary for the Sponsor or the 
regulatory authority to review any documentation relating to the study, the Investigator must 
permit access to such records. 
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. Authorship and manuscript 
composition will reflect joint cooperation between multiple Investigators and sites and Corcept 
personnel. Authorship will be established before writing of the manuscript. Because this study 
involves multiple centers, no individual publications will be allowed before completion of the 
final report of the multicenter study except as agreed with Corcept. 


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Version 7.0, 15 January 2018 
12 
REFERENCE LIST 
Burnsides C, Corry J, Alexander J, et al. Ex vivo stimulation of whole blood as a means to 
determine glucocorticoid sensitivity. J Inflamm Res. 2012;5:89-97. 
Caldwell JM, Blanchard C, Collins MH, et al. Glucocorticoid-regulated genes in eosinophilic 
esophagitis: a role for FKBP51. J Allergy Clin Immunol. 2010;125(4):879-88. 
Cuevas-Ramos D, Fleseriu M. Treatment of Cushing’s disease: a mechanistic update. 
J Endocrinol. 2014;223(2):R19-39. 
Chun E, Lee HS, Bang BR, et al. Dexamethasone-induced FKBP51 expression in peripheral 
blood mononuclear cells could play a role in predicting the response of asthmatics to treatment 
with corticosteroids. J Clin Immunol. 2011;31:122-7. 
CTCAE. 2010. Common Terminology Criteria for Adverse Events, version 4.03, dated 14 June 
2010. US Department of Health and Human Services, National Institutes of Health, National 
Cancer Institute. Accessed at http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf 
Eckstein N, Haas B, Hass, MDS, Pfeifer V. Systemic therapy of Cushing’s syndrome. Orphanet J 
Rare Dis. 2014;9:122. 
Fassnacht M, Arlt W, Bancos I, et al. Management of adrenal incidentalomas: European Society 
of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the 
Study of Adrenal Tumors. Eur J Endocrinol. 2016;154(2):G1-G34. 
Giraldi FP, Pivonello R, Ambrogio AG, et al. The dexamethasone-suppressed corticotropin-
releasing hormone stimulation test and the desmopressin test to distinguish Cushing’s syndrome 
from pseudo-Cushing’s states. Clin Endocrinol. 2007;66:251-257. 
James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high 
blood pressure in adults: report from the panel members appointed to the Eighth Joint National 
Committee (JNC 8). JAMA. 2014;311(5):507-20. 
Maltese P, Palma L, Sfara C, et al. Glucocorticoid resistance in Crohn’s disease and ulcerative 
colitis: an association study investigating GR and FKBP5 gene polymorphisms. 
Pharmacogenomics. 2012;12:432-8. 
Nieman LK, Biller BMK, Findling JW, et al. The Diagnosis of Cushing’s syndrome: an 
endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2008;93(5):1526-1540. 
Nieman LK, Biller BM, Findling JW, et al. Treatment of Cushing’s syndrome: an endocrine 
society clinical practice guideline. J Clin Endocrinol Metab. 2015;100(8):2807-31. 
O’Brien E, Parati G, Stergiou G, et al. European Society of Hypertension position paper on 
ambulatory blood pressure monitoring. J Hypertens. 2013;31:1731-1768. 
Standards of Medical Care in Diabetes—2015. American Diabetes Association. Diabetes Care. 
2015;38(Suppl 1).  


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Version 7.0, 15 January 2018 
Vermeer H, Hendriks-Stegeman BI, van der Burg B, van Buul-Offers SC, Jansen M. 
Glucocorticoid-induced increase in lymphocytic FKBP51 messenger ribonucleic acid expression: 
a potential biomarker for glucocorticoid sensitivity, potency, and bioavailability. J Endocrinol 
Metab. 2003;88:277-84. 
Vermeer H, Hendriks-Stegeman BI, van Suylekom D, Rijkers GT, van Buul-Offers SC, 
Jansen M. An in vitro bioassay to determine individual sensitivity to glucocorticoids: induction 
of FKBP51 mRNA in peripheral blood mononuclear cells. Mol Cell Endocrinol. 2004;15:49-55. 
Webb SM, Badia X, Barahona MJ, et al. Evaluation of health-related quality of life in patients 
with Cushing’s syndrome with a new questionnaire. Eur J Endocrinol. 2008;158(5):623-30. 
Yanovski JA, Cutler Jr GB, Chrousos GP, Nieman LK. Corticotropin-releasing hormone 
stimulation following low-dose dexamethasone administration: a new test to distinguish 
Cushing’s syndrome from pseudo-Cushing’s states. JAMA. 1993;269(17):2232-2238. 
Yanovski JA, Cutler Jr GB, Chrousos GP, Nieman LK. The dexamethasone-suppressed 
corticotropin-releasing hormone stimulation test differentiates mild Cushing’s disease from 
normal physiology. J Clin Endocrinol Metab. 1998;83(2):348-352. 


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13 
APPENDICES 
 


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Version 7.0, 15 January 2018 
13.1 
Schedule of Events for Group 1 
Assessment/Procedure  
 
Treatment Period 
 
Visit Name Screening 
Baseline 
Week  
1 
Week  
2 
Week  
3 
Week  
4 
Week  
5 
Week 
6 
Week  
7 
Week  
8 
Week  
9 
Week  
10 
Week 
11 
Week 12/ 
Early 
Term a 
Week 16 
Follow-
Up b 
Day Number/ 
Window 
Day −42 
to Day −1 
Day  
1 
Day 
7±1 
Day 
14±2 
Day 
21±1 
Day 
28±2 
Day 
35±1 
Day 
42±2 
Day 
49±1 
Day 
56±2 
Day 
63±1 
Day 
70±2 
Day 
77±1 
Day 
84±2 
Day 
112+7 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication washout c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and baseline 
disease characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history, medication 
history d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dexamethasone suppression 
test 
X e 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug dispensing 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Study drug compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient diary  
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Efficacy Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Waist circumference 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
24-hour UFC with creatinine  
(Ca, Na collection) f 
X c, g 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Salivary cortisol f 
X c, h 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
2-hour oGTT i 
X c 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
24-hour ambulatory BP test  
X c, j 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
HbA1c 
X k 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Fructosamine 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Adiponectin  
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Lipid panel l 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Sit-to-stand test 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Menstrual cycle information m 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 


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Version 7.0, 15 January 2018 
Assessment/Procedure  
 
Treatment Period 
 
Visit Name Screening 
Baseline 
Week  
1 
Week  
2 
Week  
3 
Week  
4 
Week  
5 
Week 
6 
Week  
7 
Week  
8 
Week  
9 
Week  
10 
Week 
11 
Week 12/ 
Early 
Term a 
Week 16 
Follow-
Up b 
Day Number/ 
Window 
Day −42 
to Day −1 
Day  
1 
Day 
7±1 
Day 
14±2 
Day 
21±1 
Day 
28±2 
Day 
35±1 
Day 
42±2 
Day 
49±1 
Day 
56±2 
Day 
63±1 
Day 
70±2 
Day 
77±1 
Day 
84±2 
Day 
112+7 
Sex hormone levels n 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Coagulation panel o 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
GR activity biomarkers test 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Bone laboratory parameters p 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
HPA axis tests q 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
ACTH precursors  
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
High sensitivity C-reactive 
protein 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
IGF-1 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Thyroid tests r 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Trail making test 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
CushingQoL questionnaire 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
BDI-II questionnaire 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Physician’s Global 
Assessment 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Pharmacokinetic Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK serial blood samples s 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
PK trough s 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
examination 
X 
X  
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Vital signs t 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Electrocardiogram, 12-lead 
(2 h ±30 min after study drug 
dosing) u 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Pregnancy test  
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Chemistry and hematology  
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Adverse event monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Version 7.0, 15 January 2018 
ACTH = adrenal corticotropic hormone; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BP = blood pressure; BDI-II = Beck Depression Inventory; Ca = calcium;  
DHEA-S = dehydroepiandrosterone sulfate; EAS = ectopic ACTH secretion; ET = early termination; HbA1c = glycated hemoglobin; IGF = insulin-like growth factor; oGTT = oral glucose tolerance 
test; Na = sodium; RBC = red blood cell; T3 = triiodothyronine; T4 = thyroxine; UFC = urinary free cortisol; WBC = white blood cell 
 
Note: Collect pituitary MRI radiographic scans and assessments in patients with Cushing disease that are obtained up to 6 months before Day 1 and up to 1 month after last CORT125134 dose if they 
are available. 
a 
For patients rolling over from Group 1 to Group 2, the Group 1 Week 12 visit will serve as the baseline visit for their Group 2 treatment period. 
b 
This visit is not necessary for patients who roll over from Group 1 to Group 2.  
c 
Medications used in the treatment of Cushing’s syndrome are prohibited and require washout (as applicable) during screening provided the intervals specified in Exclusion Criterion 14 fit within the 
screening window. Patients requiring washout of a medication for Cushing’s syndrome must complete the screening/baseline 24-hour UFC tests, salivary cortisol tests, oGTTs, and 24-hour 
ambulatory BP monitoring tests after washout and within 3 weeks before Day 1 dosing.  
d 
Medication history only for medications taken to treat Cushing’s syndrome, hypertension, or diabetes within 3 months before screening. 
e 
Dexamethasone suppression test only if needed for study entry. 
f 
Within 7 days before the Week 2, 4, 6, 8, 10, and 12 visits, samples will be collected by the patient at home twice for each time point.  
g 
The 24-hour UFC will be collected by the patient at home at least two times and up to four times during screening. For screening, the average of the results will serve as “baseline”.  
h 
Salivary cortisol test will be performed by the patient at home at least two and up to four times on different nights during screening. The average of the results will serve as “baseline”. 
i 
oGTTs during the Treatment Period (including on Day 1) will be performed in the impaired glucose tolerance/diabetes subgroup only. During the 2-hour oGTT, blood samples for plasma glucose 
and insulin will be collected before the glucose drink and 0.5, 1, 1.5, and 2 hours after the glucose drink. 
j 
The 24-hour ambulatory BP will be assessed for all patients during the screening period. For the subgroup of patients who qualify for the hypertension subgroup, there must be a 24-hour ambulatory 
BP test done within 3 weeks before Day 1; this result will be used as “baseline”. If the initial screening test was done within 3 weeks before Day 1, it does not need to be repeated. Ambulatory BP 
measurements during the Treatment Period will be performed in the hypertension subgroup only. 
k 
Not required to be collected at screening if results available within 3 months of first dose of study drug at baseline/Day 1.  
l 
Total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, very low-density lipoprotein-cholesterol, and triglycerides. 
m Only in premenopausal female patients not taking hormonal birth control. 
n 
Estradiol, total and free testosterone, sex hormone binding globulin, follicle-stimulating hormone, and luteinizing hormone. 
o 
Activated partial thromboplastin time, Factor VIII, Factor IX, Factor X, and von Willebrand factor, d-dimer, fibrinogen, and thrombin-antithrombin. 
p 
Blood: osteocalcin, bone alkaline phosphatase; urine: N-telopeptides of type 1 collagen.  
q 
Blood samples for analysis of plasma ACTH, serum cortisol, 17-OH-progesterone, 11-deoxycortisol, DHEA-S, and androstenedione. 
r 
Thyroid function tests will include the following: free T4, free T3, reverse T3, thyroid-stimulating hormone.  
s 
Blood levels of CORT125134 and metabolites will be measured predose and at 1, 2, 4, 6, and 8 hours postdose at Weeks 2, 6, and 10 and predose only at Weeks 4, 8, and 12/ET. 
t 
BP, heart rate, respiratory rate, oral body temperature. 
u 
Triplicate ECGs at screening; duplicate ECGs at other study visits. 
 
 


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Version 7.0, 15 January 2018 
13.2 
Schedule of Events for Group 2 
Assessment/Procedure  
 
Treatment Period 
 
Visit Name 
Screening a 
Baseline b 
Week  
1 
Week  
2 
Week  
3 
Week  
4 
Week  
5 
Week  
6 
Week  
7 
Week  
8 
Week  
9 
Week  
10 
Weeks 11,  
13, 15 
Week  
12 
Week 
14 
Week 16/ 
Early 
Term  
Week 20 
Follow-
Up  
Day Number/ 
Window 
Day −42 to 
Day −1 
Day  
1 
Day 
7±1 
Day 
14±2 
Day 
21±1 
Day 
28±2 
Day 
35±1 
Day 
42±2 
Day 
49±1 
Day 
56±2 
Day 
63±1 
Day 
70±2 
Days 77, 
91, 105±1 
Day 
84±2 
Day 
98±2 
Day 
112±2 
Day 
140+7 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication washout c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and 
baseline disease 
characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history, 
medication history d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dexamethasone 
suppression test 
X e 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug dispensing 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
Study drug compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient diary  
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
Efficacy Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Waist circumference 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
X 
24-hour UFC with 
creatinine  
(Ca, Na collection) f 
X c,g 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
Salivary cortisol f 
X c,h 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
2-hour oGTT i 
X c 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
24-hour ambulatory BP 
test  
X c,j 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
HbA1c 
X k 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Fructosamine 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
Adiponectin  
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
Lipid panel l 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
X 
Sit-to-stand test 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
Menstrual cycle 
information m 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 


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Version 7.0, 15 January 2018 
Assessment/Procedure  
 
Treatment Period 
 
Visit Name 
Screening a 
Baseline b 
Week  
1 
Week  
2 
Week  
3 
Week  
4 
Week  
5 
Week  
6 
Week  
7 
Week  
8 
Week  
9 
Week  
10 
Weeks 11,  
13, 15 
Week  
12 
Week 
14 
Week 16/ 
Early 
Term  
Week 20 
Follow-
Up  
Day Number/ 
Window 
Day −42 to 
Day −1 
Day  
1 
Day 
7±1 
Day 
14±2 
Day 
21±1 
Day 
28±2 
Day 
35±1 
Day 
42±2 
Day 
49±1 
Day 
56±2 
Day 
63±1 
Day 
70±2 
Days 77, 
91, 105±1 
Day 
84±2 
Day 
98±2 
Day 
112±2 
Day 
140+7 
Sex hormone levels n 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Coagulation panel o 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
GR activity biomarkers 
test 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
Bone laboratory 
parameters p 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
HPA axis tests q 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
ACTH precursors  
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
High sensitivity 
C-reactive protein 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
IGF-1 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
Thyroid tests r 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
Trail making test 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
CushingQoL 
questionnaire 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
X 
BDI-II questionnaire 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
Physician’s Global 
Assessment 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Pharmacokinetic Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK serial blood samples s 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
PK trough s 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
examination 
X 
X  
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Vital signs t 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Electrocardiogram, 
12-lead (2 h ±30 min 
after study drug dosing) u 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Pregnancy test v 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Chemistry and 
hematology w 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Adverse event monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Clinical Study Protocol CORT125134-451 
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Version 7.0, 15 January 2018 
ACTH = adrenal corticotropic hormone; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BP = blood pressure; BDI-II = Beck Depression Inventory; Ca = 
calcium;  
DHEA-S = dehydroepiandrosterone sulfate; EAS = ectopic ACTH secretion; ET = early termination; HbA1c = glycated hemoglobin; IGF = insulin-like growth factor; oGTT = 
oral glucose tolerance test; Na = sodium; RBC = red blood cell; T3 = triiodothyronine; T4 = thyroxine; UFC = urinary free cortisol; WBC = white blood cell 
 
Note: Collect pituitary MRI radiographic scans and assessments in patients with Cushing disease that are obtained up to 6 months before Day 1 and up to 1 month after last 
CORT125134 dose if they are available. 
a 
This visit is not necessary for patients rolling from Group 1 to Group 2. 
b 
For patients rolling over from Group 1 to Group 2, the Group 1 Week 12 visit will serve as the baseline visit for their Group 2 treatment period. 
c 
Medications used in the treatment of Cushing’s syndrome are prohibited and require washout (as applicable) during screening provided the intervals specified in Exclusion Criterion 14 fit within the 
screening window. Patients requiring washout of a medication for Cushing’s syndrome must complete the screening/baseline 24-hour UFC tests, salivary cortisol tests, oGTTs, and 24-hour 
ambulatory BP monitoring tests after washout and within 3 weeks before Day 1 dosing.  
d 
Medication history only for medications taken to treat Cushing’s syndrome, hypertension, or diabetes within 3 months before screening. 
e 
Dexamethasone suppression test only if needed for study entry. 
f 
The Week 2, 4, 6, 8, 10, 12, 14, and 16 samples will be collected by the patient at home twice for each time point.  
g 
The 24-hour UFC will be collected by the patient at home at least two times and up to four times during screening. For screening, the average of the results will serve as “baseline”.  
h 
Salivary cortisol test will be performed by the patient at home at least two and up to four times on different nights during screening. The average of the results will serve as “baseline”. 
i 
oGTTs during the Treatment Period (including on Day 1) will be performed in the impaired glucose tolerance/diabetes subgroup only. During the 2-hour oGTT, blood samples for plasma glucose 
and insulin will be collected before the glucose drink and 0.5, 1, 1.5, and 2 hours after the glucose drink. 
j 
The 24-hour ambulatory BP will be assessed for all patients during the screening period. For the subgroup of patients who qualify for the hypertension subgroup, there must be a 24-hour ambulatory 
BP test done within 3 weeks before Day 1; this result will be used as “baseline”. If the initial screening test was done within 3 weeks before Day 1, it does not need to be repeated. Ambulatory BP 
measurements during the Treatment Period will be performed in the hypertension subgroup only. 
k 
Not required to be collected at screening if results available within 3 months of first dose of study drug at baseline/Day 1.   
l 
Total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, very low-density lipoprotein-cholesterol, and triglycerides. 
m Only in premenopausal female patients not taking hormonal birth control. 
n 
Estradiol, total and free testosterone, sex hormone binding globulin, follicle-stimulating hormone, and luteinizing hormone. 
o 
Activated partial thromboplastin time, Factor VIII, Factor IX, Factor X, and von Willebrand factor, d-dimer, fibrinogen, and thrombin-antithrombin. 
p 
Blood: osteocalcin, bone alkaline phosphatase; urine: N-telopeptides of type 1 collagen.  
q 
Blood samples for analysis of plasma ACTH, serum cortisol, 17-OH-progesterone, 11-deoxycortisol, DHEA-S, and androstenedione. 
r 
Thyroid function tests will include the following: free T4, free T3, reverse T3, thyroid-stimulating hormone.  
s 
Blood levels of CORT125134 and metabolites will be measured predose and at 1, 2, 4, 6, and 8 hours postdose at Weeks 2, 6, 10, and 14 and predose only at Weeks 4, 8, 12, and 16/ET. 
t 
BP, heart rate, respiratory rate, oral body temperature. 
u 
Triplicate ECGs at screening; duplicate ECGs at other study visits. 
V Screening blood pregnancy test; all subsequent tests are urine tests. 
w Chemistry parameters will include a full chemistry profile (albumin, alkaline phosphatase, ALT, AST, blood urea nitrogen, calcium, chloride, cholesterol, creatinine, glucose, lactate dehydrogenase, 
magnesium, phosphorus, potassium, sodium, total creatine kinase, total and direct bilirubin, total protein, uric acid). Hematology parameters will include a complete blood count (hematocrit, 
hemoglobin, mean corpuscular hemoglobin, mean corpuscular hemoglobin volume, mean corpuscular volume, mean platelet volume, platelet count, red blood cell distribution width, RBC count, 
and WBC count) and differential (percent and absolute for the following: basophils, eosinophils, lymphocytes, monocytes, and neutrophils). 
 


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Version 7.0, 15 January 2018 
13.3 
Study Patient Identification Card 
At study enrollment, all patients will be given a card to carry with them that identifies their 
potential risk for excessive GR blockade. A copy of the card is provided below: 
CORT125134-451 Study Participant Information Card 
_____________________________is a participant in a clinical trial for Cushing’s syndrome. 
Name 
This participant was, and may still be, receiving CORT125134, a glucocorticoid antagonist 
which blocks the effects of the hormone cortisol. This individual may be at increased risk for 
the development of excessive glucocorticoid receptor (GR) blockade. He/She may require 
supplemental treatment with glucocorticoids in the setting of shock, surgery, or serious illness 
or injury (eg, infection, fracture, bleeding). In such cases, administration of dexamethasone  
(4–10 mg intravenously or intramuscularly), fluid resuscitation, and supportive medical care 
should be administered. Additional glucocorticoid should be continued and adjusted according 
to the clinical course. 
In case of suspected excessive GR blockade, please contact the investigator/study physician 
immediately at: 
__________________________________ 
Phone number 
__________________________________________________________________ 
Name of Investigator 
 


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Version 7.0, 15 January 2018 
13.4 
Summary of Changes in Protocol CORT125134-451 Version 7.0  
Significant changes in Version 7.0 of the protocol (dated 15 January 2018) compared with 
Version 6.0, dated 16 November 2016) are summarized in Table 7. The major change is the 
addition of the 400-mg CORT125134 dose level that adds 4 more weeks of treatment to Group 2.  
Minor editorial or stylistic changes made for consistency, correction of typographical errors, and 
use of abbreviations are not summarized. Deleted text is shown as a strikethrough and new text is 
shown in bold font.  
Table 7 
Summary of Changes in Protocol CORT125134-451 Version 7 
Section 
Revision 
Rationale 
Global changes shown 
in the redline version 
Version 6.0 was changed to Version 7.0 with updated date.  
Administrative change 
 
In version 7.0, a fourth dose level (ie, 400 mg CORT125134 
daily for 4 weeks) was added to the Group 2 dose levels such 
that dose escalation increases in 50-mg increments from 
250 mg to 400 mg. This addition required changes throughout 
the protocol, including the following:  
• 
The study rationale (Section 1)  
• 
The lists of assessments (especially Section 7 and 
Section 8 and the Schedule of Assessments): 
– 
The addition of 4 weeks of CORT125134 
treatment to all descriptions of Group 2 dosing 
and administration (eg, the addition of “then 400 
mg/day for 4 weeks” to “250 mg/day for 
4 weeks, then 300 mg/day for 4 weeks, 
then 350 mg/day for 4 weeks”) 
– 
The addition of the assessment time points for 
Group 2 (eg, “For Group 2, blood levels of 
CORT125134 and metabolites will be measured 
predose and at 1, 2, 4, 6, and 8 hours postdose at 
Weeks 2, 6, 10, and 14, and predose only at 
Weeks 4, 8, 12, and 16/ET.”) 
– 
The addition of new subsections in Section 8 
Procedures that outline activities for Group 2 
Weeks 12–16 
– 
A new, separate table in Appendix 13.2 to show 
the schedule of assessments for Group 2 
• 
Extension of the study duration from “up to 
34 weeks” to “up to 38 weeks” 
• 
Extension of the study treatment period from “up to 
24 weeks” to “up to 28 weeks" 
 
 
 
 
 
 
 
 
 
 
 
 The 400-mg 
dose was 
 endorsed 
by the 2nd DRC 
meeting. 
Global changes that 
are not shown in the 
redline version 
In Section 7, where assessments were stated to occur on “the 
Week 2, Week 4, Week 6, Week 8, Week 10, and Week 12/ET 
visits”, the text was changed to “Weeks 2, 4, 6, 8, 12, and 
12/ET” to improve readability.  
Editorial changes 


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Version 7.0, 15 January 2018 
Section 
Revision 
Rationale 
The International Nonproprietary Name “relacorilant” was 
added to the cover page.  
Where appropriate, “subject” was changed to “patient”.  
All section numbers, figure numbers, and table numbers were 
revised to reflect the additions and revisions in the text. 
Minor stylistic (eg, formatting) and editorial changes (eg, 
punctuation) were made. 
Synopsis: Study Period 
Modified text 
Up to 3438 weeks, including up to 6 weeks for screening, 
up to 2428 weeks of treatment, and 4 weeks of follow-up 
Extended the study 
period to allow patients 
in Group 2 to escalate 
to 400 mg 
CORT125134   
Synopsis: Duration of 
Treatment 
Updated the duration of treatment: 
Up to 2428 weeks 
Extended the treatment 
period to allow patients 
in Group 2 to escalate 
to 400 mg 
CORT125134   
Synopsis: Study 
Design and 
Methodology 
Updated Table S1. 
 
 The changes made in Table 3 were also made in 
Table S1. 
 
 
Synopsis: Study 
Design and 
Methodology, 
Section 3.1 Overview 
of Study Design 
Text for the following two bullets were updated: 
• Group 2: projected doses are CORT125134 250 mg/day for 
4 weeks, then 300 mg/day for 4 weeks, then 350 mg/day for 
4 weeks, then 400 mg/day for 4 weeks. Patients who 
discontinue prior to Week 10 may be replaced to ensure that 
at least 12 patients provide serial PK data through Week 10 
in Group 1 and Group 2. 
• The DRC will also meet during Group 2, when steady-state 
PK data at Week 10 are available for 6 patients, who have 
reached their highest CORT125134 dose (ie, Week 10 if 
350 mg and Week 14 if 400 mg) and at the end of the study. 
Text describing the timing of patient visits for Group 2 was 
added. 
Updated to include the 
400-mg dose level in 
Group 2 
 
Updated the study design figure. 
Prior version of study design figure: 
Updated to include the 
400-mg dose level in 
Group 2 


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Version 7.0, 15 January 2018 
Section 
Revision 
Rationale 
 
Updated version of study design figure: 
 
 
Synopsis,  
Section 4.1 Inclusion 
Criteria 1, 4, 8, and 11 
Also Section 7.12.4 
Pregnancy Tests and 
Contraception 
Methods  
Modified the following inclusion criteria:  
1. Is a male or female adult, 18–7580 years of age 
Extended age range at 
study entry from 75 to 
80 years to allow 
enrollment of older 
patients 
 
4. Meets at least one of the following criteria: 
Has impaired glucose tolerance (2-hour oGTT result for 
plasma glucose in the range of ≥140 mg/dL to <200 
mg/dL) (Standards of Medical Care in Diabetes – 2015) 
 
Correction in plasma 
glucose range from 
>140 mg/dL to ≥140 
mg/dL 
 
 


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Section 
Revision 
Rationale 
8. Female patients of childbearing potential must be 
willing to use a highly effective method of contraception 
from 30 days prior to Day 1 until 30 days after the last 
dose of study drug. Male patients with a female partner 
must agree to 2 forms of contraception, one of which must 
be a double-barrier method, from Day 1 until 30 days after 
the last dose of study drug. Highly effective methods of 
contraception include abstinence, oral contraceptives 
combined with a barrier method, diaphragm with vaginal 
spermicide, intrauterine device, condom and partner using 
vaginal spermicide, and surgical sterilization (≥6 months 
postsurgery). 
 
11. Is able to participate in the study for up to 22 weeks in 
Group 1 and 26 weeks in Group 2, including returning to 
the investigative site to fulfill the safety and efficacy 
evaluations outlined in the protocol 
Clarification 
 
 
 
 
 
 
 
 
 
 
Updated to include the 
400-mg dose level in 
Group 2 
Sections 1.1.2, 1.3.1, 
and 1.3.2  
 
 
 
 
  
Section 1.1.2 Clinical 
Experience: Safety 
 
The following changes were made:  
 
 
 
 
 
 
 
 
 
 
. 
 
Text in boldface was added:  
 
 
 
 
 
 
 
 


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Section 
Revision 
Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 1.3.1 
 
 
 
 
Updated the number of cohorts from 3 to 4.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Version 7.0, 15 January 2018 
Section 
Revision 
Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
Section 1.3.2 
 
 
 
 
 
  
 
 
 
 
 
3.1 Overview of Study 
Design 
Added a new subheading  
Added for cross-
referencing 
3.2 Data Review 
Committee 
The following bullet was modified:  
• 
For oversight of Group 2: 
– 
When 6 evaluable patients have escalated to 
Dose 3 of or 4 (whichever is the patient’s 
highest Group 2 dose) and PK and safety data 
are available 
Revised to address 
inclusion of the 400-mg 
dose level 


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Version 7.0, 15 January 2018 
Section 
Revision 
Rationale 
– 
At end of study 
5.4.1 Dosing Groups 
and Dose Escalation 
Modified text as needed to include the 400-mg CORT125134 
dose level, and added a column to the tabulation to show the 
dose and number of capsules.  
 
  
Revised to address 
inclusion of the 400-mg 
dose level 
7.5 Pituitary Magnetic 
Resonance Imaging 
(MRI) Scans 
This new subsection was added with the following text: 
Pituitary MRI radiographic scans and assessments in 
patients with Cushing disease that are obtained up to 6 
months before Day 1 and up to 1 month after last 
CORT125134 dose as standard of care will be collected if 
available.  
Added to capture 
changes in pituitary 
MRI scans if the scans 
were performed as 
standard of care. 
7.12.2 Vital Sign 
Measurements 
Deleted “hypertensive” in the following sentence:  
In addition to the safety vital signs collected, a 24-hour 
ambulatory BP test will also be done by all hypertensive 
patients at screening and by patients in the hypertension 
subgroup at post-screening time points to assess the effect of 
CORT125134 on BP (see Section7.11.1.1). 
Correction; all patients 
undergo ABPM at 
screening 
7.12.5.2 Sample 
Collection, Storage, 
and Shipment 
The following changes were made: 
The total volume of blood to be collected from each patient 
will be no more than 850 731 mL for Group 1 and 908 mL 
for Group 2 during the 12-week and 16-week each 12-week 
treatment period. 
 
Correction and revision 
to add the new value for 
the 400-mg treatment 
period. 
7.13 Pregnancy 
The following prior pregnancy section was deleted:  
7.12.6.10 Pregnancy 
Pregnancy is not considered an AE, although a patient will 
be withdrawn from the study if a pregnancy occurs and the 
ET visit will be completed. The pregnancy must be 
immediately reported to the Sponsor and Medical Monitor. 
Additional follow-up may be required 
The following new subsection was added:  
7.13 Pregnancy 
All pregnancies with the estimated date of conception 
occurring during the study treatment or within 30 days of 
the last dose of study treatment should be reported 
immediately to the Sponsor or its designee. The patient will 
be followed to determine the outcome of the pregnancy, and 
the outcome will be reported. 
7.13.1   Maternal Exposure 
If a patient becomes pregnant during the study, the study 
treatment should be discontinued immediately. Pregnancy 
itself is not regarded as an AE.  
If a pregnancy occurs during the study treatment or within 
30 days of the last dose of study treatment, the Investigator 
The subsection was 
made a separate section 
from AEs because 
pregnancy is not 
considered to be an AE. 
The guidance for 
reporting and following 
a pregnancy was 
enhanced. 


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Version 7.0, 15 January 2018 
Section 
Revision 
Rationale 
or designee will inform the appropriate Sponsor 
representatives immediately but no later than 24 hours of 
when he or she becomes aware of it. The Investigator or 
designee will 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. 
7.13.2   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) should be followed and 
documented, if possible. 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. A consent form specific to this 
situation must be used. The outcome of any conception 
occurring from the date of the first dose of study drug until 
30 days after the last dose should be followed and 
documented. 
8.1 Screening 
(Day −42 to Day −1) 
Added the following statement: “Patients rolling from Group 1 
to Group 2 do not require these assessments.” 
Clarification 
8.2 Baseline Visit 
(Day 1) 
Added the following statement: “Note: for patients rolling from 
Group 1 to Group 2, the Group 1 Week 12 assessments in 
Group 1 equal the baseline visit assessments in Group 2.” 
Clarification 
8.14 through 8.20 
Assessments 
performed at specific 
visits 
These sections were updated or added to clarify what 
assessments are required for Group 2, Weeks 12–16, and for 
both groups at the end of treatment or early termination. 
Revised to address 
inclusion of the 400-mg 
dose level 
13.2 Schedule of 
Events for Group 2 
Added this new table to clearly identify the assessments 
required for Group 2. 
Revised to address 
inclusion of the 400-mg 
dose level 
 
 

SAP_001.pdf: 
Title: Phase 2 Study of the Safety and Efficacy of CORT125134 in the Treatment 
of Endogenous Cushing’s Syndrome 
 
NCT number: NCT02804750 
 
Date: 30 August 2018 


Corcept Therapeutics 
Statistical Analysis Plan
CORT125134-451 
Version 1.0; 30 August 2018
 
 
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STATISTICAL ANALYSIS PLAN 
Corcept Therapeutics 
CORT125134-451 
 
 
 
 
Protocol Title: 
Phase 2 Study of the Safety and Efficacy of CORT125134 in 
the Treatment of Endogenous Cushing’s Syndrome 
Protocol Version 
and Date: 
Version 7.0; 15 January 2018 
 
Sponsor: 
Corcept Therapeutics  
149 Commonwealth Drive 
Menlo Park, California 94025 US 
Prepared By: 
 
 
 
 
Document Version 
and Date: 
Version 1.0; 30 August 2018 
 


Corcept Therapeutics 
Statistical Analysis Plan
CORT125134-451 
Version 1.0; 30 August 2018
 
 
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1 STATISTICAL ANALYSIS PLAN APPROVAL 
Sponsor: 
Corcept Therapeutics 
Clinical Protocol Number: CORT125134-451 
Protocol Title: 
Phase 2 Study of the Safety and Efficacy of 
CORT125134 in the Treatment of Endogenous 
Cushing’s Syndrome 
Document File Name: 
Corcept_CORT-451_SAP_v1.0_27AUG2018.pdf 
Document Version and 
Effective Date: 
Version 1.0; 30 August 2018 
Approved By: 
 


Corcept Therapeutics 
Statistical Analysis Plan
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Version 1.0; 30 August 2018
 
 
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Corcept Therapeutics 
Statistical Analysis Plan
CORT125134-451 
Version 1.0; 30 August 2018
 
 
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2 TABLE OF CONTENTS 
 
1 
Statistical Analysis Plan Approval ............................................................................2 
2 
Table of Contents ........................................................................................................4 
3 
List of Abbreviations ..................................................................................................7 
4 
Introduction.................................................................................................................9 
5 
Study Objectives .........................................................................................................9 
5.1 
Primary Study Objective .......................................................................................9 
5.2 
Secondary Study Objective ...................................................................................9 
6 
Investigational Plan ....................................................................................................9 
6.1 
Overall Study Design .............................................................................................9 
6.2 
Pharmacokinetic Assessments ............................................................................11 
6.3 
Schedule of Events for Group 1 ..........................................................................12 
6.4 
Schedule of Events for Group 2 ..........................................................................15 
6.5 
Treatment .............................................................................................................18 
6.5.1 
Treatment Administered ...............................................................................18 
6.5.2 
Method of Assigning Patients to Groups .....................................................18 
6.6 
Study Assessments ...............................................................................................18 
6.6.1 
Demographic and Baseline Characteristics .................................................18 
6.6.2 
Medical History and Medication History ....................................................18 
6.6.3 
Key Efficacy Assessments..............................................................................19 
6.6.4 
Exploratory Efficacy Assessments................................................................19 
6.6.5 
Description of Safety Variables ....................................................................23 
6.6.6 
Description of Pharmacokinetics ..................................................................25 
6.7 
Data Quality Assurance .......................................................................................26 
7 
Statistical Methods ....................................................................................................26 
7.1 
General Methodology ..........................................................................................26 
7.1.1 
Reporting Conventions ..................................................................................27 
7.1.2 
Definition of Analysis Visit Windows ...........................................................27 
7.1.3 
Data Handling Rules ......................................................................................29 
7.1.4 
Standard Calculations ...................................................................................30 
7.1.5 
Definitions of Baseline ...................................................................................30 
7.2 
Analysis Populations ............................................................................................31 
7.3 
Examination of Subgroups ..................................................................................32 
7.4 
Time-Course and Dose-Course Analysis Methods ...........................................33 
7.5 
Study Patients .......................................................................................................34 
7.5.1 
Disposition of Patients ...................................................................................34 
7.5.2 
Protocol Deviations ........................................................................................34 
7.6 
Efficacy..................................................................................................................34 
7.6.1 
Demographic and Baseline Characteristics .................................................34 
7.6.2 
Measurements of Treatment Compliance ...................................................35 
7.6.3 
Key Efficacy Endpoint Analysis Methods ...................................................35 
7.6.4 
Exploratory Efficacy Endpoint Analysis Methods .....................................41 
7.6.5 
Statistical/Analytical Issues ...........................................................................44 
7.6.6 
Plasma Concentrations and Pharmacokinetic Analysis .............................46 


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7.7 
Safety Analysis .....................................................................................................46 
7.7.1 
Extent of Exposure .........................................................................................46 
7.7.2 
Adverse Events ...............................................................................................46 
7.7.3 
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events ...............................................................................................48 
7.7.4 
Clinical Laboratory Evaluation ....................................................................48 
7.7.5 
Vital Signs, Physical Findings, and Other Observations Related to 
Safety ...............................................................................................................49 
7.8 
Patient Profiles .....................................................................................................51 
7.9 
Determination of Sample Size .............................................................................51 
7.10 
Changes in the Conduct of the Study or Planned Analyses .............................51 
8 
Reference List ............................................................................................................51 
 
 
 


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TABLE OF TABLES 
Table 1 
List of Abbreviations .................................................................................7 
Table 2 
Group 1 Biweekly Interval Visit Windows (Days) ................................27 
Table 3 
Group 2 Biweekly Interval Visit Windows (Days) ................................28 
Table 4 
Group 1 Monthly Interval Visit Windows (Days) .................................28 
Table 5 
Group 2 Monthly Interval Visit Windows (Days) .................................28 
Table 6 
Examples of Data Handling Rules ..........................................................29 
 
TABLE OF FIGURES 
Figure 1 
Study Design .............................................................................................10 
 
 


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3 LIST OF ABBREVIATIONS  
Table 1 
List of Abbreviations  
Abbreviation 
Definition  
ACTH 
adrenocorticotropic hormone 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
area under the curve 
BDI-II 
Beck Depression Inventory 
BMI 
body mass index 
BP 
blood pressure 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
DHEA-S 
dehydroepiandrosterone sulfate 
DRC 
data review committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ET 
Early Termination 
GR 
glucocorticoid reception 
HbA1c 
glycated hemoglobin 
HEENT 
head, eyes, ears, nose, throat 
HOMA-IR 
homeostatic model assessment for insulin resistence 
HPA 
hypothalamic-pituitary-adrenal 
HT 
hypertension 
ICH 
International Conference on Harmonization 
IGF 
insulin-like growth factor 
IGT 
impaired glucose tolerance/diabetes 
LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model for repeated measures 
mPP 
Modified Per-Protocol 
mRNA 
messenger ribonucleic acid 
NTx 
N-telopeptides of type 1 collagen 
oGTT 
oral glucose tolerance test 


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Abbreviation 
Definition  
PK 
pharmacokinetic 
QC 
quality control 
REML 
restricted maximum likelihood 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SI 
Système International 
T3 
triiodothyronine 
T4 
thyroxine 
TEAE 
treatment-emergent adverse event 
UFC 
urinary free cortisol 
WBC 
white blood cell 
WHO 
World Health Organization 


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4 INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide comprehensive and 
detailed descriptions of the methods and presentation of data analyses proposed for 
Corcept Therapeutics Protocol CORT125134-451 (Phase 2 Study of the Safety and 
Efficacy of CORT125134 in the Treatment of Endogenous Cushing’s Syndrome). 
Descriptions of planned analyses are provided in order to avoid post hoc decisions that 
may affect the interpretation of the statistical analysis. The statistical methods applied in 
the design and planned analyses of this study are consistent with the International 
Conference on Harmonisation (ICH) guideline Statistical Principles for Clinical Trials 
(E9) (1998).  
The clinical study database will be locked following a review of all data in the database 
and resolution of all data queries. This SAP will be finalized prior to data analysis and 
before database lock to provide full details, including templates for tables, listings, and 
figures, 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; 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. 
5 STUDY OBJECTIVES 
5.1 
Primary Study Objective 
The primary objective of this study is to assess the safety of CORT125134 in patients 
with endogenous Cushing syndrome. 
5.2 
Secondary Study Objective 
The secondary objective of this study is to assess the evidence of reduction in cortisol 
activity following treatment with CORT125134 in patients with endogenous Cushing 
syndrome, based on improvement in blood glucose control and/or blood pressure (BP).  
6 INVESTIGATIONAL PLAN 
6.1 
Overall Study Design 
This is a Phase 2, open-label study to evaluate the safety and efficacy of two dose 
regimens of CORT125134 (also known as relacorilant) in patients with endogenous 
Cushing syndrome and type 2 diabetes or glucose intolerance and/or uncontrolled or 
untreated hypertension. Patients will be categorized in the impaired glucose 
tolerance/diabetes subgroup or the hypertension subgroup; a patient may be in both of 
these subgroups.  
Approximately 30 patients will be enrolled across clinical sites in the United States and 
Europe. As shown in Figure 1, two dose groups (Groups 1 and 2), including 15 patients 


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per group, will be evaluated. The study will consist of a screening period (Days −42 to 
−1); 4-week treatment periods that start with the initial dose and immediately escalate to 
the next higher dose every 4 weeks; and a follow-up period of 4 weeks. Full steady-state 
pharmacokinetic (PK) profiles will be generated at every dose level as noted in Section 
6.2. 
Figure 1 
Study Design 
 
All patients will undergo at least a two-step dose escalation (Figure 1). Patient dosing 
will be done at home, except on days of study visits. 
For Group 1, patient visits to the study site will be at screening, on Day 1 (baseline), 
Weeks 2, 4, 6, 8, 10, and 12, and after a 4-week follow-up period. For Group 2, patient 
visits to the study site will be at Day 1 (baseline), Weeks 2, 4, 6, 8, 10, 12, 14, 16, and 
after a 4-week follow-up period.  
The following safety assessments will be performed during each in-clinic visit: adverse 
event (AE) reporting, safety laboratory tests, physical examinations, vital sign 
measurements, electrocardiograms (ECGs), concomitant medication reviews, and 
pregnancy tests. Key efficacy parameters will also be measured, including effects on 
glucose tolerance, blood pressure, cortisol concentration, body/weight composition, and 
metabolism.  


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An independent data review committee (DRC) will convene at least four times to review 
safety and PK results. The details of the DRC meeting schedule are described in the DRC 
charter. The results of the assessments and recommendations regarding dose escalation 
are documented in the DRC meeting minutes. 
While the study protocol allows for the possibility of the patients from Group 1 to roll 
over into Group 2, no patients rolled over from Group 1 to Group 2. Therefore, all 
analyses will treat Group 1 and Group 2 as mutually exclusive analysis sets. 
6.2 
Pharmacokinetic Assessments 
Predose and postdose samples for serial PK will be collected at Weeks 2, 6, and 10. 
Predose trough PK samples only will be collected at Weeks 4, 8, and 12/early termination 
(ET) for patients in Group 1 and Group 2.  
For patients in Group 2 who dose-escalate to 400 mg daily, predose and postdose samples 
for serial PK will also be collected at Week 14, and key efficacy parameters as well as 
predose trough PK samples will be collected at Week 16/ET.  
Between clinic visits, weekly contact with patients will occur via email or telephone to 
capture study drug compliance, AEs, and medication changes. 
Methods for analysis of PK data are described in a separate PK analysis plan. 


Corcept Therapeutics  
Statistical Analysis Plan
CORT125134-451 
Version 1.0; 30 August 2018
 
 
Confidential 
Page 12 of 51
 
6.3 
Schedule of Events for Group 1 
 
Assessment/Procedure  
 
Treatment Period 
 
Visit Name 
Screening 
Baseline 
Week  
1 
Week  
2 
Week  
3 
Week  
4 
Week  
5 
Week 
6 
Week  
7 
Week  
8 
Week  
9 
Week  
10 
Week 11 
Week 12/ 
Early 
Term a 
Week 16 
Follow-
Up b 
Day Number/ 
Window 
Day −42 to 
Day −1 
Day  
1 
Day 7±1 
Day 
14±2 
Day 21±1 Day 28±2 
Day 
35±1 
Day 
42±2 
Day 
49±1 
Day 
56±2 
Day 
63±1 
Day 70±2 
Day 
77±1 
Day 
84±2 
Day 
112+7 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication washout c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and baseline 
disease characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history, medication 
history d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dexamethasone suppression test 
X e 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug dispensing 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Study drug compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient diary  
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Efficacy Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Waist circumference 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
24-hour UFC with creatinine  
(Ca, Na collection) f 
X c, g 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Salivary cortisol f 
X c, h 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
2-hour oGTT i 
X c 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
24-hour ambulatory BP test  
X c, j 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
HbA1c 
X k 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Fructosamine 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Adiponectin  
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Lipid panel l 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Sit-to-stand test 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 


Corcept Therapeutics  
Statistical Analysis Plan
CORT125134-451 
Version 1.0; 30 August 2018
 
 
Confidential 
Page 13 of 51
 
Assessment/Procedure  
 
Treatment Period 
 
Visit Name 
Screening 
Baseline 
Week  
1 
Week  
2 
Week  
3 
Week  
4 
Week  
5 
Week 
6 
Week  
7 
Week  
8 
Week  
9 
Week  
10 
Week 11 
Week 12/ 
Early 
Term a 
Week 16 
Follow-
Up b 
Day Number/ 
Window 
Day −42 to 
Day −1 
Day  
1 
Day 7±1 
Day 
14±2 
Day 21±1 Day 28±2 
Day 
35±1 
Day 
42±2 
Day 
49±1 
Day 
56±2 
Day 
63±1 
Day 70±2 
Day 
77±1 
Day 
84±2 
Day 
112+7 
Menstrual cycle information m 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Sex hormone levels n 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Coagulation panel o 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
GR activity biomarkers test 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Bone laboratory parameters p 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
HPA axis tests q 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
ACTH precursors  
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
High sensitivity C-reactive protein 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
IGF-1 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Thyroid tests r 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Trail making test 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
CushingQoL questionnaire 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
BDI-II questionnaire 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Physician’s Global Assessment 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Pharmacokinetic Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK serial blood samples s 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
PK trough s 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical examination 
X 
X  
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Vital signs t 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Electrocardiogram, 12-lead (2 h 
±30 min after study drug dosing) u 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Pregnancy test v 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Chemistry and hematology w 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Adverse event monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ACTH = adrenal corticotropic hormone; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BP = blood pressure; BDI-II = Beck Depression Inventory; Ca = calcium;  
DHEA-S = dehydroepiandrosterone sulfate; EAS = ectopic ACTH secretion; ET = early termination; HbA1c = glycated hemoglobin; IGF = insulin-like growth factor; oGTT = oral glucose tolerance test; Na = sodium; RBC = red 
blood cell; T3 = triiodothyronine; T4 = thyroxine; UFC = urinary free cortisol; WBC = white blood cell 
 
Note: Collect pituitary MRI radiographic scans and assessments in patients with Cushing disease that are obtained up to 6 months before Day 1 and up to 1 month after last CORT125134 dose if they are available. 


Corcept Therapeutics  
Statistical Analysis Plan
CORT125134-451 
Version 1.0; 30 August 2018
 
 
Confidential 
Page 14 of 51
 
a 
For patients rolling over from Group 1 to Group 2, the Group 1 Week 12 visit will serve as the baseline visit for their Group 2 treatment period. 
b 
This visit is not necessary for patients who roll over from Group 1 to Group 2.  
c 
Medications used in the treatment of Cushing syndrome are prohibited and require washout (as applicable) during screening provided the intervals specified in Exclusion Criterion fit within the screening window. Patients 
requiring washout of a medication for Cushing syndrome must complete the screening/baseline 24-hour UFC tests, salivary cortisol tests, oGTTs, and 24-hour ambulatory BP monitoring tests after washout and within 3 weeks 
before Day 1 dosing.  
d 
Medication history only for medications taken to treat Cushing syndrome, hypertension, or diabetes within 3 months before screening. 
e 
Dexamethasone suppression test only if needed for study entry. 
f 
Within 7 days before the Week 2, 4, 6, 8, 10, and 12 visits, samples will be collected by the patient at home twice for each time point.  
g 
The 24-hour UFC will be collected by the patient at home at least two times and up to four times during screening. For screening, the average of the results will serve as “baseline”.  
h 
Salivary cortisol test will be performed by the patient at home at least two and up to four times on different nights during screening. The average of the results will serve as “baseline”. 
i 
oGTTs during the Treatment Period (including on Day 1) will be performed in the impaired glucose tolerance/diabetes subgroup only. During the 2-hour oGTT, blood samples for plasma glucose and insulin will be collected 
before the glucose drink and 0.5, 1, 1.5, and 2 hours after the glucose drink. 
j 
The 24-hour ambulatory BP will be assessed for all patients during the screening period. For the subgroup of patients who qualify for the hypertension subgroup, there must be a 24-hour ambulatory BP test done within 3 
weeks before Day 1; this result will be used as “baseline”. If the initial screening test was done within 3 weeks before Day 1, it does not need to be repeated. Ambulatory BP measurements during the Treatment Period will be 
performed in the hypertension subgroup only. 
k 
Not required to be collected at screening if results available within 3 months of first dose of study drug at baseline/Day 1.  
l 
Total cholesterol, low-density lipoproteincholesterol, high-density -lipoproteincholesterol-, very low-density lipoprotein-cholesterol, and triglycerides. 
m Only in premenopausal female patients not taking hormonal birth control. 
n 
Estradiol, total and free testosterone, sex hormone binding globulin, follicle-stimulating hormone, and luteinizing hormone. 
o 
Activated partial thromboplastin time, Factor VIII, Factor IX, Factor X, and von Willebrand factor, d-dimer, fibrinogen, and thrombinantithrombin-. 
p 
Blood: osteocalcin, bone alkaline phosphatase; urine: N-telopeptides of type 1 collagen.  
q 
Blood samples for analysis of plasma ACTH, serum cortisol, 17-OH-progesterone, 11-deoxycortisol, DHEA-S, and androstenedione. 
r 
Thyroid function tests will include the following: free T4, free T3, reverse T3, thyroid-stimulating hormone.  
s 
Blood levels of CORT125134 and metabolites will be measured predose and at 1, 2, 4, 6, and 8 hours postdose at Weeks 2, 6, and 10 and predose only at Weeks 4, 8, and 12/ET. 
t 
BP, heart rate, respiratory rate, oral body temperature. 
u 
Triplicate ECGs at screening; duplicate ECGs at other study visits. 
v 
Screening blood pregnancy test; all subsequent tests are urine tests. 
w Chemistry parameters will include a full chemistry profile (albumin, alkaline phosphatase, ALT, AST, blood urea nitrogen, calcium, chloride, cholesterol, creatinine, glucose, lactate dehydrogenase, magnesium, phosphorus, 
potassium, sodium, total creatine kinase, total and direct bilirubin, total protein, uric acid). Hematology parameters will include a complete blood count (hematocrit, hemoglobin, mean corpuscular hemoglobin, mean 
corpuscular hemoglobin volume, mean corpuscular volume, mean platelet volume, platelet count, red blood cell distribution width, RBC count, and WBC count) and differential (percent and absolute for the following: 
basophils, eosinophils, lymphocytes, monocytes, and neutrophils). 
 
 


Corcept Therapeutics  
Statistical Analysis Plan
CORT125134-451 
Version 1.0; 30 August 2018
 
 
Confidential 
Page 15 of 51
 
6.4 
Schedule of Events for Group 2 
 
Assessment/Procedure  
 
Treatment Period 
 
Visit Name 
Screening a 
Baseline b 
Week  
1 
Week  
2 
Week  
3 
Week  
4 
Week  
5 
Week  
6 
Week  
7 
Week  
8 
Week  
9 
Week  
10 
Weeks 11,  
13, 15 
Week  
12 
Week 
14 
Week 16/ 
Early 
Term  
Week 20 
Follow-
Up  
Day Number/ 
Window 
Day −42 to 
Day −1 
Day  
1 
Day 
7±1 
Day 
14±2 
Day 
21±1 
Day 
28±2 
Day 
35±1 
Day 
42±2 
Day 
49±1 
Day 
56±2 
Day 
63±1 
Day 
70±2 
Days 77, 91, 
105±1 
Day 
84±2 
Day 
98±2 
Day 
112±2 
Day 
140+7 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication washout c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and baseline 
disease characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history, medication 
history d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dexamethasone suppression 
test 
X e 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug dispensing 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
Study drug compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient diary  
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
Efficacy Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Waist circumference 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
X 
24-hour UFC with creatinine  
(Ca, Na collection) f 
X c,g 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
Salivary cortisol f 
X c,h 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
2-hour oGTT i 
X c 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
24-hour ambulatory BP test  
X c,j 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
HbA1c 
X k 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Fructosamine 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
Adiponectin  
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
Lipid panel l 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
X 
Sit-to-stand test 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
Menstrual cycle information 
m 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
Sex hormone levels n 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Coagulation panel o 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
GR activity biomarkers test 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 


Corcept Therapeutics  
Statistical Analysis Plan
CORT125134-451 
Version 1.0; 30 August 2018
 
 
Confidential 
Page 16 of 51
 
Assessment/Procedure  
 
Treatment Period 
 
Visit Name 
Screening a 
Baseline b 
Week  
1 
Week  
2 
Week  
3 
Week  
4 
Week  
5 
Week  
6 
Week  
7 
Week  
8 
Week  
9 
Week  
10 
Weeks 11,  
13, 15 
Week  
12 
Week 
14 
Week 16/ 
Early 
Term  
Week 20 
Follow-
Up  
Day Number/ 
Window 
Day −42 to 
Day −1 
Day  
1 
Day 
7±1 
Day 
14±2 
Day 
21±1 
Day 
28±2 
Day 
35±1 
Day 
42±2 
Day 
49±1 
Day 
56±2 
Day 
63±1 
Day 
70±2 
Days 77, 91, 
105±1 
Day 
84±2 
Day 
98±2 
Day 
112±2 
Day 
140+7 
Bone laboratory parameters p 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
HPA axis tests q 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
ACTH precursors  
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
High sensitivity 
Creactive- protein 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
IGF-1 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
Thyroid tests r 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
Trail making test 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
CushingQoL questionnaire 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
X 
BDI-II questionnaire 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
Physician’s Global 
Assessment 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Pharmacokinetic Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK serial blood samples s 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
PK trough s 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
examination 
X 
X  
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Vital signs t 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Electrocardiogram, 12-lead 
(2 h ±30 min after study drug 
dosing) u 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Pregnancy test v 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Chemistry and hematology w 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Adverse event monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Corcept Therapeutics  
Statistical Analysis Plan
CORT125134-451 
Version 1.0; 30 August 2018
 
 
Confidential 
Page 17 of 51
 
ACTH = adrenal corticotropic hormone; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BP = blood pressure; BDI-II = Beck Depression Inventory; Ca = calcium;  
DHEA-S = dehydroepiandrosterone sulfate; EAS = ectopic ACTH secretion; ET = early termination; HbA1c = glycated hemoglobin; IGF = insulin-like growth factor; oGTT = oral glucose tolerance 
test; Na = sodium; RBC = red blood cell; T3 = triiodothyronine; T4 = thyroxine; UFC = urinary free cortisol; WBC = white blood cell 
 
Note: Collect pituitary MRI radiographic scans and assessments in patients with Cushing disease that are obtained up to 6 months before Day 1 and up to 1 month after last CORT125134 dose if they are 
available. 
a 
This visit is not necessary for patients rolling from Group 1 to Group 2. 
b 
For patients rolling over from Group 1 to Group 2, the Group 1 Week 12 visit will serve as the baseline visit for their Group 2 treatment period. 
c 
Medications used in the treatment of Cushing syndrome are prohibited and require washout (as applicable) during screening provided the intervals specified in Exclusion Criterion fit within the screening window. Patients 
requiring washout of a medication for Cushing syndrome must complete the screening/baseline 24-hour UFC tests, salivary cortisol tests, oGTTs, and 24-hour ambulatory BP monitoring tests after washout and within 3 weeks 
before Day 1 dosing.  
d 
Medication history only for medications taken to treat Cushing syndrome, hypertension, or diabetes within 3 months before screening.  
e 
Dexamethasone suppression test only if needed for study entry. 
f 
The Week 2, 4, 6, 8, 10, 12, 14, and 16 samples will be collected by the patient at home twice for each time point.  
g 
The 24-hour UFC will be collected by the patient at home at least two times and up to four times during screening. For screening, the average of the results will serve as “baseline”.  
h 
Salivary cortisol test will be performed by the patient at home at least two and up to four times on different nights during screening. The average of the results will serve as “baseline”. 
i 
oGTTs during the Treatment Period (including on Day 1) will be performed in the impaired glucose tolerance/diabetes subgroup only. During the 2-hour oGTT, blood samples for plasma glucose and insulin will be collected 
before the glucose drink and 0.5, 1, 1.5, and 2 hours after the glucose drink. 
j 
The 24-hour ambulatory BP will be assessed for all patients during the screening period. For the subgroup of patients who qualify for the hypertension subgroup, there must be a 24-hour ambulatory BP test done within 3 
weeks before Day 1; this result will be used as “baseline”. If the initial screening test was done within 3 weeks before Day 1, it does not need to be repeated. Ambulatory BP measurements during the Treatment Period will be 
performed in the hypertension subgroup only. 
k 
Not required to be collected at screening if results available within 3 months of first dose of study drug at baseline/Day 1.   
l 
Total cholesterol, low-density lipoproteincholesterol, high-density -lipoproteincholesterol-, very low-density lipoprotein-cholesterol, and triglycerides. 
m Only in premenopausal female patients not taking hormonal birth control. 
n 
Estradiol, total and free testosterone, sex hormone binding globulin, follicle-stimulating hormone, and luteinizing hormone. 
o 
Activated partial thromboplastin time, Factor VIII, Factor IX, Factor X, and von Willebrand factor, d-dimer, fibrinogen, and thrombinantithrombin-. 
p 
Blood: osteocalcin, bone alkaline phosphatase; urine: N-telopeptides of type 1 collagen.  
q 
Blood samples for analysis of plasma ACTH, serum cortisol, 17-OH-progesterone, 11-deoxycortisol, DHEA-S, and androstenedione. 
r 
Thyroid function tests will include the following: free T4, free T3, reverse T3, thyroid-stimulating hormone.  
s 
Blood levels of CORT125134 and metabolites will be measured predose and at 1, 2, 4, 6, and 8 hours postdose at Weeks 2, 6, 10, and 14 and predose only at Weeks 4, 8, 12, and 16/ET. 
t 
BP, heart rate, respiratory rate, oral body temperature. 
u 
Triplicate ECGs at screening; duplicate ECGs at other study visits. 
v 
Screening blood pregnancy test; all subsequent tests are urine tests. 
w Chemistry parameters will include a full chemistry profile (albumin, alkaline phosphatase, ALT, AST, blood urea nitrogen, calcium, chloride, cholesterol, creatinine, glucose, lactate dehydrogenase, magnesium, phosphorus, 
potassium, sodium, total creatine kinase, total and direct bilirubin, total protein, uric acid). Hematology parameters will include a complete blood count (hematocrit, hemoglobin, mean corpuscular hemoglobin, mean 
corpuscular hemoglobin volume, mean corpuscular volume, mean platelet volume, platelet count, red blood cell distribution width, RBC count, and WBC count) and differential (percent and absolute for the following: 
basophils, eosinophils, lymphocytes, monocytes, and neutrophils). 
 
 


Corcept Therapeutics 
Statistical Analysis Plan
CORT125134-451 
Version 1.0; 30 August 2018
 
 
Confidential 
Page 18 of 51
 
6.5 
Treatment 
6.5.1 
Treatment Administered 
CORT125134 is a synthetically prepared small molecule with the following chemical 
name: (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-1,4,5,6,7,8-
hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-
yl)methanone. 
 
CORT125134 50-mg capsules are white, size 2, hard gelatin capsules. CORT125134 50-
mg capsules will be provided in blister packs containing seven capsules per strip. 
6.5.2 
Method of Assigning Patients to Groups 
Patients who meet all of the inclusion criteria and none of the exclusion criteria (Sections 
4.1 and 4.2, respectively, in the study protocol) during the screening period and at 
baseline (Day 1) will be enrolled in the study. Patients will be enrolled sequentially into 
two groups. Fifteen patients enrolled in Group 1 will receive 100 mg/day for 4 weeks, 
then 150 mg/day for 4 weeks, then 200 mg/day for 4 weeks. 
Doses for patients enrolled in Group 2 will be 250 mg/day for 4 weeks, then 300 mg/day 
for 4 weeks, then 350 mg/day for 4 weeks, and then 400 mg for 4 weeks. 
Dose escalation decisions will take into account DRC review of PK and safety data.  
Patients enrolled in Group 2 who cannot tolerate the starting dose selected for Group 2 
will be allowed to continue on study at a lower dose level (eg, 200 or 150 mg). If the 
lower dose is well tolerated, the dose may be increased by 50 mg after at least 2 weeks of 
treatment at the lower dose and then escalated every 4 weeks according to the protocol 
schedule.  
All changes in dose, including escalations, escalation window, reductions, and 
interruptions, must be approved by the Medical Monitor. 
6.6 
Study Assessments 
6.6.1 
Demographic and Baseline Characteristics 
Patient demographic data will be collected at screening. These include age, sex, race, and 
ethnicity. Baseline disease characteristics, such as years since diagnosis, and Cushing 
syndrome type, will also be documented. 
6.6.2 
Medical History and Medication History 
Patient medical history will be obtained at screening, including the diagnosis, etiology, 
and treatment history of Cushing syndrome (including dexamethasone suppression test 


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Statistical Analysis Plan
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Version 1.0; 30 August 2018
 
 
Confidential 
Page 19 of 51
 
failure where appropriate). Surgery and radiation history will include date and type. A 
menstrual history will be obtained for all female patients. 
6.6.3 
Key Efficacy Assessments 
The key efficacy assessments in this study are glucose tolerance in the impaired glucose 
tolerance/diabetes subgroup and BP in the hypertensive subgroup. All other efficacy 
variables are considered exploratory. 
6.6.3.1 
Glucose Tolerance 
A 2-hour oral glucose tolerance test (oGTT) will be administered to all patients at 
screening and to patients in the impaired glucose tolerance/diabetes subgroup at baseline 
(Day 1) and at Weeks 4, 8, and 12/ET for Group 1 and at Weeks 4, 8, 12, and 16/ET for 
Group 2. 
During the 2-hour oGTT, blood samples for plasma glucose and insulin will be collected 
before the glucose drink and 0.5, 1, 1.5, and 2 hours after the glucose drink. 
The oGTT should be performed after an 8-hour fast. 
6.6.3.2 
Blood Pressure 
The 24-hour ambulatory BP will be assessed for all patients during the screening period. 
For patients who qualify for the hypertension subgroup, there must be a 24-hour 
ambulatory BP test done within 3 weeks before Day 1. The 24-hour ambulatory BP will 
also be measured in the hypertension subgroup at Weeks 2, 4, 6, 8, 10, and 12/ET for 
Group 1 and at Weeks 2, 4, 6, 8, 10, 12, 14, and 16/ET for Group 2. 
Mean 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.  
6.6.4 
Exploratory Efficacy Assessments  
6.6.4.1 
Physician’s Global Assessment 
At baseline, Weeks 2, 4, 6, 8, 10, 12/ET, and follow-up visit for Group 1 and at baseline, 
Weeks 2, 4, 6, 8, 10, 12, 14, 16/ET, and the follow-up visit for Group 2, the Investigator 
will consider all the patient’s signs and symptoms of Cushing syndrome and will rate the 
degree of illness on a scale of 1 to 9, where 1 = absent and 9 = incapacitating.  
6.6.4.2 
Glycated Hemoglobin (HbA1c) Concentration 
HbA1c is a glycoprotein whose concentration reflects the amount of glucose bound to 
hemoglobin. It will be assayed in blood samples drawn at baseline (Day 1) and Week 
12/ET for Group 1 and at baseline and Weeks 12 and 16/ET for Group 2. 


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6.6.4.3 
Fructosamine Concentration 
Fructosamine is a marker used to assess rapid changes in diabetes control and has an 
excellent correlation with HbA1c. Changes in fructosamine may be observed as early as 2 
weeks after beginning dosing with study drug. Serum fructosamine will be assayed in 
blood samples drawn at baseline (Day 1) and at Weeks 2, 4, 6, 8, 10, and 12/ET for 
Group 1 and at Weeks 2, 4, 6, 8, 10, 12, 14, and 16/ET for Group 2. 
6.6.4.4 
Adiponectin Concentration 
Adiponectin is a hormone secreted by adipose tissue that modulates glucose regulation 
and fatty acid metabolism. A blood sample will be collected at baseline (Day 1) and at 
Weeks 4, 8, and 12/ET for Group 1 and at Weeks 4, 8, 12, and 16/ET for Group 2. 
6.6.4.5 
24-Hour Urinary Free Cortisol (UFC) with Creatinine 
The 24-hour UFC with creatinine test will be measured by tandem mass spectrometry at 
least two times during each of the following: screening period, and within seven days 
prior to Weeks 2, 4, 6, 8, 10, and 12/ET for Group 1 and within seven days prior to 
Weeks 2, 4, 6, 8, 10, 12, 14, and 16/ET for Group 2. 
6.6.4.6 
Late-Night Salivary Cortisol Test 
This test will be performed at least two times during each of the following: screening 
period, and within seven days prior to the Week 2, 4, 6, 8, 10, and 12/ET visits for Group 
1 and within seven days prior to the Week 2, 4, 6, 8, 10, 12, 14, and 16/ET visits for 
Group 2.  
6.6.4.7 
Effects on Body Weight and Composition 
Body weight will be obtained at screening, baseline (Day 1), and the Week 2, 4, 6, 8, 10, 
12/ET, and follow-up visit for Group 1, and the Week 2, 4, 6, 8, 10, 12, 14, 16/ET, and 
the follow-up visit for Group 2. 
Waist circumference will be measured at baseline (Day 1), at Weeks 4, 8, 12/ET, and the 
follow-up visit for Group 1, and at Weeks 4, 8, 12, 16/ET, and the follow-up visit for 
Group 2.  
6.6.4.8 
Beck Depression Inventory 
The Beck Depression Inventory (BDI-II) is a 21-question self-report inventory that 
measures depression. Each answer is scored with values 0 to 3. The total score is 
determined as the sum of the 21 questions, ranging from 0 to 63. Total scores are 
classified as mild (<19), moderate (19-29), and severe depression (30-63), with larger 
scores indicating more severe depressive symptoms. Patients will complete the BDI-II at 
baseline (Day 1), and Weeks 4, 8, and 12/ET for Group 1 and Weeks 4, 8, 12, and 16/ET 
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6.6.4.9 
Trail Making Test 
The Trail Making Test is a neuropsychological test of visual attention and task switching. 
It consists of two parts in which the patient is instructed to connect a set of 25 dots as 
quickly as possible while still maintaining accuracy. It can provide information about 
visual search speed, scanning, processing speed, and mental flexibility, as well as 
executive functioning. The Trail Making Test is a two part timed test measured in 
seconds and will be administered at baseline (Day 1) and at Weeks 4, 8, and 12/ET for 
Group 1 and Weeks 4, 8, 12, and 16/ET for Group 2. 
6.6.4.10 
CushingQOL 
The CushingQoL patient questionnaire evaluates the health-related quality of life in 
patients with Cushing syndrome (Webb 2008). It comprises 12 questions, each with five 
possible answers. The CushingQoL instrument addresses known problem areas 
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. 
Lower values reflect lower quality of life. The CushingQoL 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: 
𝑌𝑌= (𝑥𝑥−12)
(60 −12) ∗100 
The questionnaire will be administered at baseline (Day 1), at Weeks 4, 8, 12/ET, and the 
follow-up visit for Group 1, and at baseline and Weeks 4, 8, 12, 16/ET, and the follow-up 
visit for Group 2. 
6.6.4.11 
Effects on Metabolism 
Lipid panel analysis, which will include total cholesterol, low-density lipoprotein-
cholesterol, high-density lipoprotein-cholesterol, very low-density lipoprotein-
cholesterol, and triglycerides, will be conducted. Blood will be collected from all enrolled 
patients at baseline (Day 1), at Weeks 4, 8, 12/ET, and the follow-up visit for Group 1 
and at Weeks 4, 8, 12, 16/ET, and the follow-up visit for Group 2. 
6.6.4.12 
Effect on Strength 
The sit-to-stand test will be performed by all enrolled patients and measures the patient’s 
ability to go from standing to sitting in a chair and then getting up again with/without the 
use of their arms or other aids. The study staff will use a stopwatch to measure the total 
time it takes for the patient to stand up and sit down five times; start time is in the seated 
position and stop time is in the final standing position. The sit-to-stand test is measured in 
seconds and will be administered at baseline (Day 1), at Weeks 4, 8, 12/ET, and the 
follow-up visit for Group 1 and at Weeks 4, 8, 12, 16/ET, and the follow-up visit for 
Group 2. 


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6.6.4.13 
Hormonal and Menstrual Cycle Effects 
Blood samples will be obtained from each patient for analysis of estradiol, total and free 
testosterone, sex hormone binding globulin, follicle stimulating hormone, and luteinizing 
hormone at baseline (Day 1) and at the Week 12/ET visit for Group 1 and at the baseline 
and Week 16/ET visit for Group 2. 
Menstrual cycle information (eg, age at menarche, current pattern of menses, and 
duration of vaginal bleed) will be recorded, along with any spotting occurrences, at every 
visit in premenopausal female patients not on hormonal birth control. 
6.6.4.14 
Coagulation Effects 
Blood samples will be obtained for coagulation tests from all enrolled patients at baseline 
(Day 1), Weeks 4, 8, and 12/ET visits for Group 1 and at Weeks 4, 8, 12, and 16/ET for 
Group 2. These include activated partial thromboplastin time, Factor VIII, Factor IX, 
Factor X, and von Willebrand factor, d-dimer, fibrinogen, and thrombin-antithrombin. 
6.6.4.15 
Glucocorticoid Reception (GR) Activity Biomarkers 
A blood sample will be obtained from all patients for analysis of messenger ribonucleic 
acid (mRNA) expression of glucocorticoid-modulated genes including FKBP5 and a 
panel of housekeeping genes. For Group 1, samples will be collected at baseline (Day 1), 
and Weeks 4, 8, and 12/ET; for Group 2, samples will be collected at baseline (Day 1), 
and Weeks 4, 8, 12, and 16/ET. 
Biomarker analysis is outside the scope of this SAP. Biomarker endpoints and analysis 
methods will be described in a separate Biomarker SAP and Biomarker report. 
6.6.4.16 
Bone Effects 
Blood and urine samples will be obtained from all patients at baseline (Day 1) and Weeks 
4, 8, and 12/ET for Group 1 and at baseline and Weeks 4, 8, 12, and 16/ET for Group 2 
for analysis of bone markers. These will include urinary N-telopeptides of type 1 collagen 
(NTx), serum bone alkaline phosphatase, and serum osteocalcin. 
6.6.4.17 
Hypothalamic-Pituitary-Adrenal (HPA) Axis Effects 
Blood samples will be obtained at screening, baseline (Day 1), Weeks 2, 4, 6, 8, 10, and 
12/ET for Group 1, and at baseline and Weeks 2, 4, 6, 8, 10, 12, 14, and 16/ET for Group 
2 for analysis of plasma adrenocorticotropic hormone (ACTH), serum cortisol, 17-OH-
progesterone, 11-deoxycortisol, dehydroepiandrosterone sulfate (DHEA-S), and 
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6.6.4.18 
ACTH Precursors 
ACTH precursors (proopiomelanocortin and pro-ACTH) will be measured at baseline 
(Day 1), Weeks 2, 4, 6, 8, 10, and 12/ET for Group 1 and at baseline and Weeks 2, 4, 6, 
8, 10, 12, 14, and 16/ET for Group 2. 
6.6.4.19 
High-Sensitivity C-reactive Protein 
High-sensitivity C-reactive protein is an endothelial inflammation marker. A blood 
sample will be collected for this assay at baseline (Day 1), Weeks 4, 8, and 12/ET for 
Group 1 and at baseline and Weeks 4, 8, 12, and 16/ET for Group 2. 
6.6.4.20 
24-Hour Urine Calcium and Sodium 
Increased urinary calcium excretion is a major risk factor in the development of kidney 
stones in patients with Cushing syndrome. Increased sodium excretion in the urine 
reflects sodium consumption and is used during the investigation of hypertension as well 
as in the differential diagnosis of failure of antihypertensive medications or medications 
that target specific causes of hypertension. 
Using the urine samples collected for UFC, calcium and sodium levels will be measured 
in all patients at screening, baseline (Day 1), Weeks 2, 4, 6, 8, 10, and 12/ET for Group 1 
and at baseline and Weeks 2, 4, 6, 8, 10, 12, 14, and 16/ET for Group 2. 
6.6.4.21 
Insulin-like Growth Factor (IGF)-1 
Insulin-like growth factor-1 is a hormone with a structure similar to that of insulin. A 
blood sample will be obtained from all patients for this determination at baseline (Day 1), 
Weeks 4, 8, and 12/ET for Group 1 and at baseline and Weeks 4, 8, 12, and 16/ET for 
Group 2. 
6.6.4.22 
 Thyroid Function Tests 
A blood sample will be obtained from all patients for thyroid function tests (free 
thyroxine [T4], free triiodothyronine [T3], reverse T3, thyroid stimulating hormone) at 
screening, baseline (Day 1), Weeks 2, 4, 6, 8, 10, and 12/ET for Group 1 and at baseline 
and Weeks 2, 4, 6, 8, 10, 12, 14, and 16/ET for Group 2.  
6.6.5 
Description of Safety Variables 
Safety will be assessed by physical examination findings, vital signs, ECG results, 
pregnancy tests, clinical laboratory test results (hematology and chemistry panels), 
adverse events, and concomitant medications.  
6.6.5.1 
Physical Examination 
A complete physical examination will be conducted at screening, baseline (Day 1), 
Weeks 2, 4, 6, 8, 10, 12/ET, and the follow-up visit for Group 1 and at baseline and 


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Weeks 2, 4, 6, 8, 10, 12, 14, 16/ET, and the follow-up visit for Group 2. A complete 
physical examination will include evaluation of general appearance, HEENT (head, eyes, 
ears, nose, throat), as well as dermatologic, cardiovascular, respiratory, gastrointestinal, 
extremities/musculoskeletal, and neurologic body systems.  
6.6.5.2 
Vital Signs 
Vital signs include BP, heart rate, respiratory rate, and oral body temperature, and will be 
collected in the clinic at screening, baseline (Day 1), Weeks 2, 4, 6, 8, 10, 12/ET, and the 
follow-up visit for Group 1 and at baseline and Weeks 2, 4, 6, 8, 10, 12, 14, 16/ET, and 
the follow-up visit for Group 2. Unscheduled assessments of vital signs can be performed 
as necessary.  
Height will be measured at the screening visit only. 
6.6.5.3 
Electrocardiogram 
Twelve-lead ECG tracings will be obtained in triplicate from all patients at screening, 
Weeks 2, 4, 6, 8, 10, 12/ET, and the follow-up visit for Group 1 and at screening and 
Weeks 2, 4, 6, 8, 10, 12, 14, 16/ET, and the follow-up visit for Group 2. Patients should 
be lying down for at least 10 minutes prior to each ECG evaluation. Post-screening ECGs 
should be performed 2 hours (± 30 minutes) after study drug dosing. 
The Investigator or designee will indicate on the site’s copy 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. 
6.6.5.4 
Pregnancy Tests 
All female patients of childbearing potential (including women <50 years old, women 
whose surgical sterilization was performed <6 months ago, and women who have had a 
menstrual period in the last two 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. 
6.6.5.5 
Safety Clinical Laboratory Tests 
Fasting blood samples will be collected for labs in all patients at screening, baseline (Day 
1), Weeks 2, 4, 6, 8, 10, 12/ET, and the follow-up visit for Group 1, and at baseline and 
Weeks 2, 4, 6, 8, 10, 12, 14, 16/ET, and the follow-up visit for Group 2. Laboratory 
samples will be analyzed at one or more central laboratories. 
Laboratory values for an analyte that are outside of the normal range for that analyte per 
the applicable central laboratory will be identified and can be repeated at the 
Investigator’s discretion. The Investigator will determine if any out-of-range laboratory 
values that emerge during the study are clinically significant. 


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Safety laboratory measurements will include the following: 
• Chemistry: 
o Full chemistry profile: albumin, alkaline phosphatase, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), blood urea 
nitrogen, calcium, chloride, total cholesterol, creatinine, glucose, lactate 
dehydrogenase, magnesium, phosphorus, potassium, sodium, total 
creatinine kinase, total and direct bilirubin, total protein, and uric acid 
• Hematology: 
o Complete blood count: hematocrit, hemoglobin, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration, mean 
corpuscular volume, mean platelet volume, platelet count, red blood cell 
distribution width, red blood cell (RBC) count, and white blood cell 
(WBC) count 
o Differential: percent and absolute for the following: basophils, 
eosinophils, lymphocytes, monocytes, and neutrophils 
6.6.5.6 
Adverse Events 
An AE is any untoward medical occurrence in a study patient administered a 
pharmaceutical product, which does not necessarily have to have a causal relationship 
with this treatment. Collection of AEs will start immediately following signing of the 
informed consent form and will continue throughout the study. 
AEs that occur after the start of study treatment up to and including 28 days after 
administration of the last dose of study drug will be considered treatment-emergent 
adverse events (TEAEs). AEs will be evaluated for incidence, severity, relationship to the 
study medication, seriousness of the AE, and what action was taken.   
6.6.5.7 
Prior and 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 medication 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.  
Prior and concomitant medications are collected at every visit from screening through 
follow-up.  
6.6.6 
Description of Pharmacokinetics 
Pharmacokinetic analysis is outside the scope of this SAP; PK endpoints and analysis 
methods will be described in a separate PK Analysis Plan and PK Study Report. 


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6.7 
Data Quality Assurance 
During the conduct of the study and until completion of the CSR, monitor(s) representing 
Corcept Therapeutics will visit the investigator(s) at regular intervals, to assure that the 
study is conducted under ICH E6 (Good Clinical Practice), including monitoring for 
study progress, completeness, consistency and accuracy of data entered on the electronic 
case report forms (eCRFs), review of outstanding data discrepancies and other aspects of 
study conduct. The investigator (or designee) is required to cooperate with the monitor. 
Laboratory tests will be analyzed at a selected central laboratory. If required, these data 
will be supplemented by laboratory tests from a site’s local laboratory. Data management 
will be performed by an outside CRO. Electronic case report form data will be subject to 
EDC database batch validations run per programmed edit specifications. Data 
Management will conduct data listing reviews. Data queries will be reviewed and closed 
upon resolution. Case report form processing will continue until all eCRFs are received 
and are “clean” (defined as passing all edit specifications, and review of the medical 
monitor and biostatistics group). All reported serious adverse events (SAEs) will be 
coded to standard system organ class and preferred terms using the Medical Dictionary 
for Regulatory Activities (MedDRA version 19.0) terminology. Medications will be 
coded using the World Health Organization (WHO Drug version 161E, enhanced) 
dictionary. Medications entered on the eCRF will be mapped to Anatomic Therapeutic 
Chemical (ATC) drug class (level 4) and drug name. 
Report summaries will be generated using validated Base SAS software, version 9.4 or 
higher, on a PC or server-based platform. Additional validated software may be used to 
generate analyses, as needed.  
All SAS programs that create outputs or supporting analysis datasets will be validated per 
vendor standard operating procedures. 
The content of the source data will be reviewed on an ongoing basis by project statistical 
programmers and statisticians as appropriate, per vendor standard operating procedures.  
7 STATISTICAL METHODS 
7.1 
General Methodology 
Data will be analyzed by Precision for Medicine, Oncology and Rare Disease biostatistics 
personnel. 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 
in Appendix 7 of the Electronic Common Technical Document Specification (Apr 2003).  
In addition to tables, figures, and listings, individual patient profiles will be generated to 
display select efficacy and safety endpoints over time, to include data from each patients’ 
entire time on study drug. 


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7.1.1 
Reporting Conventions 
Listings will be ordered by Group 1 and Group 2, site, patient number, and assessment or 
event date. Listings presenting study data over time will include the dose level the patient 
received at the time of data collection. 
Continuous variables will be summarized to indicate the population sample size (N), 
number of patients with available data (n), mean, SD, median, minimum, and maximum 
values. Categorical variables will be summarized by the population size (N), number of 
patients with available data (n), number of patients in each category, and the percentage 
of patients in each category. 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. 
Non-zero percentages will be rounded to two decimal places. 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 (ie, on the eCRF or as provided within 
an external file) and are outlined as follows: 
• The mean and median will be rounded to one more decimal place than the 
precision of the variable of summarization; 
• Measures of variability (eg, SD, SE) will be rounded to two more decimal places 
than the precision of the variable of summarization; and 
• Minimum and maximum values will be presented using the same precision as the 
variable of summarization. 
Other statistics (eg, CIs) will be presented using the same general rules outlined above, or 
assessed for the most appropriate presentation based on the underlying data. 
All statistical tests will be conducted at the two-sided, 0.05 level of significance, unless 
otherwise specified.  
7.1.2 
Definition of Analysis Visit Windows 
In analysis of data summarized by study visit, unscheduled and early termination visits 
will be reassigned a study visit where data is scheduled for collection based on the actual 
days relative to baseline.  
Table 2 defines the visit windows for the assessments taken at biweekly intervals to be 
established for Group 1 with respect to relative day from the start of study drug. 
Table 2 
Group 1 Biweekly Interval Visit Windows (Days) 
Visit 
Target Study 
Day 
Analysis Window Study Day 
Low 
High 


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Baseline 
1 
Reference Section 7.1.5 for endpoint-specific definition 
Week 2 
14 
> Baseline measurement 
21 
Week 4 
28 
22 
35 
Week 6 
42 
36 
49 
Week 8 
56 
50 
63 
Week 10 
70 
64 
77 
Week 12 
84 
78 
98 
Table 3 defines the visit windows for the assessments taken at biweekly intervals to be 
established for Group 2 with respect to relative day from the start of study drug. 
Table 3 
Group 2 Biweekly Interval Visit Windows (Days) 
Visit 
Target Study 
Day 
Analysis Window Study Day 
Low 
High 
Baseline 
1 
Reference Section 7.1.5 for endpoint-specific definition 
Week 2 
14 
> Baseline measurement 
21 
Week 4 
28 
22 
35 
Week 6 
42 
36 
49 
Week 8 
56 
50 
63 
Week 10 
70 
64 
77 
Week 12 
84 
78 
91 
Week 14 
98 
92 
105 
Week 16 
112 
106 
126 
Table 4 defines the visit windows for the assessments taken at monthly intervals to be 
established for Group 1 with respect to the relative day from the start of study drug. 
Table 4 
Group 1 Monthly Interval Visit Windows (Days) 
Visit 
Target Study 
Day 
Analysis Window Study Day 
Low 
High 
Baseline 
1 
Reference Section 7.1.5 for endpoint-specific definition 
Week 4 
28 
> Baseline measurement 
42 
Week 8 
56 
43 
70 
Week 12 
84 
71 
98 
Table 5 defines the visit windows for the assessments taken at monthly intervals to be 
established for Group 2 with respect to the relative day from the start of study drug. 
Table 5 
Group 2 Monthly Interval Visit Windows (Days) 
Visit 
Target Study 
Day 
Analysis Window Study Day 
Low 
High 
Baseline 
1 
Reference Section 7.1.5 for endpoint-specific definition 
Week 4 
28 
> Baseline measurement 
42 
Week 8 
56 
43 
70 
Week 12 
84 
71 
98 


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Week 16 
112 
99 
126 
The Week 16 follow-up window for Group 1 patients will include all unscheduled or 
scheduled follow-up visits occurring after the Week 12 visit window if patient is no 
longer on study drug. The Week 20 follow-up window for Group 2 patients will include 
all unscheduled or scheduled follow-up visits occurring after the Week 16 visit window if 
patient is no longer on study drug. If an unscheduled or scheduled visit occurs after the 
upper bound of the Week 12 (Group 1) or Week 16 (Group 2) visit window, and patient 
is still on study drug, that visit will be included in the Week 12 (Group 1) or Week 16 
(Group 2) visit window, as appropriate.  
Data collected at scheduled visits will be analyzed based on the nominal visit as reported 
in the database (ie, will not be mapped to visit windows). If an unscheduled visit is 
mapped to a 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 visits occur within a single visit window, then the closest visit to the target day 
of the visit window will be used in the analysis. If there is a tie, the later visit will be used 
in the analysis.   
In situations where a time point is missing in the oGTT measurements, preference for 
visit windowing will be given to another visit (scheduled or unscheduled) occurring in 
the same visit window that has complete oGTT data. If more than one alternative visit is 
available, preference should be given to the closest visit to the target day of the visit 
window. 
If early termination data is not labeled separately from the Week 12 visit in Group 1 or 
the Week 16 visit in Group 2 in the clinical database or external data transfers, then that 
visit data will be considered early termination data if the disposition eCRF indicates the 
patient discontinued the study early, and will be reassigned to the appropriate analysis 
visit window according to Tables 2-5, above. Otherwise, that visit data will be considered 
Week 12 or Week 16 data, as appropriate.  
7.1.3 
Data Handling Rules 
Unless otherwise noted, values reported as greater than or less than some quantifiable 
limit (eg, “<1.0”) will be summarized with the sign suppressed in summary tables and 
figures, using the next rounded down tenths place ½ step (eg, .5 or .0). Examples are 
provided in Table 6. Data will display on patient listings to include the sign. 
Table 6 
Examples of Data Handling Rules 
Laboratory Test 
Raw Data Value 
Assigned Values for Analysis 
11-deoxycortisol 
<0.58 
0.5 
Plasma ACTH 
<1.1 
1 
Salivary Cortisol 
<0.8 
0.5 


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7.1.4 
Standard Calculations 
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 will 
be determined as: 
• The assessment/event date minus the date of first dose, if the assessment/event 
date is prior to the date of first dose; and 
• The assessment/event date minus the date of first dose, plus one, if the 
assessment/event date is on or after the date of first dose. 
Other variables requiring calculations will be derived using the following formulas: 
• 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. 
• Months: A duration expressed in months will be calculated by dividing the 
duration in days by (365.25 / 12); 
• Years: A duration expressed in years will be calculated by dividing the duration 
in days by 365.25; 
• 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. 
7.1.5 
Definitions of Baseline 
The baseline for oGTT plasma glucose and insulin is defined as the last oGTT 
corresponding time point measurement prior to first dose of study drug (eg, pre-glucose 
drink, 0.5 hours post-glucose drink, 1 hour post-glucose drink, etc.). For example, the 
baseline for all post-baseline 0.5 hour post-glucose drink time points will be the last 0.5 
hour post-glucose drink time point prior to first dose of study drug. In situations where a 
time point is missing in the oGTT measurements, preference for baseline will be given to 
another visit occurring prior to first dose of study drug, if available, where all time points 
are non-missing (eg, if a Day 1 oGTT time point is missing, and a Screening visit with no 
missing time points is available, that Screening visit will be flagged as baseline). If more 


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than one alternative visit is available (scheduled or unscheduled), preference should be 
given to the last visit prior to first dose of study drug.  
The baseline for the area under the concentration-time curve for glucose (AUCglucose) and 
insulin (AUCinsulin) is defined at the same visit (unscheduled or scheduled) that the oGTT 
plasma glucose and insulin baseline is defined.  
The baseline for 24-hour UFC with creatinine, late-night salivary cortisol, 24-hour urine 
calcium, and 24-hour urine sodium 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 
triplicate readings at the last visit prior to first dose of study drug. The last visit prior to 
first dose of study drug may by an unscheduled or scheduled visit. 
The baseline for all other efficacy and safety parameters not previously mentioned is 
defined as the last measurement prior to first dose of study drug. The last visit prior to 
first dose of study drug may be an unscheduled or scheduled visit.  
7.2 
Analysis Populations 
The analysis populations are defined as follows:  
• Safety Population: Includes all enrolled patients who receive at least one dose of 
study drug. 
• Modified Intent-to-Treat (mITT) Population: Includes all enrolled patients who 
receive at least one dose of study drug and have non-missing post-baseline data 
collected. 
All efficacy analyses will be performed on the mITT Population. All safety analyses will 
be performed on the Safety Population; select safety analyses may also be performed on 
the mITT Population. 
As a sensitivity analysis of the key efficacy endpoints, a modified version of a Per-
Protocol Population will also be used, defined as follows: 
• Modified Per-Protocol (mPP) Sensitivity Population: Includes all patients in the 
mITT Population with exclusions at specific visits per patient based on clinical 
judgment and/or major or important protocol deviations that are applied on a visit 
and outcome level rather than patient level. For example, a patient with a major or 
important protocol deviation occurring between Week 10 and Week 12 may have 
data included in analyses prior to Week 12 but be dropped from the Week 12 
analysis. 
The mPP Sensitivity Population may also be used as a sensitivity analysis for select 
exploratory efficacy and safety endpoints. 


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7.3 
Examination of Subgroups 
The following subgroups are defined for the study analyses: 
1. Dose groups: 
a. Group 1: Patients enrolled plan to receive 100 mg of study drug for 4 
weeks, followed by 150 mg for 4 weeks, and then 200 mg for 4 weeks.  
b. Group 2: Patients enrolled plan to receive 250 mg of study drug for 4 
weeks, followed by 300 mg for 4 weeks, then 350 mg for 4 weeks, and 
then 400 mg for 4 weeks. 
2. Cushing syndrome comorbidity: 
a. Patients with type 2 diabetes or impaired glucose tolerance (IGT): 
Confirmed at screening visit with either a fasting glucose > 126 mg/dL 
and a 2-hour oGTT result for plasma glucose ≥ 200 mg/dL at 2 hours (for 
type 2 diabetes), or a 2-hour oGTT result for plasma glucose in the range 
of ≥ 140 mg/dL to < 200 mg/dL (for impaired glucose tolerance). 
b. Patients with hypertension (HT): Confimed at screening with a mean 
systolic BP of 130-170 mmHg and/or a mean diastolic BP of 85-110 
mmHg based on the 24-hour ambulatory BP measurement. 
3. Etiology: 
a. ACTH-Dependent: Cushing disease or ectopic 
b. Adrenal 
4. Mildly depressive patients: Patients whose baseline BDI-II total score is less than 
19. 
5. Concomitant medications in the IGT Cushing syndrome comorbidity subgroup: 
a. Patients who did not receive exogenous insulin at baseline 
b. Patients who did not receive exogenous insulin during the treatment period 
6. Menopausal status: 
a. Pre-menopausal 
b. Post-menopausal 
7. Low serum osteocalcin patients: Patients whose baseline serum osteocalcin 
measurement is less than 8 µg/L. 


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8. High HbA1c patients: Patients whose baseline HbA1c measurement is ≥ 6.5%. 
As a general rule, all efficacy data summaries will be presented by Group 1 and Group 2; 
all safety data summaries will be presented by Group 1, Group 2, and Overall. Data 
summaries by other subgroups will be implemented as described in this SAP. 
7.4 
Time-Course and Dose-Course Analysis Methods 
Because of potential events that can affect the planned dose escalations of the study (eg, 
individual dose escalation timing that differs from planned nominal time, dose reduction, 
dose interruption, and/or dose discontinuation), the data will be summarized using the 
following two methods: 
• Time-course (by visit), which evaluates assessments across visits and assumes 
protocol-defined dose-escalation; and 
• Dose-course (by dose categories), which evaluates assessments according to 
expected dose level received, as defined by the Medical Monitor. 
Time-course will be used as the primary method of analysis for efficacy assessments, and 
will follow the analysis visit windowing described in Section 7.1.2.  
Dose-course will be used as the primary method of analysis for safety assessments, and 
as a sensitivity method of analysis for efficacy assessments, including all key and 
exploratory efficacy assessments. Dose-course categories include 100, 150, 200, 250, 
300, 350, and 400 mg, and when assessments are summarized by Group 1 and Group 2, 
the following categories will be used for each: 
• Group 1: 100, 150, and 200 mg dose levels; and 
• Group 2: ≤ 200, 250, 300, 350, and 400 mg dose levels. 
The ≤ 200 mg dose level is included to account for Group 2 patients who may have their 
study drug dose reduced to 200 mg or less. The date of study drug dose administration 
per patient will be used to determine which dose-course level assessments fall in, and the 
last assessment available per patient within each dose-course level will be used as the 
final assessment for that dose level in the analysis. For example, if a patient dosed at 250 
mg, reduced to 200 mg, and escalated again to 250 mg, all assessments will be gathered 
where the patient was dosing at 250 mg, and the last available assessment will be used in 
the analysis at the 250 mg dose level.  
Dose-course categories will also include the follow-up period, where appropriate, and 
will be defined as the last assessment available for all assessments occurring after the 
date of last dose of study drug per patient. 


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7.5 
Study Patients 
7.5.1 
Disposition of Patients 
Patient disposition will be summarized for the Safety and mITT populations by Group 1, 
Group 2, and over all patients combined. Summaries will include the number and 
percentage of patients within each comorbidity subgroup (IGT/HT), etiology subgroup, 
completing the study, and terminating the study early by the primary reason for 
discontinuation.  
A summary including all patients will also be presented, including the number and 
percentage of patients screened, screen failures, and patients in each analysis population 
by Group 1, Group 2, and all patients combined. 
7.5.2 
Protocol Deviations 
Major and important protocol deviations, as collected by the Corcept team, will be 
summarized by Group 1, Group 2, over all patients combined, for the Safety Population. 
Refer to the Protocol Deviations Plan, developed under ICH E3 and ICH E3 Q&A (2012) 
for the definitions of protocol deviations and deviations categories. 
The number and percentage of patients with any major or important protocol deviations 
as well as the number and percentage of patients with deviations within each category 
will be presented.  
All major and important protocol deviations will be determined and appropriately 
categorized prior to database lock by the Corcept study team. Protocol deviations will be 
listed by Group 1, Group 2, study site, patient, and date of deviation, and will indicate if 
they are considered major or important.  
7.6 
Efficacy 
As described in Section 7.4, efficacy endpoints will be primarily summarized using a 
time-course method of analysis (by visit), and secondarily summarized using a dose-
course method of analysis (by dose categories). Although the longitudinal summaries in 
the below efficacy sections are described using the time-course method of analysis, 
language that specifies “visit” is meant to be replaceable with “dose category” when 
analyses are repeated using the dose-course method of analysis.   
All efficacy data will appear in by-patient data listings. 
7.6.1 
Demographic and Baseline Characteristics 
Demographic variables including age at the time of informed consent, sex, ethnicity and 
race, will be summarized for the Safety and mITT populations, comorbidity subgroup, 
and etiology subgroup by Group 1, Group 2, and overall patients combined.  


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Age will be summarized using descriptive statistics. Sex, ethnicity, and race will be 
summarized with the number and percentage of patients in each parameter category. 
Baseline characteristics include medical history, baseline disease characteristics (eg, time 
since diagnosis, Cushing syndrome type), height, weight, body mass index (BMI), waist 
circumference, plasma ACTH, 24-hr UFC with creatinine, late-night salivary cortisol, 
fructosamine, oGTT plasma glucose, AUCglucose, AUCinsulin, HbA1c, osteocalcin, and 
mean 24-hour systolic and diastolic BP from ambulatory BP monitoring. BMI will be 
calculated as: weight (kg) / [height (cm) / 100]2. AUCglucose and AUCinsulin definitions can 
be found in Sections 7.6.3.2.1 and 7.6.3.2.3, respectively. 
The baseline characteristics and baseline disease characteristics summary tables will be 
summarized for all patients in the Safety and mITT populations and presented by etiology 
subgroups, by Group 1, Group 2, and over all patients combined. Medical history will be 
summarized for all patients in the Safety Population and presented by etiology subgroup, 
by Group 1, Group 2, and over all patients combined. Continuous variables at baseline 
will be summarized using descriptive statistics. Frequency counts and percentages to 
summarize patients reporting medical history by system organ class (coded using 
MedDRA version 19.0) and Cushing syndrome history will be presented. Time (months) 
since diagnosis of Cushing disease will be calculated as the informed consent date minus 
the diagnosis date from the medical history eCRF, and be will be summarized using 
descriptive statistics. 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.  
7.6.2 
Measurements of Treatment Compliance 
Compliance to the study treatment regimen will be determined as the total actual dose 
received divided by the expected dose received, multiplied by 100. A patient is 
considered compliant to the treatment regimen if their compliance calculation is ≥ 80% of 
the expected dose. Expected dose received will be calculated as [(study drug stop date – 
study drug start date) + 1] x dose expected on those days, and will reflect physician 
decision per patient. Total actual dose received will be calculated as the number of 
capsules taken per visit x 50 mg, summed across all visits per patient. Dosing compliance 
will be summarized using descriptive statistics, by Group 1 and Group 2, based on the 
Safety Population. The number and percentages of patients who are < 80% compliant and 
≥ 80% compliant within each group will be summarized. 
7.6.3 
Key Efficacy Endpoint Analysis Methods 
Key efficacy endpoints will be performed on the mITT Population. As a sensitivity 
analysis, key efficacy endpoints will also be performed using the mPP Sensitivity 
Population.  
7.6.3.1 
Medications Affecting Responder Analyses 
Patients who start an additional medication of interest during the treatment period or 
increase the dosage of a concurrent medication of interest will be classified as 


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nonresponders in the responder analyses for AUCglucose (Section 7.6.3.2.1) and mean 
systolic and diastolic BP (Section 7.6.3.3.1). Concomitant medications of interest for the 
AUCglucose responder analysis include diabetes medications, as indicated by the Medical 
Monitor. Likewise, concomitant medications of interest for the mean systolic and 
diastolic BP responder analysis include antihypertensive medications, as indicated by the 
Medical Monitor. 
7.6.3.2 
Impaired Glucose Tolerance/Diabetes Subgroup Analyses 
Summary tables and figures will be repeated by the concomitant medications subgroup 
including patients who did not receive exogenous insulin during the treatment period. 
Insulin, HOMA-IR, and Matsuda Index endpoints will also be repeated by the 
concomitant medication subgroup including patients who did not receive exogenous 
insulin at baseline. 
7.6.3.2.1 
oGTT Plasma Glucose Responder Analysis 
AUCglucose will be calculated based on results of the 2-hour oGTTs taken at baseline, 
Week 4, Week 8, Week 12, and Week 16 (Group 2 only), for those patients with impaired 
glucose tolerance or diabetes at study entry. The AUCs will be calculated using the linear 
trapezoidal rule, as follows (where C1 and C2 are concentrations at times t1 and t2, 
respectively): 
𝐴𝐴𝐴𝐴𝐴𝐴= 1
2 (𝐶𝐶1 + 𝐶𝐶2)(𝑡𝑡2 −𝑡𝑡1) 
A responder will be defined as a patient who experiences at least a 25% decrease from 
baseline in AUCglucose who has not taken an additional diabetes medication during the 
treatment period or increased the dosage of a concurrent diabetes medication, as indicated 
by the Medical Monitor. Nonresponder rules apply as described in Section 7.6.3.1. The 
responder endpoint will be calculated at each visit. The primary efficacy endpoint is the 
Week 12/ET time point for Group 1, and the Week 16/ET time point for Group 2, which 
will be summarized as Last Observed (Section 7.6.5.1). The number and percentage of 
patients who are responders will be presented by Group 1 and Group 2, along with a 95% 
exact binomial two-sided CI (Clopper-Pearson).  
There will additionally be a threshold test on the lower limit of the 95% exact binomial 
CI. The null hypothesis to be tested is that there is no difference between the rate of 
spontaneous remission of Cushing syndrome and the responder rate due to study drug: 
H0: πresponder ≤ 0.2; 
Where π represents the lower limit of the 95% exact binomial CI of responders. The 
alternative hypothesis to be tested is that there is a difference between the rate of 
spontaneous remission of Cushing syndrome and the responder rate due to study drug: 
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Where the null hypothesis will be rejected in favor of the alternative if the lower limit of 
the 95% exact binomial CI for the responder rate is greater than 20%. Although there are 
anecdotal reports of spontaneous remission in Cushing syndrome, the cases are extremely 
rare. Twenty percent (20%) is an appropriate threshold to test against in this population, 
given that the spontaneous remission rate in individuals who are eligible for this study is 
close to 0%. These rare cases often occur in the setting of de novo Cushing disease and 
have been largely due to apoplexy (pituitary hemorrhage). Patients who are enrolled with 
prior pituitary radiotherapy could theoretically lead to a higher remission rate. Although 
the criteria used for establishing remission are not standardized, recent reviews document 
that the usual time to remission in those patients who respond is approximately 2 years 
depending on the modality of radiotherapy used. While control of hypercortisolism may 
occur in as many as 50-60% of patients in 3-5 years, responses are gradual, variable, and 
may be delayed for many years (Fleseriu, et al 2012). 
AUCglucose will be summarized using descriptive statistics including two-sided 95% CI of 
the mean, the geometric mean, and arithmetic CV (%), by Group 1 and Group 2. In 
addition, the following analyses of the continuous AUCglucose endpoint will be conducted: 
• A Wilcoxon signed-rank test will be conducted to evaluate if there is a significant 
change compared to baseline at each visit. 
• For each group, a restricted maximum likelihood (REML) based linear mixed 
model for repeated measures (MMRM) analysis will be calculated for both 
AUCglucose and the natural log of AUCglucose. 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; Autoregressive (1) and Toeplitz 
structures will also be explored. 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. 
Additionally, a cumulative distribution for percent change in AUCglucose from baseline to 
each visit will be presented and sorted by most improved to least improved. 
A plot of mean AUCglucose will be presented over time by Group 1 and Group 2. A 
waterfall plot of AUCglucose percent change from baseline to last observed by dose level 
and during the treatment period will be presented by Group 1 and Group 2.  
7.6.3.2.2 
oGTT Plasma Glucose 
Plasma glucose (mmol/L) will be summarized using descriptive statistics including two-
sided 95% CI of the mean by visit, time point (pre-glucose drink and 0.5, 1, 1.5, and 2 
hours post glucose drink), by Group 1, and Group 2, to include the change from baseline. 
Plasma glucose (mmol/L) will also be analyzed by a Wilcoxon signed-rank test to 
evaluate if there is a significant change compared to baseline at each time point (pre-
glucose drink and 0.5, 1, 1.5, and 2 hours post glucose drink). A column summarizing 
change from pre-glucose drink values will also be included.  


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A plot of mean plasma glucose (mmol/L) values over time will be presented by Group 1 
and Group 2. 
7.6.3.2.3 
oGTT AUCinsulin 
Change from baseline in AUCinsulin will be calculated and summarized similar to 
AUCglucose, including the Wilcoxon signed-rank test and MMRM modeling. A responder 
analysis will not be done using AUCinsulin. A plot of mean AUCinsulin will be presented 
over time by Group 1 and Group 2. AUCinsulin analyses will also be presented by 
concomitant medication subgroups. 
7.6.3.2.4 
oGTT Insulin 
Insulin (µU/mL) will be summarized similar to oGTT plasma glucose (mmol/L). Plots of 
mean insulin (µU/mL) will be presented over time by Group 1 and Group 2. Insulin 
(µU/mL) analyses will also be presented by concomitant medication subgroups. 
7.6.3.2.5 
HOMA-IR 
Plasma glucose (mmol/L) and insulin (µU/mL) pre-glucose drink values from the oGTTs 
will be used to calculate the homeostatic model assessment for insulin resistance 
(HOMA-IR) as follows: 
𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻−𝐼𝐼𝐼𝐼= 
𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔 ቀ𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚
𝐿𝐿
ቁ𝑥𝑥 𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖 (µ U
mL)
22.5
 
HOMA-IR will be summarized using descriptive statistics including two-sided 95% CI of 
the mean by visit, Group 1, and Group 2, to include the change from baseline. HOMA-IR 
will also be analyzed by a Wilcoxon signed-rank test to evaluate if there is a significant 
change compared to baseline at each visit.  
Box plots of HOMA-IR will be presented over time by Group 1 and Group 2. HOMA-IR 
analyses will also be presented by concomitant medication subgroups. 
7.6.3.2.6 
Matsuda Index 
Plasma glucose (mmol/L) and insulin (µU/mL) from the oGTTs will be used to calculate 
the Matsuda index, which is an index created to evaluate the whole body physiological 
insulin sensitivity from data obtained by oGTTs (Matsuda 1999), as follows: 
 
𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀 𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖
= 
10000
ට𝑔𝑔0 ∗18 ∗𝑖𝑖0 ∗(𝑔𝑔0 + 𝑔𝑔0.5 ∗2 + 𝑔𝑔1 ∗2 + 𝑔𝑔1.5 ∗2 + 𝑔𝑔2)
8
∗18 ∗(𝑖𝑖0 + 𝑖𝑖0.5 ∗2 + 𝑖𝑖1 ∗2 + 𝑖𝑖1.5 ∗2 + 𝑖𝑖2)
8
 
Where g corresponds to plasma glucose (mmol/L), i corresponds to insulin (µU/mL), and 
the subscripts 0, 0.5, 1, 1.5, and 2 correspond to the time points in hours during the oGTT 
test (eg, 0 = pre-glucose drink, 0.5 = 0.5 hours after glucose drink, etc.). The Matsuda 


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index will be summarized using descriptive statistics including two-sided 95% CI of the 
mean by visit, Group 1, and Group 2, to include the change from baseline. The Matsuda 
index will also be analyzed by a Wilcoxon signed-rank test to evaluate if there is a 
significant change compared to baseline at each visit. Matsuda index analyses will also be 
presented by concomitant medication subgroups. 
7.6.3.2.7 
Change in Blood Glucose Medications 
The number and percentage of patients whose dose of medications that lower blood 
glucose decreased, stayed the same, or increased from baseline to study drug dose level 
or follow-up period, as determined by blood glucose medication start date, will be 
summarized, among those patients taking such medication at baseline. Additional counts 
and percentages will be provided including patients who were not taking blood glucose 
medications at baseline. 
7.6.3.3 
Hypertension Subgroup Analysis Methods 
Change in mean diastolic and systolic BP measured by 24-hour ambulatory BP 
monitoring will be analyzed for patients with hypertension at study entry. The mean BP 
value per patient per visit will be included in the analysis if the record is labeled as 
“PASS” in the corresponding overall quality control (QC) variable provided by the 
external ambulatory BP vendor.   
7.6.3.3.1 
Blood Pressure Responder Analysis 
A responder will be defined as a patient who experiences at least a 5 mmHg decrease in 
mean diastolic or systolic BP from baseline who has not taken an additional 
antihypertensive medication during the treatment period or increased the dosage of a 
concurrent antihypertensive medication, as indicated by the Medical Monitor. 
Nonresponder rules apply as described in Section 7.6.3.1. The responder endpoint will be 
calculated at each visit. The primary efficacy endpoint is the Week 12/ET time point for 
Group 1, and the Week 16/ET time point for Group 2, which will be summarized as Last 
Observed (Section 7.6.5.1). The number and percentage of patients who are responders 
will be presented by Group 1 and Group 2, along with a 95% exact binomial two-sided 
CI (Clopper-Pearson). BP will also be summarized using descriptive statistics, including 
two-sided 95% CI of the mean, and a Wilcoxon signed-rank test to evaluate if there is a 
significant change compared to baseline at each time point. 
There will additionally be a threshold test on the lower limit of the 95% exact binomial 
CI. The null hypothesis to be tested is that there is no difference between the rate of 
spontaneous remission of Cushing syndrome and the responder rate due to study drug: 
H0: πresponder ≤ 0.2; 
Where π represents the lower limit of the 95% exact binomial CI of mean systolic or 
diastolic BP responders. The alternative hypothesis to be tested is that there is a 
difference between the rate of spontaneous remission of Cushing syndrome and the 
responder rate due to study drug: 


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H1: πresponder > 0.2; 
Where the null hypothesis will be rejected in favor of the alternative if the lower limit of 
the 95% exact binomial CI for the responder rate is greater than 20% (Fleseriu, et al 
2012; also reference Section 7.6.3.2.1).   
Also, as sensitivity analyses, the BP responder analysis will be repeated using the 
following criteria:  
1. A patient is considered a responder if once the patient meets the responder criteria 
(established above), the patient continues to meet it throughout any remaining 
post-baseline visits. This responder endpoint will be calculated only at the end of 
the study considering all post-baseline visits. 
2. A patient is considered a responder if the patient experiences at least a 5 mmHg 
decrease in mean diastolic or systolic BP from baseline. Additionally, if a patient 
has a decrease in systolic BP and an increase in diastolic BP, or vice versa, the 
patient will be classified as a nonresponder. The responder endpoint will be 
calculated at each visit. 
3. A patient is considered a responder by the criteria established in #2 and the patient 
maintains responder status throughout any remaining post-baseline visits. The 
responder endpoint will be calculated only at the end of the study considering all 
post-baseline visits.  
4. A patient is considered a responder if the patient experiences a reduction in the 
number or dose of antihypertensive medications, as indicated by the Medical 
Monitor, without experiencing a worsening of either systolic or diastolic BP. The 
responder endpoint will be calculated at each visit.  
5. A patient is considered a responder if the criteria established in #2 and/or #4 is 
met. 
Nonresponder rules, as described in Section 7.6.3.1, apply to the sensitivity responder 
analyses. 
Additionally, cumulative distributions for change in systolic and diastolic BP from 
baseline to each visit will be presented and sorted by most improved to least improved.  
7.6.3.3.2 
24-Hour Ambulatory Blood Pressure 
Mean 24-hour diastolic and systolic BP, mean daytime diastolic and systolic BP, and 
mean nighttime diastolic and systolic BP will be summarized using descriptive statistics 
including two-sided 95% CI of the mean by visit, Group 1, and Group 2, to include the 
change from baseline. Diastolic and systolic BP will also be analyzed by a Wilcoxon 
signed-rank test to evaluate if there is a significant change compared to baseline at each 
visit. Daytime diastolic and systolic BP is defined as those BP measurements collected 


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between 9am to 9pm. Nighttime diastolic and systolic BP is defined as those BP 
measurements collected between 1am to 6am.  
A plot of mean 24-hour systolic and diastolic BP values over time by Group 1 and Group 
2 will be presented. Waterfall plots of mean systolic and diastolic change from baseline 
to last observed by dose level and overall will be presented by Group 1 and Group 2. 
Plots of mean daytime and nighttime systolic and diastolic BP will also be presented over 
time by Group 1 and Group 2.  
7.6.3.3.3 
Change in Antihypertensive Medications 
The number and percentage of patients whose dose of antihypertensive medication 
decreased, stayed the same, or increased from baseline to study drug dose level or follow-
up period, as determined by antihypertensive medication start date, will be summarized, 
among those patients taking such medications at baseline. Additional counts and 
percentages will be provided including patients who were not taking antihypertensive 
medications at baseline. 
7.6.4 
Exploratory Efficacy Endpoint Analysis Methods 
All exploratory efficacy analyses will be performed on the mITT populations. As a 
sensitivity analysis, select exploratory efficacy endpoints will also be performed using the 
mPP Sensitivity Population.  
The exploratory efficacy assessments of fructosamine and adiponectin concentrations 
will be summarized using descriptive statistics including two-sided 95% CI of the mean 
by visit and Group 1 and Group 2, to include the change from baseline. These efficacy 
assessments will also be analyzed by a Wilcoxon signed-rank test to evaluate if there is a 
significant change compared to baseline at each visit.  
The exploratory efficacy assessments of 24-hour UFC with creatinine, late-night salivary 
cortisol, 24-hour urine calcium, and 24-hour urine sodium will be summarized using 
descriptive statistics including two-sided 95% CI of the mean by visit and Group 1 and 
Group 2, to include the change from baseline. These efficacy assessments will also be 
analyzed by a Wilcoxon signed-rank test to evaluate if there is a significant change 
compared to baseline at each visit. All post-baseline measurements will be averaged per 
patient per visit. As a sensitivity analysis, repeat tables of these exploratory efficacy 
assessments will be produced using baseline defined as the average of the two worst 
measurements prior to first dose of study drug. 24-hour UFC with creatinine will 
additionally be summarized over the etiology subgroups. 
Other exploratory efficacy assessments will be summarized using descriptive statistics 
including two-sided 95% CI of the mean by parameter, visit, time point (where 
appropriate), and Group 1 and Group 2, to include the change from baseline. Where 
appropriate, efficacy assessments will also be analyzed by a Wilcoxon signed-rank test to 
evaluate if there is a significant change compared to baseline at each visit. See the 
following list of included exploratory efficacy assessments:   


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• Physician’s global assessment 
• HbA1c 
• Body weight and waist circumference 
• BDI-II 
• Trail Making Test 
• CushingQOL 
• Lipid panel 
• Sit-to-stand test 
• Hormonal effects 
• Coagulation tests 
• Bone markers 
• HPA axis markers 
• ACTH precursors 
• High-sensitivity C-reactive protein 
• IGF-1 
• Thyroid function tests 
HbA1c results will also be summarized by the high HbA1c patients subgroup. 
BDI-II results will be also summarized by the mildly depressive patients subgroup. 
Bone markers will also be summarized over the menopausal status subgroups. Serum 
osteocalcin will additionally be summarized by the low serum osteocalcin patients 
subgroup. 
HPA axis markers will also be summarized over the etiology subgroups. 
Select efficacy assessments including plasma ACTH, serum cortisol, late-night salivary 
cortisol, 24-hour UFC with creatinine, fructosamine, HbA1c, and serum osteocalcin will 
be summarized by the etiology and Cushing syndrome comorbidity subgroups by visit, 
Group 1, and Group 2. The adrenal etiology subgroup summaries will only be produced if 
there is a sufficient number of patients with post-baseline data. 


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Menstrual cycle will be summarized for all females by Group 1 and Group 2, and by the 
number and percentage of patients who have had vaginal bleeding since the last visit, 
summary statistics including change from baseline for duration of vaginal bleeding (days) 
and number of tampons/pads used per day, and frequency counts and percentages for 
vaginal flow (spotting, light, etc.).  
Select efficacy assessments of plasma ACTH, 24-hour UFC with creatinine, 
fructosamine, HbA1c, osteocalcin, total cholesterol, low-density lipoprotein-cholesterol, 
high-density lipoprotein-cholesterol, triglycerides, estradiol (females only), testosterone 
(males only), and thyroid-stimulating hormone, with results classified as “low,” 
“normal,” or “high” with respect to parameter-specific reference ranges (ie, below the 
lower limit of the normal range, within the normal range, or above the upper limit of the 
normal range) will be summarized in the following three-by-three contingency tables: 
• Shift from baseline to the worst observed post-baseline value within the treatment 
period per patient in each group; 
• Shift from baseline to worst post-baseline value at each dose level per group; 
• Shift from baseline to last post-baseline value at each dose level per group; and 
• Shift from baseline to the last observed value within the treatment period per 
patient in each group. 
Summary results will include the count and percentage of patients within each shift 
category in Group 1 and Group 2, and will be summarized over the etiology subgroups.  
Similar to the responder analyses in the key efficacy endpoints, sensitivity responder 
analyses will be performed on patients in the IGT subgroup using the following criteria: 
1. A patient is considered a responder if the patient’s post-baseline HbA1c has 
decreased by ≥ 0.5%. 
2. A patient is considered a responder at each visit if the patient’s post-baseline 2-
hour oGTT plasma glucose is normalized (< 7.8 mmol/L) or decreased by ≥ 2.8 
mmol/L compared to baseline. 
3. A patient is considered a responder if the patient’s total daily insulin dose has 
decreased by ≥ 25% or total daily sulfonylurea dose has decreased from baseline 
by ≥ 50% and post-baseline HbA1c is unchanged or decreased compared to 
baseline. 
4.  A patient is considered a responder if at least one of the above criteria is met. 
Sensitivity responder analyses will additionally be performed using the above criteria for 
#2 with the added requirement that a patient is only considered a responder once the 
patient reaches the responder critera and continues to meet the criteria throughout any 


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remaining post-baseline visits. Nonresponder rules, as described in Section 7.6.3.1, apply 
to the sensitivity responder analysis described in #2.  
A histogram of mean serum osteocalcin (µg/L) will be presented by visit, Group 1, and 
Group 2, and will be repeated by the low serum osteocalcin subgroup. Plots of mean 
HbA1c, fructosamine, BDI-II total score, CushingQOL total score, and serum cortisol 
will be presented over time by Group 1 and Group 2. Plots of mean 24-hour UFC with 
creatinine and plasma ACTH will be presented over time by Group 1 and Group 2, and 
will be repeated by the etiology subgroups. Plots of plasma ACTH and serum cortisol 
will additionally be presented over all patients combined.  
7.6.5 
Statistical/Analytical Issues 
7.6.5.1 
Handling of Dropouts or Missing Data 
In the key efficacy endpoint analyses, missing data will be primarily handled as follows: 
• For the responder analyses, patients with missing data will be considered non-
responders. 
• For calculations involving AUC, including oGTT plasma glucose and insulin, the 
following rules for handling missing data will be applied: 
o If the pre-glucose drink time point and 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.  
o If more than one post-glucose drink time points are missing, no AUC 
calculation will be performed. 
o 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 
with using available data. For example, if the 90 minute time point is 
missing, a larger trapezoid will be constructed to connect the 60 minute 
and 120 minute time points.  
o 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 90 minute post-glucose drink value will be used in the 
summary tables. 
• For the analyses using an MMRM, the F-tests will be based on the Kenward-
Roger adjusted degrees of freedom to account for any missing data. 
• Otherwise, observed values only will be used. 
As a sensitivity approach to missing values for the key efficacy endpoints (including 
AUCglucose and AUCinsulin), missing data will be imputed as follows: 


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• For patients who did not adhere to protocol-defined dose escalation, missing data 
at a post-baseline visit will be imputed as the median of the non-missing values at 
that visit among patients who also did not adhere to protocol-defined dose 
escalation; and 
• For patients who did adhere to protocol-defined dose escalation, missing data at a 
post-baseline visit will be imputed as the median of the non-missing values at 
that visit among patients who also adhered to protocol-defined dose escalation. 
The above imputation will be applied by Group 1 and Group 2.  
Patients who did not adhere to protocol-defined dose escalation include all patients who 
at any point during the study did not escalate dose at a dose-escalation visit, or 
experienced a dose reduction or dose interruption. 
All efficacy by-visit analyses will include summaries for the following: 
• Observed cases only, where no imputations will be used, except for the AUC 
missing data handling rules as described above; and 
• The last observed value used in visit windowing (Section 7.1.2) prior to follow-
up per patient. For patients who do not reach the last scheduled visit per protocol, 
the last observed value per patient is carried forward, effectively mimicking a last 
observation carried forward (LOCF) imputation.  
7.6.5.2 
Interim Analyses and Data Monitoring 
As outlined in Section 6.1, an independent DRC will convene to review safety and PK 
results to confirm, revise, or adjust the Group 2 dose levels. The dose levels approved by 
the DRC for Group 2 will be based on estimated CORT125134 exposures (AUC0-24h) for 
dose levels of 250, 300, and 350 mg; those exposure estimates will be based on Group 1 
results as well as on results of PK modeling. As supervised by the DRC, the final dose 
levels for Group 2 will provide a simulated total systemic exposure 
 
 
7.6.5.3 
Multicenter Studies 
This is a multicenter study with multiple sites expected to participate. Efficacy data 
collected from all study centers will be pooled for data analysis. The effect of study 
center on the efficacy analysis results may be explored post-hoc, as needed. 
7.6.5.4 
Multiple Comparisons/Multiplicity 
There will be no adjustments for multiple comparisons in the efficacy analysis for this 
study.  


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7.6.5.5 
Active-Control Studies Intended to Show Equivalence 
This study does not include an active-control product and is not intended to demonstrate 
equivalence between any two drug products. 
7.6.6 
Plasma Concentrations and Pharmacokinetic Analysis 
The details of the PK analysis will be outlined in a separate document. 
7.7 
Safety Analysis 
All safety analyses will be performed on the Safety Population. Select safety analyses 
may also be performed on the mITT Population and the mPP Sensitivity Population. All 
safety summaries will be presented by Group 1, Group 2, and Overall. 
All safety data will appear in by-patient data listings. 
7.7.1 
Extent of Exposure 
The duration of exposure will be presented in days and calculated as the date of last dose 
of study drug minus the date of first dose of study drug, plus one. Total actual dose 
received (mg) will be calculated as the number of capsules taken per visit x 50 mg, 
summed across all visits per patient. Duration of exposure, total actual dose received 
(mg), and number of days at each dose level will be summarized using descriptive 
statistics.  
The number of patients reaching first, second, and third (Group 2 only) dose escalation, 
highest dose level received (eg, 150 to 400 mg), and the number of patients exposed at 
each dose level will be summarized by frequency counts and percentages across Group 1 
and Group 2.  
7.7.2 
Adverse Events 
Treatment-emergent adverse events 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. Treatment-emergent AEs will be 
summarized by group and displayed by dose level at AE onset, follow-up period if AE 
onset is after last dose of study drug, and overall, unless otherwise specified. Events 
reported with a partial onset date (eg, month and year are reported but the day is missing) 
will be considered to be 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 19.0.   
Summaries that are displayed by system organ class and preferred terms will be ordered 
by descending incidence of system organ class and preferred term within each system 


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organ class. Summaries displayed by preferred term only will be ordered by descending 
incidence of preferred term. Summaries of the following types will be presented: 
• Overall summary of number of unique TEAEs and treatment-emergent SAEs and 
patient incidence of TEAEs meeting various criteria; 
• Patient incidence and total number of TEAEs by MedDRA preferred term by 
Group 1, Group 2, and Overall; 
• Patient incidence and total number of TEAEs by MedDRA preferred term 
occurring in at least 10% of the population by Group 1, Group 2, and Overall;  
• Patient incidence of TEAEs by MedDRA system organ class and preferred term; 
• Patient incidence of TEAEs by CTCAE grade, MedDRA system organ class, and 
preferred term; 
• Patient incidence of TEAEs by relationship to study drug, MedDRA system organ 
class, and preferred term;  
• Patient incidence of severe (≥ CTCAE grade 3) TEAEs by MedDRA system 
organ class and preferred term; 
• Patient incidence of severe (≥ CTCAE grade 3) TEAEs related to study drug by 
MedDRA system organ class and preferred term; 
• Patient incidence of treatment-emergent SAEs by MedDRA system organ class 
and preferred term; and 
• Patient incidence of AEs during Screening by MedDRA system organ class and 
preferred term. 
At each level of summarization (eg, any AE, system organ class, and preferred term), 
patients experiencing more than one AE will be counted only once within each dose level 
or follow-up period. 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 swimmer plot of patient incidence of TEAEs occurring in at least 10% of the 
population by CTCAE grade and MedDRA preferred term will be presented by Group 1 
and Group 2. 
Adverse event data will be presented in data listings by group, patient, and event. Serious 
AEs, AEs leading to discontinuation of the study drug, and TEAEs with CTCAE greater 
than or equal to grade 3 will be presented in separate data listings. 


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7.7.3 
Deaths, Other Serious Adverse Events, and Other Significant Adverse 
Events 
All deaths during the study, including the post-treatment follow-up period, will be listed 
by patient, and will include the primary cause of death. Serious AEs and other significant 
AEs, including those that led to withdrawal, interruption, or dose reduction of the study 
drug, will be provided in separate patient data listings. 
7.7.4 
Clinical Laboratory Evaluation 
All descriptive summaries of laboratory results will be based on data analyzed by the 
central laboratory and presented in Système International (SI) units, as suggested by the 
Center for Biologics Evaluation and Research and the Center for Drug Evaluation and 
Research Position on Use of SI Units for Lab Tests (Oct 2013). All data will be included 
in by-patient data listings. Laboratory measurements identified as abnormal (ie, outside 
the normal range) will also be listed separately by patient, study visit, dose at time of 
study visit, laboratory test, and unit. 
Clinical laboratory measurements, including serum chemistry and hematology, will be 
summarized. Descriptive statistics will be presented for observed values and changes 
from baseline to the last post-baseline value within each dose level and follow-up period.  
Where applicable, laboratory results will be classified as “low,” “normal,” or “high” with 
respect to the parameter-specific reference ranges (ie, below the lower limit of the normal 
range, within the normal range, or above the upper limit of the normal range). Three-by-
three contingency tables will be presented for each laboratory parameter to summarize 
the following:  
• Shift from baseline to the worst observed post-baseline value within the treatment 
period per patient;  
• Shift from baseline to the last observed post-baseline value within each dose level 
per patient; and 
• Shift from baseline to the last observed post-baseline value within the treatment 
period per patient. 
Summary results will include the count and percentage of patients within each shift 
category.  
Hematology and chemistry results for select parameters will be assigned a toxicity grade 
based on the U.S. Department of Health and Human Services Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.03 (Jun 2010), where applicable. Grades 
will be presented as none (Grade 0), mild (Grade 1), moderate (Grade 2), severe (Grade 
3), or life-threatening (Grade 4). Death related to AE (ie, Grade 5) cannot be determined 
with available laboratory-based data collection and, thus, will not be summarized as a 
category. Summary tables will be presented for each laboratory parameter to summarize 
the following: 


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• The worst observed post-baseline CTCAE grade within each dose level and 
follow-up period per patient; and 
• The last observed post-baseline CTCAE grade within each dose level and follow-
up period per patient.  
Summary results will include the count and percentage of patients within each dose level 
and follow-up period. A by-patient data listing for hematology and chemistry values with 
toxicity grade greater than or equal to Grade 3 will also be displayed. 
Plots of mean values for ALT, AST, alkaline phosphatase, potassium, platelets, and 
absolute and total neutrophils will be presented by visit. 
7.7.5 
Vital Signs, Physical Findings, and Other Observations Related to Safety 
7.7.5.1 
Vital Signs 
Vital sign parameter measurements will be summarized. Descriptive statistics will be 
presented for results and change from baseline to the last post-baseline value within each 
dose level and follow-up period.  
7.7.5.2 
12-Lead Electrocardiogram 
Twelve-Lead ECG interval parameters will be summarized. Descriptive statistics will be 
presented for results and change from baseline to the last post-baseline visit within each 
dose level and follow-up period using the average of the triplicate readings per patient per 
visit.  
Twelve-lead ECG results will be classified by the investigator as “normal” and 
“abnormal.” A 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 subjects within each 
shift category. 
7.7.5.3 
Physical Examination 
Results of the physical examination will be presented in patient data listings by Group 1 
and Group 2, patient, study visit, dose at time of study visit, and body system. 
7.7.5.4 
Pregnancy Tests 
Results of the pregnancy tests will be presented in patient data listings by Group 1 and 
Group 2, patient, study visit, and dose at time of study visit.  


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7.7.5.5 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization (WHO Drug version 
161E, enhanced) 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 separately, and the study phase of 
each medication (if 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 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. 
If it cannot be determined whether a medication was received prior to the start of study 
drug dosing due to partial or missing medication start and/or end dates, it will be 
considered a prior medication. Likewise, if it cannot be determined whether a medication 
was received after the start of study drug dosing, it will be considered concomitant. 
For the prior medications table summary, the number and percentage of patients 
receiving any medication will be summarized by Group 1, Group 2, 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 study 
drug dose category, follow-up period, Group 1, Group 2, and all patients combined, as 
will the number and percentage receiving any medication by ATC drug class and generic 
drug name. The study drug dose category or follow-up period each concomitant 
medication is assigned to will be determined by the medication start date. 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 by descending order of incidence, as will generic drug 
names within each ATC class. The study phase during which each medication was 
received (eg, prior, concomitant, or both) 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.   
Tables summarizing reduction in antidiabetic and antihypertensive concomitant 
medications will also be presented by Group 1 and Group 2, and will include the number 
of patients taking the medication at baseline, median total daily dose at baseline, number 
of patients with a dose reduction, median reduction in total daily dose at last visit, and the 
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Prior and concomitant medications will be presented in a by-patient data listing by Group 
1 and Group 2, patient, 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 Group 1 and Group 2, patient, medication group 
(antihypertensive or antidiabetic), week on study, total daily dose, dose change from 
baseline, and trough plasma concentration of CORT125134.  
7.8 
Patient Profiles 
Individual patient profiles will be generated for all patients in the Safety Population, and 
will include graphical displays of the following: oGTT plasma glucose (mmol/L), mean 
24-hour ambulatory systolic and diastolic BP (mmHg), mean nighttime 24-hour 
ambulatory systolic and diastolic BP (mmHg), mean daytime 24-hour ambulatory 
systolic and diastolic BP (mmHg), fructosamine (µmol/L), HbA1c (%), 24-hour UFC 
with creatinine (mmol/L), serum cortisol (nmol/L), plasma ACTH (pmol/L), ALT (U/L), 
AST (U/L), waist circumference, BMI, potassium (mmol/L), BDI-II total score, and 
CushingQOL total score. Profiles will include data from each patients’ entire time on 
study drug.   
Please see Section 7.6.3.3.2 for definitions of daytime and nighttime 24-hour ambulatory 
BP. 
7.9 
Determination of Sample Size 
The study is not powered for formal hypothesis testing. The Sponsor has deemed 30 
patients (15 per dose group) as a sufficient number to evaluate efficacy and 
safety/tolerability. 
7.10 
Changes in the Conduct of the Study or Planned Analyses 
The SAP supercedes 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. 
8 REFERENCE LIST 
Fleseriu M, Biller BMK, Findling JW, et al. Mifepristone, a Glucocorticoid Receptor 
Antagonist, Produces Clinical and Metabolic Benefits in Patients with Cushing’s 
Syndrome. J Clin Endocrinol Metab. June 2012; 97(6):2039-2049. 
Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose 
tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care. 1999; 
22:1462-1470. 
Webb SM, Badia X, Barahona MJ, et al. Evaluation of health-related quality of life in 
patients with Cushing’s syndrome with a new questionnaire. Eur J Endocrinol. 2008; 
158(5):623-30.