Clinical trial NCT03697109
Conditions: Cushing Syndrome
Keywords: Cushing syndrome Cushing disease Hypercortisolemia Cushingoid Type 2 Diabetes Impaired Glucose Intolerance Hypertension Adrenocorticotropic hormone Primary Pigmented Nodular Adrenal Disease Moon Facies Dorsocervical Fat Pad Adrenal Adenoma Adrenal Autonomy Cortisol Cushing
Sponsor: Corcept Therapeutics
Start date: 2018-11-15; Completion date: 2024-04-15
Enrollment: 152 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 3, double-blind, placebo-controlled, randomized-withdrawal study to assess the efficacy, safety and pharmacokinetics (PK) of relacorilant in patients with endogenous Cushing syndrome and concurrent type 2 diabetes mellitus/impaired glucose tolerance (DM/IGT) and/or uncontrolled hypertension (HTN).

Detailed description:
The primary outcome is the assessment of efficacy of relacorilant treatment based on sustained blood pressure control during the Randomized-withdrawal (RW) Phase, wherein patients who had achieved the blood pressure response criteria during the Open-label (OL) Phase are randomized to receive either relacorilant or placebo for 12 weeks.

Patients in the OL Phase will dose-escalate in 100 mg increments to a maximum dose of 400 mg orally once daily. Patients will remain on OL treatment until Week 22 at which time they will be evaluated for the RW Phase based on predefined hyperglycemia and hypertension response criteria. Eligible patients will then be randomized to receive either relacorilant or placebo at a 1:1 ratio for 12 weeks. Patients who do not meet the criteria for the RW Phase will end treatment and may be eligible to roll over into an extension safety study. Patients who complete the RW Phase of the study may also be eligible to roll over into an extension study.

Arms: arm 1: Patients will receive relacorilant increased sequentially from 100 mg once daily to a maximum dose of 400 mg once daily. arm 2: Patients who meet any of the response criteria will advance to the RW Phase of the study and receive the same dose of relacorilant as the last dose administered in the OL Phase. arm 3: Patients who meet any of the response criteria will advance to the RW Phase of the study and receive placebo matched to study drug.
Interventions: intervention 1: Relacorilant intervention 2: Placebo
Intervention descriptions: intervention 1: Relacorilant is supplied as 100 mg capsules for oral dosing. intervention 2: Placebo matched to study drug

Protocol documents:
Prot_002.pdf: 
Title: Glucocorticoid Receptor Antagonism in the Treatment of Cushing Syndrome (GRACE): A 
Phase 3, Double-Blind, Placebo-Controlled, Randomized-Withdrawal Study of the Efficacy and 
Safety of Relacorilant 
 
 
NCT Number: NCT03697109 
 
 
Date: 17 May 2024 






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PROTOCOL SYNOPSIS 
Title 
Glucocorticoid Receptor Antagonism in the Treatment of Cushing 
Syndrome (GRACE): A Phase 3, Double-Blind, Placebo-Controlled, 
Randomized-Withdrawal Study of the Efficacy and Safety of 
Relacorilant 
Study Number 
CORT125134-455 
Name of Active Ingredient 
Relacorilant 
Name of Sponsor 
Corcept Therapeutics 
Phase 
3 
Study Centers 
Approximately 60 sites (North America and other international sites) 
Sample Size 
Approximately 162 patients 
Study Objectives  
Primary 
• To assess the efficacy of relacorilant for the treatment of endogenous Cushing syndrome based 
on blood pressure (BP) control at Week 12 of the Randomized-Withdrawal (RW) phase 
compared with placebo 
• To assess the safety of relacorilant for the treatment of endogenous Cushing syndrome 
Secondary 
• To assess changes in cortisol excess-related comorbidities (including diabetes mellitus/ impaired 
glucose tolerance [DM/IGT] and body weight) in patients with endogenous Cushing syndrome 
treated with relacorilant over the RW phase 
Study Population 
This study includes patients with endogenous Cushing syndrome and associated DM/IGT and/or 
uncontrolled hypertension.  
Number of Patients Planned 
Approximately 162 patients are planned to enroll into a 6-month Open-Label (OL) phase of the 
study to ensure the randomization of approximately 46 patients with hypertension into the subsequent 
3-month, placebo-controlled RW phase. 
Duration of Patient Participation  
Screening: Up to 6 weeks 
Open-label treatment with relacorilant: 22‒24 weeks 
Randomized, double-blind, placebo-controlled, withdrawal phase: 12 weeks 
Follow-up: 4 weeks after the last dose of study drug 
Total participation: Up to 46 weeks  
Study Design 
This is a Phase 3, double-blind, placebo-controlled, RW study to assess the efficacy, safety, and 
pharmacokinetics (PK) of relacorilant in patients with endogenous Cushing syndrome and concurrent 
DM/IGT and/or uncontrolled hypertension.  


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Figure S1 
CORT125134-455 Study Design 
 
 
Study Phases 
The study phases are as follows. 
Screening Phase 
Up to 6 weeks to determine study eligibility.  
Open-Label Phase (Baseline to Visit OL22) 
Baseline is defined as Day 1 of the OL phase. 
• The starting dose at Baseline will be 100 mg relacorilant once daily for 2 weeks  
• From Visit OL2 through OL10, the dose of relacorilant will be increased every 4 weeks by 
100 mg, as tolerated and based on improvement in signs and symptoms of Cushing syndrome, to 
a target dose of 400 mg once daily (i.e., to 200 mg at Visit OL2, to 300 mg at Visit OL6, and to 
400 mg at Visit OL10). Clinical benefit in the Open-Label Phase will be assessed by the 
Investigator either by a change from Baseline or change from the previous visit considering the 
following factors: 
­ BP measurements and anti-hypertensive medication 
­ Glucose levels and diabetes medication 
­ Body weight and waist circumference 
­ Cushingoid appearance and striae 
­ Sit-to-stand test 
­ Beck Depression inventory 
­ Cushing Quality-of-Life questionnaire 
• If all symptoms of Cushing syndrome present at Baseline have resolved, no dose escalation will 
occur beyond that visit. 
• Faster dose escalation during the open-label phase of the study for patients whose Cushing 
syndrome deteriorates may be allowed with medical monitor approval. 
• If any planned dose escalation is postponed, Visit OL14 can be used for a final dose escalation 


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• Due to the COVID-19 pandemic, dose escalation up to 200 mg may occur remotely if necessary. 
Subsequent dose escalations, however, are permitted only after completion of safety 
assessments. 
• Dose interruption, reduction, and re-escalation are permitted for safety/tolerability: 
­ The relacorilant dose can be reduced to a previous dose if it is not tolerated 
­ Re-escalation after a dose reduction is permitted until Visit OL18. 
Randomized-Withdrawal Phase (Randomization to Visit RW12)  
Patients who complete the OL phase and meet the following response criteria for DM/IGT or 
hypertension at Visit OL22 (see below and Section 3.6) will be randomized between Visit OL22 and 
up to 2 weeks after that visit in a 1:1 ratio to receive relacorilant or placebo for 12 weeks. 
• Patients with uncontrolled hypertension at Baseline must meet one of the following response 
criteria: 
­ ≥5 mm Hg decrease in mean systolic BP (SBP) and/or diastolic BP (DBP) from Baseline to 
Visit OL22, without worsening of either, based on 24-hour ambulatory BP monitoring 
(ABPM) 
Note: Increase of pre-existing blood pressure medication or initiation of new blood pressure 
medication, due to worsening in hypertension, disqualifies the patient from randomization into 
the RW phase. If a decrease in the BP medication occurred after the OL18 visit, reassess 
eligibility for randomization 4 weeks after the dose change. 
 
• Patients with DM/IGT at Baseline must meet one of the following response criteria: 
In patients with DM  
­ HbA1c has decreased by ≥0.5% from Baseline to Visit OL22 
­ The 2-hour oGTT glucose is normalized (<140 mg/dL) or decreased by ≥50 mg/dL from 
Baseline to Visit OL22 
­ Total daily insulin dose has decreased by ≥25% and HbA1c is unchanged or decreased 
compared with Baseline  
In patients with IGT 
­ The 2-hour oGTT glucose is normalized (<140 mg/dL) from Baseline to Visit OL22 
Note: Increase of pre-existing diabetes medication or initiation of new diabetes medication, due 
to worsening of hyperglycemia, disqualifies the patient from randomization into the RW phase. 
If a decrease in the insulin dose happened after the OL18 visit, reassess eligibility for 
randomization 4 weeks after the dose change. 
 
• Patients with both DM/IGT and uncontrolled hypertension at Baseline who do not meet the 
above-mentioned response criteria for both conditions must meet one of the following: 
­ Meet one of the DM or IGT response criteria with no worsening in hypertension 
­ Meet one of the uncontrolled hypertension response criteria with no worsening in DM or 
IGT 
Note: Increase of pre-existing diabetes or blood pressure medication or initiation of new 
diabetes or blood pressure medication due to worsening hyperglycemia or hypertension, 
disqualifies the patient from randomization into the RW phase. If a decrease in insulin dose or 
BP medication occurred after the Visit OL18, reassess eligibility for randomization 4 weeks 
after the dose change. 
 


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Treatment assignment and selected study assessments in the RW phase will remain blinded to the 
Investigators, the Sponsor, and the patients until after database lock.  
No changes in the dose of study drug are allowed during the RW phase. 
 
Rescue criteria during the RW Phase 
2-hour oGTT and ABPM results during the RW Phase will be reviewed by an unblinded Medical 
Monitor to monitor patient safety. The unblinded Medical Monitor is unblinded to results of study 
assessments but is blinded to the treatment assignment. 
• If a patient in the DM/IGT subgroup meets the first two of the following criteria, or if a patient 
in the hypertension subgroup meets the third criterion, the results will be communicated to the 
study site, and rescue medication may be initiated or increased as per Section 5.4.2.  
­ Fasting glucose increases by 50 mg/dL from visit OL22, AND 
­ 2-hour oGTT glucose increases by 100 mg/dL from Visit OL22 
­ Increases in mean SBP or mean DBP by ABPM of more than 10 mm Hg from Visit OL22 
Unblinding of the 2-hour oGTT or ABPM results will not result in the unblinding of study treatment.  
 
In the event of rescue medication use before Visit RW12: 
• In patients randomized to the DM/IGT subgroup, oGTT assessments will continue as planned 
until Visit RW12. 
• In patients randomized to the hypertension subgroup, ABPM assessments will continue as 
planned until Visit RW12. 
Patient Disposition 
Patient Completion 
• Patients who complete 12 weeks of the RW phase will return for the Follow-Up visit 28 days 
after the last dose of study drug. The Follow-Up visit will serve as the last study visit. 
• Patients who complete 12 weeks of the RW phase, and entered an extension study within 
28 days of the last dose of study drug, are not required to complete the Follow-Up visit. 
Visit RW12 will serve as the last study visit.  
Early Termination 
• Patients who complete the Visit OL22, but do not meet a response criterion for randomization, 
will be instructed to discontinue study drug. The Follow-Up visit will be conducted 28 days after 
the last dose of study drug and will serve as the last study visit.  
• If a patient discontinues early from the OL phase, the patient will complete an Early 
Termination visit at the time of last dose of study drug (or soon thereafter). The Follow-Up visit 
will be conducted 28 days after the last dose of study drug and will serve as the last study visit.  
• If a patient discontinues early from the RW phase, the patient will be instructed to return for 
Visit RW12 per the patient’s original dosing schedule as well as the Follow-Up visit 28 days 
after the last dose of study drug. If RW12 is the return visit following early discontinuation from 
the RW phase, a 3-week visit window (2 weeks before the scheduled visit, 1 week after the 
scheduled visit) for RW12 is permitted. 
• For patients who discontinue the study prior to the RW12 visit during the RW phase of the study 
and return for the RW12 visit, the follow up visit will be waived if the RW12 visit occurs at 
least 28 days after the last dose of administration of study drug. 


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Treatment Continuation 
• Patients who complete the RW phase of the study will be permitted to continue relacorilant 
treatment in an extension study provided that they have at least 80% adherence with prescribed 
dosing (by capsule counts), AND are, in the opinion of the Investigator, expected to maintain 
clinical benefit from the study drug. Clinical benefit will be determined by the Investigator 
based on the changes during the Open-Label Phase in the following factors: 
­ Hypertension 
­ Hyperglycemia 
­ Body weight and waist circumference 
­ Clinical appearance 
­ Sit-to-stand test 
­ Psychiatric health and cognitive function 
­ Cushing Quality-of-Life (QoL) score 
• Patients who complete the OL phase of the study, but do not meet a response criterion for 
randomization, will be permitted to continue relacorilant treatment in an extension study if, in 
the opinion of the Investigator, they have benefitted from the study drug and are expected to 
maintain that benefit as noted above. The same adherence rule applies. 
• Patients who continue on to the extension study within 28 days of last dose of study drug will 
not be required to complete the Follow-Up Visit. The last study visit for these patients will be 
either the Visit OL22 (if criterion for randomization is not met) or Visit RW12 (if the RW phase 
was completed).  
Study Enrollment 
Study enrollment will be monitored to ensure attainment of randomization targets. The number of 
patients enrolled in the OL phase may be adjusted to ensure a sufficient number of patients meeting 
response criteria to uncontrolled hypertension are randomized in the RW phase. Enrollment of patients 
may continue based on enrollment target projections.  
Study Endpoints 
Endpoints for both OL and RW phases are listed below. In the RW phase, (1) endpoints related to 
hypertension will be analyzed in those patients who met any response criterion for hypertension at 
Visit OL22; and (2) endpoints related to DM/IGT will be analyzed in those patients who met any 
response criterion for DM/IGT at Visit OL22. 
Primary Endpoints 
The primary efficacy endpoint will be assessed in the RW phase:  
• In patients with hypertension, the proportion of patients with a loss of response with respect to 
hypertension from Visit OL22 to RW12 based on 24-hour ABPM as compared between 
relacorilant and placebo arms, where loss of response is defined as follows: 
­ In patients who met only the SBP response criterion, an increase in SBP ≥5 mm Hg.  
­ In patients who met only the DBP response criterion, an increase in DBP by ≥5 mm Hg.  
­ In patients who met both the SBP and DPB response criteria, an increase in either SBP or 
DBP by ≥5 mm Hg.  
­ Any increase or modification in antihypertensive medication due to worsening hypertension. 
­ Patients discontinue treatment in RW phase for any reason. 
• In all patients, assessment of safety based on treatment-emergent adverse events (TEAEs). 


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Secondary Efficacy Endpoints in the RW Phase 
• Loss of response (AUC-based) in DM/IGT subgroup with response at OL22: proportion of 
patients with a loss of response with respect to hyperglycemic control from Visit OL22 to 
RW12, as compared between relacorilant and placebo arms, where loss of response is defined as 
a ≥10% increase from baseline in AUCglucose from Visit OL22 to RW12, use of rescue medication 
(initiation or increase in diabetes medication due to worsening of hyperglycemic control), 
treatment discontinuation for any reason in RW phase, or patients with missing RW12 AUCglucose 
values. 
• Mean change from Visit OL22 to RW12 in 24-hour average SBP as compared between 
relacorilant and placebo.  
• Mean change from Visit OL22 to RW12 in 24-hour average DBP as compared between 
relacorilant and placebo. 
• Mean change from Visit OL22 to RW12 in body weight as compared between relacorilant 
and placebo.  
• In patients with DM/IGT, the mean change in AUCglucose from Visit OL22 to RW12 as compared 
between relacorilant and placebo arms. 
• In patients with DM/IGT, the mean change in HbA1c from Visit OL22 to Visit RW12, as 
compared between relacorilant and placebo. 
• Comprehensive loss of response in DM/IGT subgroup with response at OL22: proportion of 
patients with a comprehensive loss of response with respect to hyperglycemic control from Visit 
OL22 to RW12, as compared between relacorilant and placebo arms, where the comprehensive 
loss of response is defined as follows: 
In patients with DM: 
­ Use of rescue medication (initiation or increase in diabetes medication due to worsening of 
hyperglycemic control), treatment discontinuation for any reason in RW phase, or loss to 
follow-up, 
OR 
­ HbA1c has increased by ≥0.3% at Visit RW12 (compared to OL22), 
OR 
­ The 2-hour time point of the plasma 2-hours oGTT glucose test at Visit RW12 is abnormal 
(≥140 mg/dL) and has increased by at least 50% of the reduction observed between Baseline 
and Visit OL22. 
In patients with IGT: 
­ Use of rescue medication (initiation or increase in diabetes medication due to worsening of 
hyperglycemic control), treatment discontinuation for any reason in RW phase, or loss to 
follow-up, 
OR 
­ The 2-hour time point of the plasma 2-hour oGTT glucose test at Visit RW12 is abnormal 
(≥140 mg/dL) and has increased by at least 50% of the reduction observed between Baseline 
and Visit OL22. 


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Exploratory Efficacy Endpoints in the RW Phase 
Continuous Endpoints 
• Mean change from Visit OL22 to RW12 in 24-hour average heart rate (HR) as compared 
between relacorilant and placebo (based on ABPM). 
• Mean SBP, DBP, and HR at RW12 (end of dosing interval) as compared between relacorilant 
and placebo (based on ABPM). 
• Mean difference in daytime and nighttime average SBP, DBP, and HR (based on ABPM) at 
Visit RW12 as compared between relacorilant and placebo. 
• Mean change from Visit OL22 to Visit RW12 in body fat composition measured with DXA scan 
as compared between relacorilant and placebo. 
• Mean change from Visit OL22 to Visit RW12 in Cushing Quality-of-Life (QoL) score as 
compared between relacorilant and placebo. 
• In patients with DM (HbA1c at Baseline ≥6.5%), the mean change from Visit OL22 to Visit 
RW12 in HbA1c, as compared between relacorilant and placebo. 
• In patients with IGT at Baseline, the mean change from Visit OL22 to Visit RW12 in the 2-hour 
glucose value of the plasma 2-hours oGTT test as compared between relacorilant and placebo 
arms. 
• The mean change from Visit OL22 to RW12 as compared between relacorilant and placebo in 
the following: waist circumference; lean mass measured by DXA; serum osteocalcin; the Beck 
Depression Inventory®-II (BDI-II) score; sit-to-stand test score; trail-making test score; sex-
hormone levels (estradiol, total and free testosterone, sex-hormone‒binding globulin, follicle-
stimulating hormone, and luteinizing hormone); FKBP5 and other potential biomarkers of GR 
activity; urinary free cortisol (UFC), late-night salivary cortisol and plasma adrenocorticotropic 
hormone (ACTH); AUCinsulin, Matsuda Index, homeostatic model assessment of insulin 
resistance (HOMA IR), and daytime and nocturnal average blood pressure.  
• In patients with adrenal CS, the mean change in the ACTH levels from Visit OL22 to RW12 as 
compared between relacorilant and placebo. 
Endpoints Summarized with Proportions 
• For patients in the hypertension subgroup, the proportion of patients with any increase or 
modification in antihypertensive medication due to worsening hypertension from Visit OL22 to 
Visit RW12 as compared between relacorilant and placebo. 
• Proportion of patients who worsened, as assessed by the Global Clinical Response from 
Visit OL22 to Visit RW12 (i.e., a score of –1 at Visit RW12 as compared with Visit OL22). 
• For patients in the DM/IGT subgroup, the proportion of patients with any increase in dose of 
diabetes medication from Visit OL22 to Visit RW12 as compared between relacorilant and 
placebo. 
• For patients in the DM subgroup, the proportion of patients who achieve 25% reduction in 
AUCglucose from Baseline OL to Visit RW12 as compared between relacorilant and placebo. 
• In all patients randomized in the RW phase, proportion of patients with a loss of response with 
respect to hypertension or hyperglycemia from Visit OL22 to Visit RW12 based on 24-hour 
ABPM and AUCglucose as compared between relacorilant and placebo arms, where loss of 
response is defined as follows: 
­ In patients with hypertension only at Baseline OL: 
 
In patients who met only the SBP response criterion, an increase in SBP ≥5 mm Hg. 
 
In patients who met only the DBP response criterion, an increase in DBP by ≥5 mm Hg. 
 
In patients who met both the SBP and DBP response criteria, an increase in either SBP 
or DBP by ≥5 mm Hg. 


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 
Any increase or modification in antihypertensive medication due to worsening 
hypertension. 
 
Patients discontinue treatment in RW phase for any reason. 
­ In patients with DM/IGT only at Baseline OL: 
 
A ≥10% increase from Baseline RW in AUCglucose.from Visit OL22 to Visit RW12. 
 
Use of rescue medication (initiation or increase in diabetes medication due to worsening 
of hyperglycemic control). 
 
Treatment discontinuation for any reason in RW phase. 
 
Patients with missing RW12 AUCglucose values. 
­ In patients with hypertension and DM/IGT at Baseline OL, a loss of response will be 
defined as a loss of response with respect to either hypertension or hyperglycemic control 
(AUC-based) from Visit OL22 to Visit RW12, irrespective of which response criteria 
(hypertension or DM/IGT) they met to enter the RW phase. 
Exploratory Efficacy Endpoints in the OL Phase 
Continuous Endpoints 
• In patients with uncontrolled hypertension, the mean change in SBP from Baseline to 
Visit OL22/ET. 
• In patients with uncontrolled hypertension, the mean change in DBP from Baseline to 
Visit OL22/ET. 
• Mean change in Cushing Quality-of-Life (QoL) score from Baseline to Visit OL22/ET. 
• Mean change in body-fat composition from Baseline to Visit OL22/ET, as determined by DXA. 
• Mean change in the Beck Depression Inventory®-II (BDI-II) score from Baseline to 
Visit OL22/ET. 
• Mean change in body weight from Baseline to Visit OL22/ET. 
• In patients with IGT, the mean change in 2-hour oGTT glucose from Baseline to Visit OL22/ET. 
• In patients with DM (HbA1c ≥6.5% at Baseline), the mean change in HbA1c from Baseline to 
Visit OL22/ET. 
• In patients with DM/IGT, the mean change in AUCglucose from Baseline to Visit OL22/ET. 
• The mean change from Baseline to Visit OL22/ET in the following: waist circumference;  lean 
mass measured by DXA; serum osteocalcin; the Beck Depression Inventory®-II (BDI-II) score; 
sit-to-stand test score; trail-making test score; sex-hormone levels (estradiol, total and free 
testosterone, sex-hormone‒binding globulin, follicle-stimulating hormone, and luteinizing 
hormone); FKBP5 and other potential biomarkers of GR activity; urinary free cortisol (UFC), 
late-night salivary cortisol and plasma adrenocorticotropic hormone (ACTH); AUCinsulin, 
Matsuda Index, homeostatic model assessment of insulin resistance (HOMA IR), and daytime 
and nocturnal average blood pressure. 
• In patients with adrenal Cushing syndrome (CS), the mean change in ACTH levels from 
Baseline to Visit OL22/ET. 
Endpoints Summarized with Proportions 
• In patients with hypertension, the proportion of patients who meet any of the hypertension 
response criteria at Visit OL22/ET. 
• In patients with hypertension, the proportion of patients with reduction or discontinuation of 
antihypertensive medications from Baseline to Visit OL22/ET. 
• The proportion of patients with a positive Global Clinical Response score at Visit OL22/ET. 
• In patients with DM/IGT, the proportion of patients who meet any of the DM/IGT response 
criteria at Visit OL22/ET. 


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• In patients with IGT, the proportion of patients who achieved normalization of glucose based on 
the plasma 2-hours oGTT test and/or a reduction in the 2-hour glucose by 50 mg/dL from 
Baseline to Visit OL22/ET. 
• In patients with DM (HbA1c ≥6.5% at Baseline), the proportion of patients with any decrease in 
dose of diabetes medication from Baseline to Visit OL22/ET. 
• The proportion of patients meeting any DM/IGT or hypertension response criterion at 
Visit OL22/ET by dose at which response was first reached. 
• In patients with DM/IGT, the proportion of patients with ≥25% decrease in AUCglucose from 
Baseline to Visit OL22/ET.  
• In patients with DM/IGT, the proportion of patients with ≥0.5% decrease in HbA1c from 
Baseline to Visit OL22/ET. 
Exploratory Pharmacokinetic Endpoints 
• In patients with endogenous Cushing syndrome, the steady-state plasma exposures of 
relacorilant (additional details will be summarized in the PK Analysis Plan). 
Inclusion Criteria 
To enroll in the study, each patient must meet the following inclusion criteria: 
1. Male or female, 18 to 80 years of age, inclusive. 
2. Has a confirmed biochemical diagnosis of endogenous Cushing syndrome based on the 
presence of at least 2 of the following (Nieman et al. 2008): 
- 
UFC >upper limit of normal (ULN) in at least 2 complete 24-hour tests within the 
screening window  
- 
Late night salivary cortisol >ULN in at least 2 tests (using a salivette) within the 
screening window (Note: Test is not appropriate for night shift workers and cannot be 
used to evaluate eligibility) 
- 
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 signing the informed consent. 
3. Has at least 2 of the following clinical signs and symptoms of Cushing syndrome: 
- 
Bodily characteristics of a Cushingoid appearance (e.g., facial rubor, moon facies, 
dorsocervical fat pad, supraclavicular fat pad) 
- 
Increased body weight or central obesity 
- 
Proximal muscle weakness 
- 
Low bone mass based on DXA scan 
- 
Psychiatric symptoms (including depression or psychosis) 
- 
Skin manifestations: violaceous striae, acne, and/or hirsutism 
- 
Easy bruisability. 
4. Has at least 1 of the following at Baseline: 
- 
DM (fasting plasma glucose ≥126 mg/dL and/or 2-hour oGTT plasma glucose 
≥200 mg/dL at 2 hours or HbA1c ≥6.5%), or IGT (plasma glucose ≥140 mg/dL and 
<200 mg/dL on a 2-hour oGTT) (American Diabetes Association 2020)  
- 
Uncontrolled hypertension (mean SBP ≥135 to ≤170 mm Hg and/or mean DBP ≥85 to 
≤110 mm Hg) based on 24-hour ABPM (Parati et al. 2014). 
5. If receiving medical treatment for DM/IGT or hypertension, there has been no increase in 
medication dosage for at least 4 weeks prior to Baseline assessment. 


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6. If receiving medical treatment for depression, there has been no increase in medication 
dosage for at least 6 weeks prior to Baseline. 
7. For women of childbearing potential, has a negative serum pregnancy test at Screening and 
negative urine pregnancy test at Baseline. 
Exclusion Criteria 
Patients who meet any of the following criteria will not be permitted entry to the study: 
1. Has severe, uncontrolled hypertension (mean SBP >170 mm Hg or mean DBP >110 mm 
Hg at Screening), based on 24-hour ABPM. 
2. Has poorly controlled DM (HbA1c >12% at Screening). 
3. Has a known “long term” history of both hypertension and diabetes (defined as both 
hypertension and diabetes diagnosed >10 years prior to the initial diagnosis of endogenous 
CS). 
4. Has a history of cyclic Cushing’s syndrome with fluctuating clinical manifestations. 
5. Has DM Type 1. 
6. Has abnormal liver test results (total bilirubin >1.5×ULN or elevated alanine 
aminotransferase or aspartate aminotransferase >3×ULN at Baseline). 
7. Has severe renal insufficiency (glomerular filtration rate ≤29 mL/min at Baseline). 
8. Has uncontrolled, clinically significant hypothyroidism or hyperthyroidism. 
9. Has prolonged QT interval corrected for heart rate using Fridericia’s equation (QTcF) 
(>450 ms for men and >470 ms for women) with normal QRS interval (<120 ms) or QTcF 
interval >500 ms with wide QRS interval (≥120 ms). 
10. Has received stereotactic radiation therapy for a Cushing syndrome-related tumor within 
24 months of Baseline or conventional pituitary radiation therapy within 36 months of 
Baseline. 
11. Has undergone pituitary surgery <3 months prior to Screening.  
12. Has used or plans to use any of the following treatments for Cushing syndrome within 
4 weeks prior to Baseline: 
- 
Mifepristone 
- 
Adrenostatic medications: metyrapone, osilodrostat, ketoconazole, fluconazole, 
aminoglutethimide, or etomidate 
- 
Serotonin antagonists: cyproheptadine, ketanserin, or ritanserin  
- 
Dopamine agonists: bromocriptine or cabergoline  
- 
Gamma-aminobutyric acid agonists: sodium valproate 
- 
Short-acting somatostatin analogs: octreotide, lanreotide, or pasireotide. 
13. Has used or plans to use somatostatin receptor ligands: long-acting octreotide or 
pasireotide within 8 weeks prior to Baseline. 
14. Patients who require inhaled glucocorticoid use and have no alternative option if their 
condition deteriorates during the study. 
15. Has adrenocortical carcinoma.  
16. Has used mitotane prior to Baseline. 
17. Has ectopic Cushing syndrome and a life expectancy of <3 years or receiving 
chemotherapy.  
18. Has pseudo-Cushing syndrome. Patients with known or suspected pseudo-Cushing 
syndrome based on medical history (such as patients with severe obesity, major 
depression, or a history of alcoholism) should undergo a dexamethasone-CRH DDAVP 
stimulation test (Yanovski et al.1993, Giraldi et al. 2007, Yanovski et al. 1998) to rule-in 
or rule-out this possibility. 


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19. Has taken any investigational drug within 4 weeks prior to Baseline, or within less than 
5 times the drug’s half-life, whichever is longer. 
20. Ongoing use of antidiabetic, antihypertensive, antidepressant or lipid-lowering medications 
that are highly dependent on CYP3A for clearance and that cannot undergo dose 
modification upon coadministration with strong CYP3A inhibitors.  
21. Ongoing use of any strong CYP3A4 inducer or any other prohibited medications 
(Section 5.4.4). 
22. Is pregnant or lactating. 
23. Is a female patient 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) who cannot use a highly effective method of 
contraception (Section 4.6.2). 
24. Has an acute or unstable medical problem that could be aggravated by treatment with the 
investigational study drug. 
25. Has a history of hypersensitivity or severe reaction to the study drug, to a similar class of 
drug, or to the study drug’s excipient. 
26. In the Investigator’s opinion, should not participate in the study or may not be capable of 
following the study schedule. 
27. Has known HIV or hepatitis B or C infection. 
28. Is a family member of one of the Sponsor’s employees, the Investigator, or the site staff 
directly working on the study. 
29. Has a history of unexplained vaginal bleeding or unexplained endometrial abnormalities. 
Investigational Treatment, Dose, and Mode of Administration 
The study drug will be administered orally and once daily, as capsules containing 100 mg of 
relacorilant (or matching placebo, as applicable).   
The starting dose at Baseline will be 100 mg once daily for 2 weeks. 
During dose escalation, all patients will be escalated in a stepwise manner from 100 mg to 400 mg 
once daily, based on tolerability and improvement in hypertension and/or hyperglycemia. The starting 
dose at Baseline will be 100 mg relacorilant once daily for 2 weeks, after which the dose will be 
increased to 200 mg. Then the dose will increase in 100 mg increments every 4 weeks. Dose escalation 
will be performed based on tolerability considering the following factors (only in patients whose 
current dose is well tolerated). 
In patients with hypertension only, the mean 24-hour BP (based on ABPM): 
• SBP is ≥130 mm Hg or 
• SBP is <130 mm Hg and has not decreased by ≥5 mm Hg from Baseline. 
• DBP is ≥80 mm Hg or 
• DBP is <80 mm Hg and has not decreased by ≥5 mm Hg from Baseline. 
In patients with DM/IGT only, the 2-hour glucose based on oGTT: 
Note: For visit OL2, the fasting glucose assessment from the chemistry laboratory panel will be 
used for dose escalation purposes. 
• is ≥140 mg/dL or fasting glucose is >100 mg/dL or 
• is <140 mg/dL and has not decreased by ≥30 mg/dL from Baseline. 
In patients with both DM/IGT and hypertension: 
The mean 24-hour BP (based on ABPM): 


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• SBP is ≥130 mm Hg or 
• SBP is <130 mm Hg and has not decreased by ≥5 mm Hg from Baseline. 
• DBP is ≥80 mm Hg or 
• DBP is <80 mm Hg and has not decreased by ≥5 mm Hg from Baseline. 
AND 
• is ≥140 mg/dL or fasting glucose is >100 mg/dL or 
• is <140 mg/dL and has not decreased by ≥30 mg/dL from Baseline.  
• Dose escalation may be held if the patient cannot safely tolerate escalation to the next dose. 
• Faster dose escalation for patients whose Cushing syndrome deteriorates during the study may 
be allowed on a case-by-case basis after discussion and approval by the medical monitor. 
• If any planned dose escalation is postponed, Visit OL14 can be used for a final dose escalation. 
• If access of patients to the study site is restricted due to the COVID-19 pandemic, dose 
escalation up to 200 mg may occur remotely if necessary. Subsequent dose escalations, 
however, are permitted only after completion of safety assessments. 
• Dose escalations start the day after the Visit at which they are approved by the Investigator. 
• After normalization of hypertension and/or hyperglycemia, further dose escalation will be 
allowed considering the following factors: 
­ Body weight and waist circumference  
­ Cushingoid appearance and striae 
­ Sit-to-stand test 
­ Beck Depression inventory 
­ Cushing Quality-of-Life questionnaire 
• If all symptoms of Cushing syndrome present at Baseline have resolved, no dose escalation will 
occur beyond that visit. 
Pharmacokinetics 
Blood concentrations of relacorilant will be measured and PK examined in all patients at Visit OL18.  
Statistical Methods 
Analysis Populations 
The ITT-RW population will include all patients who were randomized in the double-blind RW phase 
and received at least one dose of study drug. The mITT-RW population will include all patients in the 
ITT-RW population with at least one post-randomization efficacy assessment for primary efficacy 
endpoint (ABPM).  
The per-protocol analysis population (PP-RW) will include all patients in the mITT-RW population 
who had no major protocol deviations that might impact the validity of the primary efficacy analysis. 
The ITT-RW population will be used for the analysis of the primary endpoint in the RW Phase. The 
mITT-RW and PP-RW populations will be used for supportive efficacy analyses of all endpoints in the 
RW Phase. 
The ITT-OL population will include all enrolled patients who received at least one dose of study drug. 
The mITT-OL population will include all patients in the ITT-OL population with at least one post-
baseline efficacy assessment for secondary efficacy endpoints. The per-protocol analysis (PP-OL) 
population will include all patients in the mITT-OL population who had no major protocol deviations 
that might impact the validity of the primary efficacy analysis. The ITT-OL, mITT-OL, and PP-OL 
populations will be used for supportive efficacy analyses of all endpoints in the OL Phase. 
The safety population will consist of all enrolled patients who received at least 1 dose of study drug.  


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Statistical Analyses 
All statistical hypotheses will be tested at a 2-sided 0.05 significance level, unless otherwise specified. 
No adjustments for multiplicity will be made for secondary and exploratory endpoints. 
The primary efficacy endpoint will be assessed in the RW phase. The study will be considered to have 
a positive outcome if the primary endpoint reaches statistical significance. 
Analysis of Primary Efficacy Endpoint  
For the hypertension subgroup of the ITT-RW population, the primary analysis will be a responder 
analysis and the odds ratio for loss of response in hypertension control will be reported, as well as the 
percentage of patients with loss of response and 95% CI (using Clopper-Pearson method). The loss of 
response with respect to hypertension will be compared between treatment and placebo arms at Visit 
RW12 using a logistic regression model with 2 independent variables (treatment arm and stratification 
factor). In the hypertension subgroup, this stratification factor identifies patients with or without 
DM/IGT. 
In the hypertension subgroup, loss of response in the RW phase is defined as: use of rescue medication 
for hypertension after randomization but before Visit RW12, discontinuation of treatment before Visit 
RW12, or increase in SBP/DBP of >5 mmHg documented after randomization. 
This will be considered the primary analysis for the endpoint loss of response with respect to 
hypertension at Visit RW12 in the hypertension subgroup of the ITT-RW population. 
Sensitivity analyses will be pre-specified in the SAP. 
Analysis of Secondary Endpoints in the RW Phase 
For continuous endpoints in the RW phase of the study the analysis will be performed using a linear 
MMRM model. Restricted maximum-likelihood (REML) estimation will be used. The MMRM model 
will include Visit OL22 value (for the respective endpoint) as a covariate; treatment, visit, treatment by 
visit interaction, and stratification factor as fixed effects; patients within treatment groups as random 
effects. An unstructured covariance structure will be used to model within-patient error, and the 
Kenward-Roger approximation will be used to model denominator degrees of freedom. This model is 
used after imputation of missing data at Visit RW12, using the retrieved drop-out approach. If fewer 
than 10 retrieved dropouts are available for the endpoint, then the main analysis will use a wash-out 
multiple imputation method instead of the retrieved dropout approach. 
The analysis for each of the endpoints will determine whether there is a difference between treatment 
groups in terms of change from Randomization to Visit RW12. This will be accomplished by using 
appropriate linear contrasts of the parameters in the MMRM model described above. Additional details 
will be described in the SAP.  
For all endpoints described as proportions in the RW phase, the point estimate and the 2-sided 95% CI 
will be calculated.  
Sensitivity analyses will be pre-specified in the SAP. 
Safety Analyses 
TEAEs are defined as AEs that start or worsen after the first dose of study drug through 28 days after 
the last dose of study drug. 
TEAEs will be displayed using the Medical Dictionary for Regulatory Activities (MedDRA) system 
organ class and preferred term, as well as by severity and relationship to the study drug.  
TEAEs will be summarized separately in the following four categories: Overall TEAEs, TEAEs that 
start prior to Randomization, TEAEs that start after randomization through the end of RW phase, 
TEAEs by treatment group, and TEAEs that start during the follow-up period by treatment group. 


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TEAEs for patients who were not randomized will be summarized separately. Serious AEs and TEAEs 
that lead to study-drug withdrawal or withdrawal from the study will be listed by patient. 
Clinical laboratory test results (chemistry and hematology), vital sign measurements, and ECG 
interval results will be summarized as changes over the OL phase and RW phase by parameter and 
visit using descriptive statistics. Changes in the laboratory results during the follow-up period will be 
summarized separately. 
Sample Size 
Approximately 162 patients are planned to enroll into a 6-month OL phase of the study to ensure the 
randomization of approximately 46 patients with hypertension into the subsequent 3-month, placebo-
controlled RW phase.  
This calculation assumes that enrolled patients will consist of approximately 25% with DM/IGT only, 
25% with hypertension only, and 50% with both DM/IGT and hypertension at Screening. Attainment 
of the randomization targets within the hypertension subgroup in the RW phase further assumes that 
75% of patients that present with hypertension only randomize to the RW phase and 20% of patients 
that present with both comorbidities (DM/IGT and hypertension) respond to hypertension criteria at 
Visit OL22 and randomize to the RW phase. With these assumptions, a total of approximately 46 
patients meeting response criteria will be randomized into the hypertension subgroup of the ITT-RW 
analysis population. Forty-six patients with hypertension (23 per treatment group) will ensure at least 
90% power to detect the difference between placebo and treatment arms in loss of response (assuming 
a loss of response in 25% of patients in the treatment arm and 75% in the placebo arm). These 
calculations are based on a Fisher’s exact test of proportions at the alpha=0.05 two-sided significance 
level. 
 
 


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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL CORT125134-455 .................................................................. 1 
SPONSOR SIGNATURE PAGE ................................................................................................... 2 
PROTOCOL SYNOPSIS ............................................................................................................... 3 
TABLE OF CONTENTS .............................................................................................................. 17 
LIST OF TABLES ........................................................................................................................ 23 
LIST OF FIGURES ...................................................................................................................... 23 
LIST OF ABBREVIATIONS AND DEFINITIONS ................................................................... 24 
1 
INTRODUCTION: BACKGROUND INFORMATION AND 
SCIENTIFIC RATIONALE ............................................................................................. 27 
1.1 
Therapeutic Area ............................................................................................................... 27 
1.2 
Clinical Summary ............................................................................................................. 27 
1.3 
Rationale for Study Design and Dose Regimen ............................................................... 30 
1.3.1 Rationale for Study Design ................................................................................... 30 
1.3.2 Rationale for Dose Selection and Regimen .......................................................... 31 
1.4 
Rationale for Selection of Primary Endpoint .................................................................... 32 
1.5 
Rationale for Selection Criteria for Patients Eligible in the Randomized Withdrawal Phase
........................................................................................................................................... 32 
1.6 
Benefits and Risks............................................................................................................. 33 
1.6.1 Study Conduct during COVID-19 Pandemic ....................................................... 34 
2 
STUDY OBJECTIVES ..................................................................................................... 37 
2.1 
Primary Objectives............................................................................................................ 37 
2.2 
Secondary Objective ......................................................................................................... 37 
3 
STUDY DESIGN.............................................................................................................. 38 
3.1 
Overall Design .................................................................................................................. 38 
3.1.1 Screening Phase .................................................................................................... 38 
3.1.2 Open-Label Phase (Baseline to Visit OL22) ........................................................ 38 
3.1.3 Randomized-Withdrawal Phase (Randomization to Visit RW12) ....................... 39 
3.2 
Patient Disposition ............................................................................................................ 41 
3.2.1 Patient Completion................................................................................................ 41 
3.2.2 Early Termination ................................................................................................. 41 


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3.2.3 Treatment Continuation ........................................................................................ 41 
3.3 
Number of Patients and Study Participation ..................................................................... 42 
3.3.1 Number of Patients ............................................................................................... 42 
3.3.2 Patient Study Participation .................................................................................... 42 
3.4 
Definitions: End of Treatment and End of Study ............................................................. 42 
3.4.1 End of Treatment .................................................................................................. 42 
3.4.2 End of Study ......................................................................................................... 43 
3.5 
Study Termination by Sponsor ......................................................................................... 43 
3.6 
Study Endpoints ................................................................................................................ 43 
3.6.1 Primary Endpoints ................................................................................................ 43 
3.6.2 Secondary Efficacy Endpoints in the Randomized-Withdrawal Phase ................ 44 
3.6.3 Exploratory Efficacy Endpoints in the Randomized Withdrawal Phase .............. 45 
3.6.4 Exploratory Efficacy Endpoints in the Open-Label Phase ................................... 46 
3.6.5 Exploratory Pharmacokinetic Endpoints .............................................................. 47 
4 
STUDY POPULATION ................................................................................................... 48 
4.1 
Inclusion Criteria .............................................................................................................. 48 
4.2 
Exclusion Criteria ............................................................................................................. 49 
4.3 
Screen Failures .................................................................................................................. 51 
4.4 
Early Patient Discontinuation or Withdrawal ................................................................... 51 
4.5 
Replacement of Patients .................................................................................................... 52 
4.6 
Restrictions During Study ................................................................................................. 52 
4.6.1 Dietary Restrictions .............................................................................................. 52 
4.6.2 Contraception ........................................................................................................ 52 
4.6.3 Radiation Therapy and Radiation Surgery ............................................................ 53 
5 
STUDY TREATMENTS AND MANAGEMENT .......................................................... 54 
5.1 
Study Drug and Placebo.................................................................................................... 54 
5.2 
Dose-Escalation Process ................................................................................................... 55 
5.3 
Dose Modifications ........................................................................................................... 56 
5.3.1 Dose Interruption and/or Discontinuation: Special Safety Events ....................... 56 
5.4 
Concomitant Medications ................................................................................................. 58 


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5.4.1 Rules for Antidiabetic and Antihypertensive Medication Use During the 
Open-Label Phase ................................................................................................. 58 
5.4.2 Rules for Antidiabetic and Antihypertensive Medication Use During the 
Randomized-Withdrawal Phase ............................................................................ 59 
5.4.3 Rules for Other Permitted Concomitant Medications ........................................... 61 
5.4.4 Prohibited Medications ......................................................................................... 61 
5.5 
Method of Treatment Assignment and Randomization .................................................... 61 
5.6 
Blinding/Unblinding ......................................................................................................... 62 
5.7 
Dosing Diary ..................................................................................................................... 63 
5.8 
Product Accountability and Treatment Adherence ........................................................... 63 
5.9 
Continued Access to Study Treatment .............................................................................. 63 
5.10 
External Data Review Committees ................................................................................... 63 
5.10.1 Data Review Board for Evaluation of Global Clinical Response ......................... 63 
5.10.2 Independent Data Monitoring Committee to Monitor Patient Safety ................... 64 
6 
DESCRIPTION OF STUDY ASSESSMENTS AND PROCEDURES AND 
APPROPRIATENESS OF MEASUREMENTS .............................................................. 65 
6.1 
Informed Consent and Screening ...................................................................................... 65 
6.1.1 Dexamethasone Suppression Test......................................................................... 65 
6.2 
History............................................................................................................................... 66 
6.2.1 Cushing-Syndrome‒Medication Washout ............................................................ 66 
6.2.2 Demographics and Baseline Disease Characteristics ........................................... 66 
6.2.3 Medical and Medication History .......................................................................... 66 
6.3 
Safety Assessments ........................................................................................................... 66 
6.3.1 Physical Examination............................................................................................ 66 
6.3.2 Vital Signs ............................................................................................................. 67 
6.3.3 Electrocardiogram ................................................................................................. 67 
6.3.4 Adverse Events ..................................................................................................... 67 
6.3.5 Clinical Laboratory Assessments .......................................................................... 68 
6.3.6 Pituitary Magnetic Resonance Imaging Scan ....................................................... 70 
6.3.7 Pregnancy Test ...................................................................................................... 70 
6.4 
Efficacy Assessments........................................................................................................ 70 


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6.4.1 Glucose Tolerance ................................................................................................ 70 
6.4.2 Ambulatory Blood Pressure Monitoring (ABPM) ................................................ 70 
6.4.3 Glycated Hemoglobin (HbA1c) ............................................................................ 71 
6.4.4 Body-Fat Composition (DXA Scan) ..................................................................... 71 
6.4.5 Cushing Quality-of-Life Questionnaire ................................................................ 71 
6.4.6 Body Weight and Waist Circumference ............................................................... 71 
6.4.7 Biochemical Markers of Bone Remodeling .......................................................... 72 
6.4.8 Beck Depression Inventory-II ............................................................................... 72 
6.4.9 Global Clinical Response ...................................................................................... 72 
6.4.10 Photography for Assessment of Cushingoid Features .......................................... 72 
6.4.11 Sit-to-Stand ........................................................................................................... 73 
6.4.12 Trail-Making Test ................................................................................................. 73 
6.4.13 Sex-Hormone Levels ............................................................................................ 73 
6.4.14 Menstrual Cycle Information ................................................................................ 73 
6.4.15 Glucocorticoid Receptor Activity Biomarker Tests ............................................. 73 
6.5 
Pharmacokinetic Assessments .......................................................................................... 74 
6.6 
Pharmacodynamic Assessments ....................................................................................... 74 
6.6.1 Fasting Serum Cortisol ......................................................................................... 74 
6.6.2 Urinary Free Cortisol ............................................................................................ 74 
6.6.3 Late-Night Salivary Cortisol ................................................................................. 74 
6.6.4 Hypothalamic-Pituitary-Adrenal Axis Parameters ............................................... 75 
6.7 
Appropriateness of the Measures ...................................................................................... 75 
6.8 
Blood Storage.................................................................................................................... 75 
7 
STUDY ASSESSMENTS AND PROCEDURES BY STUDY VISIT ............................ 76 
7.1 
Scheduled Visits................................................................................................................ 76 
7.1.1 Screening Visit (−42 to −1 day) ............................................................................ 77 
7.1.2 Baseline Visit (B) (Day 1) .................................................................................... 78 
7.1.3 Open-Label Visit 2 (OL2) (±3 days) .................................................................... 79 
7.1.4 Open-Label Visit 6 (OL6) (±3 days) .................................................................... 79 
7.1.5 Open-Label Visit 10 (OL10) (±3 days) ................................................................ 80 


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7.1.6 Open-Label Visit 14 (OL14) (±7 days) ................................................................ 80 
7.1.7 Open-Label Visit 18 (OL18) (±7 days) ................................................................ 81 
7.1.8 Open-Label Visit 22 (OL22) (±7 days) ................................................................ 82 
7.1.9 Randomization Visit (R) (+14 days) ..................................................................... 83 
7.1.10 Randomized-Withdrawal Visit 4 (RW4) (±7 days) .............................................. 83 
7.1.11 Randomized-Withdrawal Visit 8 (RW8) (±7 days) .............................................. 83 
7.1.12 Randomized-Withdrawal Visit 12 (RW12) (±7 days) .......................................... 84 
7.1.13 Early-Termination Visit (±7 days) ........................................................................ 85 
7.1.14 Follow-up Visit (±7 days) ..................................................................................... 86 
7.2 
Unscheduled Visits ........................................................................................................... 86 
8 
SAFETY EVENT DOCUMENTATION AND REPORTING ........................................ 87 
8.1 
Investigator’s Responsibilities .......................................................................................... 87 
8.2 
Monitoring Safety Data During Study .............................................................................. 87 
8.3 
Definition of an Adverse Event ........................................................................................ 87 
8.4 
Definition of a Serious Adverse Event ............................................................................. 87 
8.5 
Clinical Significance ......................................................................................................... 88 
8.6 
Clinical Laboratory Adverse Events ................................................................................. 88 
8.7 
Documentation of Adverse Events ................................................................................... 88 
8.8 
Adverse-Event Classification............................................................................................ 89 
8.8.1 Intensity Grades of Adverse Events ...................................................................... 89 
8.8.2 Relationship of Adverse Event to Study Drug or Procedure ................................ 89 
8.9 
Procedures for Reporting a Serious Adverse Event .......................................................... 90 
8.10 
Adverse Event Follow-up ................................................................................................. 90 
8.11 
Pregnancy .......................................................................................................................... 90 
8.11.1 Maternal Exposure ................................................................................................ 90 
8.11.2 Paternal Exposure ................................................................................................. 91 
8.12 
Treatment of Overdose ..................................................................................................... 91 
8.13 
Emergency Sponsor Contact ............................................................................................. 91 
9 
STATISTICAL METHODS ............................................................................................. 92 
9.1 
Analysis Populations ......................................................................................................... 92 


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9.2 
General Statistical Considerations .................................................................................... 92 
9.3 
Hypothesis Testing............................................................................................................ 93 
9.4 
Sample-Size Calculation ................................................................................................... 93 
9.5 
Analysis Plan .................................................................................................................... 93 
9.5.1 Patient Disposition ................................................................................................ 93 
9.5.2 Demographic and Baseline Data ........................................................................... 94 
9.5.3 Prior and Concomitant Medications ..................................................................... 94 
9.5.4 Analysis of Efficacy Endpoints ............................................................................ 94 
9.5.5 Safety Analyses ..................................................................................................... 96 
9.5.6 Pharmacodynamic Analysis .................................................................................. 96 
9.5.7 Pharmacokinetic Analysis ..................................................................................... 96 
10 
ETHICAL AND LEGAL CONSIDERATIONS .............................................................. 97 
10.1 
Compliance with IRB/IEC Regulations ............................................................................ 97 
10.2 
Ethical Conduct of the Study ............................................................................................ 97 
10.3 
Protection of Human Patients ........................................................................................... 97 
10.3.1 Compliance with Informed-Consent Regulations ................................................. 97 
10.3.2 Patient Confidentiality .......................................................................................... 98 
10.3.3 Patient Privacy ...................................................................................................... 98 
10.3.4 Data Protection...................................................................................................... 98 
11 
ADMINISTRATIVE CONSIDERATIONS ................................................................... 101 
11.1 
Quality Management ....................................................................................................... 101 
11.2 
Study Monitoring ............................................................................................................ 101 
11.3 
Documentation ................................................................................................................ 102 
11.3.1 Source Documents .............................................................................................. 102 
11.3.2 Case Report Forms .............................................................................................. 102 
11.3.3 Retention of Essential Study Documents ............................................................ 102 
11.3.4 Sample Collection, Preparation, and Shipping ................................................... 103 
11.4 
Long-Term Retention of Biological Samples ................................................................. 103 
11.5 
Clinical Supplies ............................................................................................................. 104 
11.5.1 Inventory, Reconciliation, Return, and Disposition of Clinical Supplies ........... 104 


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11.5.2 Clinical-Supply Inventory ................................................................................... 104 
11.5.3 Return or Destruction of Study Drug and/or Supplies ........................................ 104 
11.5.4 Study Drug Destroyed by the Site ...................................................................... 104 
11.5.5 Study Drug Returned to Sponsor for Destruction ............................................... 104 
11.5.6 Drug Accountability............................................................................................ 105 
11.6 
Post-Trial Care ................................................................................................................ 105 
11.7 
Protocol Noncompliance ................................................................................................. 105 
11.8 
Financial Disclosure........................................................................................................ 105 
11.9 
Publication and Disclosure Policy .................................................................................. 105 
11.10 Electronic Systems .......................................................................................................... 106 
12 
REFERENCES ............................................................................................................... 107 
13 
APPENDICES ................................................................................................................ 109 
Appendix A: Schedule of Events ................................................................................................ 109 
Appendix B: Summary of Changes ............................................................................................ 113 
LIST OF TABLES 
Table 1 
Study Drug and Placebo: Formulation, Administration, Packaging, and Storage .54 
Table 2 
Criteria for Dose Modification or Discontinuation Due to Special Safety Events 
(Until Visit OL18)..................................................................................................57 
Table 3  
Clinical Laboratory Variables Evaluated During the Study ..................................69 
Table 4 
Time Window for Collection of 2-hour oGTT Blood Samples .............................70 
Table 5 
Time Windows for Collection of Pharmacokinetic Samples .................................74 
Table 6 
Adverse Event Grades Based on the Common Terminology Criteria for 
Adverse Events ......................................................................................................89 
Table 7 
Causal Attribution Guidance for Adverse Events ..................................................90 
Table 8 
Schedule of Visits and Procedures .......................................................................109 
Table 9 
Summary of Changes in Protocol CORT125134-455 Amendment 6 .................114 
LIST OF FIGURES 
Figure 1 
CORT125134-455 Study Design ...........................................................................38 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS 
Abbreviation 
Definition 
ABPM 
ambulatory blood pressure monitoring 
ACTH 
adrenocorticotropic hormone 
ADME 
absorption, distribution, metabolism, and excretion 
AE 
adverse event 
AUC0–24h 
area under the concentration-versus-time curve from time 0 to 24 hours after dosing 
AUCglucose 
area under the concentration-time curve for glucose  
AUCinf 
area under plasma concentration-versus-time curve extrapolated to infinity 
AUClast 
area under the concentration-versus-time curve at the last quantifiable time point 
BDI-II 
Beck Depression Inventory®-II 
BP 
blood pressure 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cmax 
maximum plasma concentration 
CT 
computed tomography 
CYP 
cytochrome P450 
DBP 
diastolic blood pressure 
DDI 
drug-drug interaction 
DHEA-S 
dehydroepiandrosterone sulfate 
DM/IGT 
diabetes mellitus/impaired glucose tolerance 
DRB 
Data Review Board 
DST 
dexamethasone suppression test 
DXA 
dual energy X-ray absorptiometry 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ET 
early termination 
FDA 
Food and Drug Administration 
FKBP5 
FK506-binding protein 5 


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Abbreviation 
Definition 
GCP 
Good Clinical Practice 
GR 
glucocorticoid receptor 
HbA1c 
glycated hemoglobin 
HOMA IR 
homeostatic model assessment of insulin resistance 
HPA 
hypothalamic-pituitary-adrenal 
HR 
heart rate 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation  
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IWRS 
interactive web response system 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
mITT-RW 
modified intent-to-treat–randomized withdrawal 
MMRM 
mixed model for repeated measures 
MRI 
magnetic resonance imaging 
oGTT 
oral glucose tolerance test 
OL 
open-label 
PD 
pharmacodynamic 
PK 
pharmacokinetics 
PPG 
postprandial glucose 
PR 
progesterone receptor 
QoL 
quality-of-life 
QTc 
corrected QT interval 
QTcF 
QT interval corrected for heart rate using Fridericia’s equation 
REML 
restricted maximum likelihood 
RW 
randomized withdrawal 


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Abbreviation 
Definition 
s 
serum 
SAE 
serious adverse event 
SBP 
systolic blood pressure 
t1/2 
half-life 
T3 
triiodothyronine 
T4 
thyroxine 
TEAE 
treatment-emergent adverse event 
u 
urine 
UFC 
urinary free cortisol 
ULN 
upper limit of normal 
US 
United States 


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1 
INTRODUCTION: BACKGROUND INFORMATION AND 
SCIENTIFIC RATIONALE 
1.1 
Therapeutic Area 
Endogenous Cushing syndrome is a rare multisystem disorder that results from overproduction 
of the glucocorticoid hormone cortisol. In both adults and children, Cushing syndrome is most 
commonly caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor 
(Cushing disease). Other forms of Cushing 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 cause of the excess cortisol. Depending on 
the nature of the underlying tumor (i.e., benign versus malignant, localized versus metastatic), 
the selected treatment may be surgery, radiotherapy, medical therapy, or a combination of these. 
Pharmacological treatment serves to control the disease after unsuccessful surgery or recurrence 
(Nieman et al. 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 four United States (US) Food and Drug Administration (FDA)-approved 
medical therapies for endogenous Cushing syndrome. The first, mifepristone (Korlym®), was 
approved for the control of diabetes mellitus/impaired glucose tolerance (DM/IGT) secondary to 
hypercortisolism in adult patients with endogenous Cushing syndrome who have DM/IGT and 
have failed surgery or are not candidates for surgery. The second, pasireotide (Signifor®), is a 
somatostatin receptor agonist approved for the treatment of adult patients with Cushing disease 
for whom pituitary surgery is not an option or has not been curative. The third, osilodrostat 
(Isturisa®) is a cortisol-synthesis inhibitor approved for the treatment of adult patients with 
Cushing’s disease for whom pituitary surgery is not an option or has not been curative. The 
fourth, levoketoconazole (Recorlev®), is a cortisol synthesis inhibitor indicated for the treatment 
of endogenous hypercortisolemia in adult patients with Cushing syndrome for whom surgery is 
not an option or has not been curative. 
Relacorilant (CORT125134) is a potent, selective glucocorticoid receptor (GR) antagonist being 
developed for the treatment of Cushing syndrome. Relacorilant is a high-affinity antagonist of 
the GR (inhibition constant <1 nM in a human GR binding assay and <10 nM in a human 
functional assay). Although the mechanism of action of relacorilant is similar to that of 
mifepristone, relacorilant does not bind to the progesterone receptor (PR). Given its selective and 
potent GR antagonism, relacorilant has the potential advantage compared with mifepristone of 
not having any antiprogesterone effects, including endometrial hypertrophy and the potential for 
irregular vaginal bleeding. 
1.2 
Clinical Summary 
A brief summary of relacorilant clinical studies is presented. Further details on the studies, 
design, and results are presented in the Investigator’s Brochure.  


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In the first study of relacorilant, a Phase 1 single-ascending dose/multiple-ascending dose study 
(Study CORT125134-120; NCT03508635), 84 healthy subjects received single doses of up to 
500 mg or repeated doses of up to 250 mg daily (“clinical-pharmacology” formulation, an earlier 
formulation with a higher bioavailability than the current “clinical-trial formulation”). 
Pharmacodynamic data were generated following administration of prednisone alone and 
in combination with relacorilant. Single doses of 500 mg of relacorilant or multiple doses 
of 250 mg daily prevented changes in lymphocytes, eosinophils, and osteocalcin induced by 
prednisone alone, as well as changes in the mRNA expression of glucocorticoid-regulated genes 
(FK506 binding protein 5 [FKBP5]). During the repeated-dose parts of Study CORT125134-120, 
there was a dose-related trend in subjects who reported at least 1 treatment-emergent adverse 
event (TEAE): 44.4% (50 mg), 66.7% (150 mg), and 85.7% (250 mg), compared with 50% of 
placebo-treated subjects. The most commonly reported TEAEs were within the system organ 
class musculoskeletal and connective tissue disorders. At a relacorilant dose of 500 mg once 
daily, 77.8% of subjects of in the 500 mg group reported at least one moderate or severe TEAE, 
compared with <22.5% in the groups receiving placebo and lower relacorilant doses. This 
500 mg dose level (with the higher bioavailability formulation) was terminated prematurely due 
to lack of tolerability. No serious AEs were reported in this group.  
A Phase 1 multiple-ascending-dose study was conducted to characterize the steady-state PK of 
and determine the exposure range of the clinical-trial formulation following administration of 
daily doses of 150 mg, 250 mg, or 350 mg for 14 consecutive days in healthy subjects (n=32) 
(Study CORT125134-453). Consistent with historical data, relacorilant exposure increased in a 
time-dependent and greater than dose-proportional manner. All subjects achieved steady-state 
conditions by Day 14, and all subjects had a steady-state exposure (Day 14 area under the 
concentration-time curve from 0 to 24 hours postdose, AUC0-24h) that was less than the 
40 µg•h/mL exposure limit guided by results of the toxicology studies. Relacorilant was well 
tolerated in all subjects at all dose levels. No serious or severe TEAEs have been reported. One 
subject receiving relacorilant 250 mg withdrew consent and discontinued the study due to a 
related TEAE of moderate dyspepsia. Additionally, the PK data from Study CORT125134-453 
indicate that the relacorilant exposure in healthy subjects is similar to that observed in patients 
with endogenous Cushing syndrome at the same dose level in Study CORT125134-451. 
A Phase 1 human absorption, distribution, metabolism, and excretion (ADME) study was 
conducted in healthy subjects to assess the mass balance recovery, pharmacokinetics (PK), 
metabolite profile and elimination of relacorilant. The major components in human plasma were 
CORT125336 (both diastereoisomers), metabolite m/z411, CORT125337 (first diastereoisomer), 
parent relacorilant, and metabolite CORT125295. Relacorilant represented 38% of the 
circulating radioactivity based on maximum plasma concentration (Cmax) and 6.2% based on 
AUC at the last quantifiable time point (AUClast) and suggests rapid metabolism of relacorilant. 
The mean half-life (t1/2) of relacorilant was 23.1 hours. A single dose of [14C]-relacorilant was 
well tolerated, no severe or serious TEAEs were reported, and no subject was withdrawn as a 
result of a TEAE. The mass balance recovery of total radioactivity did not differ between male 
and female subjects. 
The effect of food on a single dose of relacorilant (350 mg) was evaluated clinically (Study 
CORT125134-123; NCT03442621) in healthy subjects following administration of relacorilant 
(clinical-trial formulation) with a high-fat meal or with a standard, moderate -fat meal, relative to 


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fasting conditions. The exposure (AUC) of relacorilant increased approximately 2-fold on 
administration under fed conditions, relative to fasting conditions. The increase in relacorilant 
exposure was similar with both meal types. A serious adverse event (SAE; pulmonary embolism) 
occurred in 1 subject 20 days after receiving the last dose of relacorilant.  
The potential effect of relacorilant as a perpetrator of cytochrome P450 (CYP)-mediated drug-
drug interactions (DDI) was evaluated clinically (Study CORT125134-126; NCT03457597). 
Healthy subjects received single oral doses of the probe substrates midazolam (CYP3A), 
metoprolol (CYP2D6), pioglitazone (CYP2C8), tolbutamide (CYP2C9), and omeprazole 
(CYP219) in the presence or absence of steady-state concentrations of relacorilant (350 mg 
once-daily; clinical-trial formulation). Following single-dose administration of probe substrates 
of CYP activity in the presence of steady-state concentrations of relacorilant, no relevant effect 
of relacorilant was observed on CYP2D6, CYP2C8, CYP2C9, CYP2C19, However, relacorilant 
was shown to be a strong CYP3A inhibitor, resulting in midazolam AUC extrapolated to infinity 
(AUCinf) and Cmax of 8.8-fold and 3.3-fold higher, respectively, relative to midazolam alone; 
additional guidance is provided in Section 5.4.4. One subject discontinued due to an AE of 
pancreatitis, acute, Grade 3 (severe), not serious, not related to either relacorilant or probe 
substrates. No other treatment-related adverse events (TEAEs) led to withdrawal of study drug, 
study-drug interruption, or reduction of dose. 
The effect of a strong inhibitor of CYP3A on a single dose of relacorilant was evaluated in 
healthy subjects (Study CORT125134-124; NCT03512548, Part 1). Following coadministration 
of a single dose of relacorilant (350 mg; clinical-trial formulation) with itraconazole (200 mg), 
relacorilant AUCinf and Cmax were 3.5-fold and 2.0-fold higher, respectively, versus relacorilant 
alone. No TEAEs were reported that led to withdrawal of study drug, study-drug interruption, or 
reduction of dose. Further evaluation is ongoing to determine the potential effect of a strong 
CYP3A inhibitor on steady-state concentrations of relacorilant. Because relacorilant is a strong 
CYP3A inhibitor as well as a CYP3A substrate, it undergoes autoinhibition, and the addition of 
another strong CYP3A inhibitor is not expected to result in a substantial DDI. 
Study CORT125134-451 (Study of the Safety and Efficacy of CORT125134 in the Treatment of 
Endogenous Cushing’s Syndrome; NCT02804750) is a Phase 2, open-label, multicenter, dose-
escalation study in patients with endogenous Cushing syndrome. The study is ongoing, dosing 
has completed, CSR is under preparation. Group 1 (n=17) had a two-step dose escalation 
(monthly) of once-daily relacorilant (dose range, 100–200 mg, clinical-trial formulation; total 
treatment period, 12 weeks), and Group 2 (n=18) had a three-step dose escalation (monthly) of 
once-daily relacorilant (dose range, 250–400 mg, clinical-trial formulation; total treatment 
period, 16 weeks). 
Applying the response criteria selected for this Phase 3 study (Section 3.1.3.1) to the data from 
Study 451, among patients with hyperglycemia, 15% of patients in Group 1 and 50% percent of 
patients in Group 2 responded. Among patients with hypertension, 41.7% of patients in Group 1 
and 63.7% of patients in Group 2 responded.  
Of the 17 patients enrolled in Group 1, all but 1 patient completed the study. A total of 
101 TEAEs were reported, with 88.2% of patients reporting at least one. The majority of patients 
(70.6%) experienced events that were considered related to relacorilant. The most common 
TEAEs in Group 1 were back pain, pain in extremity, diarrhea, and headache, each with 23.5% 


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of patients experiencing each of these TEAEs at some point in the study. Most of the events were 
mild or moderate, and none were serious. One patient discontinued study at 6 weeks due to 
worsening hypertension that was not attributed to relacorilant. Study drug was withdrawn for the 
subject who discontinued.  
Of the 18 patients enrolled in Group 2, 8 (44.4%) completed the study, 13 patients (72.2%) 
completed Week 12. In Group 2, 228 TEAEs were reported, with all patients reporting at least 
one TEAE. The majority of patients (83.3%) experienced events considered related to 
relacorilant. The most common TEAEs in Group 2 were back pain (38.9%), nausea and 
headache (27.8%), and arthralgia, dizziness, myalgia, abdominal pain, pain in extremity, 
dyspepsia (22.2% each).  
Eight patients in Group 2 had TEAEs that led to study-drug discontinuation, including 3 patients 
with TESAEs and 5 patients with nonserious TEAEs (musculoskeletal AEs for 3 patients and 
peripheral neuropathy and abnormal glucocorticoids for 1 patient each). All events that led to 
study-drug discontinuation in Group 2 were considered related to study drug with the exception 
of one TEAE of neck pain. The musculoskeletal TEAEs improved with dose decreases, but 
returned on dose re-escalation. In those patients, decrease of the dose of relacorilant improved 
the adverse events.  
For the entire study, five TESAEs were reported in 4 patients. All TESAEs were Grade 3 in 
severity. Three patients (8.57%) had TESAEs (polyneuropathy, myopathy, and acute myocardial 
infarction) that were considered related to study drug and led to study-drug discontinuation. 
Relacorilant exposure in patients with endogenous Cushing syndrome (Study CORT125134-451) 
remained well below the 40 µg∙h/mL cap (exposure limit guided by results of the toxicology 
studies) at doses up to 400 mg. 
1.3 
Rationale for Study Design and Dose Regimen  
1.3.1 Rationale for Study Design 
The activity of relacorilant has been demonstrated in various in vitro assays, and relacorilant was 
shown to be well tolerated in several clinical studies. The combination of the preclinical and 
clinical findings supports the continued evaluation of relacorilant in patients with Cushing 
syndrome. 
The study design includes an open-label (OL) phase, followed by a 12-week, randomized, 
double-blind, placebo-controlled withdrawal phase. Only patients meeting response criteria at the 
end of the OL phase will be eligible for the randomized-withdrawal (RW) phase. An RW design 
provides predictive enrichment for the comparison of active treatment to placebo. 
The OL phase for the determination of responders (i.e., the population to be randomized) has two 
precedents: First, mifepristone, another GR antagonist, was approved following an OL study that 
demonstrated clinical improvement in glucose control of individual patients, using each patient 
as his or her own control. Second, the Phase 2 study of relacorilant (Study CORT125134-451) 
demonstrated clinical improvement in glucose control as well as in hypertension. 
The use of an OL phase followed by a placebo-controlled randomized withdrawal phase has been 
used in two clinical trials in this indication (i.e., studies of levoketoconazole and LCI699). 


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Patients randomized to placebo are expected to experience a gradual loss of response during the 
12-week RW phase, and to return toward their baseline status. Increases in antidiabetic or 
antihypertensive medications are allowed during the RW phase if needed (Section 5.4.2). 
This study will evaluate the efficacy and safety of GR antagonism by relacorilant, with an 
emphasis on blood pressure (BP) control, in patients with endogenous Cushing syndrome. To 
examine the many manifestations of Cushing syndrome in the study patients, several other 
efficacy assessments will be used to assess clinical benefit, including the use of antidiabetic 
and/or antihypertensive medications, glycated hemoglobin (HbA1c), and body-fat composition. 
Clinical benefit will also be assessed according to the exploratory efficacy endpoints detailed in 
Section 3.6. 
This design of this study accounts for relevant US FDA regulatory guidance and will be 
conducted in compliance with the protocol, Good Clinical Practice (GCP) guidelines, and the 
applicable regulatory requirements. 
1.3.2 Rationale for Dose Selection and Regimen 
Dose selection for this study was based on PK and safety results from Phase 1 studies in healthy 
subjects (CORT125134-120, CORT125134-123, and CORT125134-453) and safety, efficacy, 
and PK results in a Phase 2 study in patients with Cushing syndrome (CORT125134-451). 
Across all of these studies, exposure to relacorilant (as AUC0-24h) at steady-state was well below 
40 µg·h/mL and was consistent between healthy subjects and patients with Cushing syndrome. 
The PK of relacorilant support daily dosing. 
In the Phase 2, open-label, multicenter Study CORT125134-451, 35 patients with endogenous 
Cushing syndrome received relacorilant in escalating doses ranging from 100 mg/day to 
200 mg/day (Group 1, 12 weeks) and ranging from 250 mg/day to 400 mg/day (Group 2, 
16 weeks). Preliminary results indicate that treatment with relacorilant in patients with 
endogenous Cushing syndrome results in improved glycemic and hypertension control. 
In Group 1, clinically significant changes in DM/IGT and hypertension control were generally 
observed starting with the 200-mg dose, which was well tolerated. In Group 2, a higher 
proportion of patients responded based on the Phase 3 response criteria (Section 1.2), but also 
a higher proportion experienced TEAEs (especially musculoskeletal complaints) and/or 
discontinued study. 
The Phase 2 data suggest that most responders will achieve clinical benefit along with good 
tolerability at a relacorilant dose of 200 mg or 300 mg daily, but that some patients (analogous to 
experience with the predecessor drug, mifepristone), will require higher doses. Based on these 
safety, efficacy, and PK considerations, the dose range for the examination of both safety and 
efficacy in the protocol is 200‒400 mg, the dose range already tested in the Phase 2 study. 
The Phase 2 experience suggests that patients may best tolerate a gradual dose escalation. The 
exposures in the patients with Cushing syndrome receiving 200 mg (in Group 1) and patients 
receiving 250 mg were similar. However, patients in Group 2, who started dosing with 250 mg 
relacorilant, experienced TEAEs (especially musculoskeletal symptoms) at a higher frequency 
and with greater intensity compared with patients who received 200 mg after a slow titration 
starting from 100 mg daily. Therefore, to maximize treatment persistence, patients in this 


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Phase 3 study will start at 100 mg daily for the first 2 weeks of dosing before escalating 
to 200 mg daily and continuing with subsequent dose escalations to a target dose of 400 mg once 
daily, as tolerated.  
1.4 
Rationale for Selection of Primary Endpoint 
Due to the mechanism of action of relacorilant (a GR antagonist), cortisol levels cannot be used 
as a primary endpoint as they are in studies of steroidogenesis or ACTH secretion inhibitors. 
Therefore, clinical endpoints must be used, as in the case of the marketed drug, mifepristone 
(Korlym®). The primary indicator of clinical response in this protocol is improvement in 
hypertension, which is a very common manifestation of Cushing syndrome and for which there 
are robust, objective measures. In this protocol, the response criteria for BP control and for blood 
glucose control determine the selection of patients who will enter the placebo-controlled portion 
of the study.  
For hypertension control, the protocol employs 24-hour ambulatory blood pressure monitoring 
(ABPM), the gold-standard measurement. For this test, a decrease of 5 mm Hg in either systolic 
or diastolic BP is clinically significant, and this is the BP response criterion. Unlike the 
predecessor drug, mifepristone, relacorilant has not caused significant increases in cortisol levels 
in Phase 2 patients with Cushing syndrome. Therefore, relacorilant does not pose any concern 
that improvement in BP due to general improvement in Cushing syndrome could be offset by 
cortisol stimulation of the mineralocorticoid receptor (which increases BP). Thus, the 
improvements in hypertension seen in the Phase 2 study are expected to be confirmed in this 
Phase 3 study.  
For the RW phase, the criterion for loss of response in regards to HTN control is the same (but 
reverse) as for response in the OL phase of the study—an increase of 5 mm Hg or greater. For 
blood pressure, a responder analysis is preferred due to absence of a single parameter that 
incorporates both systolic BP (SBP) and diastolic BP (DBP). 
1.5 
Rationale for Selection Criteria for Patients Eligible in the Randomized Withdrawal 
Phase 
Selection of patients eligible for randomization in the RW phase is based on the improvement of 
common comorbidities observed in patients with Cushing syndrome, hypertension, or 
hyperglycemia. Hypertension response criteria are described in Section 1.4. 
For glucose control, the evaluation of clinical benefit depends on the circumstances at Baseline. 
The response criteria in this protocol are based on 1) decreases in HbA1c, 2) decreases in the 
2-hour glucose level in the oral glucose tolerance test (oGTT), and 3) reduction in diabetes 
medication and are intended to encompass the range of clinically significant improvements seen 
in patients experiencing better control of their hyperglycemia. 
For any patient with hyperglycemia, a reduction in HbA1c of ≥0.5% is clinically significant 
(Prandin 2017; Starlix 2018; Gerich 2013; Esposito et al. 2004; EMA/CHMP 2014; Castinetti et 
al. 2014). For patients with lesser degrees of hyperglycemia, improvements may not be reflected 
in changes in HbA1c (which is less sensitive below a starting point of 6.5%), but will be evident 
from the oGTT. The 2-hour oGTT glucose level has been used as an endpoint in several trials 
with diabetes drugs (Prandin 2017; Starlix 2018; Gerich 2013; Esposito et al. 2004). In these 


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studies, a change in the 2-hour postprandial glucose (PPG) by 50 mg/dL was associated with a 
clinically meaningful improvement in the HbA1c, and this change is regarded by diabetologists 
as clinically meaningful. Finally, a substantial reduction in diabetes medication—a 25% 
reduction in total daily insulin dose triggered by the treating physician either to prevent 
hypoglycemia after observing significant fasting or postprandial glucose reductions or after 
observing hypoglycemic values in a patient to prevent future hypoglycemic episodes without 
worsening of the HbA1c represents a significant clinical benefit. 
1.6 
Benefits and Risks 
Glucocorticoid receptor antagonism is a proven mechanism of action for the treatment of the 
DM/IGT secondary to hypercortisolism in adult patients with Cushing syndrome (Fleseriu et al. 
2012). Because the mechanism of action of relacorilant is similar to that of mifepristone, with the 
exception that it does not bind the PR, relacorilant is expected to effectively treat Cushing 
syndrome, but without the drawbacks of progesterone receptor antagonism that may result in 
untoward reproductive effects and/or interruption of therapy. 
In the Phase 2 study (Study CORT125134-451) in patients with endogenous Cushing syndrome, 
relacorilant showed evidence of clinical benefit based on improvement of cortisol-excess‒related 
comorbidities. The drug was generally well tolerated, with the upper bound on dosing being 
typically musculoskeletal complaints, a tolerability issue that patients can report. 
Compared with the predecessor drug mifepristone, relacorilant offers two key safety advantages: 
lack of affinity for the PR, and lack of significant cortisol rise (a driver of hypokalemia in the 
marketed GR antagonist mifepristone). 
Based on the mechanism of action of relacorilant, there is a theoretical risk of excessive GR 
antagonism, which could manifest by weakness, tiredness, dizziness, hypoglycemia, dehydration, 
weight loss, nausea, vomiting, diarrhea, and muscle aches. Since relacorilant does not affect the 
mineralocorticoid receptor, it is unlikely that hypotension would occur in the absence of 
antihypertensive medication. Because plasma glucocorticoid levels are not decreased with 
relacorilant administration, a biochemical diagnosis of excessive GR antagonism is not possible; 
diagnosis must rely on clinical assessment. In cases of suspected excess GR antagonism, study 
drug will be interrupted for 3 days and supplemental glucocorticoid will be given in high doses 
to overcome the GR antagonism (Table 2).  
The safety profile of relacorilant in study patients will be monitored by AEs, physical 
examinations, measurement of vital signs, 12-lead electrocardiograms (ECGs), and blood tests 
for analysis of clinical chemistry and hematology parameters.  
Patients meeting response criteria will be randomized 1:1 to continue relacorilant or receive a 
placebo equivalent (i.e., have relacorilant withdrawn). Patients proceeding into the RW phase 
will be at risk for relapse of symptoms of Cushing syndrome, including worsening of diabetes, 
hypertension, and weight gain. 
In vitro data indicate that relacorilant is metabolized by multiple CYP enzymes (CYP3A4, 
CYP2C8, and CYP3A5) and by carbonyl reductases. Data also indicate the potential for 
relacorilant to perpetuate drug-drug interactions via inhibition of CYP3A and transporter 
pathways. Patients taking any prohibited medication are excluded from this study (refer to 


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Section 5.4). If a concomitant medication is required to treat an AE, in selecting the appropriate 
concomitant medication, the Investigator must consider the risk of drug-drug interaction. The 
Medical Monitor must approve all concomitant medications required to treat an AE if there is a 
potential for drug-drug interaction. If necessary, the patient will be withdrawn from the study. 
Study procedures include venous blood sampling and noninvasive procedures, including ECG 
recording, imaging, and vital-sign measurement. During cannulation, more than 1 attempt may 
be needed to insert the cannula in a vein of a patient, and it is possible that bruising and/or 
inflammation may be experienced at the site of cannulation. The total volume of blood collected 
will not exceed 850 mL unless the Investigator or designee considers additional unplanned 
collection(s) are required for safety laboratory tests. 
More information on the risks and benefits of relacorilant is provided in the Investigator’s 
Brochure. 
1.6.1 Study Conduct during COVID-19 Pandemic 
The United States (US) Food and Drug Administration (FDA), as well as the European 
Medicines Agency (EMA), acknowledge the impact of COVID-19 on the health system 
and broader society, and recognize the impact it could have on trials and trial participants 
(FDA 2020, EMA 2020). Both agencies underscore that safety of trial participants is paramount.  
In addition to the risks/potential benefits to trial participation, the added challenges of conducting 
a clinical trial during the time of the public health emergency related to COVID-19 require the 
Sponsor to perform initial and ongoing risk assessment to determine its potential impact on the 
safety and confidentiality/privacy of the trial participant, integrity of the trial, and the benefit of 
the trial for participants and society. 
With regard to Protocol CORT125134-455, Corcept has been working with clinical investigators 
and Institutional Review Boards (IRBs)/Ethics Committees (ECs) on a continuing basis to ensure 
that the patient’s safety, welfare, and rights are best served by participating in this trial. Corcept 
will continue to communicate guidance and provide support to clinical study sites during the 
COVID-19 pandemic. 
• Corcept recognizes that the protocol may require modification to ensure integrity of the 
trial and appropriate safety monitoring are implemented for all enrolled participants. This 
may involve alternative methods for safety and study assessments (i.e., phone contact, 
virtual study visits, use of alternative locations for assessment, including local labs or 
imaging centers, etc.). New processes or modification of protocol-described processes 
may be required, depending on the specific situation. 
• Corcept also recognizes that, depending on the specific situation, treatment with the 
investigational product may be ended or paused.  
• Lastly, Corcept recognizes that if the study cannot be properly conducted under the 
existing protocol, it could be necessary to amend the protocol, stop recruitment, and/or 
withdraw trial participants. 
All decisions will be properly documented. Risk assessment will be made on an ongoing basis.  
As required, information pertaining to protocol modifications (including study visits, remote 
study monitoring, investigational drug supply distribution, etc.) as a result of COVID-19 will be 


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recorded and submitted to Regulatory Agencies and/or IRBs/ECs in accordance with COVID-19 
guidances issued at country level and/or by IRB/EC, unless otherwise requested/required by 
these entities. 
As described in the EMA guideline, “It is expected that the sponsor performs a risk assessment 
of each individual ongoing trial and the investigator of each individual trial participant and 
implement measures, which prioritise trial participant safety and data validity. In case these two 
conflict, trial participant safety always prevails.” 
The following risk assessments and aspects of trial conduct will be considered by Corcept on an 
ongoing basis in conjunction with clinical investigators and IRBs/IECs, as applicable, to ensure 
that the safety of trial participants can be maintained:  
• Whether the limitations imposed by the COVID-19 public health emergency on protocol 
implementation pose new safety risks to trial participants, and whether it is feasible to 
mitigate these risks by amending study processes and/or procedures. 
• Whether there will be continued availability of the clinical investigator/sub-investigators 
to provide oversight of the trial, and properly assess and manage safety issues that may 
emerge. 
• Whether there will be sufficient trial support staff given the evolving COVID-19 
situation, and that staff are appropriately trained and could be available to handle the 
expected tasks, and that they have adequate equipment and materials. 
• Whether clinical investigator sites will remain open to trial participants for required in 
person assessments or whether the clinical investigator has the ability to provide required 
in-person assessments at an acceptable alternate location(s), or whether such protocol-
specified in-person assessments can instead be conducted virtually. 
• Whether there is continued supply of the investigational product and/or trial supplies 
essential to maintaining appropriate safety monitoring or other key trial procedures for 
trial participants. 
• Whether there is continued availability of, and support for, information technology 
systems and any other technological tools needed to support the trial. 
• Whether there will be continued operations of, and adequate communications with, 
IRB/EC, if applicable, to support trial needs. 
• Whether it is feasible to conduct the trial in light of any COVID-19 public health 
measures implemented by Federal/Government, state, and/or local authorities to control 
the virus. 
Depending on the specific situation, additional assessments may be added. Study participants 
will be informed of changes to the study and monitoring plans that could affect them. Processes 
for remote monitoring will include the protection of trial participant data privacy and 
confidentiality. Study participants may choose not to participate in this study or may leave this 
study at any time, without having to give a reason. Study participants will still receive care for 
their condition and will not be penalized or lose any benefits to which they are otherwise 
entitled. They will not lose any rights they are entitled to as a study participant. 
Patients with endogenous Cushing syndrome are immunocompromised due to a direct 
suppressive effect of high cortisol on the bone marrow and immune cells, as well as due to an 
effect on the immune system of the cortisol-excess‒related comorbidities (e.g., diabetes, 


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hypertension, obesity). Patients with Cushing syndrome who remain untreated are at high risk 
for infections from common and uncommon pathogens. Infection is the second most common 
cause of death among patients with overt Cushing syndrome (Dekkers et al. 2013) and in 
patients with milder forms of hypercortisolism due to cortisol-secreting adrenal adenomas 
(Debono et al. 2014). In Study CORT125134-451, in which patients with endogenous Cushing 
syndrome were treated with relacorilant, in the high-dose group, we observed an overall increase 
in the number of lymphocytes (which is often suppressed in this patient population).  
In addition, should a patient in the study become infected with COVID-19, the Investigator 
should consult the Medical Monitor regarding any possible interactions of relacorilant with the 
various treatment options.  


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2 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
• To assess the efficacy of relacorilant for the treatment of endogenous Cushing syndrome 
based on BP control at Week 12 of the Randomized-Withdrawal (RW) phase compared 
with placebo 
• To assess the safety of relacorilant for the treatment of endogenous Cushing syndrome 
2.2 
Secondary Objective 
• To assess changes in cortisol excess-related comorbidities (including DM/IGT, and body 
weight) in patients with endogenous Cushing syndrome treated with relacorilant over the 
RW phase  


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3 
STUDY DESIGN 
3.1 
Overall Design 
This is a Phase 3, double-blind, placebo-controlled, RW study to assess the efficacy, safety, and 
PK of relacorilant in patients with endogenous Cushing syndrome and concurrent DM/IGT 
and/or uncontrolled hypertension (Figure 1). 
Figure 1 
CORT125134-455 Study Design 
 
 
The study phases are as follows: 
3.1.1 Screening Phase  
Up to 6 weeks to determine study eligibility.  
3.1.2 Open-Label Phase (Baseline to Visit OL22) 
Baseline is defined as Day 1 of the OL phase. 
• The starting dose at Baseline will be 100 mg relacorilant once daily for 2 weeks.  
• From Visit OL2 through Visit OL10, the dose of relacorilant will be increased every 
4 weeks by 100 mg, as tolerated and based on improvement in signs and symptoms of 
Cushing syndrome, to a target dose of 400 mg once daily (i.e., to 200 mg at Visit OL2, to 
300 mg at Visit OL6, and to 400 mg at Visit OL10). Clinical benefit in the Open-Label 
Phase will be assessed by the Investigator either by a change from Baseline or change 
from the previous visit considering the following factors:  
– BP measurements and anti-hypertensive medications 


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– Glucose levels and diabetes medication 
– Body weight and waist circumference 
– Cushingoid appearance and striae 
– Sit-to-stand test 
– Beck Depression inventory 
– Cushing Quality-of-Life questionnaire 
• If all symptoms of Cushing syndrome present at Baseline have resolved, no dose 
escalation will occur beyond that visit. 
• If any planned dose escalation is postponed, Visit OL14 can be used for a final dose 
escalation. 
• Faster dose escalation during the open-label phase of the study for patients whose 
Cushing syndrome deteriorates may be allowed with medical monitor approval. 
• If access of patients to the study site is restricted due to the COVID-19 pandemic, dose 
escalation up to 200 mg may occur remotely if necessary. Subsequent dose escalations, 
however, are permitted only after completion of safety assessments. 
• Dose interruption, reduction and re-escalation are permitted for safety/tolerability. 
– The relacorilant dose can be reduced to a previous dose if it is not tolerated 
– Re-escalation after a dose reduction is permitted until Visit OL18. 
3.1.3 Randomized-Withdrawal Phase (Randomization to Visit RW12) 
3.1.3.1 
Response Criteria 
Patients who complete the OL phase and meet the following response criteria for DM/IGT or 
hypertension at Visit OL22 (see below and Section 3.6) will be randomized between Visit OL22 
and up to 2 weeks after that visit in a 1:1 ratio to receive relacorilant or placebo for 12 weeks: 
• Patients with uncontrolled hypertension at Baseline must meet one of the following 
response criteria: 
– ≥5 mm Hg decrease in mean systolic BP (SBP) and/or diastolic BP (DBP) from 
Baseline to Visit OL22, without worsening of either, based on 24-hour ambulatory 
BP monitoring (ABPM) 
Note: Increase of pre-existing blood pressure medication or initiation of new blood 
pressure medication, due to worsening in hypertension, disqualifies the patient from 
randomization into the RW phase. If a decrease in the BP medication occurred after the 
OL18 visit, reassess eligibility for randomization 4 weeks after the dose change. 
• Patients with DM/IGT at Baseline must meet one of the following response criteria: 
In patients with DM 
– HbA1c has decreased by ≥0.5% from Baseline to Visit OL22  
– The 2-hour oGTT glucose is normalized (<140 mg/dL) or decreased by ≥50 mg/dL 
from Baseline to Visit OL22 
– Total daily insulin dose has decreased by ≥25% and HbA1c is unchanged or 
decreased compared with Baseline  


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In patients with IGT 
– The 2-hour oGTT glucose is normalized (<140 mg/dL) from Baseline to Visit OL22 
Note: Increase of pre-existing diabetes medication or initiation of new diabetes 
medication, due to worsening of hyperglycemia, disqualifies the patient from 
randomization into the RW phase. If a decrease in the insulin dose happened after 
Visit OL18, reassess eligibility for randomization 4 weeks after the dose change. 
• Patients with both DM/IGT and uncontrolled hypertension at Baseline who do not 
meet the above-mentioned response criteria for both conditions must meet one of the 
following: 
– Meets one of the DM or IGT response criteria with no worsening in hypertension 
– Meets one of the uncontrolled hypertension response criteria with no worsening in 
DM or IGT 
– Worsening in hypertension is defined as ≥5 mm Hg increase in either systolic BP 
and/or diastolic BP from Baseline to Visit OL22.  
– Worsening in DM is defined as a ≥0.5% increase in HbA1c from Baseline to 
Visit OL22. 
– Worsening in IGT is defined as a ≥50 mg/dL increase in the 2-hour oGTT from 
Baseline to Visit OL22.  
– Patients who meet either the DM/IGT criteria or the uncontrolled hypertension 
criteria will be randomized in the respective strata. 
Note: Increase of pre-existing diabetes or blood pressure medication or initiation of new 
diabetes or blood pressure medication due to worsening hyperglycemia or hypertension, 
disqualifies the patient from randomization into the RW phase. If a decrease in insulin 
dose or BP medication occurred after Visit OL18, reassess eligibility for randomization 
4 weeks after the dose change. 
Randomization will be stratified to ensure balance in treatment assignment for patients that meet 
response criteria within the DM/IGT and hypertension subgroups (Section 9.1). 
Treatment assignment and selected study assessments in the RW phase will remain blinded to the 
Investigators, the Sponsor, and the patients until after database lock. 
No changes in the dose of study drug are allowed during the RW phase. 
3.1.3.2 
Rescue Criteria during Randomized Withdrawal Phase 
2-hour oGTT and ABPM results during the RW Phase will be reviewed by an unblinded Medical 
Monitor to monitor patient safety. The unblinded Medical Monitor is unblinded to results of 
study assessments but is blinded to the treatment assignment. 
• If a patient in the DM/IGT subgroup meets the first two of the following criteria, or if a 
patient in the hypertension subgroup meets the third criterion, the results will be 
communicated to the study site, and rescue medication may be initiated or increased as 
per Section 5.4.2.  
– Fasting glucose increases by 50 mg/dL from visit OL22, AND 


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– 2-hour oGTT glucose increases by 100 mg/dL from Visit OL22 
– Increases in mean SBP or mean DBP by ABPM of more than 10 mm Hg from 
Visit OL22 
Unblinding of the 2-hour oGTT or ABPM results will not result in the unblinding of 
study treatment.  
In the event of rescue medication use before Visit RW12: 
• In patients randomized to the DM/IGT subgroup, oGTT assessments will continue as 
planned until Visit RW12. 
• In patients randomized to the hypertension subgroup, ABPM assessments will continue 
as planned until Visit RW12. 
3.2 
Patient Disposition 
3.2.1 Patient Completion 
• Patients who complete 12 weeks of the RW phase will return for the Follow-Up visit 
28 days after the last dose of study drug. The Follow-Up visit will serve as the last 
study visit.  
• Patients who complete 12 weeks of the RW phase, and entered an extension study within 
28 days of the last dose of study drug, are not required to complete the Follow-Up visit. 
Visit RW12 will serve as the last study visit.  
3.2.2 Early Termination 
• Patients who complete Visit OL22, but do not meet a response criterion for 
randomization, will be instructed to discontinue study drug. The Follow-Up visit will be 
conducted 28 days after the last dose of study drug and will serve as the last study visit.  
• If a patient discontinues early from the OL phase, the patient will complete an Early 
Termination visit at the time of last dose of study drug (or soon thereafter). The 
Follow-Up visit will be conducted 28 days after the last dose of study drug and will serve 
as the last study visit.  
• If a patient discontinues early from the RW phase, the patient will be instructed to return 
for Visit RW12 per the patient’s original dosing schedule as well as for the Follow-Up 
visit 28 days after the last dose of study drug. If RW12 is the return visit following early 
discontinuation from the RW phase, a 3-week visit window (2 weeks before the 
scheduled visit, 1 week after the scheduled visit) for RW12 is permitted. 
• For patients who discontinue the study prior to the RW12 visit during the RW phase of 
the study and return for the RW12 visit, the follow up visit will be waived if the RW12 
visit occurs at least 28 days after the last dose of administration of study drug. 
3.2.3 Treatment Continuation 
• Patients who complete the RW phase of the study will be permitted to continue 
relacorilant treatment in an extension study provided that they have at least 
80% adherence with prescribed dosing (by capsule counts), and are, in the opinion of the 
Investigator, expected to maintain clinical benefit from the study drug. Clinical benefit 


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will be determined by the Investigator based on the changes during the Open-Label Phase 
in the following factors: 
– Hypertension 
– Hyperglycemia 
– Body weight and waist circumference 
– Clinical appearance 
– Sit-to-stand test 
– Psychiatric health and cognitive function 
– Cushing Quality-of-Life (QoL) score 
• Patients who complete the OL phase of the study, but who do not meet a response 
criterion for randomization, will be permitted to continue relacorilant treatment in an 
extension study if, in the opinion of the Investigator, they have benefitted from the study 
drug and are expected to maintain that benefit as noted above. The same adherence rule 
applies. 
• Patients who continue on to the extension study within 28 days of the last dose of study 
drug will not be required to complete the follow-up visit. The last study visit for these 
patients will be either the Visit OL22 (if criterion for randomization is not met) or 
Visit RW12 (if the RW phase was completed).  
3.3 
Number of Patients and Study Participation 
3.3.1 Number of Patients 
Approximately 162 patients are planned to enroll into a 6-month OL phase of the study to ensure 
the randomization of approximately 46 patients with hypertension into the subsequent 3-month, 
placebo-controlled RW phase.  
Study enrollment will be monitored to ensure attainment of randomization targets. The number 
of patients enrolled in the OL phase may be adjusted to ensure a sufficient number of patients 
meeting response criteria to uncontrolled hypertension are randomized in the RW phase. 
Enrollment of patients may continue based on enrollment target projections. 
The sample size calculation is described in Section 9.4. 
3.3.2 Patient Study Participation 
The maximum expected duration of a patient’s participation is 46 weeks, including up to 6 weeks 
for Screening, 22–24 weeks of OL treatment, 12 weeks of double-blind treatment, and a Follow-
up visit 4 weeks after the last dose of study drug. Based on the availability of all data, after the 
OL22 visit, there could be up to 2 weeks until a patient is randomized.  
3.4 
Definitions: End of Treatment and End of Study  
3.4.1 End of Treatment 
The end of treatment is defined as the date on which the patient received his or her last dose of 
study drug, which may be the end of the RW phase or earlier if the patient prematurely 
discontinues. 


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3.4.2 End of Study 
The end of study is defined as the date of last contact (visit, telephone, e-mail) with any study 
patient. Corcept will ensure that the Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) and the regulatory authority(ies) are notified that the study has finished 
according to Corcept’s standard operating procedures and/or local or national regulations. 
3.5 
Study Termination by Sponsor 
If the Sponsor, Investigator, Study Monitor, or regulatory officials discover conditions arising 
during the study that indicate that the study should be halted or that the study site’s participation 
should be terminated, this action may be taken after appropriate consultation between the 
Sponsor and Investigator. Conditions that may warrant termination of the study include, but are 
not limited to, the following: 
• Discovery of an unexpected, serious, or unacceptable risk to the patients enrolled in the 
study. 
• Decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of the product. 
Study termination and follow-up will be performed in compliance with applicable regulations. 
3.6 
Study Endpoints 
Endpoints for both OL and RW phases are listed below. In the RW phase, (1) endpoints related 
to hypertension will be analyzed in those patients who met any response criterion for 
hypertension at Visit OL22; and (2) endpoints related to DM/IGT will be analyzed in those 
patients who met any response criterion for DM/IGT at Visit OL22. 
3.6.1 Primary Endpoints 
The primary efficacy endpoint will be assessed in the RW phase. The study will be considered to 
have a positive outcome if the primary efficacy endpoint reaches statistical significance: 
• In patients with hypertension, the proportion of patients with a loss of response with 
respect to hypertension from Visit OL22 to RW12 based on 24-hour ABPM as compared 
between relacorilant and placebo arms, where loss of response is defined as follows: 
− In patients who met only the SBP response criterion, an increase in SBP ≥5 mm Hg. 
− In patients who met only the DBP response criterion, an increase in DBP by 
≥5 mm Hg. 
− In patients who met both the SBP and DPB response criteria, an increase in either 
SBP or DBP by ≥5 mm Hg. 
− Any increase or modification in antihypertensive medication due to worsening 
hypertension. 
− Patients discontinue treatment in RW phase for any reason. 
• In all patients, assessment of safety based on TEAEs. 


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3.6.2 Secondary Efficacy Endpoints in the Randomized-Withdrawal Phase 
• Loss of response (AUC-based) in DM/IGT subgroup with response at OL22: proportion 
of patients with a loss of response with respect to hyperglycemic control from Visit OL22 
to RW12, as compared between relacorilant and placebo arms, where loss of response is 
defined as a ≥10% increase from baseline in AUCglucose from Visit OL22 to RW12, use of 
rescue medication (initiation or increase in diabetes medication due to worsening of 
hyperglycemic control), treatment discontinuation for any reason in RW phase, or 
patients with missing RW12 AUCglucose values. 
• Mean change from Visit OL22 to RW12 in 24-hour average SBP as compared between 
relacorilant and placebo. 
• Mean change from Visit OL22 to RW12 in 24-hour average DBP as compared between 
relacorilant and placebo. 
• Mean change from Visit OL22 to RW12 in body weight as compared between 
relacorilant and placebo. 
• In patients with DM/IGT, the mean change in AUCglucose from Visit OL22 to RW12 as 
compared between relacorilant and placebo arms. 
• In patients with DM/IGT, the mean change in HbA1c from Visit OL22 to Visit RW12, as 
compared between relacorilant and placebo. 
• Comprehensive loss of response in DM/IGT subgroup with response at OL22: proportion 
of patients with a comprehensive loss of response with respect to hyperglycemic control 
from Visit OL22 to RW12, as compared between relacorilant and placebo arms, where 
the comprehensive loss of response is defined as follows: 
 
In patients with DM: 
– Use of rescue medication (initiation or increase in diabetes medication due to 
worsening of hyperglycemic control), treatment discontinuation for any reason in 
RW phase, or loss to follow-up, 
OR 
– HbA1c has increased by ≥0.3% at Visit RW12 (compared to OL22), 
OR 
– The 2-hour time point of the plasma 2-hours oGTT glucose test at Visit RW12 is 
abnormal (≥140 mg/dL) and has increased by at least 50% of the reduction observed 
between Baseline and Visit OL22. 
In patients with IGT: 
– Use of rescue medication (initiation or increase in diabetes medication due to 
worsening of hyperglycemic control), treatment discontinuation for any reason in 
RW phase, or loss to follow-up, 
OR 
– The 2-hour time point of the plasma 2-hour oGTT glucose test at Visit RW12 is 
abnormal (≥140 mg/dL) and has increased by at least 50% of the reduction observed 
between Baseline and Visit OL22. 


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3.6.3 Exploratory Efficacy Endpoints in the Randomized Withdrawal Phase 
Continuous Endpoints 
• Mean change from Visit OL22 to RW12 in 24-hour average heart rate (HR) as compared 
between relacorilant and placebo (based on ABPM). 
• Mean SBP, DBP, and HR at RW12 (end of dosing interval) as compared between 
relacorilant and placebo (based on ABPM). 
• Mean difference in daytime and nighttime average SBP, DBP, and HR (based on ABPM) 
at Visit RW12 as compared between relacorilant and placebo. 
• Mean change from Visit OL22 to Visit RW12 in body fat composition measured with 
DXA scan as compared between relacorilant and placebo. 
• Mean change from Visit OL22 to Visit RW12 in Cushing Quality-of-Life (QoL) score as 
compared between relacorilant and placebo. 
• In patients with DM (HbA1c at Baseline ≥6.5%), the mean change from Visit OL22 to 
Visit RW12 in HbA1c, as compared between relacorilant and placebo. 
• In patients with IGT at Baseline, the mean change from Visit OL22 to Visit RW12 in the 
2-hour glucose value of the plasma 2-hours oGTT test as compared between relacorilant 
and placebo arms. 
• The mean change from Visit OL22 to RW12 as compared between relacorilant and 
placebo in the following: waist circumference; lean mass measured by DXA; serum 
osteocalcin; the Beck Depression Inventory®-II (BDI-II) score; sit-to-stand test score; 
trail-making test score; sex-hormone levels (estradiol, total and free testosterone, 
sex-hormone‒binding globulin, follicle-stimulating hormone, and luteinizing hormone); 
FKBP5 and other potential biomarkers of GR activity; urinary free cortisol (UFC), 
late-night salivary cortisol and plasma adrenocorticotropic hormone (ACTH); AUCinsulin, 
Matsuda Index, homeostatic model assessment of insulin resistance (HOMA IR), and 
daytime and nocturnal average blood pressure. 
• In patients with adrenal CS, the mean change in the ACTH levels from Visit OL22 to 
RW12 as compared between relacorilant and placebo. 
Endpoints Summarized with Proportions 
• For patients in the hypertension subgroup, the proportion of patients with any increase 
or modification in antihypertensive medication due to worsening hypertension from 
Visit OL22 to Visit RW12 as compared between relacorilant and placebo. 
• Proportion of patients who worsened, as assessed by the Global Clinical Response from 
Visit OL22 to Visit RW12 (i.e., a score of –1 at Visit RW12 as compared with 
Visit OL22). 
• For patients in the DM/IGT subgroup, the proportion of patients with any increase in 
dose of diabetes medication from Visit OL22 to Visit RW12 as compared between 
relacorilant and placebo. 
• For patients in the DM subgroup, the proportion of patients who achieve 25% reduction 
in AUCglucose from Baseline OL to Visit RW12 as compared between relacorilant and 
placebo. 
• In all patients randomized in the RW phase, proportion of patients with a loss of response 
with respect to hypertension or hyperglycemia from Visit OL22 to Visit RW12 based on 


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24-hour ABPM and AUCglucose as compared between relacorilant and placebo arms, 
where loss of response is defined as follows: 
– In patients with hypertension only at Baseline OL: 
 In patients who met only the SBP response criterion, an increase in SBP 
≥5 mm Hg. 
 In patients who met only the DBP response criterion, an increase in DBP by 
≥5 mm Hg. 
 In patients who met both the SBP and DBP response criteria, an increase in either 
SBP or DBP by ≥5 mm Hg. 
 Any increase or modification in antihypertensive medication due to worsening 
hypertension. 
 Patients discontinue treatment in RW phase for any reason. 
– In patients with DM/IGT only at Baseline OL: 
 A ≥10% increase from Baseline RW in AUCglucose.from Visit OL22 to 
Visit RW12 
 Use of rescue medication (initiation or increase in diabetes medication due to 
worsening of hyperglycemic control). 
 Treatment discontinuation for any reason in RW phase. 
 Patients with missing RW12 AUCglucose values. 
– In patients with hypertension and DM/IGT at Baseline OL, a loss of response will be 
defined as a loss of response with respect to either hypertension or hyperglycemic 
control (AUC-based) from Visit OL22 to Visit RW12, irrespective of which response 
criteria (hypertension or DM/IGT) they met to enter the RW phase. 
3.6.4 Exploratory Efficacy Endpoints in the Open-Label Phase 
Continuous Endpoints 
• In patients with uncontrolled hypertension, the mean change in SBP from Baseline to 
Visit OL22/ET. 
• In patients with uncontrolled hypertension, the mean change in DBP from Baseline to 
Visit OL22/ET. 
• Mean change in Cushing Quality-of-Life (QoL) score from Baseline to Visit OL22. 
• Mean change in body-fat composition from Baseline to Visit OL22/ET, as determined by 
DXA. 
• Mean change in the Beck Depression Inventory®-II (BDI-II) score from Baseline to 
Visit OL22/ET. 
• Mean change in body weight from Baseline to Visit OL22/ET. 
• In patients with IGT, the mean change in 2-hour oGTT glucose from Baseline to 
Visit OL22/ET. 
• In patients with DM (HbA1c ≥6.5% at Baseline), the mean change in HbA1c from 
Baseline to Visit OL22/ET. 
• In patients with DM/IGT, the mean change in AUCglucose from Baseline to 
Visit OL22/ET. 


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• The mean change from Baseline to Visit OL22/ET in the following: waist circumference; 
lean mass measured by DXA; serum osteocalcin; the Beck Depression Inventory®-II 
(BDI-II) score; sit-to-stand test score; trail-making test score; sex-hormone levels 
(estradiol, total and free testosterone, sex-hormone‒binding globulin, follicle-stimulating 
hormone, and luteinizing hormone); FKBP5 and other potential biomarkers of GR 
activity; urinary free cortisol (UFC), late-night salivary cortisol and plasma 
adrenocorticotropic hormone (ACTH); AUCinsulin, Matsuda Index, homeostatic model 
assessment of insulin resistance (HOMA IR), and daytime and nocturnal average blood 
pressure. 
• In patients with adrenal Cushing syndrome (CS), the mean change in ACTH levels from 
Baseline to Visit OL22/ET. 
Endpoints Summarized with Proportions 
• In patients with hypertension, the proportion of patients who meet any of the 
hypertension response criteria at Visit OL22/ET. 
• In patients with hypertension, the proportion of patients with reduction or discontinuation 
of antihypertensive medications from Baseline to Visit OL22/ET. 
• The proportion of patients with a positive Global Clinical Response score at 
Visit OL22/ET. 
• In patients with DM/IGT, the proportion of patients who meet any of the DM/IGT 
response criteria at Visit OL22/ET. 
• In patients with IGT, the proportion of patients who achieved normalization of glucose 
based on the plasma 2-hours oGTT test and/or a reduction in the 2-hour glucose by 
50 mg/dL from Baseline to Visit OL22/ET. 
• In patients with DM (HbA1c ≥6.5% at Baseline), the proportion of patients with any 
decrease in dose of diabetes medication from Baseline to Visit OL22/ET. 
• The proportion of patients meeting any DM/IGT or hypertension response criterion at 
Visit OL22/ET by dose at which response was first reached. 
• In patients with DM/IGT, the proportion of patients with ≥25% decrease in AUCglucose 
from Baseline to Visit OL22/ET.  
• In patients with DM/IGT, the proportion of patients with ≥0.5% decrease in HbA1c from 
Baseline to Visit OL22/ET. 
3.6.5 Exploratory Pharmacokinetic Endpoints 
• In patients with endogenous Cushing syndrome, the steady-state plasma exposures of 
relacorilant (additional details will be summarized in the PK Analysis Plan). 


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4 
STUDY POPULATION 
This study includes patients with endogenous Cushing syndrome and associated DM/IGT and/or 
uncontrolled hypertension. 
The following eligibility criteria are designed to select patients for whom treatment with 
relacorilant is considered appropriate. All relevant medical and nonmedical conditions will be 
taken into consideration when deciding whether treatment with relacorilant is suitable for a 
particular patient.  
Possible etiologies of Cushing syndrome include Cushing disease, ectopic ACTH-secreting, 
ectopic corticotropin releasing hormone-secreting tumors, adrenal cortisol-secreting adenomas, 
adrenocortical carcinoma, primary pigmented nodular adrenal disease, and primary 
macronodular adrenal hyperplasia. 
4.1 
Inclusion Criteria 
Each patient must meet all of the following criteria to be enrolled in the study: 
Inclusion Criteria 
To enroll in the study, each patient must meet the following key inclusion criteria: 
1. Male or female, 18 to 80 years of age, inclusive. 
2. Has a confirmed biochemical diagnosis of endogenous Cushing syndrome based on the 
presence of at least 2 of the following (Nieman et al. 2008):  
• UFC >upper limit of normal (ULN) in at least 2 complete 24-hour tests within the  
screening window.  
• Late night salivary cortisol >ULN in at least 2 tests (using a salivette) within the  
screening window (Note: Test is not appropriate for night-shift workers and cannot be 
used to evaluate eligibility).  
• Lack of cortisol suppression (>1.8 μg/dL serum cortisol) on either 1mg overnight or 2 mg 
48-hour dexamethasone suppression testing during Screening, or within 12 weeks before 
signing the informed consent. 
3. Has at least 2 of the following clinical signs and symptoms of Cushing syndrome: 
• Bodily characteristics of a Cushingoid appearance (e.g., facial rubor, moon facies, 
dorsocervical fat pad, supraclavicular fat pad). 
• Increased body weight or central obesity. 
• Proximal muscle weakness. 
• Low bone mass based on DXA scan. 
• Psychiatric symptoms (including depression or psychosis). 
• Skin manifestations: violaceous striae, acne, and/or hirsutism. 
• Easy bruisability. 
4. Has at least 1 of the following at Baseline: 


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• DM (fasting plasma glucose ≥126 mg/dL and/or 2-hour oGTT plasma glucose 
≥200 mg/dL at 2 hours or HbA1c ≥6.5%), or IGT (plasma glucose ≥140 mg/dL and 
<200 mg/dL on a 2-hour oGTT glucose) (American Diabetes Association 2020).  
• Uncontrolled hypertension (mean SBP ≥135 to ≤170 mm Hg and/or mean DBP ≥85 to 
≤110 mm Hg) based on 24hour ABPM (Parati et al. 2014). 
5. If receiving medical treatment for DM/IGT or hypertension, there has been no increase in 
medication dosage for at least 4 weeks prior to Baseline assessment. 
6. If receiving medical treatment for depression, there has been no increase in medication 
dosage for at least 6 weeks prior to Baseline. 
7. For women of childbearing potential, has a negative serum pregnancy test at Screening and 
negative urine pregnancy test at Baseline. 
4.2 
Exclusion Criteria 
Patients who meet any of the following criteria will not be permitted entry to the study: 
1. Has severe, uncontrolled hypertension (mean SBP >170 mm Hg or mean DBP >110 mg at 
Screening), based on 24-hour ABPM. 
2. Has poorly controlled DM (HbA1c >12% at Screening). 
3. Has a known “long term” history of both hypertension and diabetes (defined as both 
hypertension and diabetes diagnosed >10 years prior to the initial diagnosis of 
endogenous CS). 
4. Has a history of cyclic Cushing’s syndrome with fluctuating clinical manifestations. 
5. Has DM Type 1. 
6. Has abnormal liver test results (total bilirubin >1.5×ULN or elevated alanine 
aminotransferase or aspartate aminotransferase >3×ULN at Baseline). 
7. Has severe renal insufficiency (glomerular filtration rate ≤29 mL/min at Baseline). 
8. Has uncontrolled, clinically significant hypothyroidism or hyperthyroidism. 
9. Has prolonged QT interval corrected for heart rate using Fridericia’s equation (QTcF) 
(>450 ms for men and >470 ms for women) with normal QRS interval (<120 ms) or QTcF 
interval >500 ms with wide QRS interval (≥120 ms). 
10. Has received stereotactic radiation therapy for a Cushing syndrome-related tumor within 
24 months of Baseline or conventional pituitary radiation therapy within 36 months of 
Baseline. 
11. Has undergone pituitary surgery <3 months prior to Screening. 
12. Has used or plans to use any of the following treatments for Cushing syndrome within 
4 weeks prior to Baseline: 
• Mifepristone 
• Adrenostatic medications: metyrapone, osilodrostat, ketoconazole, fluconazole, 
aminoglutethimide, or etomidate 


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• Serotonin antagonists: cyproheptadine, ketanserin, or ritanserin  
• Dopamine agonists: bromocriptine or cabergoline  
• Gammaaminobutyric acid agonists: sodium valproate 
• Short-acting somatostatin analogs: octreotide, lanreotide, or pasireotide. 
13. Has used or plans to use somatostatin receptor ligands: long-acting octreotide or pasireotide 
within 8 weeks prior to Baseline. 
14. Patients who require inhaled glucocorticoid use and have no alternative option if their 
condition deteriorates during the study. 
15. Has adrenocortical carcinoma.  
16. Has used mitotane prior to Baseline.  
17. Has ectopic Cushing syndrome and a life expectancy of <3 years or receiving chemotherapy.  
18. Has pseudo-Cushing syndrome. Patients with known or suspected pseudo-Cushing 
syndrome based on medical history (such as patients with severe obesity, major depression, 
or a history of alcoholism) should undergo a dexamethasone-CRH DDAVP stimulation test 
(Yanovski et al. 1993, Giraldi et al. 2007, Yanovski et al. 1998) to rule-in or rule-out this 
possibility. 
19. Has taken any investigational drug within 4 weeks prior to Baseline, or within less than 
5 times the drug’s half-life, whichever is longer. 
20. Ongoing use of antidiabetic, antihypertensive, antidepressant, or lipid-lowering medications 
that are highly dependent on CYP3A for clearance and that cannot undergo dose 
modification upon coadministration with strong CYP3A inhibitors. 
21. Ongoing use of any strong CYP3A4 inducer or any other prohibited medications 
(Section 5.4.4). 
22. Is pregnant or lactating. 
23. Is a female patient 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) who cannot use a highly effective method of 
contraception (Section 4.6.2). 
24. Has an acute or unstable medical problem that could be aggravated by treatment with the 
investigational study drug. 
25. Has a history of hypersensitivity or severe reaction to the study drug, to a similar class of 
drug, or to the study drug’s excipient. 
26. In the Investigator’s opinion, should not participate in the study or may not be capable of 
following the study schedule. 
27. Has known HIV or hepatitis B or C infection. 
28. Is a family member of one of the Sponsor’s employees, the Investigator, or the site staff 
directly working on the study. 
29. Has a history of unexplained vaginal bleeding or unexplained endometrial abnormalities. 


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4.3 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study but are not 
subsequently entered in the study.  
Patients who fail Screening due to a laboratory result may be retested within the Screening 
period without prior Corcept approval. Other laboratory tests, not directly impacting patient 
eligibility, during the Screening period may be repeated at the Investigator’s discretion. The 
24-hour ABPM may be repeated if there is a technical problem with the test. 
Whenever patients are rescreened, they must sign an informed consent form (ICF) each time. 
The Screening assessments that do not need to be repeated during rescreening are the 2-hour 
oGTT glucose (if performed within 2 weeks of the Baseline Visit) and the dexamethasone 
suppression test (if performed within 12 weeks of consent). 
4.4 
Early Patient Discontinuation or Withdrawal  
Patients may withdraw their consent to participate in the study at any time for any reason without 
prejudice. The Investigator should make a reasonable attempt to document the specific reason 
why consent is withdrawn. 
The Investigator also has the right to withdraw patients from the study for the following reasons: 
The Investigator decides it is in the patient’s best interest to discontinue study drug and/or 
participation in the study. Reasons may include, but are not limited to, the patient requiring or 
starting a prohibited medication(s), or not adhering to protocol procedures. 
• The patient experiences an AE or any of the special safety events outlined in Table 2, 
Section 5.3.1 that the Investigator believes requires withdrawal from the study. 
• Patient becomes 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. 
• Patients whose Cushing syndrome deteriorates during the open-label phase of the study 
on the maximum tolerated dose of relacorilant. 
• Patients whose Cushing syndrome deteriorates significantly during the RW phase and 
cannot be controlled with symptomatic management of the comorbidities until the 
RW12 visit. 
Patients who discontinue study drug early should be encouraged to complete the 
end-of-treatment and follow-up assessments and to report any AEs, including SAEs, for 28 days 
after the last administration of study drug. The date when the patient discontinues study drug and 
the reason for discontinuation must be recorded on the electronic case report form (eCRF).  
For patients who withdraw consent to participate in the study, every effort should be made to 
determine whether the withdrawal of consent was related to an AE or a specific aspect of the 
study. If a patient wishes to withdraw consent to further participation in the study entirely—
including follow-up, this should be clearly documented (1) in the patient’s medical record and 
signed by the Investigator and (2) in the eCRF. 


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Before a patient is determined to be lost to follow-up, reasonable efforts (i.e., 3 documented 
attempts) will be made to contact the patient and complete study termination procedures. 
For guidelines about temporary interruption of study drug or study-drug modifications, see 
Section 5.3. 
4.5 
Replacement of Patients 
The proportion of patients who complete the OL phase and are randomized in the RW phase will 
be reviewed periodically. To maintain sufficient power to detect treatment difference, the 
number of patients enrolled in the OL phase may be adjusted to ensure a sufficient number of 
patients meeting response criteria to DM/IGT and/or uncontrolled hypertension are randomized 
in RW phase. 
4.6 
Restrictions During Study 
The following restrictions apply to patients in this study (prohibited medications are described in 
Section 5.4.4). 
4.6.1 Dietary Restrictions 
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. Each dose should be taken with 240 mL water. 
Patients must abstain from grapefruit, grapefruit juice, or grapefruit-containing products during 
the study. 
4.6.2 Contraception 
All female patients of childbearing potential (including all women <50 years old, women whose 
surgical sterilization was performed <6 months ago, and women who have had a menstrual 
period in the last 2 years) will take pregnancy tests at every visit from Screening through 
Follow-up. The Screening pregnancy test will be a blood test. All subsequent pregnancy tests 
will be urine tests. 
Female patients of 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 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 (e.g., male condom or a diaphragm plus a vaginal spermicidal 
cream) 


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If a patient is usually not sexually active but becomes active, they, with their partner, must 
comply with the contraceptive requirements detailed above. In addition, male patients should not 
donate sperm until 30 days after the last dose of study drug.  
4.6.3 Radiation Therapy and Radiation Surgery 
Patients may not undergo conventional pituitary radiation therapy or stereotactic pituitary 
radiation therapy (e.g., gamma knife radiosurgery) during the study.  


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5 
STUDY TREATMENTS AND MANAGEMENT 
Study drug is defined as relacorilant (during the OL phase) and relacorilant or placebo 
(RW phase). 
5.1 
Study Drug and Placebo 
Relacorilant and placebo equivalent, including dose and regimen, formulation, packaging, and 
storage, are described in Table 1.  
Table 1 
Study Drug and Placebo: Formulation, Administration, Packaging, 
and Storage 
 
Study Drug and Placebo 
Specifications 
Relacorilant 
Placebo 
Description  
For each capsule, relacorilant is prepared 
as a 
 
 
  
The placebo for relacorilant capsule is 
designed to match the study drug in 
appearance. Each placebo capsule 
contains a formulation of 
 
  
Supplied 
Capsules, 30-count in a white bottle with 
induction seal and child-resistant closure 
and labeled as required per country 
requirement. 
Capsules, 30-count in a white bottle with 
induction seal and child-resistant closure 
and labeled as required per country 
requirement. 
Appearance 
Yellow, oblong, 
capsules 
Yellow, oblong 
 capsules 
Unit dose strength 
100 mg relacorilant/capsule 
Placebo equivalent 
Dose levels 
100, 200, 300, or 400 mg 
Placebo equivalent 
Administration  
Orally, with 240 mL of water under fasted 
conditions 
Orally, with 240 mL of water under fasted 
conditions 
Regimen 
1–4 capsules, once daily 
1–4 capsules, once daily 
Restrictions 
Refer to Section 4.6.1  
Refer to Section 4.6.1 
Dispensing study drug 
Dispense to patients at the visits specified 
in Appendix A  
Dispense to patients at the visits specified 
in Appendix A  
Storage 
Store as follows:  
• 
In a secure location 
• 
At 
, 
excursions permitted 
 
 
• 
Out of reach and sight of children 
Store as follows:  
• 
In a secure location 
• 
At 
 
excursions permitted 
 
 
• 
Out of reach and sight of children 
Note: Procedures for inventory, reconciliation, and destruction or return of study drug are provided in Section 11.5. 


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5.2 
Dose-Escalation Process 
• The starting dose at Baseline will be 100 mg relacorilant once daily for 2 weeks.  
During dose escalation, all patients will be escalated in a stepwise manner from 100 mg to 
400 mg once daily, based on tolerability and improvement in hypertension and/or 
hyperglycemia. The starting dose at Baseline will be 100 mg relacorilant once daily for 2 weeks, 
after which the dose will be increased to 200 mg. Then the dose will increase in 100 mg 
increments every 4 weeks. Dose escalation will be performed based on tolerability considering 
the following factors (only in patients whose current dose is well tolerated). 
In patients with hypertension only, the mean 24-hour BP (based on ABPM): 
• SBP is ≥130 mm Hg or 
• SBP is <130 mm Hg and has not decreased by ≥5 mm Hg from Baseline. 
• DBP is ≥80 mm Hg or 
• DBP is <80 mm Hg and has not decreased by ≥5 mm Hg from Baseline. 
In patients with DM/IGT only, the 2-hour glucose based on oGTT: 
Note: For visit OL2, the fasting glucose assessment from the Chemistry laboratory panel will 
be used for dose escalation purposes. 
• is ≥140 mg/dL or fasting glucose is >100 mg/dL or 
• is <140 mg/dL and has not decreased by ≥30 mg/dL from Baseline. 
In patients with both DM/IGT and hypertension: 
The mean 24-hour BP (based on ABPM): 
• SBP is ≥130 mm Hg or 
• SBP is <130 mm Hg and has not decreased by ≥5 mm Hg from Baseline. 
• DBP is ≥80 mm Hg or 
• DBP is <80 mm Hg and has not decreased by ≥5 mm Hg from Baseline. 
AND 
• is ≥140 mg/dL or fasting glucose is >100 mg/dL or 
• is <140 mg/dL and has not decreased by ≥30 mg/dL from Baseline.  
• Dose escalation may be held if the patient cannot safely tolerate escalation to the next 
dose.  
• Faster dose escalation for patients whose Cushing syndrome deteriorates during the study 
may be allowed on a case-by-case basis after discussion and approval by the medical 
monitor. 
• If any planned dose escalation is postponed, Visit OL14 can be used for a final dose 
escalation. 
• If access of patients to the study site is restricted due to the COVID-19 pandemic, dose 
escalation up to 200 mg may occur remotely if necessary. Subsequent dose escalations, 
however, are permitted only after completion of safety assessments. 
• Dose escalations start the day after the Visit at which they are approved by the 
Investigator. 


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• After normalization of hypertension and/or hyperglycemia, further dose escalation will be 
allowed considering the following factors: 
• Body weight and waist circumference  
• Cushingoid appearance and striae 
• Sit-to-stand test 
• Beck Depression inventory 
• Cushing Quality-of-Life questionnaire 
• If all symptoms of Cushing syndrome present at Baseline have resolved, no dose 
escalation will occur beyond that visit 
5.3 
Dose Modifications 
Every effort should be made to administer study drug on the planned dose and schedule.  
Dose interruption, or reduction and re-escalation, are permitted for safety/tolerability, as follows: 
• Dose interruptions or reductions may occur at any time, including between visits, during 
the OL phase.  
• No changes in the dose of study drug are allowed during the RW phase. 
• Re-escalation after a dose reduction is permitted, with the approval of the Medical 
Monitor, until Visit OL18 (so that the OL period ends on a stable dose). 
• During study-drug interruptions, patients will continue on the same visit schedule.  
Dose reductions to manage excessive GR antagonism are outlined in Section 5.3.1. 
5.3.1 Dose Interruption and/or Discontinuation: Special Safety Events 
Based on the mechanism of action of relacorilant, there is a theoretical risk of excessive GR 
antagonism, which could manifest with findings such as weakness, tiredness, dizziness, 
hypoglycemia, dehydration, weight loss, nausea, vomiting, diarrhea, or muscle aches. Because 
relacorilant does not affect the mineralocorticoid receptor, it is unlikely that hypotension would 
occur in the absence of antihypertensive medication. 
The actions outlined in Table 2 should be taken if a patient: 
• Exhibits signs and symptoms of excessive GR antagonism. 
• Experiences significant trauma, surgery, or medical illness occurring at any time during 
the study (through 2 weeks after last dose). 
At study enrollment, all patients will be given a card to carry with them that identifies their 
potential risk for excessive GR antagonism. The card will contain the following information: 
• Mention use of relacorilant (“glucocorticoid receptor antagonist”). 
• Potential need for glucocorticoid use in setting of shock, surgery, serious illness, or 
injury. 
• Recommended dose of replacement steroids (4 to 10 mg dexamethasone intramuscularly 
or intravenously). 
• Investigator contact information. 
 


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Table 2 
Criteria for Dose Modification or Discontinuation Due to Special Safety Events (Until Visit OL18) 
 
Criteria for Interrupting and Restarting or Modifying Study Drug and Patient Management 
Criteria for Stopping 
Study Treatment 
Excessive GR 
antagonism 
Criteria: Signs and symptoms of excessive GR antagonism 
Management:  
• Immediately interrupt relacorilant treatment for at least 3 days and start standard supportive care, 
including fluid resuscitation, as indicated. 
• If appropriate, administer supplemental glucocorticoids given in high doses to overcome the GR 
antagonism produced by relacorilant. Initially, consider parenteral dexamethasone (4 to 10 mg), 
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, consider 
discontinuing it or adjusting the dose, particularly in the presence of hypotension. 
• Restart relacorilant treatment only if the potential benefits outweigh the risks and after a 
discussion with the Medical Monitor.  
­ 
Restart relacorilant at the lowest tolerable dose previously administered to the patient.  
­ 
After 2 weeks, resume the current dose or increase by 100 mg with the approval of the 
Medical Monitor.  
A combination of at least 2 
of the following Grade 3 or 
higher events can lead to 
stopping/reducing dose: 
fatigue, anorexia, 
nausea/vomitinga 
(associated with decreased 
oral intake), or abdominal 
pain, seen either at the 
200-mg dose level or at 
other dose levels for which 
the Investigator deems 
dose reduction is not an 
option. 
Significant trauma, 
surgery, or medical 
illness at any time 
during the study 
(through 2 weeks after 
last dose) 
Management: 
• As medically indicated, interrupt relacorilant treatment and provide supplemental glucocorticoids 
to offset the glucocorticoid receptor antagonism even in patients not experiencing signs and 
symptoms of excessive antagonism.  
• After resolution of the physiological stress associated with the event and if still within the 
Treatment Period, resume relacorilant at the last dose level the patient was receiving before 
interruption. 
 
GR, glucocorticoid receptor. 
a For the purpose of this assessment, nausea and vomiting are considered 1 criterion. 
 


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In the event of study-drug discontinuation before Visit RW12: 
• In patients randomized to the DM/IGT subgroup, oGTT assessments will continue as 
planned until Visit RW12. 
• In patients randomized to the hypertension subgroup, ABPM assessments will continue 
as planned until Visit RW12. 
5.4 
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, and/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 drug on Day 1 and ending at the Follow-up Visit. 
Medications that the patient started and ended before the first dose of study drug will be noted as 
prior medications.  
Patients are prohibited from taking antidiabetic, antihypertensive, antidepressant and/or 
lipid-lowering medications that are highly dependent on CYP3A for clearance and cannot 
undergo dose modifications on coadministration with strong CYP3A inhibitors. For example, the 
FDA provides a current list of Substrates, Inhibitors and Inducers of CYP3A at the following 
website.  
https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteracti
onslabeling/ucm093664.htm#table4-1 
The list may not be inclusive of all currently available Substrates, Inhibitors and Inducers of 
CYP3A worldwide. The Investigator should contact the Medical Monitor with any questions.  
Patients on such medications at Screening will need to be switched to an alternative antidiabetic, 
antihypertensive, antidepressant, or lipid-lowering medications and be on a stable dose of the 
alternative medication for at least 4 weeks to be eligible to participate in this study. 
Information about concomitant medications will be collected from all patients at each visit from 
Screening through the Follow-up Visit. If access of patients to the study site is restricted due to 
the COVID-19 pandemic, a review of concomitant medications may involve alternative methods 
(e.g., phone contact or virtual study visits). Any changes in medications since the last visit will 
be captured and recorded.  
Efficacy assessments include the total daily dose of insulin for patients with DM/IGT and 
antihypertensive medications for patients with uncontrolled hypertension. 
5.4.1 Rules for Antidiabetic and Antihypertensive Medication Use During the 
Open-Label Phase 
In patients with DM/IGT at Baseline: 
• Medication for control of blood glucose should be maintained at a stable dose. 


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• Patients should not take antidiabetic medications before the oGTT; they may be taken 
with food after the oGTT. Long-acting insulin may be taken the prior evening. 
• Reduction or discontinuation of insulin and insulin secretagogues should be considered 
only if fasting or postprandial blood glucose is <70 mg/dL on at least 2 home 
measurements or 1 serum glucose measurement associated with symptoms of 
hypoglycemia. 
– For basal and prandial insulin, consider decreasing dosage by 20%. 
– For insulin secretagogues, consider decreasing dosage by 50%; discontinue if 
recurrent. 
– Reductions of insulin and/or insulin secretagogues can be adjusted depending on the 
degree of hypoglycemia and the current total dose of insulin. 
• In patients with hypoglycemia unawareness, changes in insulin and insulin secretagogues 
should be considered if fasting or postprandial glucose is <70 mg/dL on at least 2 home 
measurements or 1 serum glucose measurement.  
• If any modification of existing diabetes medications, or initiation of new diabetes 
medication is being considered, a 2-hour oGTT glucose should be obtained prior to 
modification of medications. 
In patients with uncontrolled hypertension at Baseline: 
• Antihypertensive medications should be maintained at a stable dose. 
• Reduction or discontinuation should be considered only if: 
– Blood pressure decreases below 100 mm Hg systolic or 60 mm Hg diastolic 
by ABPM 
– Symptoms of hypotension (including orthostatic hypotension) occur. 
• In patients in whom a reduction or discontinuation of antihypertensive medication is 
being considered, an ABPM should be performed prior to modification of medications. 
The measurement from the last ABPM prior to dose modification will be used in the 
primary study analysis. 
5.4.2 Rules for Antidiabetic and Antihypertensive Medication Use During the 
Randomized-Withdrawal Phase 
In patients with DM/IGT at Baseline: 
• Medication for control of blood glucose should be maintained at a stable dose. 
• Patients should not take antidiabetic medications before the oGTT; they may be taken 
with food after the oGTT. Long-acting insulin may be taken the prior evening. 
• Reduction or discontinuation of insulin and insulin secretagogues should be considered 
only if fasting or postprandial blood glucose <70 mg/dL on at least 2 home measurements 
or 1 serum glucose measurement associated with symptoms of hypoglycemia 
– For basal and prandial insulin, consider decreasing dosage by 20%. 
– For insulin secretagogues, consider decreasing dosage by 50%; discontinue if 
recurrent. 
– Reductions of insulin and/or insulin secretagogues can be adjusted depending on the 
degree of hypoglycemia and the current total dose of insulin. 


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• In patients with hypoglycemia unawareness, changes in insulin and insulin secretagogues 
should be considered if fasting or postprandial glucose is <70 mg/dL on at least 2 home 
measurements or 1 serum glucose measurement. 
• If any modification of existing diabetes medications or initiation of new diabetes 
medication is being considered, a 2-hour oGTT glucose should be obtained prior to 
modification of medications. 
• The unblinded Medical Monitor will notify the site if fasting or postprandial values from 
the 2-hour oGTT are below 70 mg/dL. Unblinding of fasting or postprandial glucose 
from the 2-hour oGTT will not result in the unblinding of study treatment. 
Rescue criteria during the RW phase  
• 2-hour oGTT results during the RW Phase will be reviewed by an unblinded Medical 
Monitor to monitor patient safety.  
– If a patient meets the following criteria, the results will be communicated to the study 
site, and rescue medication may be initiated or increased.  
 Fasting glucose increases by 50 mg/dL from visit OL22, AND 
 2-hour oGTT glucose increases by 100 mg/dL from Visit OL22 
• Unblinding of the 2-hour oGTT will not result in the unblinding of study treatment.  
• If antidiabetic medication is increased or initiated during the RW phase, oGTTs will be 
performed up to RW12 visit. 
In patients with uncontrolled hypertension at Baseline: 
• Antihypertensive medications should be maintained at a stable dose. 
• Reduction or discontinuation of antihypertensive medications should be considered 
only if: 
– Blood pressure decreases below 100 mm Hg systolic or 60 mm Hg diastolic by office 
measurement on at least two measurements obtained 15 min apart with symptoms of 
orthostatic hypotension. 
– Symptoms of hypotension (including orthostatic hypotension) occur  
• The unblinded Medical Monitor will notify the site if BP decreases below 100 mm Hg 
mean SBP or 60 mm Hg mean diastolic by ABPM. 
• Unblinding of ABPM results will not result in the unblinding of study treatment. 
• If any modification of existing antihypertensive medication or initiation of new 
antihypertensive medication is being considered, an ABPM should be performed prior to 
modification of medications.  
Rescue criterion during the RW phase  
• ABPM results during the RW Phase will be reviewed by an unblinded Medical Monitor 
to monitor patient safety.  
– If a patient meets the following criterion, the results will be communicated to the 
study site, and rescue medication may be initiated or increased.  
 Increases in mean SBP or mean DBP by ABPM of more than 10 mm Hg from 
Visit OL22. 
• Unblinding of ABPM results will not result in the unblinding of study treatment.  


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• If antihypertensive medication is increased or initiated during the RW phase, ABPM tests 
will be performed up to RW12 visit. 
5.4.3 Rules for Other Permitted Concomitant Medications 
• Lipid-lowering drugs: No increases in dose are allowed from 4 weeks before Baseline 
through the Follow-up Visit, unless clinically necessary. 
• Antidepressant drugs: No increases in dose are allowed from 6 weeks before Baseline 
through the end of study-drug dosing, unless clinically necessary. 
5.4.4 Prohibited Medications 
Relacorilant is a strong inhibitor of CYP3A. Medications that are highly dependent on CYP3A 
for clearance for which elevated plasma concentrations are associated with SAEs and for which 
dose modification is not an option with strong CYP3A inhibitors should be avoided (consult the 
prescribing information of the respective concomitant medications for further details). 
Additionally, the following medications used in the treatment of Cushing syndrome are 
prohibited during treatment with study drug in this study: 
• Adrenostatic medications: metyrapone, osilodrostat, ketoconazole, fluconazole, 
aminoglutethimide, mitotane, 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, octreotide long-acting release, pasireotide, pasireotide long-acting release, 
lanreotide), and mifepristone. 
• Strong CYP3A inducers.  
• Antidiabetic, antihypertensive, antidepressant, and/or lipid-lowering medications that are 
highly dependent on CYP3A for clearance and cannot undergo dose modifications upon 
coadministration with strong CYP3A inhibitors. 
• Systemic corticosteroids [with exception of temporary use for treatment of excessive GR 
antagonism], potent (group III) topical corticosteroids in extended body surface areas, 
and intra-articular corticosteroids unless other treatment options fail/contraindicated. 
• Other investigational agents. 
5.5 
Method of Treatment Assignment and Randomization 
At the Randomization visit, patients meeting response criteria described in Section 3.1 will be 
randomized 1:1 to continue their dose of relacorilant from the OL phase or to receive placebo. 
Patients switched to placebo will continue taking the same number of capsules per dose. 
Randomization of patients will be stratified by one factor (i.e., response at Visit OL22) with 
3 levels:  
• Response by DM/IGT criteria only  
• Response by hypertension criteria only  
• Response by DM/IGT and hypertension criteria 




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5.7 
Dosing Diary 
A dosing diary will be dispensed at the time points specified in Appendix A for patients to record 
each self-administered dose of study drug and any concomitant medications. Entries should 
include the number of capsules as well as the date and time of study-drug administration. Time 
and dose administered should be documented in the clinic charts. 
Patients will be instructed to return all unused study drug and the dosing diary at the patient 
visits. 
5.8 
Product Accountability and Treatment Adherence  
Study drug will be dispensed to each patient at applicable visits as outlined in the schedule of 
assessments. Sufficient study drug will be provided for the period between study visits. To 
mitigate the potential of patients not being able to return for scheduled study visits due to the 
COVID-19 pandemic, additional study drug may be dispensed. 
The Investigator is responsible for the accountability of all used and unused study drug. All 
investigational materials should be kept in a secure area inaccessible to unauthorized individuals. 
Drug accountability records must be maintained at the site and be available for monitoring by the 
Sponsor or its representatives. At a minimum, records will be maintained to document receipt of 
supplies, dispensing of supplies to specific patients, and return of unused product by patients.  
Opened and unopened bottles 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. 
Under no circumstances will the Investigator allow the study drug to be used other than as 
directed by the protocol. 
Adherence to the study-drug regimen will be determined by review of the dosing diary and 
counting the number of capsules taken and returned at each study visit. 
5.9 
Continued Access to Study Treatment 
All patients completing the study will be eligible for rollover to the extension study, provided 
that they have had at least 80% adherence to prescribed dosing, according to capsule counts, and 
are expected to maintain or receive clinical benefit from relacorilant, in the opinion of the 
Investigator.  
5.10 
External Data Review Committees 
5.10.1 Data Review Board for Evaluation of Global Clinical Response 
The Global Clinical Response will be evaluated by a 3-member Data Review Board (DRB) that 
has expertise in Cushing syndrome. Each member of the DRB will independently review, assess, 
and assign a single overall clinical score of worsening, no change, or improvement. Details of the 
of the evaluation of this endpoint and the meeting frequency and composition of the DRB will be 
specified in the DRB charter. 


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5.10.2 Independent Data Monitoring Committee to Monitor Patient Safety 
An Independent Data Monitoring Committee (IDMC) will be established to conduct periodic 
reviews of data to ensure the safety of patients. The IDMC will be composed of at least 3 voting 
members: two physicians and one statistician. The IDMC will meet at least quarterly. Further 
details describing the IDMC composition, contents of data reports, responsibilities, and decision 
rules will be described in the IDMC Charter.  


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6 
DESCRIPTION OF STUDY ASSESSMENTS AND PROCEDURES AND 
APPROPRIATENESS OF MEASUREMENTS 
Study procedures and their timing are summarized in the Schedule of Events (SOE; 
Appendix A).  
The Investigator and Sponsor will conduct the study in accordance with International Council for 
Harmonisation (ICH) GCP and local regulations. Adherence to the study design requirements, 
including those specified in the SOE, is essential and required for study conduct, and the 
Investigator must ensure that study procedures are performed as described in the protocol. 
During the study, procedures and observations will be monitored to confirm that study 
requirements are being followed, as outlined in the SOE. 
In the event that a patient is unable to come to the clinic to participate in study-related visits or 
procedures due to the COVID-19 pandemic, Sponsor-approved alternative options may be 
provided to the Investigator sites based on the needs and safety of patients. This may include the 
provision of study drug dispensation and delivery outside of the clinic. 
6.1 
Informed Consent and Screening 
Prior to performing any study-related procedures, the patient must sign and date an IRB-
approved- ICF (Section 10.3.1 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 sign consent up to 6 weeks prior to the first dose of study drug on Day 1. Remote consenting 
will be permitted if access of patients to the study site is restricted due to the COVID-19 
pandemic. IRB guidelines should be followed. 
All Screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of all 
patients screened and to confirm eligibility or record reasons for Screening failure (Section 4.3), 
as applicable. Screening assessments performed during the 6-week screening window can be 
used as Baseline data, and assessments do not need to be repeated (with the exception of the 
2-hour oGTT glucose test, HbA1c, and ABPM, which must be performed within 2 weeks of the 
Baseline Visit) and unless otherwise noted. Eligibility criteria will be confirmed at Baseline. 
6.1.1 Dexamethasone Suppression Test 
The dexamethasone suppression test (DST) should be performed during Screening if an 
additional test is required to confirm endogenous Cushing syndrome (e.g., if either the 24-hour 
UFC or late-night salivary test results are within normal range, the dexamethasone suppression 
test is required to confirm Cushing syndrome). Dexamethasone will be administered either as a 
1-mg dose overnight or a 2-mg dose over 48 hours; a blood sample will be drawn and will be 
tested at a local laboratory.  
Patients who had a DST performed within 12 weeks prior to the ICF date are not required to 
repeat the test at Screening.  


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6.2 
History 
6.2.1 Cushing-Syndrome‒Medication Washout 
Medications used in the treatment of Cushing syndrome are prohibited and require washout (as 
applicable) during Screening, provided the intervals specified in Exclusion Criteria 12 and 13 fit 
within the Screening window. Patients requiring washout of a medication for Cushing syndrome 
must complete the Screening/Baseline oGTT, HbA1c, and 24-hour ABPM tests after washout 
and within 2 weeks before Day 1 dosing; 24-hour UFC tests, and salivary cortisol tests must be 
completed after washout. 
6.2.2 Demographics and Baseline Disease Characteristics 
Patient demographic data, including age, sex, race, and ethnicity, and Baseline disease 
characteristics, such as years since diagnosis and Cushing syndrome type (e.g., ectopic ACTH 
secretion, primary pigmented nodular adrenocortical disease, primary macronodular adrenal 
hyperplasia), will be documented at Screening.  
6.2.3 Medical and Medication History 
Patient medical history, including the diagnosis, etiology, and treatment history of Cushing 
syndrome (including dexamethasone suppression test failure where appropriate), diagnosis of 
DM/IGT and/or hypertension, as well as other illnesses and allergies, date(s) of onset, and 
whether conditions are currently ongoing will be recorded at Screening and Baseline 
(Appendix A). Surgery and radiation history will include date and type.  
A menstrual history will be obtained for all female patients at Screening. 
At Screening, a list of current medications will be obtained, including start date, dosage, and 
route of administration, along with any medications taken in the 3 months before start of study to 
treat Cushing syndrome, diabetes, and/or hypertension. 
6.3 
Safety Assessments 
Safety parameters, including physical examination findings, vital signs, ECG results, pregnancy 
tests, clinical laboratory test results (hematology and chemistry), thyroid function tests, lipid 
profile, AEs, and concomitant medications, will be assessed at the time points specified 
Appendix A. In patients with pituitary Cushing syndrome, a pituitary magnetic resonance 
imaging (MRI) scan will be performed to evaluate tumor size. During the RW phase, clinical 
laboratory test results (hematology and chemistry), thyroid functions tests, and lipid profiles will 
remain blinded.  
In the event study visits are shortened due to the COVID-19 pandemic, safety assessments 
should be prioritized. 
6.3.1 Physical Examination 
A complete physical examination, including evaluation of general appearance, head, eyes, ears, 
nose, and throat, as well as dermatologic, cardiovascular, respiratory, gastrointestinal, 
extremities/musculoskeletal, and neurologic body systems, will be performed (Appendix A). 


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Any clinically significant abnormalities observed during Screening should be reported in the 
patient’s medical history; if observed any time after the first dose of study drug (Day 1) up to 
28 days after the last dose of study drug, they will be considered treatment-emergent adverse 
events (TEAEs). 
Height will only be measured at Screening (Appendix A).  
6.3.2 Vital Signs  
Vital signs, including BP, heart rate, respiratory rate, and oral body temperature, will be obtained 
at the time points specified in Appendix A. Blood pressure will be measured in both arms at 
Screening and the arm with the higher diastolic reading will be recorded and used for all 
subsequent measurements. Blood pressure and heart rate will be taken after the patient has rested 
in a sitting position for approximately 15 minutes and ≥30 minutes after smoking or caffeine 
intake. Automated BP machines can be used to standardize measurements. 
Unscheduled assessments of vital signs can be performed as necessary.  
In addition to the safety vital signs collected, a 24-hour ABPM will also be done by all patients 
at Screening and by patients with hypertension (Section 6.4.2) during treatment at the time points 
specified in Appendix A. 
6.3.3 Electrocardiogram 
Twelve-lead ECG tracings will be obtained in triplicate at Screening and in duplicate at other 
time points (2 hours ±30 minutes after study-drug dosing) as designated in Section 7 and in 
Appendix A. Patients should lie down for at least 10 minutes before each ECG evaluation. 
Electrocardiogram data will be submitted to a central reviewer; instructions will be provided in 
the study manual. A Sponsor-approved alternative option for ECGs (i.e., use of alternative 
locations for assessment) is permitted in the event of site closures due to the COVID-19 
pandemic. 
The Investigator or designee will indicate in the source documents whether the ECG was normal; 
abnormal, but not clinically significant; or abnormal and clinically significant. Any new or 
worsened abnormality noted as clinically significant will be reported as an AE. 
In patients with an abnormal QTc interval at Screening in which no concomitant drugs known 
to prolong QTc and no electrolyte abnormalities are present, triplicate ECG recordings should be 
obtained. The final decision on excluding a patient should be based on the average QTcF interval 
across the recordings. If an electrolyte abnormality is present, it should be corrected before the 
ECG is repeated. If the patient is taking a concomitant medication known to cause QT 
prolongation, an alternative medication may be considered, and the ECG repeated after an 
appropriate washout period. 
6.3.4 Adverse Events 
Details on definitions and reporting of AEs are provided in Section 8. 
All AEs will be recorded from the time of signing of the ICF until 28 days after the last dose of 
study drug. Patients should be monitored for AEs throughout the study. 


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6.3.5 Clinical Laboratory Assessments 
6.3.5.1 
Laboratory Parameters 
Fasting blood samples will be collected for the analysis of safety at the time points specified in 
Appendix A. Laboratory samples will be analyzed at 1 or more central laboratories; instructions 
will be provided in the laboratory manual.  
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 whether any out-of-range laboratory values that 
emerge during the study are clinically significant. Any clinically significant laboratory value will 
be reported as an AE. 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. 
During the RW phase, the results for all laboratory assessments will remain blinded. The 
unblinded Medical Monitor will review laboratory values and will notify the Investigator and 
study-site staff of any critical out-of-range laboratory values. To maintain the blind investigators 
should not repeat laboratory tests locally unless medically necessary. 
The Investigator will review all laboratory reports, evaluate the results, and sign/date the reports.  
Laboratory parameters, inclusive of efficacy, safety, PK, and pharmacodynamic (PD) parameters 
to be assessed are listed in Table 3. 


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Table 3  
Clinical Laboratory Variables Evaluated During the Study 
Hematology 
Red blood cell count  
Hemoglobin  
Hematocrit  
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin volume 
Mean corpuscular volume  
Platelet count 
Mean platelet volume 
Red blood cell distribution width 
White blood cell count  
Neutrophils (percent and absolute) 
Lymphocytes (percent and absolute) 
Monocytes (percent and absolute) 
Eosinophils (percent and absolute) 
Basophils (percent and absolute) 
Serum Chemistry 
Sodium  
Potassium  
Calcium  
Chloride  
Phosphorus  
Magnesium  
Creatinine 
Creatine kinase 
Bilirubin (total and direct) 
Albumin  
Alkaline phosphatase 
Lactate dehydrogenase 
Aspartate aminotransferase  
Alanine aminotransferase 
Glucose  
2-hour oGTT glucose 
2-hour oGTT insulin 
HbA1c 
Blood urea nitrogen 
Uric acid  
Bicarbonate  
Total protein  
Glucocorticoid-Receptor 
Activity 
FKBP5 and other potential 
biomarkers of GR activity 
 
Pregnancy 
Serum/urine pregnancy test 
Thyroid Function 
Thyroid-stimulating hormone  
Total T3 Reflex 
Free T4 Reflex 
Sex Hormones 
Estradiol 
Testosterone (total and free) 
Sex-hormone‒binding globulin 
Follicle-stimulating hormone 
Luteinizing hormone 
Pharmacokinetic 
Relacorilant 
Pharmacodynamic 
Urinary free cortisol 
Salivary cortisol 
Hypothalamic-pituitary-adrenal 
(HPA)-axis parameters: 
Plasma ACTH 
Serum DHEA-S 
Fasting serum cortisol 
Biochemical Markers for Bone 
Remodeling 
Serum osteocalcin 
Lipid Panel 
Total cholesterol 
Low-density lipoprotein-cholesterol 
High-density lipoprotein-cholesterol 
Very low-density lipoprotein 
cholesterol 
Triglycerides 
ACTH, adrenocorticotropic hormone; DHEA-S, dehydroepiandrosterone sulfate; FKBP5, FK506 binding protein 5; 
HbA1c, glycated hemoglobin; oGTT, oral glucose tolerance test; T3, triiodothyronine; T4, thyroxine.  
 
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 and GR activity biomarkers will also be provided. 
6.3.5.2 
Blood-Volume Summary 
Blood samples will be used for analysis of safety laboratory, efficacy, PK, and 
pharmacodynamic parameters. The total volume of blood to be collected from each patient will 
be no more than 500.5 mL for his/her entire study participation. 


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6.3.6 Pituitary Magnetic Resonance Imaging Scan 
In patients with pituitary Cushing syndrome, a pituitary MRI scan will be performed to evaluate 
tumor size (Appendix A). If the MRI cannot be performed with contrast (e.g., because of an 
allergy) it can be done without. The reason the MRI was performed without contrast should be 
documented. If the patient is contraindicated for MRI, a CT Scan may be performed instead. The 
reason the patient is contraindicated for MRI should be documented.  
6.3.7 Pregnancy Test 
All female patients of childbearing potential (including all women <50 years old, women whose 
surgical sterilization was performed <6 months ago, and women who have had a menstrual 
period in the last 2 years) will undergo pregnancy tests. The Screening pregnancy test will be a 
blood test; all subsequent pregnancy tests will be urine tests, as specified in Appendix A. 
6.4 
Efficacy Assessments 
All efficacy assessments will be performed at the time points specified in Appendix A. 
6.4.1 Glucose Tolerance 
A 2-hour oGTT will be used to assess the effect of relacorilant on glucose tolerance and insulin 
resistance (Matsuda Index and HOMA IR) following an 8-hour fast at the time points specified 
in Appendix A. 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 (Table 4). 
In general, patients 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. During the RW phase, the results to the study 
2-hour oGTT will remain blinded.  
Table 4 
Time Window for Collection of 2-hour oGTT Blood Samples  
Nominal Time 
Reporting Standards 
0.5, 1, 1.5, and 2 hours after the glucose drink 
±10 minutes 
 
In the event study visits are shortened due to the COVID-19 pandemic, the oGTT assessment 
should be prioritized. 
6.4.2 Ambulatory Blood Pressure Monitoring (ABPM) 
Ambulatory BP monitoring (ABPM) will be assessed. 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 (or under the condition of a Sponsor-approved alternative option in 
the event a patient is unable to come to the study site due to the COVID-19 pandemic). The 
patient should use the monitor during a time when a full 24-hour recording can be made. The 
patient should perform the ABPM under consistent conditions. ABPM will be performed at the 
time points specified in Appendix A. The patient will bring the monitor to each study visit or will 
send it to the study site in advance of the next study visit. ABPM should be initiated at the end of 


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the visit after collection of blood samples at each study visit. If more than 2 consecutive hours, 
or 5 hours over the entire period are missing then the data is considered missing and test should 
be repeated. During the RW phase, the results to the study 24-hour ABPM will remain blinded.  
In the event study visits are shortened due to the COVID-19 pandemic, the ABPM assessment 
should be prioritized. 
6.4.3 Glycated Hemoglobin (HbA1c) 
Blood samples will be collected from patients to measure HbA1c, a glycoprotein whose 
concentration reflects the amount of glucose bound to hemoglobin, at the time points specified in 
Appendix A. During the RW phase, the HbA1c results will remain blinded.  
In the event study visits are shortened due to the COVID-19 pandemic, the HbA1c assessment 
should be prioritized. 
6.4.4 Body-Fat Composition (DXA Scan) 
Change in the percent and absolute amounts of total body and regional fat and lean tissue (whole 
body, trunk, and leg) from Baseline (±6 weeks of the Baseline Visit) as measured by DXA scan 
(Shepherd et al. 2017) for all patients, at the time points specified in Appendix A.  
6.4.5 Cushing Quality-of-Life Questionnaire 
The Cushing QoL patient questionnaire, which evaluates the health-related QoL in patients 
with Cushing syndrome (Webb et al. 2008), will be administered to all patients at the time points 
specified in Appendix A. It comprises 12 questions, each with 5 possible answers. The total 
score ranges from 12‒60. The Cushing QoL 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.  
In the event a patient is unable to come to the study site due to the COVID-19 pandemic, the 
Cushing QoL patient questionnaire may be completed remotely and sent back to the site. 
6.4.6 Body Weight and Waist Circumference 
Body weight and waist circumference will be measured for all patients at the time points 
specified in Appendix A. Weight will be measured without overcoat and shoes and with only 
light clothing. Clinical sites will be provided with tape measures to ensure consistency of waist 
circumference measurements. Waist circumference measurements should be obtained to the 
nearest 0.5 cm (1/4 inch) following removal of clothing from the waistline. Detailed instructions 
for measurement of waist circumference will be provided in the study manual. 
In the event study visits are shortened due to the COVID-19 pandemic, the waist circumference 
assessment should be prioritized if a DXA scan is unable to be completed. 


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6.4.7 Biochemical Markers of Bone Remodeling 
Blood samples for analysis of serum osteocalcin will be obtained from all patients at the time 
points specified in Appendix A. During the RW phase, the serum osteocalcin results will 
remain blinded. 
6.4.8 Beck Depression Inventory-II 
The BDI-II, a 21-question self-report inventory that measures depression (Beck 1996), will be 
completed by all patients at the time points specified in Appendix A. Each answer is scored with 
values 0 to 3. The total score ranges from 0 to 63. Scores of 0 to 13 indicate minimal depression, 
14 to 19; mild depression; 20 to 28; moderate depression; 29 to 63; severe depression. 
6.4.9 Global Clinical Response 
The DRB (see Section 5.10.1) will evaluate all patients for Global Clinical Response at the time 
points specified in Appendix A. The Global Clinical Response assessment (adapted from 
Katznelson et al. 2014) comprises items from 7 clinical categories: 
1. Glucose: fasting blood glucose, 2-hour oGTT (Section 6.4.1), HbA1c (Section 6.4.3), 
change in diabetes medications 
2. Blood pressure: systolic and diastolic blood pressure (Section 6.4.2), change in 
antihypertensive medications 
3. Body composition: DXA Scan (Section 6.4.4), body weight and waist circumference 
(Section 6.4.6) 
4. Clinical appearance (according to review of patient photographs): Cushingoid appearance 
and striae (Section 6.4.10) 
5. Strength: sit-to-stand test (Section 6.4.11) 
6. Psychiatric health/cognitive function: Beck Depression Inventory®-II (BDI-II) 
(Section 6.4.8), change in antidepressant medications, trail-making test 
7. Quality of life: Cushing QoL score (Section 6.4.5) 
Each of 3 members of the DRB will review the 7 categories of clinical parameters above to 
evaluate whether a patient’s signs and symptoms of Cushing syndrome have changed, and will 
rate the patient’s overall response based on the totality of signs and symptoms as +1 (improved), 
0 (unchanged), or −1 (worsened) at every visit after Baseline. Each patient’s final score will be 
the median of the 3 ratings.  
During the OL phase, the change will be assessed with respect to Baseline, and during the 
RW Phase, it will be assessed with respect to the pre-randomization visit (Visit OL22). 
6.4.10 Photography for Assessment of Cushingoid Features 
Members of the DRB will review patient photographs to assess Cushingoid features (Colao et al. 
2012) graphs at the time points specified in Appendix A. A digital camera will be supplied to 
take patient photographs. Detailed instructions for obtaining photographs will be provided in the 
study manual. A central vendor will collect patient photographs prior to assessment by the DRB. 
As a mitigation to the COVID-19 pandemic, patients will be allowed the option to perform 
self-capture for clinical photography, which will be completed on a mobile device. With this 


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method, it is possible that not all views may be captured. A central vendor will collect the 
self-captured photographs prior to the assessment by the DRB.  
6.4.11 Sit-to-Stand 
The sit-to-stand test will be performed at the time points specified in Appendix A. The 
sit-to-stand test evaluates the ability of patients to go from standing to sitting in a chair and then 
getting up again with/without the use of their arms or other aids. Patients seated in a chair will be 
asked to fold their arms across their chests and to stand up from the seated position once; if they 
are able to successfully rise from the chair, they will be asked to sit down again and then stand 
up and sit down 5 times as quickly as possible. The chair should be of standard height so that the 
patient’s legs are in flexion of approximately 90 degrees about the knee when the feet are flat on 
the floor. Patients should be advised not to place their feet far beneath chair and not to offset the 
feet in the horizontal plane (i.e., asked to place their feet under the front of the chair, not too far 
forward [in front of the chair] or too far back [under the chair seat]). The study staff will use a 
stopwatch to measure the total time it takes for the patient to stand up and sit down 5 times; start 
time is in the seated position and stop time is in the final standing position. The total time of the 
test is measured. Patients with gait or balance disorders are not required to complete the 
sit-to-stand test. The same or similar chair should be used for all measurements. 
6.4.12 Trail-Making Test 
The trail-making test will be performed at the time points specified in Appendix A. The trail-
making test is a neuropsychological test of visual attention and task switching that consists of 
2 parts in which the patient is instructed to connect a set of 25 dots as quickly as possible while 
still maintaining accuracy. It can provide information about visual search speed, scanning, 
processing speed, and mental flexibility, as well as executive functioning. The total time of the 
test is measured, with a maximum of 300 seconds. 
6.4.13 Sex-Hormone Levels 
Blood samples will be obtained from each patient at the time points specified in Appendix A for 
analysis of estradiol, total and free testosterone, sex-hormone‒binding globulin, 
follicle-stimulating hormone, and luteinizing hormone. During the RW phase, the estradiol, total 
and free testosterone, sex-hormone‒binding globulin, follicle-stimulating hormone, and 
luteinizing hormone results will remain blinded.  
6.4.14 Menstrual Cycle Information 
Menstrual cycle information (e.g., first day of last menstrual period, current pattern of menses, 
duration of vaginal bleed, compliance with hormonal birth control) will be recorded at the time 
points specified in Appendix A, along with any spotting occurrences, in premenopausal female 
patients.  
6.4.15 Glucocorticoid Receptor Activity Biomarker Tests 
A blood sample will be obtained from all patients for analysis of mRNA expression of 
glucocorticoid-modulated genes (including, among others, FKBP5) and proteins at the time 


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points specified in Appendix A. During the RW phase, the results for this assessment will remain 
blinded. 
6.5 
Pharmacokinetic Assessments 
Intensive PK sampling will be conducted in all patients following an observed dose at Visit 
OL18 (Appendix A).  
Intensive PK sampling will consist of a total of 5 samples collected at the following time points: 
predose (0 hour) and at 1, 2, 4, and 6 hours postdose (Table 5).  
Instructions for the collection and handling of the samples will detailed in the laboratory manual.  
PK sampling should be performed on the ongoing dose. 
Table 5 
Time Windows for Collection of Pharmacokinetic Samples 
Nominal Time 
Reporting Standards 
Predose 
Up to 60 minutes before dosing 
1, 2, 4, and 6 hours postdose 
±10 minutes 
Refer to Section 9.5.7 for a description of PK analysis. 
6.6 
Pharmacodynamic Assessments 
Samples for PD assessments will be collected from all patients at the time points specified in 
Appendix A. During the RW phase, the results for all PD assessments will remain blinded.  
6.6.1 Fasting Serum Cortisol 
Fasting serum cortisol samples will be obtained at the time points specified in Appendix A. 
6.6.2 Urinary Free Cortisol 
The 24-hour UFC with creatinine test will be collected by the patient at home at least 2 times 
during Screening  and in duplicate at the other time points specified in Appendix A. A minimum 
of two 24-hour urinary samples are collected during Screening, at least 1 week apart. For 
Screening, the average of the results will serve as Baseline. During the Treatment Period, the 
24-hour UFC sample should be collected in duplicate, at the patient’s home, within 7 days prior 
to the next study visit. 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. Urinary free cortisol will be measured by 
tandem mass spectrometry. 
6.6.3 Late-Night Salivary Cortisol 
To assess late-night salivary cortisol, the salivary cortisol test will be performed by the patient at 
home twice on different nights during Screening  and in duplicate at the other time points 


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specified in Appendix A. For Screening, the average of the results will serve as Baseline. The 
patient will be given supplies for the collection of saliva. Samples should be collected at 
bedtime. During the OL and RW phases, the late-night salivary cortisol sample should be 
collected in duplicate, at the patient’s home, within 7 days prior to the next study visit. Patients 
should be instructed to avoid the chewing of licorice or tobacco 60 minutes prior to completing 
the test. Complete instructions will be provided to the patient.  
6.6.4 Hypothalamic-Pituitary-Adrenal Axis Parameters 
Blood samples will be obtained for analysis of plasma ACTH and dehydroepiandrosterone 
sulfate (DHEA-S) at the time points specified in Appendix A.  
6.7 
Appropriateness of the Measures 
The assessments to be used in this study are standard for evaluation of patients with Cushing 
syndrome and are generally recognized as reliable, accurate, and relevant.  
6.8 
Blood Storage 
A portion of the blood drawn predose at all visits (except the Screening Visit, Follow-up Visit, 
ET, and Unscheduled Visits) will be frozen and stored (for additional information on sample 
retention, see Section 11.4). These stored blood samples may be used by the Sponsor for 
retesting safety laboratory parameters, for measurement of study-drug and/or concomitant-drug 
levels in the blood, or for clinical laboratory testing to provide additional safety data. No human 
genetic testing will be performed without expressed consent of study patients. 


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7 
STUDY ASSESSMENTS AND PROCEDURES BY STUDY VISIT 
A Summary of Events (SOE) is provided in Appendix A. Most assessments are for all patients; 
a few are performed only in patients in a specific subgroup (i.e., the impaired glucose 
tolerance/diabetes subgroup or the uncontrolled hypertension subgroup). 
In the event that a patient is unable to come to the clinic to participate in study-related visits or 
procedures, Sponsor-approved alternative options may be provided to the Investigator sites based 
on the needs and safety of patients. This may include the provision of study-drug dispensation 
and delivery outside of the clinic. 
Any deviation from protocol procedures will be noted in the patient’s clinical chart and eCRF. 
In addition, the Sponsor will be promptly notified of any protocol deviations. Though alternative 
methods for safety and study assessments (i.e., phone contact, virtual study visits, use of 
alternative locations for assessment, including local labs or imaging centers, etc.) are permitted 
due to the COVID-19 pandemic, any modified protocol-described processes should be recorded 
as protocol deviations. 
7.1 
Scheduled Visits 
Patients requiring washout of a medication for Cushing syndrome must complete the 
Screening/Baseline 24-hour UFC tests, salivary cortisol tests, oGTTs, HbA1c, and 24-hour 
ABPM as described in Section 6.2.1.  
The window for each study visit is relative to the Baseline or the Randomization Visit. The 
acceptable visit window is ±3 days for Visits OL2, OL6, and OL10 and ±7 days for all other 
visits (except when RW12 serves as the return visit following early discontinuation from the RW 
phase, in which case a 3-week visit window [2 weeks before the scheduled visit, 1 week after the 
scheduled visit] for RW12 is permitted). The Randomization visit (the first day of the RW phase) 
may occur up to 14 days after Visit OL22 to allow time to obtain the required test results to 
evaluate eligibility for the RW phase.  
With regard to sequence of tests and acceptable time windows: 
• Predose procedures must be completed before dosing and, where applicable, before 
breakfast. 
• Dosing will take place at the scheduled time after completion of all predose procedures.  
• At all visits beginning with OL2, study drug should be taken in the clinic during the visit 
and after initial blood draws.  
• Pharmacokinetic sampling will take precedence over other procedures when more than 
1 procedure is scheduled for the same time point relative to dosing. Acceptable time 
windows for PK samples at Visit OL18 are:  
Within 1 hour before dosing for the predose sample. 
±10 minutes for the 1-, 2-, 4-, and 6-hour postdose samples. 
• All clinical laboratory samples and predose PK samples will be collected when the 
patient is fasting (at least 4 hours). 
• Ambulatory BP monitoring will be initiated in the clinic after all blood samples are 
obtained. 


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• Study-drug dosing should occur after the completion of the 2-hour oGTT test (except for 
OL18, when oGTT may take place after dosing for logistical issues due to serial PK 
sampling that would prolong patient stay).  
• Acceptable time windows for oGTT samples are: 
±10 minutes for the 0.5-, 1-, 1.5-, and 2-hour samples. 
• Measurement of vital signs and ECG recordings will be avoided within 15 minutes after 
venipuncture or cannulation and, therefore, will normally be performed before blood 
sampling. Electrocardiogram recording should be performed 2 hours ±30 minutes after 
study-drug dosing. 
The Investigator may repeat tests in the event of a technical failure and/or if additional 
observations or samples of blood are needed to monitor patient safety; these will not be 
considered protocol deviations. 
The required procedures for each study visit are outlined in the study Schedule of Visits and 
Procedures in Appendix A.  
7.1.1 Screening Visit (−42 to −1 day) 
The purpose of the Screening visit/period is to ensure that appropriate patients are entered into 
the study and that they remain stable during the pretreatment period.  
• Obtain written informed consent prior to performing any study procedures  
• Review inclusion/exclusion criteria 
• Complete medical history and review of medications 
• Collect demographic and baseline disease characteristics information, including 
confirmation of medication washout 
• Perform a complete physical examination, including height, weight, and waist 
circumference 
• Measure vital signs 
• Collect menstrual cycle information (premenopausal women only) 
• Query for AEs 
• Review concomitant medications  
• Draw blood samples for laboratory tests 
– Serum pregnancy test (women of childbearing potential only). 
– Hematology and chemistry 
– 2-hour oGTT (after an 8-hour fast; must be performed within 2 weeks of Day 1 and 
used as Baseline) 
– HbA1c (must be collected within 2 weeks of Day 1 and will be used for Baseline) 
– HPA-axis parameters  
– GR-activity biomarker test 
• DST (if warranted for study entry). A DST performed within 12 weeks before the ICF 
date will be accepted  
• 24-hour UFC with creatinine (collected by the patient at home at least twice during 
Screening). For Screening, the average of the results will serve as “Baseline” 


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• Late-night salivary cortisol (collected by the patient at home at least twice on different 
nights during Screening). For Screening, the average of the results will serve as 
“Baseline” 
• 12-lead ECG (obtained in triplicate during Screening)  
• ABPM (24-hour) test will be assessed for all patients during Screening. For patients with 
hypertension, 24-hour ABPM must be completed within 2 weeks before Day 1 and used 
as Baseline 
• Schedule next visit  
Patients who fail Screening may be rescreened (see Section 4.3).  
7.1.2 Baseline Visit (B) (Day 1) 
• Review inclusion/exclusion criteria 
• Complete medical history and review of medications 
• Collect demographic information and baseline disease characteristics 
• Perform a complete physical examination, including weight and waist circumference 
• Measure vital signs 
• Collect menstrual-cycle information (premenopausal women only) 
• Review and record AEs 
• Review concomitant medications 
• Draw blood samples for laboratory tests 
– Hematology and chemistry 
– Lipid panel (fasting) 
– Sex-hormone levels 
– GR-activity biomarker test 
– Serum osteocalcin 
– 2-hour oGTT (after an 8-hour fast and used as Baseline—unless performed within 
2 weeks of Day 1; DM/IGT patients only) 
– HbA1c (used for Baseline—unless collected within 2 weeks of Day 1; DM/IGT 
patients only) 
– HPA-axis parameters  
– Thyroid function tests 
• Collect urine sample for pregnancy test (women of childbearing potential only) 
• Take photographs 
• ABPM (24-hour) test (unless collected within 2 weeks of Day 1; hypertension patients 
only; initiated in clinic after all blood draws are obtained) 
• DXA scan for body-fat composition (±6 weeks of the Baseline Visit) 
• Sit-to-stand test 
• Trail-making test 
• Cushing QoL questionnaire  
• Beck Depression Inventory  
• Pituitary MRI scan (for patients with pituitary Cushing syndrome) (±6 weeks of the 
Baseline Visit)  


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• Dosing diary 
• Study-drug dispensing and/or adherence 
• Administration of the Day 1 dose of study drug 
• 12-lead ECG (obtained in duplicate; 2 hours ±30 min after study-drug dosing) 
• Schedule next visit 
7.1.3 Open-Label Visit 2 (OL2) (±3 days) 
• Perform a complete physical examination, including weight and waist circumference  
• Measure vital signs 
• Review and record AEs 
• Review concomitant medications 
• Draw blood samples for laboratory tests 
– Hematology and chemistry 
• Collect urine sample for pregnancy test (women of childbearing potential only). 
• Administration of the daily dose of study drug 
• 12-lead ECG (obtained in duplicate; 2 hours ±30 min after study-drug dosing) 
• ABPM (24-hour) test (hypertension patients only; initiated in clinic after all blood draws 
are obtained) 
• Dosing diary 
• Study-drug dispensing and/or adherence 
• Schedule next visit 
7.1.4 Open-Label Visit 6 (OL6) (±3 days) 
• Perform a complete physical examination, including weight and waist circumference  
• Measure vital signs 
• Collect menstrual cycle information (premenopausal women only) 
• Review and record AEs 
• Review concomitant medications 
• Draw blood samples for laboratory tests 
– Hematology and chemistry 
– GR-activity biomarker test 
– 2-hour oGTT (after an 8-hour fast; DM/IGT patients only) 
– HPA-axis parameters  
• Take photographs 
• Collect urine sample for pregnancy test (women of childbearing potential only) 
• ABPM (24-hour) test (hypertension patients only; initiated in clinic after all blood draws 
are obtained) 
• Late-night salivary cortisol (collected by the patient in duplicate at home within 7 days 
prior to the study visit) 
• 24-hour UFC with creatinine (collected by the patient in duplicate at home within 7 days 
prior to the study visit) 
• Sit-to-stand test 


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• Trail-making test 
• Cushing QoL questionnaire  
• Beck Depression Inventory  
• Dosing diary 
• Study-drug dispensing and/or adherence 
• Administration of the daily dose of study drug 
• 12-lead ECG (obtained in duplicate; 2 hours ±30 min after study-drug dosing) 
• Schedule next visit 
7.1.5 Open-Label Visit 10 (OL10) (±3 days) 
• Perform a complete physical examination, including weight and waist circumference  
• Measure vital signs 
• Collect menstrual cycle information (premenopausal women only) 
• Review and record AEs 
• Review concomitant medications 
• Draw blood samples for laboratory tests 
– Hematology and chemistry 
– GR-activity biomarker test 
– 2-hour oGTT (after an 8-hour fast; DM/IGT patients only) 
– HbA1c  
– HPA-axis parameters  
• Take photographs 
• Collect urine sample for pregnancy test (women of childbearing potential only). 
• ABPM (24-hour) test (hypertension patients only; initiated in clinic after all blood draws 
are obtained) 
• Late-night salivary cortisol (collected by the patient in duplicate at home within 7 days 
prior to the study visit) 
• 24-hour UFC with creatinine (collected by the patient in duplicate at home within 7 days 
prior to the study visit) 
• Sit-to-stand test 
• Trail-making test 
• Cushing QoL questionnaire  
• Beck Depression Inventory  
• Dosing diary 
• Study-drug dispensing and/or adherence 
• Administration of the daily dose of study drug 
• 12-lead ECG (obtained in duplicate; 2 hours ±30 min after study-drug dosing) 
• Schedule next visit. 
7.1.6 Open-Label Visit 14 (OL14) (±7 days) 
• Perform a complete physical examination, including weight and waist circumference 
• Measure vital signs 


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• Collect menstrual cycle information (premenopausal women only) 
• Review and record AEs 
• Review concomitant medications 
• Draw blood samples for laboratory tests 
– Hematology and chemistry 
– GR-activity biomarker test 
– 2-hour oGTT (after an 8-hour fast; DM/IGT patients only) 
• Take photographs 
• Collect urine sample for pregnancy test (women of childbearing potential only). 
• ABPM (24 hour) test (hypertension patients only; initiated in clinic after all blood draws 
are obtained) 
• Late-night salivary cortisol (collected by the patient in duplicate at home within 7 days 
prior to the study visit) 
• 24-hour UFC with creatinine (collected by the patient in duplicate at home within 7 days 
prior to the study visit) 
• Sit-to-stand test 
• Trail-making test 
• Cushing QoL questionnaire  
• Beck Depression Inventory  
• Dosing diary 
• Study-drug dispensing and/or adherence 
• Administration of the daily dose of study drug 
• 12-lead ECG (obtained in duplicate; 2 hours ±30 min after study-drug dosing) 
• Schedule next visit 
7.1.7 Open-Label Visit 18 (OL18) (±7 days) 
• Perform a complete physical examination, including weight and waist circumference  
• Measure vital signs 
• Collect menstrual cycle information (premenopausal women only) 
• Review and record AEs 
• Review concomitant medications 
• Draw blood samples for laboratory tests 
– Hematology and chemistry 
– 2-hour oGTT (after an 8-hour fast; DM/IGT patients only) 
– Intensive PK sampling: predose and 1, 2, 4, and 6 hours postdose  
• Take photographs 
• Collect urine sample for pregnancy test (women of childbearing potential only). 
• ABPM (24-hour) test (hypertension patients only; initiated in clinic after all blood draws 
are obtained) 
• Sit-to-stand test 
• Trail-making test 
• Cushing QoL questionnaire  


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• Beck Depression Inventory  
• Dosing diary 
• Study-drug dispensing and/or adherence 
• Administration of the daily dose of study drug 
• Schedule next visit 
7.1.8 Open-Label Visit 22 (OL22) (±7 days) 
• Perform a complete physical examination, including weight and waist circumference. 
• Measure vital signs 
• Collect menstrual cycle information (premenopausal women only) 
• Review and record AEs 
• Review concomitant medications 
• Draw blood samples for laboratory tests 
– Hematology and chemistry 
– Lipid panel (fasting) 
– Sex-hormone levels 
– GR-activity biomarker test 
– Serum osteocalcin 
– 2-hour oGTT (after an 8-hour fast; all patients) 
– HbA1c (all patients) 
– HPA-axis parameters  
– Thyroid function tests 
• Take photographs 
• Collect urine sample for pregnancy test (women of childbearing potential only). 
• ABPM (24-hour) test (all patients; initiated in clinic after all blood draws are obtained) 
• Late-night salivary cortisol (collected by the patient in duplicate at home within 7 days 
prior to the study visit) 
• 24-hour UFC with creatinine (collected by the patient in duplicate at home within 7 days 
prior to the study visit) 
• DXA scan for body-fat composition 
• Sit-to-stand test 
• Trail-making test 
• Cushing QoL questionnaire  
• Beck Depression Inventory  
• Pituitary MRI scan (for patients with pituitary Cushing syndrome) 
• Dosing diary 
• Study-drug dispensing and/or adherence 
• Administration of the daily dose of study drug 
• 12-lead ECG (obtained in duplicate; 2 hours ±30 min after study-drug dosing) 
• Schedule next visit 


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7.1.9 Randomization Visit (R) (+14 days) 
• Review response criteria  
• Perform a complete physical examination, including weight and waist circumference  
• Measure vital signs 
• Review and record AEs 
• Review concomitant medications 
• Collect urine sample for pregnancy test (women of childbearing potential only) 
• Dosing diary 
• Randomization 
• Study-drug dispensing and/or adherence 
• Administration of the daily dose of study drug 
• Schedule next visit 
7.1.10 Randomized-Withdrawal Visit 4 (RW4) (±7 days) 
• Perform a complete physical examination, including weight and waist circumference  
• Measure vital signs 
• Collect menstrual cycle information (premenopausal women only) 
• Review and record AEs 
• Review concomitant medications 
• Draw blood samples for laboratory tests 
– Hematology and chemistry  
– 2-hour oGTT (after an 8-hour fast; DM/IGT patients only) 
• Collect urine sample for pregnancy test (women of childbearing potential only). 
• ABPM (24-hour) test (hypertension patients only; initiated in clinic after all blood draws 
are obtained) 
• Sit-to-stand test 
• Trail-making test 
• Cushing QoL questionnaire  
• Beck Depression Inventory  
• Dosing diary 
• Study-drug dispensing and/or adherence 
• Administration of the daily dose of study drug 
• Schedule next visit 
7.1.11 Randomized-Withdrawal Visit 8 (RW8) (±7 days) 
• Perform a complete physical examination, including weight and waist circumference  
• Measure vital signs 
• Collect menstrual cycle information (premenopausal women only) 
• Review and record AEs 
• Review concomitant medications 
• Draw blood samples for laboratory tests  
– Hematology and chemistry  


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– 2-hour oGTT (after an 8-hour fast; DM/IGT patients only) 
• Collect urine sample for pregnancy test (women of childbearing potential only). 
• ABPM (24-hour) test (hypertension patients only; initiated in clinic after all blood draws 
are obtained) 
• Sit-to-stand test 
• Trail-making test 
• Cushing QoL questionnaire  
• Beck Depression Inventory  
• Dosing diary 
• Study-drug dispensing and/or adherence 
• Administration of the daily dose of study drug 
• Schedule next visit 
7.1.12 Randomized-Withdrawal Visit 12 (RW12) (±7 days) 
If a patient discontinues early from the RW phase, the patient will be instructed to return for 
Visit RW12 per the patient’s original dosing schedule. If this visit is the return visit following 
early discontinuation from the RW phase, a 3-week visit window (2 weeks before the scheduled 
visit, 1 week after the scheduled visit) is permitted. 
• Perform a complete physical examination, including weight and waist circumference  
• Measure vital signs 
• Collect menstrual cycle information (premenopausal women only) 
• Review and record AEs 
• Review concomitant medications 
• Draw blood samples for laboratory tests 
– Hematology and chemistry 
– Lipid panel (fasting) 
– Sex-hormone levels 
– GR-activity biomarker test 
– Serum osteocalcin 
– 2-hour oGTT (after an 8-hour fast; all patients) 
– HbA1c (all patients) 
– HPA-axis parameters  
– Thyroid function tests 
• Take photographs 
• Collect urine sample for pregnancy test (women of childbearing potential only). 
• ABPM (24-hour) test (completed by the patient at home within 7 days prior to the study 
visit; all patients) 
• Late-night salivary cortisol (collected by the patient in duplicate at home within 7 days 
prior to the study visit) 
• 24-hour UFC with creatinine (collected by the patient in duplicate at home within 7 days 
prior to the study visit) 
• DXA scan for body-fat composition 


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• Sit-to-stand test 
• Trail-making test 
• Cushing QoL questionnaire  
• Beck Depression Inventory  
• Dosing diary 
• Study-drug dispensing and/or adherence (patients will remain on study drug up to 1 week 
post the RW12 visit until it has been confirmed that all results for efficacy and safety 
assessments are available and no repeat assessments are required) 
• 12-lead ECG (obtained in duplicate; 2 hours ±30 min after study-drug dosing) 
• Schedule next visit 
7.1.13 Early-Termination Visit (±7 days) 
If a patient discontinues prior to Visit OL22, the following assessments will be performed at the 
time of discontinuation or soon thereafter: 
• Perform a complete physical examination, including weight and waist circumference  
• Measure vital signs 
• Collect menstrual cycle information (premenopausal women only) 
• Review and record AEs 
• Review concomitant medications 
• Draw blood samples for laboratory tests 
– Hematology and chemistry 
– Lipid panel (fasting) 
– Sex-hormone levels 
– GR-activity biomarker test 
– Serum osteocalcin 
– 2-hour oGTT (after an 8-hour fast; all patients) 
– HbA1c (all patients) 
– HPA-axis parameters  
– Thyroid function tests 
• Take photographs 
• Collect urine sample for pregnancy test (women of childbearing potential only). 
• ABPM (24-hour) test (all patients; initiated in clinic after all blood draws are obtained) 
• Late-night salivary cortisol (collected by the patient in duplicate at home within 7 days 
prior to the study visit) 
• 24-hour UFC with creatinine (collected by the patient in duplicate at home within 7 days 
prior to the study visit) 
• 12-lead ECG (obtained in duplicate) 
• DXA scan for body-fat composition (should not be repeated if completed within 8 weeks 
prior to ET Visit) 
• Sit-to-stand test 
• Trail-making test 
• Cushing QoL questionnaire  


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• Beck Depression Inventory  
• Pituitary MRI Scan (for patients with pituitary Cushing syndrome; should not be repeated 
if completed within 3 months of ET Visit) 
• Dosing diary 
• Study-drug adherence. 
7.1.14 Follow-up Visit (±7 days) 
For patients who do not enroll in the extension study, the post-treatment Follow-Up visit will 
occur 28 days after the last dose of study drug.  
• Perform a complete physical examination, including weight and waist circumference.  
• Measure vital signs. 
• Review and record AEs 
• Review concomitant medications 
• Draw blood samples for laboratory tests 
– Hematology and chemistry 
• Collect urine sample for pregnancy test (women of childbearing potential only). 
• 12-lead ECG (obtained in duplicate). 
For patients who discontinue the study prior to the RW12 visit during the Randomized 
Withdrawal phase of the study and return for the RW12 visit, the follow up visit will be waived 
if the RW12 visit occurs at least 28 days after the last dose of administration of study drug. 
7.2 
Unscheduled Visits 
As appropriate, assessments deemed clinically necessary by the Investigator may be conducted at 
unscheduled visits. 


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8 
SAFETY EVENT DOCUMENTATION AND REPORTING 
8.1 
Investigator’s Responsibilities 
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for providing appropriate medical care. Investigators are required to report promptly to 
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. 
8.2 
Monitoring Safety Data During Study 
Safety results collected during the study (e.g., AEs, laboratory test results, physical findings) will 
be monitored on an ongoing basis by the Medical Monitor and Investigator. In addition, an 
Independent Data Monitoring Committee (IDMC) will be established to conduct periodic 
reviews of data to ensure the safety of patients (Section 5.10.2). During the RW phase, 2-hour 
oGTT and ABPM results will be reviewed by an unblinded Medical Monitor to monitor 
patient safety. 
8.3 
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 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. 
8.4 
Definition of a Serious Adverse Event 
An SAE is any AE that meets any of the following criteria: 
• Results in death (i.e., the AE caused or led to the fatality). 
• Is life-threatening (i.e., the AE refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe). 


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• Requires hospitalization or prolongation of existing hospitalization (i.e., hospitalizations 
for scheduled treatments and elective medical/surgical procedures are not SAEs by this 
criterion). 
• Results in persistent or significant disability/incapacity (i.e., 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 (i.e., 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 (i.e., the AE does not meet any of the 
above serious criteria but based on appropriate medical judgment, may jeopardize the 
patient or require medical or surgical intervention to prevent one of the serious outcomes 
listed in these criteria). 
8.5 
Clinical Significance 
The Investigator (or medically qualified designee) is responsible for determining whether an AE 
is clinically significant for the patient. Clinical significance will be documented in the patient’s 
medical records with the AE information. 
8.6 
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. 
8.7 
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. Illnesses present before 
the patient signs the ICF are considered pre-existing conditions and are documented on the 
medical history eCRF. Preexisting conditions that worsen during the study are entered on the AE 
eCRF. Adverse events that occur after start of study drug and up to and including 28 days after 
administration of the last dose of study drug will be considered TEAEs. Any AEs reported more 
than 28 days after the last dose of study drug will be considered posttreatment AEs and do not 
need to be reported to Corcept, unless the event meets the definition of serious (see Section 8.4) 
and the relationship to the study drug is possibly or probably related (see Section 8.8.2). In such 
cases, these posttreatment SAEs need to be reported per the process in Section 8.9. 
All AEs for enrolled patients 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 (Section 8.8.1), (4) relationship to the study drug (Section 8.8.2), 
(5) “serious” criteria, if applicable (Section 8.4), 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 


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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 that are possibly or probably related to the study drug and unexpected (not reported in 
the Investigator’s Brochure or greater severity or frequency than that described in the 
Investigator’s Brochure) must be reported to the governing IRB/Independent Ethics Committee 
(IEC)/Health Authorities, as required. 
8.8 
Adverse-Event Classification 
8.8.1 Intensity 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 
Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0 (NCI-CTCAE 
2017). For events not listed in the CTCAE, the definitions from the CTCAE provided in Table 6 
should be used to evaluate the grade of severity of the AE.  
Table 6 
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 (e.g., preparing meals, shopping for groceries or 
clothes, using the telephone, and managing money) 
3 
Severe: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
activities of daily living (e.g., bathing, dressing and undressing, feeding self, using the 
toilet, taking medications, and not bedridden) 
4 
Life-threatening: Life-threatening consequences; urgent intervention indicated 
5 
Death: Death related to AE 
CTCAE; Common Terminology Criteria for Adverse Events; NCI, National Cancer Institute 
Source: NCI-CTCAE 2017  
8.8.2 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 7. The Investigator’s 
assessment of causality must be provided for all AEs (serious and nonserious). 


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Table 7 
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, or for which it is temporally implausible to 
be related to use of the study drug. The cause must be noted on the AE eCRF. 
Possibly related to 
study drug 
An AE that might be due to the use of the drug. The relationship in time is 
reasonable; therefore, a causal relationship cannot be excluded. An alternative 
explanation is inconclusive, e.g., concomitant drug(s), concurrent disease(s). 
Probably related to 
study drug 
An AE that might be due to the use of the drug. The relationship in time is 
suggestive. An alternative explanation is less likely, e.g., concomitant drug(s) or 
concurrent disease(s). 
 
8.9 
Procedures for Reporting a Serious Adverse Event 
Any SAE occurring from the time of signing of the ICF and for at least 28 days after the last 
dose of study drug must be reported immediately (latest 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 (e.g., autopsy reports and terminal medical reports). 
Serious AE reporting details are provided below, as well as in the study manual.  
Reporting Contact Details: 
clinicalsafety@corcept.com  
8.10 
Adverse Event Follow-up 
All AEs considered to be possibly or probably related (Section 8.8.2) to the study drug and all 
SAEs 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. 
8.11 
Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to Corcept during the study and 
within 28 days of the last dose of study drug. The patient will be followed to determine the 
outcome of the pregnancy, and the outcome will be reported. 
8.11.1 Maternal Exposure 
If a patient becomes pregnant during the study, the study drug should be discontinued 
immediately. Pregnancy itself is not regarded as an AE.  
If a pregnancy occurs during the study or within 28 days of the last dose of study drug, 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 by completing the Pregnancy report 
form and submitting via email to clinicalsafety@corcept.com. 


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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. 
8.11.2 Paternal Exposure 
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth or 
congenital abnormality) should if possible be followed and documented. To capture information 
about a pregnancy from the partner of a male patient, the Investigator or designee must first 
obtain the consent of the male patient’s partner; the male patient should not be asked to provide 
this information. A consent form specific to this situation must be used. The outcome of any 
conception occurring from the date of the first dose until 28 days after dosing should be followed 
and documented. 
8.12 
Treatment of Overdose 
There is currently no experience with overdose of relacorilant. For monitoring symptoms of 
excessive GR antagonism, refer to Section 5.3.1. If clinically significant GR antagonism is 
suspected, dexamethasone may be administered. 
8.13 
Emergency Sponsor Contact 
In a medical emergency (i.e., 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 listed on the cover page. 


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9 
STATISTICAL METHODS 
9.1 
Analysis Populations 
The ITT-RW population will include all patients who were randomized in the double-blind RW 
phase and received at least one dose of study drug. The mITT-RW population will include all 
patients in the ITT-RW population with at least one post-randomization efficacy assessment for 
the primary efficacy endpoint (ABPM). The ITT-RW population will be used for the analysis of 
the primary endpoint in the RW Phase. 
The per-protocol analysis population (PP-RW) will include all patients in the mITT-RW 
population who completed the study according to protocol specifications without a major 
deviation. Protocol deviations resulting in exclusion from the PP population will be identified in 
the Statistical Analysis Plan (SAP). The determination of the PP analysis population will be 
finalized prior to database lock. Patients in the PP population who complete the RW phase 
without a major deviation will be used in sensitivity analyses of the primary endpoint and the 
secondary endpoints in the RW phase.  The mITT-RW and PP-RW populations will be used for 
supportive efficacy analyses of all endpoints in the RW Phase. 
The ITT-OL population will include all enrolled patients who received at least one dose of study 
drug. The mITT-OL population will include all patients in the ITT-OL population with at least 
one post-baseline efficacy assessment for efficacy endpoints. The per-protocol analysis (PP-OL) 
population will include all patients in the mITT-OL population who had no major protocol 
deviations that might impact the validity of the primary efficacy analysis. The ITT-OL, mITT-
OL, and PP-OL populations will be used for supportive efficacy analyses of all endpoints in the 
OL Phase. 
Analyses of glycemic control response measures will be performed on all patients in the 
ITT population with DM/IGT regardless of whether they have hypertension at Baseline. 
Analyses of hypertension response measures will be performed on all patients in the ITT 
population with hypertension, regardless of whether they have DM/IGT at Baseline.  
The Safety Population will consist of all enrolled patients who received at least 1 dose of study 
drug. It will be used for all safety analyses. 
9.2 
General Statistical Considerations 
The statistical analysis will be conducted by the Sponsor and/or its designee. Statistical methods 
will be prespecified and documented in detail in a statistical analysis plan, to be finalized before 
database lock. 
All continuous variables will be summarized using descriptive statistics (number of patients, 
means, percentiles, standard deviations) and confidence intervals (CIs) for values measured at 
each visit, as well as changes from Baseline. For categorical variables, counts, percentages, and 
their 95% CIs will be presented for each visit. 
Predose measurements on Day 1 will be considered the Baseline values for the OL phase 
(Baseline). If a Day 1 predose value is not available, the Screening measurement may be used as 
the Baseline value. For patients who were randomized in the RW phase, the measurements 


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collected at the visit prior to RW phase will be considered as the Baseline for the RW phase 
(RW Baseline). 
9.3 
Hypothesis Testing 
All statistical hypotheses will be tested at a 2-sided 0.05 significance level unless otherwise 
specified. No adjustments for multiplicity will be made for secondary and exploratory endpoints. 
9.4 
Sample-Size Calculation 
Approximately 162 patients are planned to enroll into a 6-month OL phase of the study to ensure 
the randomization of approximately 46 patients with hypertension into the subsequent 3-month, 
placebo-controlled RW phase.  
This calculation assumes that enrolled patients will consist of approximately 25% with DM/IGT 
only, 25% with hypertension only, and 50% with both DM/IGT and hypertension at Screening. 
Attainment of the randomization targets within the hypertension subgroup in the RW phase 
further assumes that 75% of patients that present with hypertension only randomize to the 
RW phase and 20% of patients that present with both comorbidities (DM/IGT and hypertension) 
respond to hypertension criteria at Visit OL22 (hypertension only or DM/IGT and hypertension 
as described in Section 3.1) and randomize to the RW phase. These assumptions will result in 
approximately 30 patients from the hypertension subgroup, and 16 patients from the DM/IGT 
and hypertension subgroup randomizing to the RW phase; thus, a total of approximately 
46 patients meeting response criteria will be randomized into the hypertension subgroup of the 
ITT-RW analysis population. 
Study enrollment will be monitored to ensure attainment of randomization targets. To maintain 
sufficient power to detect treatment difference, the number of patients enrolled in the OL phase 
may be adjusted to ensure a sufficient number of patients meeting response criteria to 
uncontrolled hypertension are randomized in the RW phase. Enrollment of patients may continue 
based on enrollment target projections. 
Forty-six patients with hypertension (23 per treatment group) will ensure at least 90% power to 
detect the difference between placebo and treatment arms in loss of response, assuming a loss of 
response in 25% of patients in the treatment arm and 75% in the placebo arm. These calculations 
are based on a Fisher’s exact test of proportions at the alpha=0.05 two-sided significance level. 
In summary, randomization of patients in the RW phase will continue to ensure enrollment of 
46 patients meeting response criteria within the hypertension subgroup. This sample size will 
provide sufficient power to detect the target differences in the primary endpoint for the 
hypertension subgroup. 
9.5 
Analysis Plan 
9.5.1 Patient Disposition 
The numbers of patients who were screened and who participated in the OL and RW phases 
along with the reasons for withdrawal in each phase will be summarized. 


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9.5.2 Demographic and Baseline Data 
Demographics and baseline characteristics will be summarized for the Safety Population, 
ITT-OL, and ITT-RW populations. The summaries will include frequencies and percentages for 
categorical variables, and mean, standard deviation, median, minimum, and maximum for 
continuous variables.  
These summaries will include patient medical history, including the diagnosis, etiology, and 
treatment history of Cushing syndrome. 
9.5.3 Prior and Concomitant Medications 
A list of all medications for diabetes, hypertension, or Cushing-syndrome–related comorbidities 
used at Baseline and each study visit will be generated.  
9.5.4 Analysis of Efficacy Endpoints 
9.5.4.1 
Analysis of the Primary Efficacy Endpoint 
For the hypertension subgroup of the ITT-RW population, the primary analysis will be a 
responder analysis and the odds ratio for loss of response in hypertension control will be 
reported, as well as the percentage of patients with loss of response and 95% CI (using Clopper-
Pearson method). The loss of response with respect to hypertension will be compared between 
treatment and placebo arms at Visit RW12 using a logistic regression model with 2 independent 
variables (treatment arm and stratification factor). In the hypertension subgroup, this 
stratification factor identifies patients with or without DM/IGT. 
In the hypertension subgroup, loss of response in the RW phase is defined as: use of rescue 
medication for hypertension after randomization but before Visit RW12, discontinuation of 
treatment before Visit RW12, or increase in SBP/DBP of >5 mmHg documented after 
randomization. This will be considered the primary analysis for the endpoint loss of response 
with respect to hypertension at Visit RW12 in the hypertension subgroup of the ITT-RW 
population. 
A sensitivity analysis of the primary endpoint by region will be done. Details will be described in 
the SAP. Additional sensitivity analyses may be pre-specified in the SAP. 
9.5.4.2 
Approach to Missing Data Analysis 
All efforts will be made to prevent missing data. In the hypertension subgroup of the ITT-RW 
population, patients that discontinue treatment prior to Visit RW12, use rescue medication prior 
to Visit RW12, or for whom SBP/DBP measurements were not collected at Visit RW12, and 
therefore have missing data at Visit RW12 will be considered as non-responders in the primary 
analysis for loss of response in hypertension control. 
Imputation of missing data at Visit RW12 for the secondary continuous endpoints (i.e., SBP, 
DBP) related to assessment of hypertension control will be performed based on data from 
retrieved dropouts, with similar baseline characteristics, within the same treatment arm. For 
patients who use rescue medication for hypertension before Visit RW12, a placebo-based mean 
imputation method will be used to impute the Visit RW12 value. If fewer than 10 retrieved 


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dropouts are available, then the main analysis will use a wash-out multiple imputation method 
instead of the retrieved dropout approach. 
In patients in the DM/IGT subgroup, imputation of missing data at Visit RW12 for the secondary 
endpoint of change in AUCglucose from Visit OL22 to Visit RW12 will be performed depending 
on whether or not patient takes rescue medication. For patients who do not use rescue medication 
for DM/IGT before Visit RW12 (regardless if they discontinue treatment), all values for 
AUCglucose up to the Visit RW12, will be used in the analysis (including values from retrieved 
dropouts). Patients who do not take rescue medication for whom AUCglucose at Visit RW12 is 
missing will have data imputed based on data from retrieved dropouts, with similar baseline 
characteristics, within the same treatment arm. For patients who use rescue medication for 
DM/IGT before Visit RW12, the values measured after the use of rescue medication are 
considered irrelevant to the clinical question of interest. In this case, a placebo-based mean 
imputation method will be used. 
The guidance on The Prevention and Treatment of Missing Data in Clinical Trials (National 
Research Council 2010) will be followed when these methods are applied.  
9.5.4.3 
Multiplicity Adjustment for Secondary Efficacy Endpoints 
No adjustment for multiplicity will be made for secondary and exploratory endpoints. 
9.5.4.4 
Analysis of the Secondary Efficacy Endpoints in the RW Phase  
For continuous endpoints in the RW phase of the study, the analysis will be performed using a 
linear MMRM model. Restricted maximum likelihood (REML) estimation will be used. The 
MMRM model will include Visit OL22 value (for the respective endpoint) as a covariate; 
treatment, visit, treatment by visit interaction, and stratification factor as fixed effects; and 
patients within treatment groups as random effects. An unstructured covariance structure will be 
used to model within-patient error, and the Kenward-Roger approximation will be used to model 
denominator degrees of freedom. This model is used after imputation of missing data at Visit 
RW12, using the retrieved drop-out approach. If fewer than 10 retrieved dropouts are available 
for the endpoint, then the main analysis will use a wash-out multiple imputation method instead 
of the retrieved dropout approach. 
The analysis for each of the endpoints will determine whether there is a difference between 
treatment groups in terms of change from Randomization to Visit RW12. This will be 
accomplished by using appropriate linear contrasts of the parameters in the MMRM model 
described above. Additional details will be described in the SAP. 
For all endpoints described as proportions in the RW phase, the point estimate and the 2-sided 
95% CI will be calculated.  
Sensitivity analyses will be pre-specified in the SAP. 
9.5.4.5 
Analyses of Exploratory Efficacy Endpoints  
The Exploratory Endpoints listed in Section 3.6.3 will be analyzed using methods similar to the 
analyses of secondary endpoints described in Section 9.5.4.4 and will be detailed further in the 
SAP.  


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9.5.5 Safety Analyses 
Safety variables will be analyzed for the Safety Population, defined as all patients who received 
at least 1 dose of study drug.  
TEAEs will be summarized separately in the following four categories: Overall TEAEs; TEAEs 
that start prior to Randomization; TEAEs that start after randomization through the end of RW 
phase, summarized by treatment group; and TEAEs that start during the follow-up period 
summarized by treatment group. TEAEs for patients who were not randomized will be 
summarized separately. Serious AEs and TEAEs that lead to study drug withdrawal or 
withdrawal from the study will be listed by patient. 
TEAEs will be summarized by study period and treatment, as applicable, and displayed using the 
Medical Dictionary for Regulatory Activities (MedDRA) system organ class and preferred term, 
as well as by intensity and relationship to the study drug. Serious AEs and treatment-emergent 
AEs that lead to study drug withdrawal or withdrawal from the study will be listed by patient.  
Clinical laboratory test results (chemistry and hematology), vital sign measurements, and ECG 
interval results will be summarized as changes over the OL phase and RW phase by parameter 
and visit using descriptive statistics. Changes in the laboratory results during the Follow-up 
period will be summarized separately. Shift tables will describe changes from Baseline in clinical 
laboratory values. 
9.5.6 Pharmacodynamic Analysis 
Analysis of PD endpoints, which include changes from Baseline to Visit OL22/ET in fasting 
serum cortisol, UFC, late-night salivary cortisol, and plasma ACTH levels, will be described in 
the SAP finalized before database lock. 
9.5.7 Pharmacokinetic Analysis 
The details of the PK analysis will be outlined in a separate document. 


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10 
ETHICAL AND LEGAL CONSIDERATIONS 
10.1 
Compliance with IRB/IEC Regulations 
This study is to be conducted in accordance with IRB regulations (US 21 Code of Federal 
Regulations [CFR] Part 56.103), IEC regulations, or applicable local regulations. The protocol, 
ICFs, recruitment materials, and all patient materials will be submitted to the IRB/IEC for review 
and approval. Approval of both the protocol and the ICF must be obtained before any patient is 
enrolled, and the Investigator must submit written approval to the Sponsor, before enrolling any 
patient. The Investigator is responsible for informing the IRB/IEC of any amendment to the 
protocol in accordance with local requirements. The protocol must be re-approved by the IRB or 
IEC on receipt of amendments and annually, as local regulations require. 
All changes to the ICF must be approved by the IRB/IEC; a determination will be made 
regarding whether previously consented patients need to be re-consented. 
Corcept is to be notified immediately if the responsible IRB/IEC has been disqualified or if 
proceedings leading to disqualification have begun. Copies of all IRB/IEC correspondence with 
the Investigator should be provided to Corcept. 
Progress reports and notifications of SAEs will be provided to the IRB or IEC according to local 
regulations and guidelines. 
10.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP and applicable regulatory 
requirements. 
The Principal Investigator will ensure that the study procedures outlined in this protocol will be 
conducted in accordance with applicable country and local regulations. 
10.3 
Protection of Human Patients 
10.3.1 Compliance with Informed-Consent Regulations  
Written informed consent is to be obtained from each patient before enrollment into the study.  
The Principal Investigator(s) at each study site 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. 


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The patient’s signed and dated ICF must be obtained before conducting any study procedures. 
The Principal Investigator(s) must maintain the original, signed ICF. A copy of the signed ICF 
must be given to the patient. 
10.3.2 Patient Confidentiality 
To maintain patient privacy, all study reports and communications will identify the patient by 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 as required by applicable laws and regulations. 
10.3.3 Patient Privacy 
The Investigator or designee must explain to each patient, before enrollment into the study, that 
for evaluation of study results, the patient’s protected health information obtained during the 
study may be shared with the Sponsor, regulatory agencies, and IRBs/IECs/Research Ethics 
Board. It is the Investigator’s (or designee’s) responsibility to obtain written permission to use 
protected health information per country-specific regulations from each patient. If permission to 
use protected health information is withdrawn, it is the Investigator’s responsibility to obtain a 
written request, to ensure that no further data are collected from the patient and that the patient is 
removed from the study. 
Written authorization is to be obtained from each patient before enrollment into the study in 
accordance with the applicable privacy requirements. 
10.3.4 Data Protection 
Corcept, as Data Controller, ensures that all processing activities involving personal data 
performed in the scope of this study are compliant with, but not limited to, the requirements set 
by EU General Data Protection Regulation (GDPR 679/2016), its subsequent amendments and 
any additional national laws on Data Protection, recommendations and guidelines as applicable. 
To comply with the applicable rules on the protection of personal data, specifically regarding the 
implementation of the organizational and technical arrangements aiming to avoid unauthorized 
access, disclosure, dissemination, alteration or loss of information and processed personal data, 
Corcept has implemented and maintains the following measures: 
• Restriction and monitoring of physical access to the offices and information processing 
facilities to employees, personnel and approved visitors; 
• Appropriate and restricted user access relevant to the function and type of activity 
performed in relation to the clinical trial; 
• Effective pseudonymization of personal data in compliance with EDPB 
Recommendations 01/2020 (v2.0 adopted 18 June 2021); 
• Encryption of personal data, where appropriate; 
• Ability to ensure the ongoing confidentiality, integrity, availability and resilience of 
processing systems and services;  


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• Network, application and database security by means of firewalls and antivirus/anti-
malware; ensuring detection of malware purposed for unauthorized deletion, blocking, 
copying of information, disabling security measures and response to such attacks; 
• Means to restore the availability and access to personal information in a timely manner in 
the event of a physical or technical incident;  
• Logging of security events/incidents in information systems;  
• Procedures that cover reporting, analysis, monitoring and resolution of security incidents; 
• Ensuring that information systems, computers and software involved in the performance 
of the services provided in the study are backed up; 
• A process for regularly testing, assessing and evaluating the effectiveness of technical 
and organizational measures for ensuring the security of the processing;  
• Procedures to capture in a timely manner if a personal data breach has occurred; 
• Procedures and practices for destruction of paper documents containing personal data; 
• Business continuity procedures ensuring that Corcept can continue to provide services 
through operational interruption. 
All locations, personnel and information systems that are used to perform services for the study 
will be covered; 
Corcept will ensure technical and organizational security measures described above, are 
regularly reviewed and updated to take into account any evolution on technological 
developments. 
Corcept may apply additional specific statutory requirements, where applicable in the national 
laws, and will implement the necessary security measures even if they are not expressly listed 
above. 
Besides the already above-mentioned technical and organizational measures, Corcept, by means 
of internal measures and imposed contractual clauses to the selected vendors and partners (in 
their role of processors), ensures the confidentiality of records and personal data of subjects. 
With exception of the activities in the scope of the on-site monitoring, inspections, or audits , the 
name of the patient will neither be asked for, nor recorded by the Corcept. An identification 
number will be allocated to each patient registered in the study. This number will identify the 
patient and will be included on all case report forms and corresponding material and data 
associated with the patient.  
Monitors acting on behalf of the Corcept will have access to fully identifiable information only 
in the scope of the on-site monitoring visits, and only for the source data verification mandatory 
under clinical trial framework, including the ICH-GCP obligations applicable to the conduct of 
the study. Staff involved in the performance of this task is bound by any additional stricter 
confidentiality clauses imposed upon them, as compared to other staff members.  
Corcept has put in place a functional process of reporting of any data breach occurring at Corcept  
or its vendor’s and partner’s (in their role of processor) facilities and premises. In case of the 
occurrence of any data breach, Corcept will immediately apply relevant measures to mitigate the 
risks to data subjects as appropriate in relation to the specific context of the data breach, taking 
into account its source, underlying intentions, possibilities of recovery, etc. Any data breach 
presenting risks to the rights and freedoms of data subjects will be reported to the relevant 


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supervisory data protection authority within 72 hours of Corcept becoming aware of the data 
breach. In addition, in case of occurrence of a high-risk breach, data subjects will be informed by 
the Corcept (via clinical-study site). 


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11 
ADMINISTRATIVE CONSIDERATIONS 
11.1 
Quality Management 
As part of quality management based on a risk-based approach per ICH E6(R2): risk reduction 
activities may be incorporated in protocol design and implementation, monitoring plans, 
agreements between parties defining roles and responsibilities, systematic safeguards to ensure 
adherence to standard operating procedures, and training in processes and procedures.  
Predefined quality tolerance limits should be established, taking into consideration the medical 
and statistical characteristics of the variables as well as the statistical design of the trial, to 
identify systematic issues that can impact subject safety or reliability of trial results. Detection of 
deviations from the predefined quality tolerance limits should trigger an evaluation to determine 
if action is needed.  
Study sites, the study database, and study documentation will be monitored regularly and may be 
subject to a quality assurance audit during the study by the IRB/IEC and/or the Sponsor or its 
designee. In addition, inspections may be conducted by regulatory agencies at their discretion.  
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks will be run on the database. Any missing data or data anomalies will be 
communicated to the study site(s) for clarification/resolution.  
Following written SOPs, the study-specific monitoring plan, the monitors will verify that the 
clinical study is conducted, data are generated, documented (recorded), and reported in 
compliance with the protocol, GCP, and the applicable regulatory requirements (e.g., Good 
Laboratory Practices, Good Manufacturing Practices). 
Upon request, the investigational site will provide direct access and allow the Sponsor (or its 
representative including monitors and/or auditors), IRB/IEC and regulatory authorities to review 
and inspect all trial-related sites, drug storage area, study-drug stock, drug accountability records, 
patient charts, source documents, and other records related to study conduct. 
The Investigator should contact the Sponsor or their designee immediately if contacted by a 
regulatory agency regarding an inspection. 
11.2 
Study Monitoring 
The Sponsor, or designee, will be responsible for the monitoring of the study. Study monitors 
will contact and visit the Investigators at regular intervals throughout the study to answer study 
questions, and to systematically and independently examine all study-related activities, verify 
adherence to the protocol, and assess the completeness, consistency, and accuracy of the data.  
Monitoring may include, but is not limited to: 
• Reviewing eCRFs for accuracy and completeness. 
• Assessing compliance with the protocol and adherence to regulatory and GCP 
requirements. 
• Verifying that the site maintains an adequate supply of study drugs, any necessary 
supplies, and that appropriate storage conditions are maintained. 


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Monitoring visits will be conducted according to the ICH Guideline for GCP and all applicable 
country and local regulations and guidance. 
By agreeing to participate in this research study, the Investigators agree to co-operate with the 
study monitor to ensure that any problems detected during the monitoring visits are promptly 
resolved.  
Monitoring methods, responsibilities, and requirements will be outlined in the study monitoring 
plan. 
11.3 
Documentation 
11.3.1 Source Documents 
Source documents provide all original records of clinical findings, observations, or other 
information from a clinical trial necessary for the reconstruction and evaluation of the trial 
(e.g., a patient’s medical records, hospital charts, clinic charts, the Investigator’s patient study 
files, results of diagnostic tests, including x-rays, laboratory tests and ECGs). All source data 
should be attributable, legible, contemporaneous, original, accurate, and completed. Changes to 
source data should be traceable (i.e., dated and initialed), should not obscure the original entry, 
and should be explained, if necessary.  
Investigators must retain all original source documents. The Sponsor or its designee will notify 
Investigators in writing when the trial-related records are no longer needed. 
11.3.2 Case Report Forms 
The Investigator must generate and maintain complete, adequate, accurate, reliable, and legible 
records in a timely manner to enable full documentation of study conduct. All data entered into 
CRFs (paper or electronic) must be substantiated by and consistent with a source document.  
Discrepancies between CRFs and their respective source documents should be explained. All 
changes in eCRF data entry at the study site will be performed by designated site personnel and 
will be in the clinical database audit trail. In the event paper CRFs are utilized, any change or 
correction to a CRF should be dated, initialed, and explained (if necessary) and should not 
obscure the original entry.  
All changes in CRF data entry at the study site will be performed by designated site personnel.  
11.3.3 Retention of Essential Study Documents 
The Investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified.  
Study essential documents, which include the patient identification code list (i.e., patient names 
and corresponding study numbers), should be retained for a minimum of 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed since 
the formal discontinuation of clinical development of the study drug. These documents should be 
retained for a longer period, however, if required by local regulations.  


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No records will be destroyed without the written consent of the Sponsor, if applicable. If the 
Investigator can no longer maintain the records, it is the responsibility of the Investigator to 
contact the Sponsor. These documents may be transferred to another responsible party, 
acceptable to the Sponsor, who agrees to abide by the retention policies. Written notification of 
transfer must be submitted to the Sponsor. It is the responsibility of the Sponsor to inform the 
Investigator when these documents no longer need to be retained. It is the responsibility of the 
Sponsor to inform the Investigator when these documents no longer need to be retained. 
11.3.4 Sample Collection, Preparation, and Shipping 
Instructions for collection, preparation, and shipping of all laboratory samples will be provided 
in the Study Laboratory Manual. 
11.4 
Long-Term Retention of Biological Samples 
All biological samples will be retained by the Sponsor or designee under the original informed 
consent of the patient and the IRB/IEC approval. Samples will be held for a period up to 15 years 
after completion of the clinical study report. The Sponsor or its designee may store the patient’s 
sample(s) longer if required to address regulatory agency questions; in this event, the patient’s 
sample(s) will be destroyed after all questions are adequately answered. 
An individual patient can choose to withdraw consent to have their samples used for future 
research at any time without affecting their participation in the study or their care by the health 
provider. After receipt of a request for sample destruction, that patient’s sample(s) will then no 
longer be used for future research purposes beyond the current study, and their sample(s) will be 
destroyed. However, if there are ongoing regulatory questions, the patient’s sample(s) will be 
destroyed after all questions are adequately answered. 
The long-term retention samples will be coded to allow de-identification according to applicable 
regulatory guidelines. It is the responsibility of the trial site to ensure that samples are 
appropriately labeled in accordance with trial procedures to comply with all applicable laws. 
Biological samples collected from participants as part of this trial will be transported, stored, 
accessed, and processed in accordance with all applicable laws relating to the use and storage of 
human tissue for research purposes. 
Such activities shall at least meet the requirements as set out in the 2004 Human Tissue Act and 
the 2006 Human Tissue (Scotland) Act. 
Samples may be subject, but not limited to European Directives 2002/58/EC, the General Data 
Protection Regulation 2016/679, and any legislation and/or regulation implementing or made 
pursuant to them, or which amends, replaces, re-enacts, or consolidates any of them, and all other 
applicable laws relating to processing of personal data and privacy that may exist in any relevant 
jurisdiction. 


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11.5 
Clinical Supplies 
11.5.1 Inventory, Reconciliation, Return, and Disposition of Clinical Supplies 
All study drug and related materials should be stored, inventoried, reconciled, and destroyed or 
returned according to applicable state and federal regulations/government health authorities and 
study procedures. Storage of study drug is described in Table 1. 
11.5.2 Clinical-Supply Inventory 
Each clinical site is required to complete and maintain a detailed inventory for all study drug. 
The study drug is to be used in accordance with the protocol by patients who are under the direct 
supervision of an Investigator. The study drug must be dispensed only by an appropriately 
designated and qualified person to patients in the study.  
Unused study drug must be kept in a secure location for accountability and reconciliation by the 
study monitor. The Investigator or their designee must provide an explanation for any destroyed 
or missing study drug or study materials. 
The Investigator or their designee is responsible for maintaining accurate records (including 
dates and quantities) of study drug(s) received, patients to whom study drug is dispensed 
(patient-by-patient dose-specific accounting), and study drug lost or accidentally or deliberately 
destroyed. The Investigator or their designee must retain all unused or expired study supplies 
until the study monitor (on-site clinical research associate) has confirmed the accountability data 
and Sponsor has approved return or destruction. 
11.5.3 Return or Destruction of Study Drug and/or Supplies 
At the end of the study, after final drug-inventory reconciliation by the study monitor, the study 
site will either return study drug and/or supplies to the Sponsor or designee, or destroy all unused 
study drug and/or supplies, including empty containers, according to institutional policy. 
11.5.4 Study Drug Destroyed by the Site 
Unused/undispensed study drug and/or supplies may be destroyed on site, per the site’s SOPs, 
but only after Sponsor has granted approval for drug destruction. The study monitor must 
account for all study drug in a formal reconciliation process, before study drug destruction. All 
study drug destroyed on site must be documented.  
Any destruction of study drug on site must be documented. Documentation must be provided to 
the Sponsor and retained in the Investigator study files. 
11.5.5 Study Drug Returned to Sponsor for Destruction 
If a site is unable to destroy unused/undispensed study drug and/or supplies appropriately, the 
site can request return of study drug and/or supplies to the Sponsor or designee.  
The return of study drug and/or supplies must be accounted for on a Study Drug Return Form 
provided by the Sponsor or designee. 


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11.5.6 Drug Accountability 
It is the responsibility of the Investigator to maintain drug accountability at the study site and 
ensure that a current record of study drug disposition is maintained. It is the responsibility of the 
Investigator to ensure that the study drug is used only in accordance with the approved protocol. 
This includes acknowledgment of receipt of each shipment of study product (quantity and 
condition), patient dispensing records, and returned, lost, or accidentally or deliberately 
destroyed study product.  
Dispensing records will document quantities received from the Sponsor (or its designee) and 
quantities dispensed to patients, including lot number, date dispensed, patient identifier number, 
patient initials, the initials of the person dispensing the drug, quantities of drug returned by the 
patients and disposal/return of returned study drug. 
11.6 
Post-Trial Care 
There is provision of continued access to study drug by way of a roll-over/extension study 
(Section 3.2.3). 
11.7 
Protocol Noncompliance 
A protocol deviation is any noncompliance with requirements in the clinical-trial protocol, GCP, 
or the manual of procedures (MOP) requirements. The noncompliance may be on the part of the 
patient, the Investigator, or the study-site staff. As a result of deviations, corrective actions 
consistent with ICH E6(R2) may be implemented.  
Prospective approval of deviations from the inclusion and exclusion criteria, known as protocol 
waivers or exemptions, is not permitted. Changes to the conduct of the protocol may not be 
made, except to address an immediate risk to the patient, unless the change has been submitted to 
the regulatory authorities for review and the change has been approved by the IRB/IEC.  
Sponsor clinical-study staff and contractors may acknowledge, but not approve, protocol 
deviations reported by a site that have happened or are planned to happen.  
Any significant protocol deviations affecting patient eligibility and/or safety or data integrity 
must be submitted to the IRB/IEC and regulatory authorities, as applicable, prior to 
implementation.  
After the protocol is approved by the Sponsor and by IRB/IEC, any change that might affect the 
approval of the IRB/IEC must be documented in the form of a protocol amendment. The 
amended protocol must be approved by the IRB/IEC and annually, as local regulations require.  
11.8 
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.  
11.9 
Publication and Disclosure Policy 
Corcept, as the Sponsor, has a proprietary interest in this study.  


Protocol CORT125134-455
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Amendment 7 | 17 May 2024 
Confidential 
Page 106 of 116 
No individual publications will be allowed before publication of the multicenter results, except 
as agreed with the Sponsor. The Investigator agrees to submit all manuscripts or abstracts to the 
Sponsor for review before submission to the publisher. 
The Sponsor will comply with the requirements for publication of study results and 
determination of authorship in accordance with standard editorial and ethical practice and with 
the International Committee of Medical Journal Editors (ICMJE) requirements. 
11.10 Electronic Systems 
All electronic systems, including clinical study sites, clinical operations, data management, 
biostatistics, safety, and CRO systems, etc., used to collect, manage, and storage study data 
should be validated and in compliance with 21 CFR Part 11 and EU Annex 11 guideline. The 
validation documentation should be made available at all times during inspection or Sponsor 
audits. Any modification to the validated system should be documented via a quality change 
control process and justified for their intended use.  


Protocol CORT125134-455
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Amendment 7 | 17 May 2024 
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Page 107 of 116 
12 
REFERENCES 
American Diabetes Association. 2020. 9. Pharmacologic Approaches to Glycemic Treatment: 
Standards of Medical Care in Diabetes—2020. Diabetes Care. Jan;43(Suppl 1): S98–
S110. 
Beck AT, Steer RA, Brown GK. 1996. Beck Depression Inventory®-II(BDI®-II) Manual. 
Pearson Publishing Company, London, UK. 
Castinetti F, Guignat L, Giraud P, et al. 2014 . Ketoconazole in Cushing's disease: Is it worth a 
try? J Clin Endocrinol Metab. 99(5):1623–1630. doi: 10.1210/jc.2013-3628.  
Colao A, Petersenn S, Newell-Price J, et al. 2012. A 12-month phase 3 study of pasireotide in 
Cushing’s disease. N Engl J Med. 366:914–924. doi: 10.1056/NEJMoa1105743. 
Cuevas-Ramos D, Fleseriu M. 2014. Treatment of Cushing’s disease: a mechanistic update. 
J Endocrinol. 223(2):R19–39. doi: 10.1530/JOE-14-0300. 
Debono M, Bradburn M, Bull M, Harrison B, Ross RJ, Newell-Price J. 2014. Cortisol as a 
marker for increased mortality in patients with incidental adrenocortical adenomas. J Clin 
Endocrinol Metab. Dec;99(12):4462‒4470. doi: 10.1210/jc.2014-3007. 
Dekkers OM, Horváth-Puho´ E, Jørgensen JO, Cannegieter SC, Ehrenstein V, Vandenbroucke 
JP, et al. 2013. Multisystem morbidity and mortality in Cushing’s syndrome: a cohort 
study. J Clin Endocrinol Metab. Jun;98(6):2277–2284. doi: 10.1210/jc.2012-3582. 
EMA 2020. European Medicines Agency Guidance on the Management of Clinical Trials during 
the COVID-19 (Coronavirus) pandemic, Version 3 (28/04/2020). 
EMA/CHMP (European Medicines Agency/Committee for Medicinal Products for Human Use). 
2014. Ketoconazole HRA. Assessment Report, EMA/CHMP/534845/2014. Procedure 
No. EMEA/H/C/003906/0000. Accessed at: http://www.ema.europa.eu/docs/en_GB/ 
document_library/EPAR_Public_assessment_report/human/003906/WC500181493.pdf. 
Esposito K, Giugliano D, Nappo F, et al. 2004. Regression of carotid atherosclerosis by 
control of postprandial hyperglycemia in type 2 diabetes mellitus. Circulation. 
13;110(2):214–219. 
FDA (US Food and Drug Administration). 2020. Conduct of Clinical Trials of Medical Products 
During the COVID-19 Public Health Emergency. Guidance for Industry, Investigators, 
and Institutional Review Boards; December 4, 2020. 
Fleseriu M, Biller BM, Findling JW, et al. 2012. Mifepristone, a glucocorticoid receptor 
antagonist, produces clinical and metabolic benefits in patients with Cushing's syndrome. 
J Clin Endocrinol Metab. 97(6):2039–2049. doi: 10.1210/jc.2011-3350. 
Gerich J. 2013. Pathogenesis and management of postprandial hyperglycemia: Role of incretin-
based therapies. Int J Gen Med. 6:877–895. doi: 10.2147/IJGM.S51665. 
Giraldi FP, Pivonello R, Ambrogio AG, et al. 2007. The dexamethasone-suppressed 
corticotropin-releasing hormone stimulation test and the desmopressin test to distinguish 
Cushing’s syndrome from pseudo-Cushing’s states. Clin Endocrinol. 66:251–257. 


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Katznelson L, Loriaux DL, Feldman D, et al. 2014. Global clinical response in Cushing’s 
syndrome patients treated with mifepristone. Clin Endocrinol. 80:562–569. doi: 
10.1111/cen.12332. 
NCI (National Cancer Institute). 2017. Common Terminology Criteria for Adverse Events, 
version 5.0 published: November 27, 2017. US Department of Health and Human 
Services, National Institutes of Health, Accessed at https://ctep.cancer.gov/ 
protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x 
11.pdf.  
National Research Council. 2010. The Prevention and Treatment of Missing Data in Clinical 
Trials. Panel on Handling Missing Data in Clinical Trials. Committee on National 
Statistics, Division of Behavioral and Social Sciences and Education. Washington, DC: 
The National Academies Press.  
Nieman LK, Biller BMK, Findling JW, et al. 2008. The diagnosis of Cushing’s syndrome: An 
Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 93(5):1526–1540. 
doi: 10.1210/jc.2008-0125. 
Nieman LK, Biller BM, Findling JW, et al. 2015. Treatment of Cushing’s syndrome: An 
Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 100(8): 
2807–2831. doi: 10.1210/jc.2015-1818. 
Parati G, Stergiou G, O’Brien E, et al. 2014. European Society of Hypertension practice 
guidelines for ambulatory blood pressure monitoring. J Hypertens. 32:1359–66. doi: 
10.1097/HJH.0000000000000221. 
Prandin 2017. Prescribing information. Novo Nordisk, Plainsboro, NJ. Accessed at: 
https://www.novo-pi.com/prandin.pdf.  
Shepherd JA, Ng BK, Sommer MJ, et al. 2017. Body composition by DXA. Bone. 104:101–105. 
doi: 10.1016/j.bone.2017.06.010. 
Starlix. 2018. Prescribing information. Novartis Pharmaceuticals Corporation, East Hanover, NJ. 
Accessed at: https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/ 
files/Starlix.pdf.  
Webb SM, Badia X, Barahona MJ, et al. 2008. Evaluation of health-related quality of life in 
patients with Cushing’s syndrome with a new questionnaire. Eur J Endocrinol. 158: 
623–630. doi: 10.1530/EJE-07-0762. 
Yanovski JA, Cutler Jr GB, Chrousos GP, et al. 1993. Corticotropin-releasing hormone 
stimulation following low-dose dexamethasone administration: a new test to distinguish 
Cushing’s syndrome from pseudo-Cushing’s states. JAMA. 269(17):2232–2238. 
Yanovski JA, Cutler Jr GB, Chrousos GP, et al. 1998. The dexamethasone-suppressed 
corticotropin-releasing hormone stimulation test differentiates mild Cushing’s disease 
from normal physiology. J Clin Endocrinol Metab. 83(2):348–352. 
 


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13 
APPENDICES 
Appendix A: Schedule of Events 
Table 8 
Schedule of Visits and Procedures 
Study Procedure 
Screening a Baseline 
Open-Label Phase 
Weeks 1 to 22 
Random
-ization 
Randomized-
Withdrawal Phase 
(Weeks 1 to 12) 
Early 
Term-
ination 
Follow
-up b 
Visit Name 
— 
B 
OL2 
OL6 OL10 OL14 OL18 OL22 
R 
RW4 RW8 RW12 
ET 
— 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Visit Window (d) −42 to −1 
— 
±3d 
±3d 
±3d 
±7d 
±7d 
±7d 
+14 
±7d 
±7d 
±7daa 
±7d 
±7d 
Informed consent 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Inclusion/exclusion criteria 
X 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Response criteria 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
- 
- 
Medical and medication history c 
X 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Demographics/baseline disease 
characteristics 
X 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Physical examination d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Waist circumference 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events f 
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 
Photographs g 
- 
X 
- 
X 
X 
X 
X 
X 
- 
- 
- 
X 
X 
- 
12-Lead ECG h 
X 
X 
X 
X 
X 
X 
- 
X 
- 
- 
- 
X 
X 
X 
Pregnancy test (women only) i 
X (s) 
X (u) 
X (u) X (u) X (u) X (u) X (u) X (u) 
X (u) 
X (u) X (u) 
X (u) 
X (u) 
X (u) 
Chemistry j, Hematology k 
X 
X 
X 
X 
X 
X 
X 
X 
- 
X 
X 
X 
X 
X 
Lipid panel (fasting) l 
- 
X 
- 
- 
- 
- 
- 
X 
- 
- 
- 
X 
X 
- 


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Study Procedure 
Screening a Baseline 
Open-Label Phase 
Weeks 1 to 22 
Random
-ization 
Randomized-
Withdrawal Phase 
(Weeks 1 to 12) 
Early 
Term-
ination 
Follow
-up b 
Visit Name 
— 
B 
OL2 
OL6 OL10 OL14 OL18 OL22 
R 
RW4 RW8 RW12 
ET 
— 
Sex-hormone levels m 
- 
X 
- 
- 
- 
- 
- 
X 
- 
- 
- 
X 
X 
- 
GR activity biomarker tests 
X 
X 
- 
X 
X 
X 
- 
X 
- 
- 
- 
X 
X 
- 
Serum osteocalcin n 
- 
X 
- 
- 
- 
- 
- 
X 
- 
- 
- 
X 
X 
- 
2-hour oGTT o 
X 
Xbb 
- 
X 
X 
X 
X 
X 
- 
X 
X 
X 
X 
- 
HbA1c p 
X 
Xbb 
- 
- 
X 
- 
- 
X 
- 
- 
- 
X 
X 
- 
HPA-axis parameters q 
X 
X 
- 
X 
X 
- 
- 
X 
- 
- 
- 
X 
X 
- 
Thyroid function tests r 
- 
X 
- 
- 
- 
- 
- 
X 
- 
- 
- 
X 
X 
- 
Intensive PK sampling s 
- 
- 
- 
- 
- 
- 
X s 
- 
- 
- 
- 
- 
- 
- 
24-hour UFC with creatinine t 
X 
- 
- 
X 
X 
X 
- 
X 
- 
- 
- 
X 
X 
- 
DST u 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Late-night salivary cortisol t 
X 
- 
- 
X 
X 
X 
- 
X 
- 
- 
- 
X 
X 
- 
Menstrual cycle information v 
X 
X 
- 
X 
X 
X 
X 
X 
- 
X 
X 
X 
X 
- 
DXA scan for body-fat 
composition  
- 
X w 
- 
- 
- 
- 
- 
X 
- 
- 
- 
X 
X w 
- 
ABPM (24-hour) test x 
X 
Xbb  
X 
X 
X 
X 
X 
X 
- 
X 
X 
X 
X 
- 
Sit-to-stand test 
- 
X 
- 
X 
X 
X 
X 
X 
- 
X 
X 
X 
X 
- 
Trail-making test 
- 
X 
- 
X 
X 
X 
X 
X 
- 
X 
X 
X 
X 
- 
Cushing QoL questionnaire  
- 
X 
- 
X 
X 
X 
X 
X 
- 
X 
X 
X 
X 
- 
Beck Depression Inventory  
- 
X 
- 
X 
X 
X 
X 
X 
- 
X 
X 
X 
X 
- 
Pituitary MRI scan  
- 
X y 
- 
- 
- 
- 
- 
X 
- 
- 
- 
- 
X y 
- 
Dosing diary 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Study-drug dispensing and/or 
adherence z 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xcc 
X 
- 


Protocol CORT125134-455
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Amendment 7 | 17 May 2024 
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ABPM, ambulatory blood pressure monitoring; BP, blood pressure; DM/IGT, diabetes mellitus/impaired glucose tolerance; DRB, Data Review Board; DST, 
dexamethasone suppression test; DXA, dual-energy x-ray absorptiometry; ECG, electrocardiogram; ET, early termination; GR, glucocorticoid receptor; HbA1c, 
glycated hemoglobin; HPA, hypothalamic-pituitary-adrenal; MRI, magnetic resonance imaging; oGTT, oral glucose tolerance test; OL, open-label; PK, 
pharmacokinetics, QoL, quality-of-life; RW, randomized withdrawal; (s), serum; (u), urine; UFC, urinary free cortisol. 
 
a Medications used in the treatment of Cushing syndrome are prohibited and require washout (as applicable) during Screening if the intervals specified in 
Exclusion Criteria 12 and 13 fit within the Screening window. Patients requiring washout of a medication for Cushing syndrome must complete the 
Screening/Baseline HbA1c tests, oGTTs, and 24-hour ABPM tests after washout and within 2 weeks before Day 1 dosing; 24-hour UFC tests and salivary 
cortisol tests must be completed after washout.  
Screening assessments performed during the 6-week screening window can be used as Baseline data and assessments do not need to be repeated unless 
otherwise noted. 
b For patients who do not enroll in an extension study, the Follow-up visit will occur 28 days after the last dose of study drug. For patients who discontinue the 
study prior to the RW12 visit during the Randomized Withdrawal phase of the study and return for the RW12 visit, the follow up visit will be waived if the 
RW12 visit occurs at least 28 days after the last dose of administration of study drug. 
c Medication history for medications taken to treat Cushing syndrome, hypertension, or diabetes within 3 months before start of study. 
d Height is measured at Screening only. At all visits, Investigators will assess the general physical appearance of patients during the examination. 
e Vital signs: BP, heart rate, respiratory rate, oral body temperature. 
f 
Adverse events will be collected after the informed consent form is signed. Events ongoing at study entry are considered medical history.  
g Members of the DRB will review patient photographs to assess Cushingoid features.  
h ECGs will be obtained in triplicate at Screening and in duplicate at other study visits. ECGs will be obtained 2 hours ±30 minutes after study-drug dosing. 
i 
Pregnancy tests: for women of childbearing potential: (s)=serum pregnancy test at Screening; (u)=urine pregnancy test at other time points. 
j 
Chemistry parameters: full chemistry profile that includes albumin, alkaline phosphatase, ALT, AST, bicarbonate, 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. Results will remain blinded during the RW phase. 
k Hematology parameters: a complete blood count and differential. Results will remain blinded during the RW phase. 
l 
Lipid panel: total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, very low-density lipoprotein-cholesterol, and 
triglycerides. Results will remain blinded during the RW phase.  
m Sex hormones: estradiol, total and free testosterone, sex-hormone‒binding globulin, follicle-stimulating hormone, and luteinizing hormone. Results will 
remain blinded during the RW phase.  
n Results will remain blinded during the RW phase.  
o oGTT: the 2-hour oGTT will be performed on all patients during Screening. A 2-hour oGTT will be performed only in patients with DM/IGT except Visit 
OL22, Visit RW12, and ET Visit (if applicable), when a 2-hour oGTT will be performed for all patients. During the 2-hour oGTT, blood samples for plasma 
glucose and insulin are collected before the glucose drink and 0.5, 1, 1.5, and 2 hours after the glucose drink. Screening visit oGTT glucose results must be 
collected within 2 weeks of Day 1 and will be used for Baseline. Results will remain blinded during the RW phase. In patients randomized to the DM/IGT 
subgroup, oGTT assessments will continue as planned until Visit RW12. 
p HbA1c: Screening visit HbA1c results must be collected within 2 weeks of Day 1 and will be used for Baseline. During treatment with study drug, HbA1c 
will be performed in all patients during Screening, Visit OL10, Visit OL22, Visit RW12, and ET Visit (if applicable) and only in patients with DM/IGT 
during other indicated visits. Unless collected within 2 weeks of Day 1, HbA1c will be performed at Baseline (in DM/IGT patients only). Results will remain 
blinded during the RW phase. 
q HPA-axis: plasma ACTH, fasting serum cortisol, and DHEA-S. Results will remain blinded during the RW phase. 


Protocol CORT125134-455
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Amendment 7 | 17 May 2024 
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Page 112 of 116 
r 
Thyroid function tests: free T4 Reflex, Total T3 Reflex, thyroid-stimulating hormone. Results will remain blinded during the RW phase. 
s 
PK at OL18: blood samples will be collected in all patients following the observed dose at Visit OL18, predose (0 hour) and at 1, 2, 4, and 6 hours postdose. 
t 
UFC and salivary cortisol: 24-hour UFC and salivary cortisol test samples will be collected by the patient at home at least twice during Screening. A 
minimum of two 24-hour urinary samples are collected during Screening, at least 1 week apart. The average of the results will serve as Baseline. During the 
treatment with study drug, the 24-hour UFC and late-night salivary cortisol samples should be collected in duplicate, at the patient’s home, within 7 days 
prior to the next study visit. Results will remain blinded during the RW phase. 
u DST: 1-mg overnight or 2-mg 48-hour test may be performed during Screening or within 12 weeks before signing the informed consent, if necessary. 
v Menstrual cycle information: obtain only from premenopausal female patients. 
w DXA scan: Baseline assessment may be performed ±6 weeks prior to Baseline Visit; scan should not be repeated if completed within 8 weeks before the 
ET Visit. 
x ABPM: The 24-hour ABPM will be assessed for all patients during Screening. For patients with uncontrolled hypertension, a 24-hour ABPM test must be 
performed within the 2 weeks prior to Day 1; this result will be used as Baseline. ABPM measurements during the study will be performed only for patients 
with hypertension except for Visit OL22, Visit RW12, and ET Visit (if applicable) when ABPM measurements will be assessed for all patients. Results will 
remain blinded during the RW phase. In patients randomized to the hypertension subgroup, ABPM assessments will continue as planned until Visit RW12. 
y Pituitary MRI: Baseline assessment may be performed ±6 weeks prior to Baseline Visit; scan does not need to be repeated if completed within 3 months of 
ET Visit. 
z At ET visit, only study adherence needs to be performed; no study drug should be dispensed. Administration of study drug is the last procedure at applicable 
visits, other than at visit OL18, when it should be administered prior to blood draws for PK assessment. 
aa If this visit is the return visit following early discontinuation from the RW phase, a 3-week visit window (2 weeks before the scheduled visit, 1 week after the 
scheduled visit) is permitted. 
bb oGTT (in DM/IGT patients only), HbA1c (in DM/IGT patients only), and ABPM (in hypertension patients only) will only be performed at Baseline if the 
prior assessment was not performed within 2 weeks.  
cc Patients will remain on study drug up to 1 week post RW12 visit until it has been confirmed that all results for efficacy and safety assessments are available 
and no repeat assessments are required. 
 


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Amendment 7 | 17 May 2024 
Confidential 
Page 113 of 116 
Appendix B: Summary of Changes 
Significant changes in Amendment 7 of the protocol dated 17 May 2024 compared with 
Amendment 6 dated 22 April 2024 are summarized below with additional details in Table 9; 
deleted text is shown as a strikethrough and new text is shown in bold.  
Minor editorial or stylistic changes made for consistency are not summarized and may not be 
shown in the redline version of the amendment (e.g., punctuation, spelling, abbreviations). 
Table of Contents, lists of tables or figures are updated without redline.  
Significant revisions to the protocol include the following: 
• Secondary and exploratory endpoints and their analysis methods were revised 


Protocol CORT125134-455
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Amendment 7 | 17 May 2024 
Confidential 
Page 114 of 116 
Table 9 
Summary of Changes in Protocol CORT125134-455 Amendment 6  
Section 
Summary of 
Change 
Revisions 
Global changes  
Updated 
version and 
date of the 
protocol. 
Amendment 6Amendment 7 
22 April 202417 May 2024 
Synopsis 
Updated text in 
synopsis to 
align with 
changes in the 
protocol body. 
-- 
3.6.2 Secondary 
Efficacy 
Endpoints in the 
Randomized-
Withdrawal 
Phase 
Added 
secondary 
endpoint; no 
longer 
distinguishing 
between key 
secondary and 
other 
secondary 
endpoints. 
Key Secondary Endpoint 
-- 
Other Secondary Endpoints 
-- 
• 
In patients with DM/IGT, the mean change in HbA1c from Visit 
OL22 to Visit RW12, as compared between relacorilant and placebo. 
3.6.3 
Exploratory 
Efficacy 
Endpoints in the 
Randomized 
Withdrawal 
Phase 
Added 
exploratory 
endpoint. 
• 
In all patients randomized in the RW phase, proportion of patients 
with a loss of response with respect to hypertension or hyperglycemia 
from Visit OL22 to Visit RW12 based on 24-hour ABPM and 
AUCglucose as compared between relacorilant and placebo arms, 
where loss of response is defined as follows: 
­ 
In patients with hypertension only at Baseline OL: 
 
In patients who met only the SBP response criterion, an 
increase in SBP ≥5 mm Hg. 
 
In patients who met only the DBP response criterion, 
an increase in DBP by ≥5 mm Hg. 
 
In patients who met both the SBP and DBP response 
criteria, an increase in either SBP or DBP by ≥5 mm 
Hg. 
 
Any increase or modification in antihypertensive 
medication due to worsening hypertension. 
 
Patients discontinue treatment in RW phase for any 
reason. 
­ 
In patients with DM/IGT only at Baseline OL: 
 
A ≥10% increase from Baseline RW in AUCglucose.from 
Visit OL22 to Visit RW12. 
 
Use of rescue medication (initiation or increase in 
diabetes medication due to worsening of hyperglycemic 
control). 
 
Treatment discontinuation for any reason in RW phase. 
 
Patients with missing RW12 AUCglucose values. 
• 
In patients with hypertension and DM/IGT at Baseline OL, a loss of 
response will be defined as a loss of response with respect to either 


Protocol CORT125134-455
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Amendment 7 | 17 May 2024 
Confidential 
Page 115 of 116 
Section 
Summary of 
Change 
Revisions 
hypertension or hyperglycemic control (AUC-based) from Visit OL22 
to Visit RW12, irrespective of which response criteria (hypertension 
or DM/IGT) they met to enter the RW phase. 
3.6.4 
Exploratory 
Efficacy 
Endpoints in the 
Open-Label 
Phase 
Exploratory 
endpoints 
added. 
Endpoints Summarized with Proportions 
-- 
• 
In patients with DM/IGT, the proportion of patients with ≥25% 
decrease in AUCglucose from Baseline to Visit OL22/ET. 
• 
In patients with DM/IGT, the proportion of patients with ≥0.5% 
decrease in HbA1c from Baseline to Visit OL22/ET. 
 
9.3 Hypothesis 
Testing 
Revised 
analysis 
methods. 
In order to ensure experiment-wise Type I error control, the secondary endpoints 
will be tested using a hierarchical testing approach at a 2-sided alpha level of 0.05. 
If the null hypothesis is rejected for the primary endpoint, secondary endpoints 
will be sequentially tested following the gatekeeping hierarchy specified in the 
SAP. No adjustments for multiplicity will be made for secondary and exploratory 
endpoints. 
9.5.4.1 Analysis 
of the Primary 
Efficacy 
Endpoint 
Revised 
analysis 
methods. 
As a sensitivity analysis, patients for whom loss of response in hypertension 
control at Visit RW12 is missing because ABPM measurements are not available 
(non-retrieved dropouts), will have data imputed based on data from retrieved 
dropouts, with similar baseline characteristics, within the same treatment arm. 
9.5.4.2 
Approach to 
Missing Data 
Analysis 
Clarified 
analysis 
methods. 
If fewer than 10 retrieved dropouts are available, then the main analysis will 
use a wash-out multiple imputation method instead of the retrieved dropout 
approach. 
9.5.4.3 
Multiplicity 
Adjustment for 
Secondary 
Efficacy 
Endpoints 
Clarified 
analysis 
methods. 
Details regarding adjustment for multiplicity across primary and secondary 
endpoints will be provided in the SAP. No adjustment for multiplicity will be 
made for secondary and exploratory endpoints. 
 
9.5.4.4 Analysis 
of the Secondary 
Efficacy 
Endpoints in the 
RW Phase 
Revised 
analysis 
methods based 
on no longer 
differentiating 
between key 
secondary and 
other 
secondary 
endpoints; 
clarified 
analysis 
methods. 
The loss of response (AUC-based) with respect to hyperglycemic control will be 
compared between treatment and placebo arms at Visit RW12 using a logistic 
regression model with 2 independent variables (treatment arm and stratification 
factor). In the DM/IGT subgroup, this stratification factor identifies patients with 
or without hypertension. 
For all endpoints described as proportions in the RW phase, the point estimate and 
the 2 sided 95% CI will be calculated. 
-- 
This model is used after imputation of missing data at Visit RW12, using the 
retrieved drop-out approach. If fewer than 10 retrieved dropouts are 
available for the endpoint, then the main analysis will use a wash-out multiple 
imputation method instead of the retrieved dropout approach. 
-- 


Protocol CORT125134-455
Corcept Therapeutics  
Amendment 7 | 17 May 2024 
Confidential 
Page 116 of 116 
Section 
Summary of 
Change 
Revisions 
For all endpoints described as proportions in the RW phase, the point 
estimate and the 2 sided 95% CI will be calculated. 
Sensitivity analyses will be pre-specified in the SAP. 
12 References 
Reference list 
updated to 
remove 
citations no 
longer 
referenced. 
-- 
 
 

SAP_001.pdf: 
Title: Glucocorticoid Receptor Antagonism in the Treatment of Cushing Syndrome (GRACE): A 
Phase 3, Double-Blind, Placebo-Controlled, Randomized-Withdrawal Study of the Efficacy and 
Safety of Relacorilant 
 
 
NCT Number: NCT03697109 
 
 
Date: 17 May 2024 


Corcept Therapeutics Incorporated  
 Clinical Study Report 
16.1.9 Documentation of Statistical Methods  
 CORT125134-455 
Confidential 
 Page 1  
DOCUMENTATION OF STATISTICAL METHODS 
Document Title and Version 
Date 
Statistical Analysis Plan, Version 2.0 
17 May 2024 


 
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STATISTICAL ANALYSIS PLAN 
STUDY CORT125134-455 
Title 
Glucocorticoid Receptor Antagonism in the Treatment of 
Cushing Syndrome (GRACE): A Phase 3, Double-Blind, 
Placebo-Controlled, Randomized-Withdrawal Study of the 
Efficacy and Safety of Relacorilant 
IND Number 
128625 
EudraCT Number 
2018-003096-35 
Investigational Product 
Relacorilant (CORT125134) 
Indication 
Cushing syndrome 
Study Protocol 
CORT125134-455 
Protocol Version 
Amendment 7 (17 May 2024) and Germany Amendment 5.1 (04 
April 2023) 
Phase  
3 
Sponsor 
Corcept Therapeutics Incorporated 
149 Commonwealth Drive 
Menlo Park, California 94025 USA 
+1 (650) 327-3270 
Document Author  
 
Version 
V2.0, 17 May 2024 
 


 
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APPROVAL SHEET 
 
STATISTICAL ANALYSIS PLAN 
CORT125134-455: Glucocorticoid Receptor Antagonism in the Treatment of Cushing  
Syndrome (GRACE): A Phase 3, Double-Blind, Placebo-Controlled, Randomized-Withdrawal 
Study of the Efficacy and Safety of Relacorilant 
 
Reviewed and Accepted at Corcept Therapeutics by 
 
 
 


 
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CONTENTS 
STATISTICAL ANALYSIS PLAN STUDY CORT125134-455 .................................................. 1 
APPROVAL SHEET ...................................................................................................................... 2 
CONTENTS .................................................................................................................................... 3 
List of Tables .................................................................................................................................. 6 
List of Figures ................................................................................................................................. 7 
LIST OF ABBREVIATIONS AND DEFINITIONS ..................................................................... 8 
1 
INTRODUCTION ............................................................................................................ 11 
2 
STUDY OVERVIEW ....................................................................................................... 12 
2.1 
Overall Design .................................................................................................................. 12 
3 
STUDY OBJECTIVES ..................................................................................................... 16 
3.1 
Primary Objectives............................................................................................................ 16 
3.2 
Secondary Objectives........................................................................................................ 16 
4 
STUDY ENDPOINTS ...................................................................................................... 17 
4.1 
Primary Endpoint .............................................................................................................. 17 
4.2 
Primary Safety Endpoints ................................................................................................. 17 
4.3 
Secondary Efficacy Endpoints in the RW Phase .............................................................. 17 
4.4 
Exploratory Efficacy Endpoints ........................................................................................ 18 
4.4.1 Exploratory Efficacy Endpoints in the RW Phase ................................................ 18 
4.4.2 Exploratory Efficacy Endpoints in the OL Phase ................................................. 20 
5 
SAMPLE SIZE CONSIDERATION ................................................................................ 22 
6 
ANALYSIS POPULATION ............................................................................................. 23 
6.1 
Intent-to-Treat Analysis Population in Open-Label Phase (ITT-OL)............................... 23 
6.2 
Safety Population in Open-Label Phase (Safety-OL) ....................................................... 23 
6.3 
Modified Intent-to-Treat Analysis Population in Open-Label Phase (mITT-OL)............ 23 
6.4 
Per-Protocol Analysis Population in Open-Label Phase (PP-OL) .................................... 23 
6.5 
Intent-to-Treat Analysis Population in Randomized-Withdrawal Phase (ITT-RW) ........ 23 
6.6 
Safety Population in Randomized-Withdrawal Phase (Safety-RW) ................................ 23 


 
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6.7 
Modified Intent-to-Treat Analysis Population in Randomized-Withdrawal Phase (mITT-
RW) ................................................................................................................................... 23 
6.8 
Per-Protocol Analysis Population in Randomized-Withdrawal Phase (PP-RW) ............. 24 
6.9 
ABPM Population ............................................................................................................. 24 
6.10 
Key Subgroups .................................................................................................................. 24 
6.11 
Additional Subgroups ....................................................................................................... 24 
7 
DEFINITIONS, COMPUTATIONS, AND CONVENTIONS ........................................ 26 
7.1 
Definitions......................................................................................................................... 26 
7.1.1 Definitions of Baseline ......................................................................................... 26 
7.1.1.1 OL Phase ................................................................................................ 26 
7.1.1.2 RW Phase ............................................................................................... 27 
7.1.2 Definition of Analysis Visit Windows .................................................................. 27 
7.2 
Reporting Conventions ..................................................................................................... 28 
7.3 
Summarization by Visit .................................................................................................... 29 
7.4 
Data Handling Rules ......................................................................................................... 30 
7.5 
Standard Calculations ....................................................................................................... 30 
7.6 
Handling Missing Data ..................................................................................................... 31 
7.6.1 Handling Missing Data for Primary Efficacy Endpoint in RW Phase.................. 31 
7.6.1.1 Loss of Response with Respect to Hypertension Control ...................... 31 
7.6.2 Handling Missing Data for Secondary Efficacy Endpoints .................................. 31 
7.6.2.1 Secondary Endpoints Summarized with Proportions ............................ 31 
7.6.2.2 Continuous Secondary Efficacy Endpoints ........................................... 31 
7.6.3 Handling Missing Data for Exploratory Efficacy Endpoints ................................ 34 
7.6.3.1 Handling Missing Data for Efficacy Endpoints in the Open-Label Phase
................................................................................................................ 35 
7.6.4 Handling Incomplete or Missing Dates for Adverse Events, Medical History and 
Concomitant Medications ..................................................................................... 35 
7.6.5 Handling Incomplete or Missing Dates for Cushing Syndrome Medical History 36 
8 
TIMING OF ANALYSES ................................................................................................ 37 
8.1 
Interim Analysis ................................................................................................................ 37 


 
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8.2 
Final Analyses and Reporting ........................................................................................... 37 
9 
STATISTICAL METHODS ............................................................................................. 38 
9.1 
General Statistical Consideration ...................................................................................... 38 
9.2 
Patient Disposition ............................................................................................................ 38 
9.3 
Protocol Deviations ........................................................................................................... 39 
9.4 
Demographic Characteristics and Baseline Characteristics .............................................. 39 
9.5 
Medical History ................................................................................................................ 40 
9.6 
Prior and Concomitant Medications ................................................................................. 40 
9.7 
Extent of Exposure and Study Drug Compliance ............................................................. 41 
9.8 
Efficacy Analyses ............................................................................................................. 42 
9.8.1 Multiple Comparisons/Multiplicity Adjustment ................................................... 42 
9.8.2 Primary Efficacy Endpoint ................................................................................... 42 
9.8.2.1 Loss of Response with Respect to Hypertension Control in RW Phase 42 
9.8.2.2 Primary Efficacy Endpoint for Patients with Uncontrolled Hypertension
................................................................................................................ 43 
9.8.2.3 Sensitivity Analysis for Primary Efficacy Endpoint .............................. 44 
9.8.2.4 Supplementary Analyses for Primary Efficacy Endpoint in Subgroups 45 
9.8.3 Secondary Efficacy Endpoints .............................................................................. 45 
9.8.3.1 Patients with DM/IGT: Loss of Response (AUC-based) in RW Phase . 46 
9.8.3.2 24-Hour Average Ambulatory Blood Pressure in RW Phase ................ 47 
9.8.3.3 Body Weight in RW Phase .................................................................... 50 
9.8.3.4 AUCglucose for Patients with Response to DM/IGT Criteria in RW Phase
................................................................................................................ 50 
9.8.3.5 Patients with DM/IGT: Comprehensive Loss of Response in RW Phase
................................................................................................................ 52 
9.8.3.6 HbA1c in RW Phase .............................................................................. 53 
9.8.4 Exploratory Efficacy Endpoints ............................................................................ 54 
9.8.4.1 Analysis of the Exploratory Efficacy Endpoints in the RW Phase ........ 54 
9.8.4.2 Analysis of the Exploratory Efficacy Endpoints in the OL Phase ......... 63 
9.8.5 Multicenter Studies ............................................................................................... 70 
9.9 
Subgroup Analyses ........................................................................................................... 70 


 
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9.10 
Pharmacodynamic Analysis .............................................................................................. 71 
9.11 
Pharmacokinetic Analysis ................................................................................................. 71 
9.12 
Safety Analyses ................................................................................................................. 71 
9.12.1 Adverse Events ..................................................................................................... 71 
9.12.2 Special Safety Topics ............................................................................................ 76 
9.12.3 Deaths ................................................................................................................... 77 
9.12.4 Clinical Laboratory Tests ...................................................................................... 77 
9.12.5 Vital Signs ............................................................................................................. 78 
9.12.6 Electrocardiograms ............................................................................................... 78 
9.12.7 Physical Examination............................................................................................ 78 
9.12.8 Pituitary MRI ........................................................................................................ 78 
9.12.9 Pregnancy Tests .................................................................................................... 78 
10 
CHANGES FROM PROTOCOL IN STUDY CONDUCT OR STATISTICAL 
ANALYSIS PLAN ........................................................................................................... 79 
11 
REFERENCES ................................................................................................................. 80 
12 
APPENDIX ....................................................................................................................... 82 
APPENDIX 1 ................................................................................................................................ 83 
APPENDIX 2 ................................................................................................................................ 84 
APPENDIX 3 ................................................................................................................................ 85 
APPENDIX 4 ................................................................................................................................ 86 
APPENDIX 5 ................................................................................................................................ 87 
 
List of Tables 
Table 1 
Analysis Visit Windows for Efficacy Assessments in OL Phase ..........................28 
Table 2 
Analysis Visit Windows for Efficacy Assessments in RW Phase .........................28 
Table 3 
Sensitivity Analyses for Loss of Response in Patients with Hypertension ...........44 
Table 4 
Subgroup Analyses for Loss of Response In Patients with Hypertension .............45 
Table 5 
Items in Subscales of the Cushing QoL .................................................................57 
 


 
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List of Figures 
Figure 1 
CORT125134-455 Study Design ...........................................................................12 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS 
Abbreviation 
Definition 
ABPM 
ambulatory blood pressure monitoring 
ACTH 
adrenocorticotropic hormone 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase  
ATC 
Anatomic Therapeutic Chemical 
AUC 
area under the concentration-time curve  
AUCglucose 
area under the concentration-time curve for glucose  
BDI-II 
Beck Depression Inventory®-II 
BMI 
body mass index 
BP 
blood pressure 
CHM 
Cochran-Mantel-Haenszel 
CI 
confidence interval 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events  
CV (%) 
coefficient of variation (%) 
DBP 
diastolic blood pressure 
DM 
diabetes mellitus 
DXA 
dual energy X-ray absorptiometry 
EAIR 
exposure adjusted incidence rate 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ET 
early termination 
FDA 
Food and Drug Administration 
GR 
glucocorticoid receptor 


 
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Abbreviation 
Definition 
HbA1c 
hemoglobin A1c 
HPA 
hypothalamic-pituitary-adrenal 
HR 
heart rate 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) 
IDMC 
Independent Data Monitoring Committee 
IGT 
impaired glucose tolerance 
IRT 
Interactive Response System 
ITT-OL 
intent-to-treat analysis population in open-label phase 
ITT-RW 
intent-to-treat in randomized-withdrawal phase 
LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT-OL 
modified intent-to-treat in open-label phase 
mITT-RW 
modified intent-to-treat in randomized-withdrawal phase 
MMRM 
mixed model for repeated measures 
MRI 
magnetic resonance imaging 
mRNA 
messenger RNA 
oGTT 
oral glucose-tolerance test 
OL 
open label 
PD 
pharmacodynamic 
PK 
pharmacokinetics 
PP-OL 
per-protocol analysis population in open-label phase 
PP-RW 
per-protocol analysis population in randomized-withdrawal phase 
QoL 
quality-of-life 
REML 
restricted maximum likelihood 
ROW 
rest of world 
RW 
randomized withdrawal 


 
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Abbreviation 
Definition 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SE 
standard error 
SI 
Système International 
TEAE 
treatment-emergent adverse event 
UFC 
urinary free cortisol 
US 
United States 
WHO 
World Health Organization 
 


 
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1 
INTRODUCTION 
The purpose of the statistical analysis plan (SAP) is to provide a detailed description of the 
principal features of the analysis described in the protocol and to include detailed procedures for 
executing the statistical analysis of the primary and secondary endpoints and other data for 
Corcept Study CORT125134-455.  
This SAP contains definitions of analysis populations and endpoints, outlines the timing of 
statistical analyses, and provides a comprehensive description of statistical analyses to be 
implemented to assess the clinical efficacy and safety of treatment with relacorilant as per 
Protocol CORT125134-455: Glucocorticoid Receptor Antagonism in the Treatment of Cushing 
Syndrome (GRACE): A Phase 3, Double-Blind, Placebo-Controlled, Randomized-Withdrawal 
Study of the Efficacy and Safety of Relacorilant. The statistical methods applied in the design 
and planned analyses of this study are consistent with the International Conference on 
Harmonization of Technical Requirements for Pharmaceuticals for Human Use, Guidance for 
Industry: E9 Statistical Principles for Clinical Trials (ICH E9 1998) and E9 (R1) Statistical 
Principles for Clinical Trials: Addendum: Estimands and Sensitivity Analysis in Clinical Trials 
(ICH E9[R1] 2021).  
This SAP will be finalized before database lock and unblinding and prior to data analysis to 
provide full details of statistical analysis to be presented in the clinical study report (CSR). Any 
changes between the statistical methods provided in the clinical study protocol and this SAP will 
be explained herein; any changes or deviations from this SAP relative to the final analysis will be 
fully documented in the CSR. Minor changes or deviations from the templates for tables, figures, 
and listings need not be documented in the CSR.  
 


 
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2 
STUDY OVERVIEW 
The study design includes an open-label (OL) phase, followed by a 12-week, double-blind, 
placebo-controlled, randomized-withdrawal (RW) phase. Patients meeting prespecified response 
criteria at the end of the OL phase will be eligible for the RW phase. An RW design provides 
predictive enrichment for the comparison of active treatment to placebo. 
2.1 
Overall Design  
Study CORT125134-455 is a Phase 3, double-blind, placebo-controlled, RW study to assess the 
efficacy, safety and pharmacokinetics (PK) of relacorilant in patients with endogenous Cushing 
syndrome and concurrent diabetes mellitus (DM)/impaired glucose tolerance (IGT) and/or 
uncontrolled hypertension (Figure 1). 
Figure 1 
CORT125134-455 Study Design 
 
 
The study phases are as follows: 
Screening Phase 
Up to 6 weeks to determine study eligibility.  
Open-Label Phase (Baseline to Visit OL22) 
Baseline is defined as Day 1 of the OL phase. 
 The starting dose at Baseline will be 100 mg relacorilant once daily for 2 weeks.  
 From Visit OL2 through Visit OL10, the dose of relacorilant will be increased every 
4 weeks by 100 mg, as tolerated and based on improvement in signs and symptoms of 


 
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Cushing syndrome, to a target dose of 400 mg once daily (i.e., to 200 mg at Visit OL2, to 
300 mg at Visit OL6, and to 400 mg at Visit OL10). Clinical benefit in the Open-Label 
Phase will be assessed by the Investigator either by a change from Baseline or change 
from the previous visit considering the following factors:  
– BP measurements and anti-hypertensive medications 
– Glucose levels and diabetes medication 
– Body weight and waist circumference 
– Cushingoid appearance and striae 
– Sit-to-stand test 
– Beck Depression inventory 
– Cushing Quality-of-Life questionnaire 
 If all symptoms of Cushing syndrome present at Baseline have resolved, no dose 
escalation will occur beyond that visit. 
 If any planned dose escalation is postponed, Visit OL14 can be used for a final dose 
escalation. 
 Faster dose escalation during the open-label phase of the study for patients whose 
Cushing syndrome deteriorates may be allowed with medical monitor approval (not 
applicable in Germany). 
 If access of patients to the study site is restricted due to the COVID-19 pandemic, dose 
escalation up to 200 mg may occur remotely if necessary. Subsequent dose escalations, 
however, are permitted only after completion of safety assessments. 
 Dose interruption, reduction and re-escalation are permitted for safety/tolerability. 
– The relacorilant dose can be reduced to a previous dose if it is not tolerated 
– Re-escalation after a dose reduction is permitted until Visit OL18. 
Randomized-Withdrawal Phase (Randomization to Visit RW12)  
Patients who complete the OL phase and meet the following response criteria for DM/IGT or 
hypertension at Visit OL22 will be randomized between Visit OL22 and up to 2 weeks after that 
visit in a 1:1 ratio to receive relacorilant or placebo for 12 weeks: 
 Patients with uncontrolled hypertension at Baseline must meet one of the following 
response criteria: 
– ≥5 mm Hg decrease in mean systolic BP (SBP) and/or diastolic BP (DBP) from 
Baseline to Visit OL22, without worsening of either, based on 24-hour ambulatory 
BP monitoring (ABPM) 
Note: Increase of pre-existing blood pressure medication or initiation of new blood pressure 
medication, due to worsening in hypertension, disqualifies the patient from randomization 
into the RW phase. If a decrease in the BP medication occurred after the OL18 visit, reassess 
eligibility for randomization 4 weeks after the dose change. 


 
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 Patients with DM/IGT at Baseline must meet one of the following response criteria: 
In patients with DM 
– HbA1c has decreased by ≥0.5% from Baseline to Visit OL22  
– The 2-hour plasma oGTT glucose is normalized (<140 mg/dL) or decreased by 
≥50 mg/dL from Baseline to Visit OL22 
– Total daily insulin dose has decreased by ≥25% and HbA1c is unchanged or 
decreased compared with Baseline  
In patients with IGT 
– The 2-hour plasma oGTT glucose is normalized (<140 mg/dL) from Baseline to Visit 
OL22 
Note: Increase of pre-existing diabetes medication or initiation of new diabetes medication, 
due to worsening of hyperglycemia, disqualifies the patient from randomization into the RW 
phase. If a decrease in the insulin dose happened after Visit OL18, reassess eligibility for 
randomization 4 weeks after the dose change. 
 Patients with both DM/IGT and uncontrolled hypertension at Baseline who do 
not meet the above-mentioned response criteria for both conditions must meet one of 
the following: 
– Meets one of the DM or IGT response criteria with no worsening in hypertension 
– Meets one of the uncontrolled hypertension response criteria with no worsening in 
DM or IGT 
– Worsening in hypertension is defined as ≥5 mm Hg increase in either systolic BP 
and/or diastolic BP from Baseline to Visit OL22.  
– Worsening in DM is defined as a ≥0.5% increase in HbA1c from Baseline to Visit 
OL22. 
– Worsening in IGT is defined as a ≥50 mg/dL increase in the 2-hour oGTT from 
Baseline to Visit OL22.  
– Patients who meet either the DM/IGT criteria or the uncontrolled hypertension 
criteria will be randomized in the respective strata. 
Note: Increase of pre-existing diabetes or blood pressure medication or initiation of new 
diabetes or blood pressure medication due to worsening hyperglycemia or hypertension, 
disqualifies the patient from randomization into the RW phase. If a decrease in insulin dose 
or BP medication occurred after Visit OL18, reassess eligibility for randomization 4 weeks 
after the dose change. 
Randomization will be stratified to ensure balance in treatment assignment for patients that meet 
response criteria within the DM/IGT and hypertension subgroups. 
Treatment assignment and selected study assessments in the RW phase will remain blinded to the 
Investigators, the Sponsor, and the patients until after database lock. 
No changes in the dose of study drug are allowed during the RW phase. 


 
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Rescue criteria during the RW Phase 
2-hour oGTT and ABPM results during the RW Phase will be reviewed by an unblinded Medical 
Monitor to monitor patient safety. The unblinded Medical Monitor is unblinded to results of 
study assessments but is blinded to the treatment assignment. 
 If a patient in the DM/IGT subgroup meets the first two of the following criteria, or if 
a patient in the hypertension subgroup meets the third criterion, the results will be 
communicated to the study site, and rescue medication may be initiated or increased.  
– Fasting glucose increases by 50 mg/dL from visit OL22, AND 
– 2-hour plasma oGTT glucose increases by 100 mg/dL from Visit OL22 
– Increases in mean SBP or mean DBP by ABPM of more than 10 mm Hg from Visit 
OL22 
Unblinding of the 2-hour oGTT or ABPM results will not result in the unblinding of 
study treatment.  
In the event of rescue medication use before Visit RW12: 
 In patients randomized to the DM/IGT subgroup, oGTT assessments will continue as 
planned until Visit RW12. 
 In patients randomized to the hypertension subgroup, ABPM assessments will 
continue as planned until Visit RW12. 


 
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3 
STUDY OBJECTIVES 
3.1 
Primary Objectives 
 To assess the efficacy of relacorilant for the treatment of endogenous Cushing 
syndrome based on BP control at Week 12 of the RW phase compared with placebo 
 To assess the safety of relacorilant for the treatment of endogenous Cushing 
syndrome 
3.2 
Secondary Objectives 
 To assess changes in cortisol excess-related comorbidities (including DM/IGT, and 
body weight) in patients with endogenous Cushing syndrome treated with relacorilant 
over the RW phase  


 
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4 
STUDY ENDPOINTS 
Endpoints for both OL and RW phases are listed below. In the RW phase, (1) endpoints related 
to hypertension will be analyzed in those patients who met any response criterion for 
hypertension at Visit OL22; and (2) endpoints related to DM/IGT will be analyzed in those 
patients who met any response criterion for DM/IGT at Visit OL22. 
4.1 
Primary Endpoint 
The primary efficacy endpoint will be assessed in the RW phase. The study will be considered to 
have a positive outcome if the primary efficacy endpoint reaches statistical significance 
(Section 9.8.2.2): 
 In patients with hypertension, the proportion of patients with a loss of response 
with respect to hypertension from Visit OL22 to Visit RW12 based on 24-hour 
ABPM as compared between relacorilant and placebo arms, where loss of response is 
defined as follows: 
– In patients who met only the SBP response criterion, an increase in SBP ≥5 mm Hg. 
– In patients who met only the DBP response criterion, an increase in DBP by 
≥5 mm Hg. 
– In patients who met both the SBP and DBP response criteria, an increase in either 
SBP or DBP by ≥5 mm Hg. 
– Any increase or modification in antihypertensive medication due to worsening 
hypertension. 
– Patients discontinue treatment in RW phase for any reason. 
4.2 
Primary Safety Endpoints 
 In all patients, assessment of safety based on TEAEs. 
4.3 
Secondary Efficacy Endpoints in the RW Phase 
 Loss of response (AUC-based) in DM/IGT subgroup with response at OL22: 
proportion of patients with a loss of response with respect to hyperglycemic control 
from Visit OL22 to RW12, as compared between relacorilant and placebo arms, 
where loss of response is defined as a ≥10% increase from baseline in AUCglucose 
from Visit OL22 to RW12, use of rescue medication (initiation or increase in diabetes 
medication due to worsening of hyperglycemic control), treatment discontinuation for 
any reason in RW phase, or patients with missing RW12 AUCglucose values.  
 Mean change from Visit OL22 to Visit RW12 in 24-hour average SBP as compared 
between relacorilant and placebo. 
 Mean change from Visit OL22 to Visit RW12 in 24-hour average DBP as compared 
between relacorilant and placebo. 
 Mean change from Visit OL22 to Visit RW12 in body weight as compared between 
relacorilant and placebo. 


 
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 In patients with DM/IGT, the mean change in AUCglucose from Visit OL22 to Visit 
RW12 as compared between relacorilant and placebo arms. 
 In patients with DM/IGT, the mean change in HbA1c from Visit OL22 to Visit 
RW12, as compared between relacorilant and placebo. 
 Comprehensive loss of response in DM/IGT subgroup with response at OL22: 
proportion of patients with a comprehensive loss of response with respect to 
hyperglycemic control from Visit OL22 to RW12, as compared between relacorilant 
and placebo arms, where the comprehensive loss of response is defined as follows:  
In patients with DM: 
– Use of rescue medication (initiation or increase in diabetes medication due to 
worsening of hyperglycemic control), treatment discontinuation for any reason in RW 
phase, or loss to follow-up, 
OR 
– HbA1c has increased by ≥0.3% at Visit RW12 (compared to OL22), 
OR 
– The 2-hour time point of the 2-hour plasma oGTT glucose test at Visit RW12 is 
abnormal (≥140 mg/dL) and has increased by at least 50% of the reduction observed 
between Baseline and Visit OL22. 
In patients with IGT: 
– Use of rescue medication (initiation or increase in diabetes medication due to 
worsening of hyperglycemic control), treatment discontinuation for any reason in RW 
phase, or loss to follow-up, 
OR 
– The 2-hour time point of the 2-hour plasma oGTT glucose test at Visit RW12 is 
abnormal (≥140 mg/dL) and has increased by at least 50% of the reduction observed 
between Baseline and Visit OL22. 
4.4 
Exploratory Efficacy Endpoints 
Exploratory efficacy endpoints are listed below by study phase (RW or OL) and the type of 
endpoint. 
4.4.1 Exploratory Efficacy Endpoints in the RW Phase 
Continuous Endpoints 
 Mean change from Visit OL22 to Visit RW12 in 24-hour average heart rate (HR) as 
compared between relacorilant and placebo (based on ABPM). 
 Mean difference in daytime and nighttime average SBP, DBP, and HR (based on 
ABPM) at Visit RW12 as compared between relacorilant and placebo. 


 
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 Mean change from Visit OL22 to Visit RW12 in body fat composition measured with 
DXA scan as compared between relacorilant and placebo. 
 Mean change from Visit OL22 to Visit RW12 in Cushing Quality-of-Life (QoL) 
score as compared between relacorilant and placebo. 
 In patients with DM (HbA1c at Baseline ≥6.5%), the mean change from Visit OL22 
to Visit RW12 in HbA1c, as compared between relacorilant and placebo. 
 In patients with IGT at Baseline, the mean change from Visit OL22 to Visit RW12 in 
the 2-hour glucose value of the plasma 2-hours oGTT test as compared between 
relacorilant and placebo arms. 
 The mean change from Visit OL22 to Visit RW12 as compared between relacorilant 
and placebo in the following: waist circumference; lean mass measured by DXA; 
serum osteocalcin; the Beck Depression Inventory®-II (BDI-II) score; sit-to-stand test 
score; trail-making test score; sex-hormone levels (estradiol, total and free 
testosterone, sex-hormone‒binding globulin, follicle-stimulating hormone, and 
luteinizing hormone);  urinary free cortisol (UFC), late-night salivary cortisol and 
plasma adrenocorticotropic hormone (ACTH); AUCinsulin, Matsuda Index, 
homeostatic model assessment of insulin resistance (HOMA-IR), and daytime and 
nighttime average blood pressure. 
 In patients with adrenal Cushing syndrome (ACTH independent), the mean change in 
the ACTH levels from Visit OL22 to Visit RW12 as compared between relacorilant 
and placebo. 
Endpoints Summarized with Proportions 
 For patients in the hypertension subgroup, the proportion of patients with any 
increase or modification in antihypertensive medication due to worsening 
hypertension from Visit OL22 to Visit RW12 as compared between relacorilant and 
placebo. 
 Proportion of patients who worsened, as assessed by the Global Clinical Response 
from Visit OL22 to Visit RW12 (i.e., a score of –1 at Visit RW12 as compared with 
Visit OL22). 
 For patients in the DM/IGT subgroup, the proportion of patients with any increase in 
dose of diabetes medication from Visit OL22 to Visit RW12 as compared between 
relacorilant and placebo. 
 For patients in the DM subgroup, the proportion of patients who achieve 25% 
reduction in AUCglucose from Baseline OL to Visit RW12 as compared between 
relacorilant and placebo. 
 In all patients randomized in the RW phase, proportion of patients with a loss of 
response with respect to hypertension or hyperglycemia from Visit OL22 to Visit 
RW12 based on 24-hour ABPM and AUCglucose as compared between relacorilant and 
placebo arms, where loss of response is defined as follows: 
- In patients with hypertension only at Baseline OL 
 In patients who met only the SBP response criterion, an increase in SBP 
≥5 mm Hg. 


 
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 In patients who met only the DBP response criterion, an increase in DBP 
by ≥5 mm Hg. 
 In patients who met both the SBP and DBP response criteria, an increase 
in either SBP or DBP by ≥5 mm Hg. 
 Any increase or modification in antihypertensive medication due to 
worsening hypertension. 
 Patients discontinue treatment in RW phase for any reason. 
- In patients with DM/IGT only at Baseline OL: 
 A ≥10% increase from Baseline RW in AUCglucose from Visit OL22 to 
Visit RW12.. 
 Use of rescue medication (initiation or increase in diabetes medication due 
to worsening of hyperglycemic control). 
 Treatment discontinuation for any reason in RW phase. 
 Patients with missing RW12 AUCglucose values. 
- In patients with hypertension and DM/IGT at Baseline OL, loss of response will 
be defined as a loss of response with respect to either hypertension or 
hyperglycemic control (AUC-based) from Visit OL22 to Visit RW12, irrespective 
of which response criteria (hypertension or DM/IGT) they met to enter the RW 
phase  
4.4.2 Exploratory Efficacy Endpoints in the OL Phase 
Continuous Endpoints 
 In patients with uncontrolled hypertension, the mean change in SBP from Baseline to 
Visit OL22/ET. 
 In patients with uncontrolled hypertension, the mean change in DBP from Baseline to 
Visit OL22/ET. 
 Mean change in Cushing Quality-of-Life (QoL) score from Baseline to Visit OL22. 
 Mean change in body-fat composition from Baseline to Visit OL22/ET, as determined 
by DXA. 
 Mean change in the Beck Depression Inventory®-II (BDI-II) score from Baseline to 
Visit OL22/ET. 
 Mean change in body weight from Baseline to Visit OL22/ET. 
 In patients with IGT, the mean change in 2-hour plasma oGTT glucose from Baseline 
to Visit OL22/ET. 
 In patients with DM (HbA1c ≥6.5% at Baseline), the mean change in HbA1c from 
Baseline to Visit OL22/ET. 
 In patients with DM/IGT, the mean change in AUCglucose from Baseline to 
Visit OL22/ET. 
 The mean change from Baseline to Visit OL22/ET in the following: waist 
circumference; lean mass measured by DXA; serum osteocalcin; the Beck Depression 
Inventory®-II (BDI-II) score; sit-to-stand test score; trail-making test score; sex-
hormone levels (estradiol, total and free testosterone, sex-hormone‒binding globulin, 


 
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follicle-stimulating hormone, and luteinizing hormone);  urinary free cortisol (UFC), 
late-night salivary cortisol and plasma adrenocorticotropic hormone (ACTH); 
AUCinsulin, Matsuda Index, homeostatic model assessment of insulin resistance 
(HOMA-IR), and daytime and nighttime average blood pressure. 
 In patients with adrenal Cushing syndrome (CS) (ACTH independent), the mean 
change in ACTH levels from Baseline to Visit OL22/ET. 
Endpoints Summarized with Proportions 
 In patients with hypertension, the proportion of patients who meet any of the 
hypertension response criteria at Visit OL22/ET. 
 In patients with hypertension, the proportion of patients with reduction or 
discontinuation of antihypertensive medications from Baseline to Visit OL22/ET. 
 The proportion of patients with a positive Global Clinical Response score at 
Visit OL22/ET. 
 In patients with DM/IGT, the proportion of patients who meet any of the DM/IGT 
response criteria at Visit OL22/ET. 
 In patients with IGT, the proportion of patients who achieved normalization of 
glucose based on the plasma 2-hours oGTT test and/or a reduction in the 2hour 
glucose by 50 mg/dL from Baseline to Visit OL22/ET. 
 In patients with DM (HbA1c ≥6.5% at Baseline), the proportion of patients with any 
decrease in dose of diabetes medication from Baseline to Visit OL22/ET. 
 The proportion of patients meeting any DM/IGT or hypertension response criterion at 
Visit OL22/ET by dose at which response was first reached. 
 In patients with DM/IGT, the proportion of patients with ≥25% decrease in AUCglucose 
from Baseline to Visit OL22/ET.  
 In patients with DM/IGT, the proportion of patients with ≥0.5% decrease in HbA1c 
from Baseline to Visit OL22/ET. 
 


 
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5 
SAMPLE SIZE CONSIDERATION 
Approximately 162 patients are planned to enroll into a 6-month OL phase of the study to 
ensure the randomization of approximately 46 patients with hypertension into the subsequent 3-
month, placebo-controlled RW phase.   
This calculation assumes that enrolled patients will consist of approximately 25% with DM/IGT 
only, 25% with hypertension only, and 50% with both DM/IGT and hypertension at Screening. 
Attainment of the randomization targets within the hypertension subgroup in the RW phase 
further assumes that 75% of patients that present with hypertension only randomize to the RW 
phase and 20% of patients that present with both comorbidities (DM/IGT and hypertension) 
respond to hypertension criteria at Visit OL22 (hypertension only or DM/IGT and hypertension 
as described in Section 2.1) and randomize to the RW phase. This projected sample size will 
result in approximately 30 patients from the hypertension subgroup, and 16 patients from the 
DM/IGT and hypertension subgroup randomizing to the RW phase; thus, a total of 
approximately 46 patients meeting response criteria will be randomized into the hypertension 
subgroup. 
Study enrollment will be monitored to ensure attainment of randomization targets. To maintain 
sufficient power to detect treatment difference, the number of patients enrolled in the OL phase 
may be adjusted to ensure a sufficient number of patients meeting response criteria to 
uncontrolled hypertension are randomized in the RW phase. Enrollment of patients with 
hypertension only may continue based on enrollment target projections. 
Forty-six patients with hypertension (23 per treatment group with allocation ratio of 1:1) will 
ensure at least 90% power to detect the difference between placebo and treatment arms in 
proportion of patients with loss of response, assuming a loss of response in 25% of patients in the 
treatment arm and 75% in the placebo arm. These calculations are based on a Fisher’s exact test 
of proportions at the α=0.05 two-sided significance level. 
In summary, randomization of patients in the RW phase will continue to ensure enrollment of 
46 patients meeting response criteria within the hypertension subgroup. This sample size will 
provide sufficient power to detect the target differences in the primary endpoint for the 
hypertension subgroup. 
 


 
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6 
ANALYSIS POPULATION 
6.1 
Intent-to-Treat Analysis Population in Open-Label Phase (ITT-OL) 
The intent-to-treat analysis population in open label phase (ITT-OL) will include all enrolled 
patients who received at least one dose of study drug. It will be used for analyses of exploratory 
efficacy endpoints in the OL phase. 
6.2 
Safety Population in Open-Label Phase (Safety-OL) 
The Safety Population will include all enrolled patients who received at least one dose of study 
drug. It will be used for all safety analyses in the OL phase.  
6.3 
Modified Intent-to-Treat Analysis Population in Open-Label Phase (mITT-OL) 
The modified intent-to-treat analysis population in open-label phase (mITT-OL) will include all 
patients in the ITT-OL population with at least one post-baseline efficacy assessment. It will be 
used for analyses of exploratory efficacy endpoints in the OL phase. 
6.4 
Per-Protocol Analysis Population in Open-Label Phase (PP-OL) 
The per-protocol analysis population in open-label phase (PP-OL) will include all patients in the 
mITT-OL population who had no important protocol deviations that might impact the validity of 
the ABPM analysis. Patients in the PP-OL population who complete the OL phase without an 
important deviation will be used in sensitivity analyses of the exploratory efficacy endpoints in 
the OL phase. 
6.5 
Intent-to-Treat Analysis Population in Randomized-Withdrawal Phase (ITT-RW) 
The intent-to-treat analysis population in randomized-withdrawal phase (ITT-RW) will include 
all patients who were randomized in the double-blind RW phase and received at least one dose of 
study drug post randomization. The ITT-RW population will be used for the analysis of the 
primary endpoint in the RW phase, as well as all secondary and exploratory efficacy endpoints. 
6.6 
Safety Population in Randomized-Withdrawal Phase (Safety-RW) 
The Safety Population (Safety-RW) will include all patients who were randomized in the double-
blind RW phase and received at least one dose of study drug post randomization. It will be used 
for all safety analyses in the RW phase. 
6.7 
Modified Intent-to-Treat Analysis Population in Randomized-Withdrawal Phase 
(mITT-RW) 
The modified intent-to-treat analysis population in randomized-withdrawal phase (mITT-RW) 
will include all patients in the ITT-RW population with at least one post-randomization efficacy 
assessment for the primary efficacy endpoint (ABPM). The mITT-RW population will be used in 
sensitivity analyses for the analysis of the primary endpoint in the RW phase.  


 
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6.8 
Per-Protocol Analysis Population in Randomized-Withdrawal Phase (PP-RW) 
The per-protocol analysis population in randomized-withdrawal phase (PP-RW) will include all 
patients in the mITT-RW population who completed the study according to protocol 
specifications without an important deviation. The determination of the PP analysis population 
will be finalized prior to database lock and unblinding. Patients in the PP-RW population who 
complete the RW phase without an important deviation will be used in sensitivity analyses of the 
primary endpoint and the secondary efficacy endpoints in the RW phase.  
6.9 
ABPM Population 
The ABPM analysis population will include all patients in the ITT-OL population who have 
ABPM results available at Baseline OL and Visit OL22, are randomized, have ABPM results 
available at Visit RW12 while on study drug and in whom compliance was acceptable (patient 
has at least 80% compliance [defined in Section 9.7] with prescribed dosing, by capsule counts, 
during OL and RW phases). The ABPM population will be used in sensitivity analysis of 
primary efficacy endpoint if at least 10 patients are included in this subgroup.  
6.10 
Key Subgroups 
Key Subgroups in the Open-Label Phase 
Cushing Syndrome Comorbidity Type: 
 Patients with DM (fasting plasma glucose ≥126 mg/dL and/or 2-hour plasma oGTT 
glucose ≥200 mg/dL at 2 hours or HbA1c ≥6.5%), or impaired glucose tolerance (plasma 
glucose ≥140 mg/dL and <200 mg/dL on a 2-hour oGTT).  
 Patients with uncontrolled hypertension (mean SBP ≥135 to ≤170 mm Hg and/or mean 
DBP ≥85 to ≤110 mm Hg based on 24-hour ABPM). 
Key Subgroups in the Randomized-Withdrawal Phase 
Cushing Syndrome Comorbidity Type by Response: 
 DM/IGT subgroup of the ITT-RW population are patients with DM/IGT at Baseline OL 
that respond to DM/IGT criteria at Visit OL22 and are randomized to the RW phase. 
 Hypertension subgroup of the ITT-RW population are patients with hypertension at 
Baseline OL that respond to hypertension criteria at Visit OL22 and are randomized to 
the RW phase. 
6.11 
Additional Subgroups 
Additional Subgroups in the Open-Label Phase  
Patients with uncontrolled hypertension at Baseline OL (mean SBP ≥135 to ≤170 mm Hg and/or 
mean DBP ≥85 to ≤110 mm Hg based on 24-hour ABPM): 
 Treated with antihypertensive medications. 
 Not treated with antihypertensive medications. 


 
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Patients with controlled hypertension at Baseline OL (mean SBP <135 mm Hg and mean DBP 
<85 mm Hg based on 24-hour ABPM) and medical history of hypertension: 
 Treated with antihypertensive medications. 
 Not treated with antihypertensive medications. 
Patients with DM at Baseline OL: 
 Treated with antidiabetic medications. 
 Not treated with antidiabetic medications. 
DM or IGT subgroup at Baseline OL: 
 Patients with IGT (plasma glucose ≥140 mg/dL and <200 mg/dL on a plasma 2-hours 
oGTT test). 
 Patients with DM (fasting plasma glucose ≥126 mg/dL and/or 2-hour plasma oGTT 
glucose ≥200 mg/dL at 2 hours or HbA1c ≥6.5%). 
Additional Subgroups in the Randomized-Withdrawal Phase  
Patients with uncontrolled hypertension at Baseline OL in the ITT-RW population: 
 Treated with antihypertensive medications. 
 Not treated with antihypertensive medications. 
Patients with controlled hypertension at Baseline OL in the ITT-RW population: 
 Treated with antihypertensive medications. 
 Not treated with antihypertensive medications. 
DM/IGT subgroup of the ITT-RW population: 
 DM at Baseline OL.  
 IGT at Baseline OL. 
Other subgroups of interest for the ITT-RW population: 
 Patients with systolic hypertension at Baseline OL. 
 Patients with diastolic hypertension at Baseline OL. 


 
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7 
DEFINITIONS, COMPUTATIONS, AND CONVENTIONS 
The statistical principles applied in the design and planned analyses of this study are consistent 
with Guidance for Industry: E9 Statistical Principles for Clinical Trials (ICH E9 1998) and 
E9(R1), Statistical Principles for Clinical Trials: Addendum: Estimands and Sensitivity Analyses 
in Clinical Trials (ICH E9[R1] 2021). 
All statistical analyses detailed in this SAP will be conducted using SAS version 9.4 or higher. 
Additional validated software may be used to generate analyses, as needed.  
All SAS programs that create tables, listings or figures and supporting analysis datasets will be 
validated per standard operating procedures. 
7.1 
Definitions 
Study day: Study day will be calculated in reference to the date of first dose of relacorilant in the 
OL phase (Study Day 1). For assessments conducted on or after the first dose date, study day is 
calculated as (assessment date – first dose date + 1). For assessments conducted before the first 
dose date, study day is calculated as (assessment date – first dose date). There is no Study Day 0.  
Study day for efficacy in RW Phase (RW Day): Study day in RW phase will be calculated in 
reference to the date of Randomization (RW Day 1). For assessments conducted on or after the 
randomization date, study day is calculated as (assessment date – randomization date + 1). For 
assessments conducted before the randomization date, RW Day is calculated as (assessment date 
– randomization date). There is no RW Day 0. 
Treatment-emergent period in OL Phase: The treatment-emergent period is defined as the period 
of time from the date of the first dose of study drug through 28 days after the last dose of study 
drug but prior to date of the first dose of study drug in the RW phase. The treatment-emergent 
period will be used in the summaries of treatment-emergent adverse events (TEAEs). 
Treatment-emergent period in RW Phase: The treatment-emergent period in RW phase is defined 
as the period of time from the date of the first dose of study drug in RW phase through 28 days 
after the last dose of study drug. The treatment-emergent period in RW phase will be used in the 
summaries of TEAEs presented by treatment arm for the RW phase. 
7.1.1 Definitions of Baseline  
7.1.1.1 
OL Phase 
The baseline for plasma 2-hours oGTT test is defined as the last oGTT corresponding time point 
measurement prior to first dose of study drug (e.g., pre-glucose drink, 0.5 hours post-glucose 
drink, 1-hour post-glucose drink, etc.) with enough timepoints to accurately calculate AUCglucose. 
If no baseline exists with enough timepoints to accurately calculate AUCglucose, then the last non-
missing prior to treatment start date should be used. 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 


 
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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 (e.g., 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 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) is defined 
at the same visit (unscheduled or scheduled) that the plasma 2-hours oGTT test is defined.  
The baseline for 24-hour UFC, 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 Screening. 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.  
7.1.1.2 
RW Phase 
For patients who were randomized in the RW phase, the last measurement available prior to 
randomization date will be considered as the Baseline for the RW phase (Baseline RW). 
7.1.2 Definition of Analysis Visit Windows 
In analysis of data summarized by study visit, unscheduled and early termination visits will be 
reassigned an analysis visit where data are scheduled for collection based on the planned visit 
Study Day. 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. 
The window for each study visit is relative to the Baseline or the Randomization visit. The 
acceptable visit window is ±3 days for Visits OL2, OL6, and OL10 and ±7 days for all other 
visits. The Randomization visit (the first day of the RW phase) may occur up to 28 days 
after Visit OL22 to allow time to obtain the required test results to evaluate eligibility 
for the RW phase. For the RW phase, the randomization day is considered Study Day 1. Table 1 
and Table 2 outline the analysis visit windows. 


 
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Table 1 
Analysis Visit Windows for Efficacy Assessments in OL Phase 
Visit Name 
Start Day 
Target Day 
End Day 
Baseline 
 
1 
 
OL2 
2 
15 
29 
OL6 
30 
43 
57 
OL10 
58 
71 
85 
OL14 
86 
99 
113 
OL18 
114 
126 
140 
OL22 
141 
155 
162 
ET 
 
Study day of last dose of 
study drug 
 
Follow-up 
Study day of last dose of 
study drug +21 
Study day of last dose of 
study drug +28 
Study day of last dose of 
study drug +35 
 
Table 2 
Analysis Visit Windows for Efficacy Assessments in RW Phase 
Visit Name 
Start Day 
Target Day 
End Day 
Randomization  
 
1 
 
RW4 
2 
29 
43 
RW8 
44 
57 
71 
RW12 
72 
84 
91 
Follow-up 
Study day of last dose of 
study drug +21 
Study day of last dose of 
study drug +28 
Study day of last dose of 
study drug +35 
7.2 
Reporting Conventions  
Unless otherwise specified, the following conventions will be applied to all analyses: 
 Continuous variables will be summarized to indicate the population sample size (N), 
number of patients with available data (n), mean, standard deviation (SD), median, 
inter-quartile range (Q1, Q3), minimum, maximum and 95% confidence intervals (CI). 
 Categorical variables will be summarized by the population size (N), number of patients 
with available data (n), number of patients in each category, percentage of patients in 
each category and 95% CI. Unless otherwise noted, the denominator to determine the 
percentage of patients in each category will be based on the number of patients with 
available data (n).  
 Select ordinal data may be summarized using both descriptive statistics and counts and 
percentages of patients in each category, as appropriate. 


 
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 Confidence intervals (CIs), when presented, will generally be constructed at the 95% 
level. For binomial variables, exact methods will be employed unless otherwise specified. 
 Rounding conventions for presentation of summary statistics will be based on the 
precision of the variable of summarization, as it is collected in its rawest form (i.e., on the 
eCRF or as provided within an external file) and are outlined as follows: 
o The mean and median will be rounded to one more decimal place than the 
precision of the variable of summarization. 
o Measures of variability (e.g., SD, SE) will be rounded to two more decimal places 
than the precision of the variable of summarization. 
o Minimum and maximum values will be presented using the same precision as the 
variable of summarization. 
o Non-zero percentages will be rounded to 1 decimal place. Number and percentage 
values will be presented as xx (xx.x%). 
 Analysis and summary tables will have the analysis population sample size (i.e., number 
of patients). 
 Laboratory data will be reported using standard international (SI) and conventional units; 
as central laboratories are used for this study. 
 1 inch = 2.54 cm.  
 For by-visit observed data analyses, percentages will be calculated based on the number 
of patients with non-missing data as the denominator unless otherwise specified. 
 P-values will be rounded to 4 decimal places. P-values that round to 0.0000 will be 
presented as ‘<0.0001’ and p-values that round to 1.000 will be presented as ‘>0.9999’. 
 Medical history and adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA version 26.0). Adverse event severity will be evaluated 
using the National Cancer Institute Common Terminology Criteria for Adverse Events 
(CTCAE) v.5.0 (NCI-CTCAE 2017).  
 Prior therapies and concomitant medications will be coded using the World Health 
Organization (WHO) Drug Dictionary (version WHODrug Global B3 March 1, 2020) 
and summarized by Anatomical Therapeutic Chemical (ATC) medication class and 
preferred names. 
 All statistical hypotheses will be tested at a two-sided 0.05 significance level unless 
otherwise specified.  
 Listings for OL phase will be presented in the order of comorbidity type (hypertension, 
DM/IGT, or DM/IGT and hypertension), patient identifier, and visit (or date of procedure 
or event, when applicable), unless stated otherwise. 
 Listings for RW phase will be presented in the order of treatment arm, comorbidity type 
(hypertension, DM/IGT, or DM/IGT and hypertension), patient identifier, and visit (or 
date of procedure or event, when applicable), unless stated otherwise. 
7.3 
Summarization by Visit 
Data collected at scheduled visits will be analyzed based on the nominal visit as reported in 
the database. If an unscheduled assessment is mapped to an analysis visit window that already 


 
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has a non-missing assessment for the corresponding scheduled visit, the scheduled visit will be 
used in the analysis. Otherwise, if multiple assessments occur within a single visit window, then 
the closest assessment to the target day of the visit window will be used in the analysis. If 
distance to target visit date is the same for more than one assessment (e.g., one assessment is 
performed 2 days prior to the target visit date and one assessment is performed 2 days after the 
target visit date), the later assessment day that is still within the visit window will be used in the 
analysis.  
If there are repeated assessments of the same sample or procedure at a scheduled visit, the most 
recent value will be used for analysis. 
7.4 
Data Handling Rules  
Unless otherwise noted, values reported as greater than or less than limit of quantification (LOQ) 
(e.g., “<1.0”) will be summarized with the sign suppressed in summary tables and figures, using 
the LOQ value instead. 
7.5 
Standard Calculations 
Conventions for calculations with dates are as follows: 
 Dates will be stored as numeric variables in the SAS analysis files and reported in 
DDMMMYYYY format (i.e., the Date9. datetime format in SAS). 
 Dates recorded in comment fields will not be imputed or reported in any specific format. 
 Age at the beginning of OL phase will be calculated in years as integer part of (DATE of 
ENROLLMENT - DATE of BIRTH + 1) / 365.25. If both day and month fields are 
missing, impute missing day and month as July 1st. If the year field is missing, age will 
be set as missing. 
 Where appropriate, the calculated study day of each assessment or event will be 
presented with the assessment or event date on patient data listings, where study day is 
defined in Section 7.1. 
 Days: A duration between two dates expressed in days will be calculated using the 
following conventions: 
o (Later date - earlier date) + 1, if the earlier date is on or after the date of first dose 
of study drug; or 
o Later date - earlier date, if the earlier date is prior to the date of first dose of study 
drug. 
 Weeks: A duration expressed in Weeks will be calculated by dividing the duration in 
days by 7. 
 Months: A duration expressed in months will be calculated by dividing the duration in 
days by (30.4375 = 365.25 / 12). 
 Years: A duration expressed in years will be calculated by dividing the duration in days 
by 365.25. 


 
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Detailed rules for imputation of missing/partially missing dates for adverse events, medical 
history, and prior/concomitant medications/procedures are provided in Section 7.6.4. and 
Cushing syndrome medical history in Section 7.6.5. 
Conventions for calculations for other types of variables: 
 Change from Baseline: Change from baseline will be calculated as the post-baseline 
value minus the baseline value. 
 Percentage Change from Baseline: Percentage change from baseline will be calculated as 
the change from baseline divided by the baseline value, multiplied by 100. 
7.6 
Handling Missing Data 
The guidance on The Prevention and Treatment of Missing Data in Clinical Trials (National 
Research Council 2010) will be followed when these methods are applied.  
All efforts will be made to prevent missing data. To prevent bias caused by unavoidable missing 
data, different statistical approaches (described in Section 7.6.1 through Section 7.6.5) based on 
the nature of the endpoint will be used to handle missing data. For each endpoint in OL phase, a 
summary of missing data at each of the visits will be provided. For endpoints in RW phase, such 
summary of missing data will be presented by treatment arm and by visit. 
7.6.1 Handling Missing Data for Primary Efficacy Endpoint in RW Phase 
7.6.1.1 
Loss of Response with Respect to Hypertension Control 
Patients who started rescue medication for hypertension before Visit RW12 or who discontinued 
study treatment prior to Visit RW12 (which are the intercurrent events for the purpose of this 
estimand) will be considered as non-responders in the primary analysis for loss of response in 
hypertension control. This is a composite strategy, per ICH E9[R1] 2021, integrating the 
occurrence of the intercurrent event into the variable and therefore no imputation for missing 
data is necessary. Furthermore, patients who do not use rescue medication or who do not 
discontinue treatment, but who have missing data at Visit RW12, will be considered non-
responders. 
7.6.2 Handling Missing Data for Secondary Efficacy Endpoints  
7.6.2.1 
Secondary Endpoints Summarized with Proportions 
For endpoints that are defined as response to certain criteria, patients with missing data at Visit 
RW12 will be considered non-responders. 
7.6.2.2 
Continuous Secondary Efficacy Endpoints  
7.6.2.2.1 Handling Missing Data for Hypertension Control (SBP/DBP) 
As described in the protocol, if a patient discontinues early from the RW phase, the patient is 
instructed to return for Visit RW12 per the patient’s original dosing schedule. Retrieved dropouts 


 
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are patients who discontinue study treatment prior to Visit RW12 and return for the Visit RW12 
assessment of the SBP/DBP, as required by protocol. 
Patients that discontinue study treatment after randomization and prior to Visit RW12, and do 
not return for the Visit RW12 assessment of the SBP/DBP, are referred to as ‘non-retrieved 
dropouts’.  
The missing data at Visit RW12 for non-retrieved dropouts will be imputed based on data from 
retrieved dropouts. 
If fewer than 10 retrieved dropouts are available, then the primary analysis will use a placebo 
wash-out imputation method as described in Section 9.8.3.2.1. instead of the retrieved dropout 
approach. 
In patients in the hypertension subgroup and randomized in the RW phase, imputation of missing 
data for the secondary endpoint of change in SBP/DBP from Visit OL22 to Visit RW12 will be 
performed depending on whether patient takes rescue medication: 
 For patients who do not use rescue medication for hypertension before Visit RW12 
(regardless if they discontinue treatment), all values for SBP/DBP including the Visit 
RW12, will be used in the analysis (including values from retrieved dropouts).  
 For patients who do not take rescue medication for whom SBP/DBP at Visit RW12 is 
missing, only missing SBP/DBP values at Visit RW12 will be imputed based on data 
from retrieved dropouts, with similar baseline characteristics, within the same treatment 
arm. Details are provided in Appendix 1.  
 For patients who use rescue medication for hypertension control (including potassium 
sparing diuretics) after randomization and before Visit RW12, the values collected after 
rescue medication is first used are irrelevant to the clinical question of interest, will not 
be used in the analysis. Such ‘missing values’ in SBP/DBP at Visit RW12 in patients that 
take hypertension rescue medication will be imputed using the placebo-based mean value 
(Mehrotra et al., 2017) calculated in patients who completed Visit RW12.  
Additionally, a multiple imputation analysis based on placebo wash-out approach will be 
conducted to analyze the treatment effect of relacorilant compared with placebo. 
In this study, the treatment effect is determined by loss of response with regards to hypertension 
criteria. In this context, the placebo ‘wash-out’ analysis means the missing SBP/DBP at Visit 
RW12 data will be imputed by considering a wash-out of the effect of treatment using 
completers in the placebo arm. Specifically, SBP/DBP data for patients on the placebo arm 
without measurements at Visit RW12 will be imputed using a monotone regression model based 
on observed SBP/DBP data of completers on the placebo arm with intermediate measurements, 
baseline SBP/DBP and stratification factor (as outlined in Section 9.8.3.2). For patients on the 
relacorilant arm, missing Visit RW12 data will be imputed using monotone regression model 
based on observed SBP/DBP data of completers on the placebo arm with baseline SBP/DBP and 
stratification factor. 


 
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Missing data will be imputed by selecting random observations from a normal distribution 
centered at the value predicted by the regression model and with variance analogous to 
predicting a new observation. The imputation procedure will be iterated 100 times. 
One hundred data sets will be generated and an MMRM with the factors and covariates (as 
described in Section 9.8.3.2.1) will be run on each data set and point estimates and standard 
errors computed and the results combined to yield a multiple imputation point estimate and 
standard error. 
7.6.2.2.2 Handling Missing Data for the Purpose of Calculating AUCglucose 
For calculations involving AUC based on plasma 2-hours oGTT test, the following rules for 
handling missing data will be applied at individual timepoints: 
 If the pre-glucose drink time point or 30-minute post-glucose drink time point is missing, 
no AUC calculation will be performed. The AUC for that visit will be counted as 
missing.  
 If more than one post-glucose drink time points are missing, no AUC calculation will 
be performed. 
 If only one post-glucose drink time point is missing, and it is not the 30-minute post-
glucose drink time point, then the AUC will be calculated using the available data. For 
example, if the 90-minute time point is missing, a trapezoid will be constructed to 
connect the 60 minute and 120-minute time points.  
 If only the 120-minute post-glucose drink time point is missing, the AUC will be 
calculated using the available data, and the associated oGTT pre-glucose drink to 
90-minute post-glucose drink values and AUC will be used in the summary tables. 
 Otherwise, observed values only will be used. 
Handling Missing Data in RW Phase for AUCglucose 
As described in the protocol, if a patient discontinues early from the RW phase, the patient is 
instructed to return for Visit RW12 per the patient’s original dosing schedule. Retrieved dropouts 
are patients who discontinue study treatment prior to Visit RW12 and return for the Visit RW12 
assessment of the oGTT, as required by protocol. 
Patients that discontinue study treatment after randomization and prior to Visit RW12, and do 
not return for the Visit RW12 assessment of the oGTT, are referred to as ‘non-retrieved 
dropouts’.  
The missing data at Visit RW12 for non-retrieved dropouts will be imputed based on data from 
retrieved dropouts. 
If fewer than 10 retrieved dropouts are available, then the analysis will use a placebo wash-out 
imputation method as described in Section 9.8.3.4.1 instead of the retrieved dropout approach. 
Among patients in the DM/IGT subgroup who are randomized in the RW phase, imputation of 
missing data for the secondary endpoint of change in AUCglucose from Visit OL22 to Visit RW12 
will be performed depending on whether the patient takes rescue medication: 


 
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 For patients who do not use rescue medication for DM/IGT before Visit RW12 
(regardless of if they discontinue treatment), all values for AUCglucose including the Visit 
RW12, will be used in the analysis (including values from retrieved dropouts).  
 For patients who do not take rescue medication for whom AUCglucose at Visit RW12 is 
missing, only missing AUCglucose values at Visit RW12 will be imputed based on data 
from retrieved dropouts, with similar baseline characteristics, within the same treatment 
arm. Details are provided in Appendix 1.  
 For patients who use rescue medication for hyperglycemia control after randomization 
and before Visit RW12, the values collected after rescue medication is first used are 
irrelevant to the clinical question of interest, and thus will not be used in the analysis. 
Such ‘missing values’ in AUCglucose at Visit RW12 in patients who take diabetes rescue 
medication will be imputed using the placebo-based mean value (Mehrotra et al., 2017) 
calculated in patients who completed Visit RW12.  
Additionally, a multiple imputation analysis based on placebo wash-out approach will be 
conducted to analyze the treatment effect of relacorilant compared with placebo. 
In this study, the treatment effect is determined by loss of response with regards to response to 
DM/IGT criteria. In this context, the placebo ‘wash-out’ analysis means the missing AUCglucose at 
Visit RW12 data will be imputed by considering a wash-out of the effect of treatment using 
completers in the placebo arm. Specifically, AUCglucose data for patients on the placebo arm 
without measurements at Visit RW12 will be imputed using a monotone regression model based 
on observed AUCglucose data of completers on the placebo arm with intermediate measurements, 
baseline AUCglucose and stratification factor (as outlined in Section 9.8.3.4). For patients on the 
relacorilant arm, missing Visit RW12 data will be imputed using monotone regression model 
based on observed AUCglucose data of completers on the placebo arm with baseline AUCglucose and 
stratification factor. 
Missing data will be imputed by selecting random observations from a normal distribution 
centered at the value predicted by the regression model and with variance analogous to 
predicting a new observation. The imputation procedure will be iterated 100 times. 
One hundred data sets will be generated and an MMRM with the factors and covariates (as 
described in Section 9.8.3.4.1) will be run on each data set and point estimates and standard 
errors computed and the results combined to yield a multiple imputation point estimate and 
standard error. 
7.6.3 Handling Missing Data for Exploratory Efficacy Endpoints 
For calculations involving exploratory efficacy endpoints in RW phase, the same rules for 
handling missing data as described for secondary efficacy endpoints in RW phase (Section 7.6.2) 
will be applied. For continuous exploratory efficacy endpoints collected in the RW phase, all 
efficacy by-visit analyses will include summaries of observed cases only, where no imputations 
will be used, except for the hypertension control (Section 7.6.2.2.1) and AUC missing data 
handling rules (Section 7.6.2.2.2). 


 
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7.6.3.1 
Handling Missing Data for Efficacy Endpoints in the Open-Label Phase 
7.6.3.1.1 Endpoints from OL Phase Summarized with Proportions 
For the purpose of analyzing endpoints that are defined as response to certain criteria, patients 
with missing data at Visit OL22 will be considered non-responders. 
7.6.3.1.2 Continuous Endpoints from OL Phase 
For continuous exploratory efficacy endpoints collected in the OL phase, all efficacy by-visit 
analyses will include summaries of observed cases only, where no imputations will be used 
except for AUC as described below: 
For calculations involving AUC based on plasma 2-hours oGTT test in the OL phase, the same 
rules for handling missing data as described in (Section 7.6.2.2.2) will be applied at individual 
timepoints: 
 If the pre-glucose drink time point or 30-minute post-glucose drink time point are 
missing, no AUC calculation will be performed. The AUC for that visit will be counted 
as missing.  
 If more than one post-glucose drink time points are missing, no AUC calculation will be 
performed. 
 If only one post-glucose drink time point is missing, and it is not the 30-minute 
post -glucose drink time point, then the AUC will be calculated using the 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.  
 If only the 120-minute post-glucose drink time point is missing, the AUC will be 
calculated using the available data, and the associated oGTT pre-glucose drink to 90-
minute post-glucose drink values and AUC will be used in the summary tables. 
 Otherwise, observed values only will be used. 
7.6.4 Handling Incomplete or Missing Dates for Adverse Events, Medical History and 
Concomitant Medications  
For safety analyses, incomplete date of last dose of study drug and incomplete start date of 
concomitant medications that are missing the day of the month, the 15th of the month will be 
used to impute the missing date. When imputing partial last dose dates, the last visit date will be 
taken into consideration. The imputed dates will be used to determine the treatment-emergent 
period. 
For adverse events with a partial date, available date parts (year, month, and day) of the partial 
date will be compared with the corresponding date components of the start date and end date of 
the treatment-emergent period to determine if the event is treatment emergent. The following 
rules will be applied to impute partial dates for adverse events. 
If start date of an adverse event is partially missing, following imputation rules will be applied: 


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


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


 
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9 
STATISTICAL METHODS 
9.1 
General Statistical Consideration 
Statistical analyses will be reported with tables, figures, and listings, presented in rich text 
format, and using recommended ICH numbering. Output specifications for all tables, figures, and 
listings will be in conformance with guidelines specified by the ICH of the Electronic Common 
Technical Document Specification (ICH M2ectd 2003).  
9.2 
Patient Disposition 
Screen failure information is collected in an interactive web response system (IWRS), not on the 
eCRF, and it will not be incorporated into the Study Data Tabulation Model (SDTM) database.  
Patient disposition will be summarized for the ITT population by OL phase and RW phase. 
Participant disposition during OL phase will present the number of patients enrolled, number 
treated with study drug, and among those number of patients who completed OL phase and who 
discontinued from OL phase, study treatment and reasons for discontinuation. Primary reason for 
discontinuation of treatment, including any of the following, will be summarized: 
 Adverse Event 
 Lost to Follow-up 
 Pregnancy 
 Study Terminated by Sponsor 
 Lack of Efficacy 
 Withdrawal by Patient 
 Physician Decision 
 Death 
 Non-Compliance with study drug 
 Protocol Deviation 
 Other 
Participant disposition during RW phase will present the number of patients randomized, treated 
with study drug, completed the RW phase and who discontinued from RW phase, discontinued 
early the study treatment in the RW phase and reasons for discontinuation. Frequency counts and 
percentages of patients who complete the study and those who discontinue early for any of the 
following reasons will also be calculated: 
 Adverse Event 
 Lost to Follow-up 
 Pregnancy 
 Study Terminated by Sponsor 
 Lack of Efficacy 
 Withdrawal by Patient 
 Physician Decision 


 
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 Death 
 Non-Compliance with study drug 
 Protocol Deviation 
 Other 
A listing of all patients who discontinued from the trial and their reason for discontinuation will 
be provided.  
If applicable, eligibility violations and occurrences of emergency and accidental treatment 
unblinding during RW phase will be reported. 
Attendance at scheduled visits will be shown as the number of patients who completed each 
scheduled visit for both OL phase and RW phase. The time (in days) from OL22 to 
randomization and initiation of treatment in RW phase will be summarized.  
9.3 
Protocol Deviations 
All important protocol deviations will be determined and appropriately categorized prior to 
database lock according to protocol deviation specification document. Protocol deviations will be 
listed by OL/RW phases, study site, patient, and date of deviation, and will indicate if they are 
considered important. The number and percentage of patients with any important protocol 
deviations as well as the number and percentage of patients with deviations by comorbidity type 
(DM/IGT or hypertension), and overall, will be presented for the Safety Population. 
Additionally, COVID-19 related protocol deviations will be presented in separate listings. 
9.4 
Demographic Characteristics and Baseline Characteristics 
The following demographic characteristics will be presented in listings and summarized in 
ITT-OL Analysis Population and ITT-RW Population (by treatment arm and overall):  
 Age at beginning of OL phase 
 Sex 
 Ethnicity 
 Race  
 Geographic region: North America (United States and Canada) and ROW (Austria, 
Bulgaria, Germany, Israel, Italy, Netherlands, Poland, Romania, and Spain) 
 Age (three levels <45 vs. [45, 65) vs. ≥65) 
Age will be summarized using descriptive statistics. Sex, ethnicity, race, age, and geographic 
region will be summarized with the number and percentage of patients in each parameter 
category. 
Baseline characteristics include height, weight, body mass index (BMI), waist circumference, 
plasma ACTH, 24-hr UFC, late-night salivary cortisol, plasma 2-hour oGTT test, AUCglucose, 
HbA1c, and mean 24-hour SBP and DBP from ABPM. BMI will be calculated as: weight (kg) / 
[height (cm) / 100]2.  


 
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Demographics and baseline characteristics will be summarized for the ITT-OL and ITT-RW 
populations, including by comorbidity subgroups (DM/IGT and hypertension) in each of the 
analysis populations. Baseline characteristics will also be summarized by Cushing’s etiology 
(adrenal vs pituitary, i.e., ACTH independent vs ACTH dependent). 
9.5 
Medical History 
Medical history will be presented in listings and summarized for all patients in the ITT-OL and 
ITT-RW, and presented by comorbidity type (DM/IGT or hypertension), and overall. 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 26.0) and Cushing syndrome history will be presented. Time (months) since 
diagnosis of Cushing syndrome will be calculated as the informed consent date minus the 
diagnosis date from the medical history eCRF and will be summarized using descriptive 
statistics.  
9.6 
Prior and Concomitant Medications  
Medications will be coded using the World Health Organization (WHO) Drug Global B3 version 
March 1, 2023 or later. Medications entered on the eCRF will be mapped to ATC drug class 
(level 4) and drug name. Prior and concomitant medications will be summarized in the Safety 
Population for both OL phase and RW phase. 
Prior and concomitant medications will be summarized separately. Whether or not the 
medication is prior and/or concomitant will be determined programmatically based on 
medication start and end dates. A prior medication is defined as any medication administered 
that started prior to the date of the first dose of study drug. A concomitant medication is defined 
as any medication administered on or after the date of the first dose of study drug. A medication 
may be defined as both prior and concomitant. Imputation of partial dates apply as described in 
Section 7.6.4.  
For the prior medications table summary, the number and percentage of patients receiving any 
medication will be summarized by comorbidity type (DM/IGT or hypertension), 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, 
comorbidity type (DM/IGT or hypertension), and all patients combined, as will the number and 
percentage receiving any medication by ATC drug class and generic drug name. Additionally, a 
summary table of the number and percentage of patients receiving any medication by ATC drug 
class will be presented. The study drug dose category 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. Whether or not the medication is 
prior and/or concomitant will be presented on the listing of prior and concomitant medications. 


 
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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 
for both OL phase and RW phase; and 
 Medications used to treat diabetes or hypertension for patients in the Safety Population 
for both OL phase and RW phase.  
Tables summarizing reduction in antidiabetic, antihypertensive, and antidepressant concomitant 
medications will also be presented by comorbidity type (DM/IGT or hypertension), and will 
include the number of patients taking the medication at Baseline OL, median total daily dose at 
Baseline OL, number of patients with a dose reduction, median reduction in total daily dose at 
last visit, the number of patients with any reduction in daily dose, the number of patients with 
≥25% reduction in daily dose, the number of patients with ≥50% reduction in daily dose and the 
number of patients with complete discontinuation in daily dose. Antidiabetic and 
antihypertensive medications will be those that are entered as antidiabetic or antihypertensive on 
the eCRF, potassium sparing diuretics for antihypertensive medications, and any medications 
that were considered an antidiabetic or antihypertensive medication based on medical judgment. 
Any dose increase or new use of a mineralocorticoid antagonist (as defined in Appendix 4) 
during the study, for the treatment of either hypertension or hypokalemia, will be regarded as 
antihypertensive medication. 
Prior and concomitant medications will be presented in a by-patient data listing by comorbidity 
type (DM/IGT or hypertension), ATC class and generic drug names, medication start date, and 
study drug dose level at time of medication start date. Concomitant medication will additionally 
be listed by comorbidity type (DM/IGT or hypertension), week on study, total daily dose and 
dose change from baseline.  
9.7 
Extent of Exposure and Study Drug Compliance  
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 the sum of the actual dose administered for the duration of exposure. For patients where 
their dose received is either zero or missing, a received dose of zero is included in the total dose 
received derivation. Duration of exposure, total actual dose received (mg), and number of days at 
each dose level will be summarized using descriptive statistics in all patients by study phase 
(OL and RW) and by comorbidity type. In addition, for the OL phase, the number of patients 
reaching first, second, and third dose escalation, highest dose level received, and the number of 
patients exposed at each dose level will be summarized by frequency counts and percentages 
overall and by comorbidity type (DM/IGT or hypertension).  
Relative dose intensity will be reported. Relative dose intensity is calculated for each visit 
interval (e.g., Baseline to OL2, OL2-OL6, etc.) as the total dose received divided by the total 
dose expected between visits, multiplied by 100, for the particular visit interval and overall by 
phase. 


 
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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 prescribed dose. Expected 
dose received will be calculated as [(study drug stop date – study drug start date) + 1] multiplied 
by expected daily dose and will reflect dose escalation for each patient as entered in the eCRF. 
Dosing compliance will be summarized using descriptive statistics by study phase (OL and RW) 
overall and by comorbidity type (DM/IGT or hypertension), based on the Safety Population. The 
number and percentages of patients who are <80% compliant and ≥80% compliant within each 
comorbidity type group will be summarized.   
Extent of exposure and compliance will be reported in the Safety population in OL and 
RW phase and within each comorbidity type. 
9.8 
Efficacy Analyses 
Analysis of efficacy endpoints are described in Section 9.8.2 through Section 9.8.4. All efficacy 
data will be presented in by-patient data listings. 
9.8.1 Multiple Comparisons/Multiplicity Adjustment  
The primary efficacy analysis will be the comparison between relacorilant and placebo arms in 
the proportion of patients with a loss of response with respect to hypertension from Visit OL22 
to Visit RW12 based on 24-hour ABPM. The Type I error rate will be controlled at a 2-sided 
0.05 level for the primary efficacy analysis.  
In patients with hypertension at study entry, the proportion of patients with a loss of response 
with respect to hypertension from Visit OL22 to Visit RW12 based on 24-hour ABPM is defined 
as follows: 
 In patients who met only the SBP response criterion, an increase in SBP ≥5 mm Hg. 
 In patients who met only the DBP response criterion, an increase in DBP by ≥5 mm 
Hg. 
 In patients who met both the SBP and DBP response criteria, an increase in either 
SBP or DBP by ≥5 mm Hg. 
 Any increase or modification in antihypertensive medication due to worsening 
hypertension. 
 Patients discontinue treatment in RW phase for any reason. 
No adjustments for multiplicity will be made for secondary and exploratory endpoints. 
9.8.2 Primary Efficacy Endpoint 
9.8.2.1 
Loss of Response with Respect to Hypertension Control in RW Phase  
For patient in the hypertension subgroup of the ITT-RW population, aligned to the clinical 
question of interest, the estimand of interest is the difference between proportions of patients 
losing response with respect to hypertension control, between treatment arms from Visit OL22 to 


 
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Visit RW12 that is free from the confounding effect of rescue medication regardless of whether 
or when the assigned treatment was discontinued. 
Specifically, the estimand is difference in proportion of patients losing response between 
(continuing) relacorilant and placebo (withdrawing relacorilant) treatment in patients with initial 
response to relacorilant. 
For patient with hypertension at study entry, loss of response from Visit OL22 to Visit RW12 
based on 24-hour ABPM is defined as follows: 
 In patients who met only the SBP response criterion, an increase in SBP ≥5 mm Hg. 
 In patients who met only the DBP response criterion, an increase in DBP by ≥5 mm 
Hg. 
 In patients who met both the SBP and DBP response criteria, an increase in either 
SBP or DBP by ≥5 mm Hg. 
 Any increase or modification in antihypertensive medication due to worsening 
hypertension. 
 Patients discontinue treatment early for any reason (prior to Visit RW12). 
The proposed estimand for hypertension control in the hypertension subgroup of the ITT-RW 
population follows a composite strategy with respect to early discontinuation and use of rescue 
medication. 
9.8.2.2 
Primary Efficacy Endpoint for Patients with Uncontrolled Hypertension 
For the hypertension subgroup of the ITT-RW analysis population, the primary analysis will 
determine whether there is a difference between treatment groups in terms of the proportion of 
patients with a loss of response with respect to hypertension from Visit OL22 to Visit RW12 
based on 24-hour ABPM. This will be accomplished by using the logistic regression model, 
 
where treatment is the treatment arm (with 2 levels, relacorilant and placebo) and sfactor is the 
stratification factor at randomization in IRT (with 2 levels, with or without DM/IGT). The 
coefficients 𝛽0 indicates the intercept, 𝛽1 indicates the regression coefficient for treatment and 
𝛽2 indicates the regression coefficient for stratification factor. The exp(𝛽1) is the odds ratio (OR) 
that estimates the association between treatment and proportion of patients with a loss of 
response. 
The chi-square test statistic and p-value will be used to test the below null hypothesis, 
 
The parameter estimates and standard errors, the chi-square test statistics and p-values, along 
with the odds ratios and 95% CI will be reported (Steingrimsson et al. 2017). In case of logistic 
model convergence issues, Fisher’s exact test will be used instead.  


 
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For this endpoint (proportion of patients with loss of response), OR<1 represents lower odds of 
loss of response under treatment with relacorilant compared with treatment with placebo, in the 
RW phase.  
In addition to the primary analysis described above, the proportion of patients with a loss of 
response will be summarized for both relacorilant and placebo arms together with corresponding 
two-sided 95% CI using Clopper-Pearson method in the hypertension subgroup of the ITT-RW 
population. 
9.8.2.3 
Sensitivity Analysis for Primary Efficacy Endpoint 
9.8.2.3.1 Sensitivity Analyses to Address Confounding by Early Discontinuation 
To demonstrate the robustness of the primary analysis, the following sensitivity analyses (Table 
3) will be performed on the ITT-RW population:  
Table 3 
Sensitivity Analyses for Loss of Response in Patients with Hypertension 
 
Sensitivity Analysis 
1 
Retrieved Dropout Imputation (Section 9.8.2.3.1.1) 
2 
LOCF Analysis (Section 9.8.2.3.1.2) 
9.8.2.3.1.1 
Retrieved Dropout Imputation Sensitivity Analysis for Uncontrolled 
Hypertension 
If 10 or more discontinued patients return for Visit RW12 and their retrieved dropout data are 
available, then for patients who discontinue early for whom loss of response in hypertension 
control at Visit RW12 cannot be determined due to missing data, SBP/DBP Visit RW12 data will 
be imputed based on data from retrieved dropouts, with similar baseline characteristics, within 
the same treatment arm. Those patients who have any increase or modification in 
antihypertensive medication due to worsening hypertension will be considered a loss of 
response. The analysis for patients with loss of response to hypertension control as described in 
Section 9.8.2.2 will be performed with the imputed values.  
9.8.2.3.1.2 
LOCF Sensitivity Analysis for Uncontrolled Hypertension 
Additionally, for patients who discontinued early for any reason, the last non-missing 
observation prior to the patient discontinuing treatment will be carried forward to impute the 
missing value for Visit RW12. With the LOCF imputed values, loss of response from Visit OL22 
to Visit RW12 based on 24-hour ABPM is defined as follows: 
 In patients who met only the SBP response criterion, an increase in SBP ≥5 mm Hg. 
 In patients who met only the DBP response criterion, an increase in DBP by ≥5 mm Hg. 
 In patients who met both the SBP and DBP response criteria, an increase in either SBP or 
DBP by ≥5 mm Hg. 
 Any increase or modification in antihypertensive medication due to worsening 
hypertension. 


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The proportion of patients with a loss of response will be calculated for both relacorilant and 
placebo arms together with corresponding two-sided 95% CI using Clopper-Pearson method. 
The logistic regression model analysis for patients with uncontrolled hypertension as described 
in Section 9.8.2.2 will be performed for the loss response using LOCF values. 
9.8.2.3.2 Sensitivity Analyses to Address Mis-stratification at Randomization 
The logistic regression model described in Section 9.8.2.2 will be repeated with sfactor being the 
correct stratification factor per EDC (with 2 levels, with or without DM/IGT), instead of the 
stratification factor at randomization in IRT. 
9.8.2.4 
Supplementary Analyses for Primary Efficacy Endpoint in Subgroups 
Analysis described above in Section 9.8.2.1 through Section 9.8.2.2 will be performed for 
mITT-RW population, PP-RW population and subgroups to demonstrate the robustness of the 
results. The following subgroup analyses (Table 4) will be considered: 
Table 4 
Subgroup Analyses for Loss of Response In Patients with Hypertension 
Subgroup Analysis 
Analysis Population/Subgroups 
1 
mITT-RW 
2 
ITT-RW (by DM/IGT Subgroup within patients with hypertension) 
3 
ABPM analysis population 
4 
PP-RW 
5 
ITT-RW (by Region - North America vs. ROW) 
6 
ITT-RW (by Age Group - <45 vs. [45, 65) vs. ≥65) 
7 
ITT-RW (by Sex - Male vs. Female) 
8 
ITT-RW (by antihypertensive medications - Treated vs. Not Treated) 
All subgroup analyses mentioned in Table 4 will be performed if the subgroup consists of 10 or 
more patients. 
9.8.3 Secondary Efficacy Endpoints 
Continuous secondary endpoints in the RW phase of the study will be analyzed using a REML‒
based linear MMRM analysis for the ITT RW population to compare treatment effect between 
treatment arms at each visit. The MMRM model will include Visit OL22 value (Baseline RW for 
the respective endpoint) as a covariate; treatment, visit, treatment by visit interaction, and 
stratification factor as fixed effects; and patients within treatment arms as random effects. An 
unstructured covariance structure will be used to model within-patient error, and the Kenward-
Roger approximation will be used to model denominator degrees of freedom. Least-squares 
means will be used to determine whether there is a difference between treatment arm in terms of 
the change from Visit OL22 to Visit RW12. SAS statement that implements PROC MIXED will 


 
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be used and the sample SAS code is presented in Appendix 3 and can be modified as needed. For 
select endpoints (i.e. SBP, DBP, AUCglucose, HbA1c), missing data at Visit RW12 will be 
imputed using retrieved dropouts for patients with early treatment discontinuation and using a 
placebo-based mean imputation for patients that use rescue medication (as defined for each 
endpoint) before using the MMRM model. As indicated in Section 7.6.2.2.1, if fewer than 10 
retrieved dropouts are available, then the main analysis will use a placebo wash-out multiple 
imputation method instead of the retrieved dropout approach. 
For endpoints described as proportions in the RW phase, the point estimate and the two-sided 
95% CI will be calculated. Differences in proportions between relacorilant and placebo will be 
evaluated using a logistic regression model including effects for treatment and the stratification 
factor (Steingrimsson et al. 2017). Additionally for analyses of patients with DM/IGT, the model 
will include an effect for the continuous baseline 2-hour oGTT plasma glucose value. The 
parameter estimates and standard errors, the chi-square test statistics and p-values, along with the 
odds ratios and 95% CI will be reported. In case of logistic model convergence issues, Fisher’s 
exact test will be used instead. The stratification factor at randomization identifies patients with 
or without hypertension. 
9.8.3.1 
Patients with DM/IGT: Loss of Response (AUC-based) in RW Phase  
For patients in the DM/IGT subgroup with response at OL22, the proportion of patients with a 
loss of response with respect to hyperglycemic control (AUC-based) from Visit OL22 to RW12, 
as compared between relacorilant and placebo arms, where loss of response is defined as a ≥10% 
increase from baseline in AUCglucose from Visit OL22 to Visit RW12, use of rescue medication 
(initiation or increase in diabetes medication due to worsening of hyperglycemic control), 
treatment discontinuation for any reason in RW phase, or patients with missing RW12 AUCglucose 
values.  
The proportion of patients with a loss of response with respect to hyperglycemic control will be 
calculated for both relacorilant and placebo arms together with corresponding two-sided 95% CI 
using Clopper-Pearson method for the ITT-RW population. Differences in proportions between 
relacorilant and placebo will be evaluated using a logistic regression model effects for treatment, 
the stratification factor (at randomization in IRT), and baseline 2-hour oGTT plasma glucose 
value (Steingrimsson et al. 2017). The parameter estimates and standard errors, the chi-square 
test statistics and p-values, along with the odds ratios and 95% CI will be reported. In case of 
logistic model convergence issues, Fisher’s exact test will be used instead. The stratification 
factor at randomization identifies patients with or without response to hypertension criteria. 
A sensitivity analysis will be performed using a logistic regression model where the stratification 
factor will be based on EDC information. 
9.8.3.1.1 Patients with DM/IGT: Loss of Response (AUC-based) in RW Phase Sensitivity 
Analysis 
As a sensitivity analysis for the loss of response (AUC-based), the proportion of patients with 
loss of response with respect to hyperglycemic control will be examined separately where loss of 


 
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response is defined as 1) any increase from baseline in AUCglucose from Visit OL22 to Visit 
RW12; and 2) as ≥5% increase from baseline in AUCglucose from Visit OL22 to Visit RW12. Use 
of rescue medication (initiation or increase in diabetes medication due to worsening of 
hyperglycemic control), treatment discontinuation for any reason in RW phase, or patients with 
missing RW12 AUCglucose values will also be considered as a loss of response within these 2 
sensitivity analyses. 
Additionally, each of the three loss of response (AUC-based) definitions (any increase; ≥5% 
increase; ≥10% increase in AUCglucose) will be analyzed separately for DM/IGT patients who had 
a ≥25% decrease in AUCglucose at OL22 compared to baseline. 
9.8.3.2 
24-Hour Average Ambulatory Blood Pressure in RW Phase 
Mean 24-hour average SBP and DBP will be summarized using descriptive statistics including 
two-sided 95% CI of the mean by visit, to include the change from baseline by treatment arm for 
the ITT-RW population. A REML-based linear MMRM will be performed on the ITT-RW 
population to analyze the change in mean 24-hour average SBP and DBP from Visit OL22 
(Baseline RW) to Visit RW12. In this model, missing data at Visit RW12 will be imputed using 
retrieved dropouts for patients with early treatment discontinuation and using a placebo-based 
mean imputation for patients that use rescue medication for hypertension. 
As indicated in Section 7.6.2.2.1, if fewer than 10 retrieved dropouts are available, then the main 
analysis will use a placebo wash-out multiple imputation method as described in Section 
9.8.3.2.1 instead of the retrieved dropout approach. 
The MMRM model will include Visit OL22 value (Baseline RW for the respective endpoint) as 
a covariate; treatment, visit, treatment by visit interaction, and stratification factor as fixed 
effects; and patients within treatment groups as random effects. An unstructured covariance 
structure will be used to model within-patient error, and the Kenward-Roger approximation will 
be used to model denominator degrees of freedom.  
The analysis for each of the endpoints will determine whether there is a difference between 
treatment groups in terms of change from Randomization to Visit RW12. 
A plot of mean 24-hour average SBP and DBP values over time by treatment arm will 
be presented.  
The mean change in the average 24-hour SBP and DBP from Visit OL22 (Baseline RW) to Visit 
RW12 will be analyzed using an MMRM analysis for the subgroup of hypertension and diastolic 
hypertension patients in the ITT-RW population. The treatment difference based on 24-hour 
mean SBP change will also be reported in the subgroup of patients with systolic hypertension at 
Baseline OL in the ITT-RW population if at least 10 patients in the subgroup are randomized in 
the RW phase of this study. 
Analysis will be performed separately for patients with hypertension at Baseline OL in the ITT-
RW population and patients with no hypertension at Baseline OL in the ITT-RW population. 


 
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9.8.3.2.1 Placebo Wash-out Multiple Imputation Sensitivity Analysis for 24-Hour Average 
Ambulatory Blood Pressure 
The placebo ‘wash-out’ analysis means the missing mean 24-hour average SBP and DBP at Visit 
RW12 data will be imputed by considering a wash-out of the effect of treatment using 
completers in the placebo arm. Specifically, mean 24-hour average SBP and DBP data for 
patients on the placebo arm without measurements at Visit RW12 will be imputed using a 
monotone regression model based on observed mean 24-hour average SBP or DBP data of 
completers on the placebo arm with intermediate measurements, baseline mean 24-hour average 
SBP or DBP and stratification factor. For patients on the relacorilant arm with missing Visit 
RW12 data, the imputation model with only baseline mean 24-hour average SBP or DBP and 
stratification factor will be used. 
Missing data will be imputed by selecting random observations from a normal distribution 
centered at the value predicted by the regression model and with variance analogous to 
predicting a new observation. The imputation procedure will be iterated 100 times. 
One hundred data sets will be generated and an MMRM model with the factors and covariates 
will be run on each data set and point estimates and standard errors computed and the results 
combined to yield a multiple imputation point estimate and standard error. 
The analysis for the treatment difference will be based on an MMRM model with change from 
baseline to Visit RW12 as the dependent variable and the following covariate/factors:  
 Treatment (with 2 levels, relacorilant and placebo) 
 Visit (Scheduled), a categorical factor 
 Treatment-by-visit interaction 
 Visit OL22 mean 24-hour average SBP or DBP, a continuous covariate 
 Stratification factor (with 2 levels, with or without DM/IGT)  
The MMRM model will include patients within treatment arms as random effects. An 
unstructured covariance matrix will be used to model within-patient error. In case of 
convergence issues, the following covariance structures will be used until the convergence 
criteria is met, in this order: unstructured covariance, heterogeneous compound symmetry, 
compound symmetry. The Kenward and Roger method for calculating the denominator degrees 
of freedom for tests of fixed effects will be used. SAS code example is listed in the Appendix 3. 
9.8.3.2.2 Missing At Random (MAR) Sensitivity Analysis for 24-Hour Average 
Ambulatory Blood Pressure 
For the purpose of the secondary analysis, for patients who use rescue medication for 
hypertension control after randomization and before Visit RW12, the values after first use of 
rescue medication will not be used in the analysis and will be considered missing at random 
(MAR). As a supplementary analysis, the change in mean 24-hour average SBP and DBP from 
Visit OL22 (Baseline RW) to Visit RW12 will be performed using the hypertension subgroup of 
the ITT-RW population using a linear MMRM model with retrieved dropout data for treatment 
discontinuation at Visit RW12 and using the embedded MAR assumption for all visits after first 


 
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initiating rescue medication for hypertension. The MMRM analysis as described in Section 
9.8.3.2 will be performed using the imputed data as described above. 
Similarly, for the purpose of the secondary analysis, for patients who discontinue early in the 
RW phase or use rescue medication for hypertension control after randomization and before 
Visit RW12, the values after discontinuation or first use of rescue medication will not be used in 
the analysis and will be considered missing at random (MAR). As a supplementary analysis, the 
change in mean 24-hour average SBP and DBP from Visit OL22 (Baseline RW) to Visit RW12 
will be performed using the hypertension subgroup of the ITT-RW population using a linear 
MMRM model using the embedded MAR assumption for all visits after treatment 
discontinuation or first initiating rescue medication for hypertension. The MMRM analysis as 
described in Section 9.8.3.2 will be performed using the imputed data as described above. 
9.8.3.2.3 Tipping Point Supplementary Analysis  
The assumption behind the tipping point analysis is to modify the trajectory in patients who drop 
out from study treatment or use rescue medication for which no observations are available. This 
pattern of missingness could be represented by a series of progressively more conservative shifts 
in the mean of missing values in the treatment arm for SBP. The tipping point would correspond 
to the magnitude of the shift (denoted by δ1R and δ1P for relacorilant and placebo, respectively, in 
the description below) that reverses the study statistical conclusions from significant to 
nonsignificant. Combined with the clinical interpretation of the plausibility of the shifts, this 
approach would enable the assessment of the robustness of study conclusion to the differences 
between early discontinuations and completers. This technique will be applied to an MMRM 
model with MAR assumption. 
All observed data will be included, regardless of a patient’s adherence to treatment or use of 
prohibited medication. Therefore, we will implement this approach as follows: 
 Impute missing values (where patient’s data is not measured) for Visit RW12 using 
regression-based multiple imputations for monotone missingness. This corresponds to 
the missing at random assumption (MAR) or a shift δ1R=0 and δ1P=0. A total of 100 
imputed datasets will be created. For each imputed dataset, the same MMRM model 
specified in Sections 9.8.3.2 will be used to estimate treatment effect on change in 
SBPfrom Baseline to RW12. The combination of individual estimates for treatment 
effect and the inference based on the combined estimate will be handled by SAS 
procedure MIANALYZE. 
 At the next step, for patients with imputed values in the relacorilant and placebo arms, 
a pre-specified value δ1R=2 mmHg and δ1P=0 mmHg will be added to SBP. This will 
complete the generation of missing values at Visit RW12 for this shift value. 
 Steps 1-2 will be repeated for at least 5 more shift values to give a total of at least 6 
values for one to consider as tipping points. The value of the increment in (δ1R, δ1P) 
will be set to 2 mmHg for the following comparison pairings (2, 0), (4, 0), (4, 2), (6, 
2), and (6, 4).  


 
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 The magnitude of the shifts for SBP at the tipping point will be evaluated for clinical 
relevance in the context of their plausibility for the difference between completers 
and patients who discontinued. 
9.8.3.3 
Body Weight in RW Phase 
In patients in the ITT-RW population, body weight will be summarized using descriptive 
statistics including two-sided 95% CI of the mean by visit, to include the change from baseline 
by treatment arm. The mean change in body weight from Visit OL22 (Baseline RW) to Visit 
RW12 will be analyzed using an MMRM model including Visit OL22 (Baseline RW) body 
weight value as a covariate; treatment, visit, treatment by visit interaction, and stratification 
factor as fixed effects; and patients within treatment groups as random effects. A REML 
estimation will be used. An unstructured covariance structure will be used to model within-
patient error, and the Kenward-Roger approximation will be used to model denominator degrees 
of freedom. The analysis for each of the endpoints will determine whether there is a difference 
between treatment groups in terms of change from Randomization to Visit RW12.   
A plot of mean body weight values over time by treatment arm will be presented. 
9.8.3.4 
AUCglucose for Patients with Response to DM/IGT Criteria in RW Phase 
AUCglucose will be calculated based on results of the plasma 2-hour oGTT test taken at Baseline 
OL, OL6, OL10, OL14, OL18, OL22, RW4, RW8 and RW12. At each visit, plasma 2-hour 
oGTT test includes glucose measurements at every half hour time-interval (pre-glucose drink and 
0.5, 1, 1.5, and 2 hours after the glucose drink). 
The AUC for such half hour time-interval will be calculated using the linear trapezoidal rule, as 
follows (where C1 and C2 are concentrations at times t1 and t2, respectively): 
 
AUCglucose will be calculated as the sum of all-time intervals AUCs. Section 7.6.2.2.2 describes 
handling missing data for calculation of AUCglucose.  
The analysis for the change in AUCglucose from Visit OL22 (Baseline RW) to Visit RW12 will be 
performed using a linear MMRM model with retrieved dropout data for treatment 
discontinuation and using a placebo-based mean imputation at Visit RW12 for patients that use 
rescue medication using the DM/IGT subgroup of the ITT-RW population. The MMRM model 
will include the following fixed effects:  
 Treatment (with 2 levels, relacorilant and placebo) 
 Visit (Scheduled), a categorical factor 
 Treatment-by-visit interaction 
 Visit OL22 AUCglucose, a continuous covariate 
 Stratification factor (with 2 levels, with or without hypertension)  


 
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The MMRM model will include patients within treatment arms as random effects. REML 
estimation will be used. An unstructured covariance structure will be used to model within-
patient error. In case of convergence issues, the following covariance structures will be used until 
the convergence criteria is met, in this order: unstructured covariance, heterogeneous compound 
symmetry, compound symmetry. The Kenward and Roger method for calculating the 
denominator degrees of freedom for tests of fixed effects will be used.  
As indicated in Section 7.6.2.2.2, if fewer than 10 retrieved dropouts are available, then the main 
analysis will use a placebo wash-out multiple imputation method as described in Section 
9.8.3.4.1 instead of the retrieved dropout approach. 
For this endpoint (change in AUCglucose), a negative difference (relacorilant minus placebo) 
represents greater improvement (or less worsening) for relacorilant-treated compared with 
placebo-treated patients.  
Estimated least squares means (± SE) and 95% CIs for change in AUCglucose will be plotted by 
treatment and over time (from Visit OL22 and all visits up to Visit RW12). 
SAS statement that implements PROC MIXED will be used and the sample SAS code is 
presented in Appendix 3 and can be modified as needed.  
9.8.3.4.1 Placebo Wash-out Multiple Imputation Sensitivity Analysis for AUCglucose 
If enough patient data are collected to use a retrieved dropout imputation (10 or more retrieved 
dropouts) for the secondary analysis, then the following supplementary analysis will be 
performed for AUCglucose (Section 7.6.2.2.2) 
In this study, the treatment effect is determined by loss of response with regards to response to 
DM/IGT criteria. The placebo ‘wash-out’ analysis means the missing AUCglucose at Visit RW12 
data will be imputed by considering a wash-out of the effect of treatment using completers in the 
placebo arm. Specifically, AUCglucose data for patients on the placebo arm without measurements 
at Visit RW12 will be imputed using a monotone regression model based on observed AUCglucose 
data of completers on the placebo arm with intermediate measurements, baseline AUCglucose and 
stratification factor. For patients on the relacorilant arm with missing Visit RW12 data, the 
imputation model with only baseline AUCglucose and stratification factor will be used. 
Missing data will be imputed by selecting random observations from a normal distribution 
centered at the value predicted by the regression model and with variance analogous to 
predicting a new observation. The imputation procedure will be iterated 100 times. 
One hundred data sets will be generated and an MMRM model with the factors and covariates 
will be run on each data set and point estimates and standard errors computed and the results 
combined to yield a multiple imputation point estimate and standard error. 
 The analysis for the treatment difference will be based on an MMRM model with 
change from baseline to Visit RW12 as the dependent variable and the following 
covariate/factors: 
 Treatment (with 2 levels, relacorilant and placebo) 


 
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 Visit (Scheduled), a categorical factor 
 Treatment-by-visit interaction 
 Visit OL22 AUCglucose, a continuous covariate 
 Stratification factor (with 2 levels, with or without hypertension)  
The MMRM model will include patients within treatment arms as random effects. An 
unstructured covariance matrix will be used to model within-patient error. In case of 
convergence issues, the following covariance structures will be used until the convergence 
criteria is met, in this order: unstructured covariance, heterogeneous compound symmetry, 
compound symmetry. The Kenward and Roger method for calculating the denominator degrees 
of freedom for tests of fixed effects will be used. SAS code example is listed in the Appendix 3. 
9.8.3.4.2 Missing at Random (MAR) Imputation Sensitivity Analysis for AUCglucose 
For patients who use rescue medication for hyperglycemia control after randomization and 
before Visit RW12, the values collected after rescue medication is first used are irrelevant to the 
clinical question of interest, and thus will not be used in the analysis, and will be considered 
missing at random (MAR). As a supplementary analysis, the change in AUCglucose from Visit 
OL22 (Baseline RW) to Visit RW12 will be performed using the DM/IGT subgroup of the ITT-
RW population using a linear MMRM model with retrieved dropout data for treatment 
discontinuation at Visit RW12 and the embedded MAR assumption for all visits after first use of 
rescue medication for patients that use rescue medication for hyperglycemia control. The 
MMRM analysis as described in Section 9.8.3.4 will be performed using the imputed data as 
described above. 
Similarly, for patients for patients who discontinue early in the RW phase or use rescue 
medication for hyperglycemia control after randomization and before Visit RW12, the values 
after discontinuation or first use of rescue medication will be considered missing at random 
(MAR). As a supplementary analysis, the change in AUCglucose from Visit OL22 (Baseline RW) 
to Visit RW12 will be performed using the DM/IGT subgroup of the ITT-RW population using a 
linear MMRM model using the embedded MAR assumption for all visits after discontinuation or 
first use of rescue medication for patients that use rescue medication for hyperglycemia control. 
The MMRM analysis as described in Section 9.8.3.4 will be performed using the imputed data as 
described above. 
9.8.3.4.3 Tipping Point Supplementary Analysis  
A similar approach to the tipping point described in Section 9.8.3.2.2, will be implemented for 
AUCglucose with the increment in (δ1R, δ1P) set to 1 hr*mmol/L for the following comparison 
pairings (1, 0), (2, 0), (3, 0), (2, 1), (3, 1), and (3, 2). 
9.8.3.5 
Patients with DM/IGT: Comprehensive Loss of Response in RW Phase  
For patients in the DM/IGT subgroup in the ITT-RW population with response at OL22, the 
proportion of patients with a comprehensive loss of response with respect to hyperglycemic 
control from Visit OL22 (Baseline RW) to Visit RW12 will be calculated based on the plasma 2-


 
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hour oGTT test to compare relacorilant and placebo, where comprehensive loss of response is 
defined as follows: 
In patients with DM: 
 Use of rescue medication (initiation or increase in diabetes medication due to worsening 
of hyperglycemic control), treatment discontinuation for any reason in RW phase, or loss 
to follow-up, 
OR 
 HbA1c has increased by ≥0.3% at Visit RW12 (compared to OL22, Baseline RW), 
OR 
 The 2-hour time point of the plasma 2-hour oGTT test at Visit RW12 is abnormal (≥140 
mg/dL) and has increased by at least 50% of the reduction observed between Baseline OL 
and Visit OL22. 
In patients with IGT: 
 Use of rescue medication (initiation or increase in diabetes medication due to worsening 
of hyperglycemic control), treatment discontinuation for any reason in RW phase, or loss 
to follow-up, 
OR 
 The 2-hour time point of the plasma 2-hour oGTT test at Visit RW12 is abnormal (≥140 
mg/dL) and has increased by at least 50% of the reduction observed between Baseline OL 
and Visit OL22. 
The proportion of patients with a comprehensive loss of response with respect to hyperglycemic 
control will be calculated for both relacorilant and placebo arms together with corresponding 
two-sided 95% CI using Clopper-Pearson method for the ITT-RW population separately for both 
definitions. Differences in proportions between relacorilant and placebo will be evaluated using a 
logistic regression model effects for treatment, the stratification factor, and baseline 2-hour 
oGTT plasma glucose value (Steingrimsson et al. 2017). The parameter estimates and standard 
errors, the chi-square test statistics and p-values, along with the odds ratios and 95% CI will be 
reported. In case of logistic model convergence issues, Fisher’s exact test will be used instead. 
The stratification factor at randomization identifies patients with or without hypertension. 
9.8.3.6 
HbA1c in RW Phase  
The analysis for the change in HbA1c from Visit OL22 (Baseline RW) to Visit RW12 will be 
performed using a linear MMRM model with retrieved dropout data for treatment 
discontinuation and using a placebo-based mean imputation at Visit RW12 for patients that use 
rescue medication using the DM/IGT subgroup of the ITT-RW population.  
As indicated in Section 9.8.3 if fewer than 10 retrieved dropouts are available, then placebo 
wash-out multiple imputation method will be used instead of the retrieved dropout approach. 
The placebo ‘wash-out’ analysis means the missing HbA1c at Visit RW12 data will be imputed 
by considering a wash-out of the effect of treatment using completers in the placebo arm. 


 
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Specifically, HbA1c data for patients on the placebo arm without measurements at Visit RW12 
will be imputed using a monotone regression model based on observed HbA1c data of 
completers on the placebo arm with intermediate measurements, baseline HbA1c and 
stratification factor. For patients on the relacorilant arm with missing Visit RW12 data, the 
imputation model with only baseline HbA1c and stratification factor will be used. 
Missing data will be imputed by selecting random observations from a normal distribution 
centered at the value predicted by the regression model and with variance analogous to 
predicting a new observation. The imputation procedure will be iterated 100 times. 
One hundred data sets will be generated and an MMRM model with the factors and covariates 
will be run on each data set and point estimates and standard errors computed and the results 
combined to yield a multiple imputation point estimate and standard error. 
The analysis for the treatment difference will be based on an MMRM model with change from 
Baseline RW (Visit OL22) to Visit RW12 as the dependent variable and the following 
covariate/factors: 
 Treatment (with 2 levels, relacorilant and placebo) 
 Visit (Scheduled), a categorical factor 
 Treatment-by-visit interaction 
 Visit OL22 HbA1c, a continuous covariate 
 Stratification factor (with 2 levels, with or without hypertension)  
The MMRM model will include patients within treatment arms as random effects. An 
unstructured covariance matrix will be used to model within-patient error. In case of 
convergence issues, the following covariance structures will be used until the convergence 
criteria is met, in this order: unstructured covariance, heterogeneous compound symmetry, 
compound symmetry. The Kenward and Roger method for calculating the denominator degrees 
of freedom for tests of fixed effects will be used. SAS code example is listed in the Appendix 3. 
9.8.4 Exploratory Efficacy Endpoints  
9.8.4.1 
Analysis of the Exploratory Efficacy Endpoints in the RW Phase 
Continuous exploratory endpoints in the RW phase of the study will be analyzed using a REML‒
based linear MMRM analysis for the ITT-RW population to compare treatment effect between 
treatment arms at each visit. The MMRM model will include Visit OL22 value (Baseline RW for 
the respective endpoint) as a covariate; treatment, visit, treatment by visit interaction, and 
stratification factor as fixed effects; and patients within treatment arms as random effects. An 
unstructured covariance structure will be used to model within-patient error, and the Kenward-
Roger approximation will be used to model denominator degrees of freedom. Least-squares 
means will be used to determine whether there is a difference between treatment arm in terms of 
the change from Visit OL22 to Visit RW12. SAS statement that implements PROC MIXED will 
be used and the sample SAS code is presented in Appendix 3 and can be modified as needed. 


 
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For endpoints described as proportions in the RW phase, the point estimate and the two-sided 
95% CI will be calculated. Differences in proportions between relacorilant and placebo will be 
evaluated using a logistic regression model including effects for treatment and the stratification 
factor (Steingrimsson et al. 2017). Additionally for analyses of patients with DM/IGT, the model 
will include an effect for the continuous baseline 2-hour oGTT plasma glucose value. The 
parameter estimates and standard errors, the chi-square test statistics and p-values, along with the 
odds ratios and 95% CI will be reported. In case of logistic model convergence issues, Fisher’s 
exact test will be used instead. The stratification factor at randomization identifies patients with 
or without hypertension and/or with or without DM/IGT. 
9.8.4.1.1 24-Hour Average HR in RW Phase 
Mean 24-hour average HR (based on ABPM) will be summarized using descriptive statistics 
including two-sided 95% CI of the mean by visit, to include the change from baseline by 
treatment arm for the ITT-RW population. A REML-based linear MMRM will be performed on 
the ITT-RW population to analyze the change in mean 24-hour average HR from Visit OL22 
(Baseline RW) to Visit RW12. The MMRM model will include Visit OL22 mean 24-hour 
average HR value as a covariate; treatment, visit, treatment by visit interaction, and stratification 
factor as fixed effects; and patients within treatment groups as random effects. An unstructured 
covariance structure will be used to model within-patient error, and the Kenward-Roger 
approximation will be used to model denominator degrees of freedom. The analysis for each of 
the endpoints will determine whether there is a difference between treatment groups in terms of 
change from Randomization to Visit RW12.  
A plot of mean 24-hour average HR values over time by treatment arm will be presented. 
Analysis will be performed separately for patients with hypertension at Baseline OL in the ITT-
RW population and patients with no hypertension at Baseline OL in the ITT-RW population. 
9.8.4.1.2 Daytime and Nighttime Average SBP, DBP, and HR in RW Phase 
Daytime and Nighttime average SBP, DBP, and HR at Visit RW12 will be analyzed using a 
REML-based linear MMRM model. The MMRM model will include Visit OL22 value (Baseline 
RW for the respective endpoint) as a covariate; treatment, visit, treatment by visit interaction, 
and stratification factor as fixed effects; and patients within treatment groups as random effects. 
An unstructured covariance structure will be used to model within-patient error, and the 
Kenward-Roger approximation will be used to model denominator degrees of freedom. The 
analysis for each of the endpoints will determine whether there is a difference between treatment 
groups in terms of change from Randomization to Visit RW12.  
Two sets of Daytime and Nighttime windows will be applied:  
 Daytime (defined as 06:00 to 21:59) and Nighttime (defined as 22:00 to 05:59) 
 Daytime (defined as 09:00 to 21:00) and Nighttime (defined as 01:00 to 06:00)  
Analysis will be performed separately for patients with hypertension at Baseline OL in the ITT-
RW population and patients with no hypertension at Baseline OL in the ITT-RW population. 


 
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A plot of mean 24-hour average daytime and nighttime values over time by treatment arm will 
be presented. 
9.8.4.1.3 Body-fat Composition by DXA in RW Phase 
In patients in the ITT-RW population, changes in the percent and absolute amounts of total mass, 
lean mass and fat mass as measured by DXA scan will be summarized using descriptive statistics 
including two-sided 95% CI of the mean by visit, to include the change from baseline by 
treatment arm. Total mass, lean mass, and fat mass will also be analyzed by a Wilcoxon signed-
rank test to evaluate if there is a significant change from Visit OL22 (Baseline RW) to each visit 
up to Visit RW12 for each treatment arm. 
9.8.4.1.4 Cushing QoL in RW Phase 
The Cushing QoL questionnaire is scored as a total score (ranging from 12 to 60), and is 
standardized to a scale from 0 (worst QoL) to 100 (best QoL) with the following formula:  
𝑌=
(x−12)
(60−12) ∗ 100. 
The standardized total score will be used for analysis purposes. Additionally, the scores for the 
questions “I have trouble sleeping”, “My wounds take a long time to heal”, and “I bruise easily” 
(questions 1, 3, and 4) of the Cushing QoL questionnaire will be summed for a physical 
problems subscale and the scores for the remaining questions (questions 2, 5, 6, 7, 8, 9, 10, 11, 
and 12) will be summed for a psychosocial issues subscale (Table 5). The subscales of the 
Cushing QoL are standardized with the following formula: 
𝑌= (x −L)
(H −L) ∗ 100. 
where X is the total score of the subscale of interest, L is the lowest possible score of the 
subscale, and H is the highest possible score for the subscale. This equation transforms scores to 
a 0-to-100 scale, with 100 indicating the best possible QoL. 


 
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Table 5 
Items in Subscales of the Cushing QoL 
Physical Problems Subscale 
2. I have trouble sleeping 
3. My wounds take a long time to heal 
4. I bruise easily 
Psychosocial Issues Subscale 
2. I have pain that keeps me from leading a normal life 
5. I am more irritable. I have sudden mood swings and angry outbursts 
6. I have less self-confidence. I feel more insecure 
7. I am worried about the changes in my physical appearance due to my illness 
8. I feel less like going out or seeing relatives or friends 
9. I had to give up my social or leisure activities due to my illness 
10. My illness affects my everyday activities such as working or studying 
11. It is for me to remember things 
12. I am worried about my health in the future 
Among patients in the ITT-RW population, standardized Cushing QoL total score, physical 
problems subscale, and psychosocial issues subscale will be summarized using descriptive 
statistics including two-sided 95% CI of the mean by visit, to include the change from baseline 
by treatment arm. The mean change in Cushing QoL total score, physical problems subscale, and 
psychosocial issues subscale will be analyzed using a REML-based linear MMRM model. The 
MMRM model will include Visit OL22 (Baseline RW) standardized Cushing QoL total score 
value as a covariate; treatment, visit, treatment by visit interaction, and stratification factor as 
fixed effects; and patients within treatment groups as random effects. An unstructured covariance 
structure will be used to model within-patient error, and the Kenward-Roger approximation will 
be used to model denominator degrees of freedom. The analysis for each of the endpoints will 
determine whether there is a difference between treatment groups in terms of change from 
Randomization to Visit RW12.  
Where appropriate, Cushing QoL assessments will also be analyzed by a Wilcoxon signed-rank 
test to evaluate if there is a significant change from Visit OL22 (Baseline RW) to Visit RW12 for 
each treatment arm. 
A plot of the mean standardized Cushing QoL total score, physical problems subscale, and 
psychosocial issues subscale over time by treatment arm will be presented. 
9.8.4.1.5 HbA1c in RW Phase 
HbA1c will be summarized using descriptive statistics including two-sided 95% CI of the mean 
by visit, to include the change from baseline by treatment arm for the ITT-RW population. The 
mean change in HbA1c from Visit OL22 (Baseline RW) to Visit RW12 will be analyzed using 
an MMRM analysis for patients in the DM/IGT subgroup of the ITT-RW population with 
HbA1c ≥6.5% at Baseline OL. The MMRM model will include Visit OL22 (Baseline RW) 


 
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HbA1c value as a covariate; treatment, visit, treatment by visit interaction, and stratification 
factor as fixed effects; and patients within treatment groups as random effects. A REML 
estimation will be used. An unstructured covariance structure will be used to model within-
patient error, and the Kenward-Roger approximation will be used to model denominator degrees 
of freedom. The analysis for each of the endpoints will determine whether there is a difference 
between treatment groups in terms of change from Randomization to Visit RW12.  
A plot of mean HbA1c values over time by treatment arm will be presented. 
The analysis will be performed separately for patients with DM at Baseline OL in the ITT-RW 
population, and patients with IGT at Baseline OL in the ITT-RW population. 
9.8.4.1.6 Change in AUCglucose  
AUCglucose for all patients (DM/IGT and hypertension) in the ITT-RW population that have 
plasma 2-hour oGTT test values will be summarized using descriptive statistics including two-
sided 95% CI of the mean by visit, to include the change from baseline by treatment arm. The 
mean change in AUCglucose from Visit OL22 (Baseline RW) to Visit RW12 will be analyzed for 
patients in the ITT-RW population using an MMRM model including Visit OL22 (Baseline RW) 
AUCglucose value as a covariate; treatment, visit, treatment by visit interaction, and stratification 
factor as fixed effects; and patients within treatment groups as random effects. A REML 
estimation will be used. An unstructured covariance structure will be used to model within-
patient error, and the Kenward-Roger approximation will be used to model denominator degrees 
of freedom. The analysis for each of the endpoints will determine whether there is a difference 
between treatment groups in terms of change from Randomization to Visit RW12.  
A plot of mean AUCglucose values over time by treatment arm will be presented for the ITT-RW 
population. 
Additionally, the change in AUCglucose from Visit OL22 (Baseline RW) to Visit RW12 will be 
analyzed for DM/IGT patients in the ITT-RW population excluding those who received long-
acting insulin. 
9.8.4.1.7 oGTT Plasma Glucose in RW Phase 
Plasma glucose (mmol/L) from the 2-hour oGTT test will be summarized using descriptive 
statistics including two-sided 95% CI of the mean by visit and time point (pre-glucose drink and 
0.5, 1, 1.5, and 2 hours post glucose drink), to include the change from Visit OL22 to Visit 
RW12 by treatment arm for the ITT-RW population. For patients in the DM/IGT subgroup in the 
ITT-RW population, the mean change in plasma glucose at each timepoint from Visit OL22 
(Baseline RW) to Visit RW12 will be analyzed using an MMRM model including Visit OL22 
value (Baseline RW for the respective timepoint) as a covariate; treatment, visit, treatment by 
visit interaction, and stratification factor as fixed effects; and patients within treatment groups as 
random effects. A REML estimation will be used. An unstructured covariance structure will be 
used to model within-patient error, and the Kenward-Roger approximation will be used to model 
denominator degrees of freedom. The analysis for each of the endpoints will determine whether 
there is a difference between treatment groups in terms of change from Randomization to Visit 


 
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RW12 at each time point (pre-glucose drink and 0.5, 1, 1.5, and 2 hours post glucose drink) for 
each treatment arm. A column summarizing change from pre-glucose drink values will also be 
included.  
A plot of mean plasma glucose (mmol/L) values over time by treatment arm will be presented. 
The analysis will be performed separately for the subgroup of patients with DM at Baseline OL 
in the ITT-RW population, patients with IGT at Baseline OL in the ITT-RW population. 
9.8.4.1.8 Analysis of Other Continuous Exploratory Efficacy Endpoints in RW Phase 
The continuous exploratory efficacy endpoints include waist circumference; serum osteocalcin; 
sit-to-stand test score; trail-making test score; sex-hormone levels (estradiol, total and free 
testosterone, sex-hormone‒binding globulin, follicle-stimulating hormone, and luteinizing 
hormone) separately for male and female patients; urinary free cortisol (UFC), late-night salivary 
cortisol and plasma adrenocorticotropic hormone (ACTH); and daytime and nighttime average 
blood pressure.  
In all patients in the ITT-RW population, all continuous exploratory efficacy endpoints will be 
summarized using descriptive statistics including two-sided 95% CI of the mean by visit, to 
include the change from Visit OL22 to Visit RW12 by treatment arm. These efficacy 
assessments will also be analyzed by a Wilcoxon signed-rank test to evaluate if there is a 
significant change from Visit OL22 to Visit RW12 for each treatment arm. Fasting serum 
cortisol, UFC, late-night salivary cortisol, osteocalcin, and plasma ACTH levels will be 
presented separately for patients with ACTH independent and ACTH dependent Cushing 
syndrome. 
Continuous exploratory efficacy endpoints in the RW phase of the study will be analyzed using a 
similar approach as described in Section 9.8.3. A REML‒based linear MMRM analysis will be 
used. The MMRM model will include Visit OL22 value (for the respective endpoint) as a 
covariate; treatment, visit, treatment by visit interaction, and stratification factor as fixed effects; 
and patients within treatment arms as random effects. An unstructured covariance structure will 
be used to model within-patient error, and the Kenward-Roger approximation will be used to 
model denominator degrees of freedom. Least-squares means will be used to estimate the change 
from Visit OL22 to Visit RW12.  
A plot of the mean UFC and ACTH values over time by treatment arm will be presented 
separately for patients with ACTH independent and ACTH dependent Cushing syndrome. 
9.8.4.1.9 ACTH in Patients with Adrenal Cushing Syndrome (ACTH Independent) in 
RW Phase  
In all patients with adrenal Cushing syndrome (ACTH independent) in the ITT-RW population, 
ACTH will be summarized using descriptive statistics including two-sided 95% CI of the mean 
by visit, to include the change from Visit OL22 to Visit RW12 by treatment arm. ACTH will 
also be analyzed by a Wilcoxon signed-rank test to evaluate if there is a significant change from 
Visit OL22 to Visit RW12 for each treatment arm.  


 
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A plot of mean ACTH values over time by treatment arm will be presented.  
In patients with adrenal Cushing syndrome (ACTH independent) in the ITT-RW population, the 
ACTH in the RW phase of the study will be analyzed using a similar approach as described 
above in Section 9.8.3. A REML‒based linear MMRM analysis will be used. The MMRM model 
will include Visit OL22 value (for the respective endpoint) as a covariate; treatment, visit, 
treatment by visit interaction, and stratification factor as fixed effects; and patients within 
treatment arms as random effects. An unstructured covariance structure will be used to model 
within-patient error, and the Kenward-Roger approximation will be used to model denominator 
degrees of freedom. Least-squares means will be used to estimate the change from Visit OL22 to 
Visit RW12.  
9.8.4.1.10 Antidiabetic Medication and Antihypertensive Medication in RW Phase 
In patients with uncontrolled hypertension at Baseline OL, the number and proportion of patients 
whose dose of antihypertensive medication decreased, discontinued, stayed the same, or 
increased from Visit OL22 (Baseline RW) to Visit RW12 will be summarized, among those 
patients taking such medications at Baseline RW. Antihypertensive medications include 
potassium sparing diuretics. 
In patients with DM/IGT at Baseline OL, the number and proportion of patients whose dose of 
diabetes medication decreased, discontinued, stayed the same, or increased from Visit OL22 
(Baseline RW) to Visit RW12 will be summarized, among those patients taking such 
medications at Baseline RW. Diabetes and antihypertensive medication will be summarized 
using the ITT-RW population. Differences in proportions between relacorilant and placebo will 
be evaluated using the stratified Cochran-Mantel-Haenszel (CMH) test and the estimated risk 
ratio and corresponding 95% CIs will be presented. The stratification factor at randomization 
identifies patients with or without hypertension. 
9.8.4.1.11 Global Clinical Response Score in RW Phase 
In all patients, the DRB (Data Review Board) will evaluate Global Clinical Response 
(Katznelson et al. 2014). Each of 3 members of the DRB will review the 7 categories of clinical 
parameters evaluate whether a patient’s signs and symptoms of Cushing syndrome have changed 
and will rate the patient’s overall response based on the totality of signs and symptoms as +1 
(improved), 0 (unchanged), or −1 (worsened) at every visit after Baseline OL. Each patient’s 
final score will be the median of the 3 ratings. The change from Visit OL22 (Baseline RW) to 
Visit RW12 will be summarized using a frequency table including proportions of patients that 
worsened (with overall response category −1 (worsened)) and patients that did not worsen (with 
overall response categories of +1 [improved] or 0 [unchanged]) by visit and by treatment arm for 
the ITT-RW population. Confidence intervals (95% exact binomial two-sided CI using Clopper-
Pearson method) will also be presented. Differences in proportions between relacorilant and 
placebo will be evaluated using the stratified Cochran-Mantel-Haenszel (CMH) test and the 
estimated risk ratio and corresponding 95% CIs will be presented. The stratification factor at 
randomization identifies patients with or without hypertension. 


 
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9.8.4.1.12 Response Analysis (AUCglucose) from Baseline OL to Visit RW12 in Patients with 
DM 
For patients in the DM subgroup in the ITT-RW population, the proportion of patients who 
achieve 25% reduction in AUCglucose from Baseline OL to Visit RW12 will be analyzed. The 
number and percentage of patients who are responders will be presented along with a 95% exact 
binomial two-sided CI (Clopper-Pearson). Differences in proportions between relacorilant and 
placebo will be evaluated using the stratified Cochran-Mantel-Haenszel (CMH) test and the 
estimated risk ratio and corresponding 95% CIs will be presented. The stratification factor at 
randomization identifies patients with or without hypertension. 
For the purposes of this responder analysis, patients who, during the RW phase, initiate rescue 
medications, discontinue treatment or do not meet a 25% reduction in AUCglucose, at Visit RW12 
will be considered non-responders. If there are at least 10 patients in the subgroup of patients 
with DM/IGT, but without hypertension at Baseline OL, that continue in the RW phase, then this 
endpoint will also be analyzed in this particular subgroup of patients. 
9.8.4.1.13 Analysis of the Exploratory Efficacy Endpoints from Baseline OL to Visit RW12  
For patients in the ITT-RW population, the mean change from Baseline OL to Visit RW12 will 
be compared between relacorilant and placebo in the following:  
 sex-hormone levels (estradiol, total and free testosterone, sex-hormone‒binding globulin, 
follicle-stimulating hormone, and luteinizing hormone) separately for male and female 
patients. 
 ACTH in all patients, and separately for patients with adrenal Cushing syndrome (ACTH 
independent) and ACTH dependent Cushing syndrome.  
 AUCglucose, AUCinsulin, Matsuda Index, and HOMA-IR in all patients and separately in 
patients with DM/IGT only.  
 24hr, daytime, and nighttime average blood pressure in all patients, and separately in 
patients with uncontrolled hypertension with or without DM/IGT. 
Continuous exploratory efficacy endpoints in the RW phase of the study will be analyzed using a 
similar approach as described in Section 9.8.3. A REML‒based linear MMRM analysis will be 
used. The MMRM model will include Baseline OL value (for the respective endpoint) as a 
covariate; treatment, visit, treatment by visit interaction, and stratification factor as fixed effects; 
and patients within treatment arms as random effects. An unstructured covariance structure will 
be used to model within-patient error, and the Kenward-Roger approximation will be used to 
model denominator degrees of freedom. Least-squares means will be used to estimate the change 
from Baseline OL to Visit RW12.  
For analysis purposes, 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: 
𝐻𝑂𝑀𝐴−𝐼𝑅=
𝑔𝑙𝑢𝑐𝑜𝑠𝑒 (𝑚𝑚𝑜𝑙
𝐿
) ∗𝑖𝑛𝑠𝑢𝑙𝑖𝑛 (µ 𝑈
𝑚𝐿)
22.5
 


 
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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: 
𝑀𝑎𝑡𝑠𝑢𝑑𝑎 𝐼𝑛𝑑𝑒𝑥= 
10000
√𝑔0 ∗18 ∗𝑖0 ∗(𝑔0 + 𝑔0.5 ∗2 + 𝑔1 ∗2 + 𝑔1.5 ∗2 + 𝑔2)
8
∗18 ∗(𝑖0 + 𝑖0.5 ∗2 + 𝑖1 ∗2 + 𝑖1.5 ∗2 + 𝑖2)
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.). 
AUCinsulin will be derived similar to AUCglucose (Section 9.8.3.4). 
9.8.4.1.14 Subgroup Analysis for Patients with Response to DM/IGT and Hypertension 
In the subgroup of patients who were randomized based on improvement of both DM/IGT and 
hypertension, the following analyses will be performed for the RW phase: 
Loss of Response with Respect to Hypertension: 
For patients in the DM/IGT and hypertension subgroup in the ITT-RW population with response 
to both comorbidities at OL22, the proportion of patients with a loss of response with respect to 
hypertension control (defined in Section 9.8.2.1) from Visit OL22 (Baseline RW) to Visit RW12 
will be calculated. The proportion of patients with a loss of response with respect to hypertension 
control will be calculated for both relacorilant and placebo arms together with corresponding 
two-sided 95% CI using Clopper-Pearson method for the DM/IGT and hypertension subgroup of 
the ITT-RW population. The analysis as described in Section 9.8.2.2 will be performed for 
patients in the DM/IGT and hypertension subgroup of the ITT-RW population. 
Loss of Response with Respect to Hyperglycemic Control (AUC-based):  
For patients in the DM/IGT and hypertension subgroup in the ITT-RW population with response 
to both comorbidities at OL22, the proportion of patients with a loss of response with respect to 
hyperglycemic control (AUC-based, defined in Section 9.8.3.1 ) from Visit OL22 (Baseline RW) 
to Visit RW12 will be calculated. The proportion of patients with a loss of response with respect 
to hyperglycemic control will be calculated for both relacorilant and placebo arms together with 
corresponding two-sided 95% CI using Clopper-Pearson method for the DM/IGT and 
hypertension subgroup of the ITT-RW population. The analysis as described in Section 9.8.3.1  
will be performed for patients in the DM/IGT and hypertension subgroup of the ITT-RW 
population. 
9.8.4.1.15 Loss of Response to Hypertension or Hyperglycemia in RW Phase 
In all patients randomized in the RW phase, proportion of patients with a loss of response with 
respect to hypertension or hyperglycemia from Visit OL22 to Visit RW12 based on 24-hour 
ABPM and AUCglucose as compared between relacorilant and placebo arms, where loss of 
response is defined as follows: 
 In patients with hypertension only at Baseline OL 


 
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- In patients who met only the SBP response criterion, an increase in SBP ≥5 mm 
Hg. 
- In patients who met only the DBP response criterion, an increase in DBP by 
≥5 mm Hg. 
- In patients who met both the SBP and DBP response criteria, an increase in either 
SBP or DBP by ≥5 mm Hg. 
- Any increase or modification in antihypertensive medication due to worsening 
hypertension. 
- Patients discontinue treatment in RW phase for any reason. 
 In patients with DM/IGT only at Baseline OL: 
- A ≥10% increase from Baseline RW in AUCglucose from Visit OL22 to Visit 
RW12.. 
- Use of rescue medication (initiation or increase in diabetes medication due to 
worsening of hyperglycemic control). 
- Treatment discontinuation for any reason in RW phase. 
- Patients with missing RW12 AUCglucose values. 
 In patients with hypertension and DM/IGT at Baseline OL, loss of response will be 
defined as a loss of response with respect to either hypertension or hyperglycemic control 
(AUC-based) from Visit OL22 to Visit RW12, irrespective of which response criteria 
(hypertension or DM/IGT) they met to enter the RW phase.  
The proportion of patients with a loss of response with respect to hypertension or hyperglycemia 
will be calculated for both relacorilant and placebo arms together with corresponding two-sided 
95% CI using Clopper-Pearson method for the ITT-RW population. Differences in proportions 
between relacorilant and placebo will be evaluated using a logistic regression model effects for 
treatment and the stratification factor (at Baseline OL) (Steingrimsson et al. 2017). The 
parameter estimates and standard errors, the chi-square test statistics and p-values, along with the 
odds ratios and 95% CI will be reported. In case of logistic model convergence issues, Fisher’s 
exact test will be used instead.  
9.8.4.2 
Analysis of the Exploratory Efficacy Endpoints in the OL Phase 
Continuous exploratory endpoints in the OL phase of the study will be analyzed using a 
restricted maximum-likelihood (REML)‒based linear MMRM analysis for the mITT OL 
population. 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. The 
Kenward-Roger approximation will be used to estimate denominator degrees of freedom. Least-
squares means will be used to estimate the change from baseline treatment effect at each visit, 
including Visit OL22. The analysis using MMRM will be main result. In addition, the Wilcoxon 
signed-rank test will be used to evaluate if there is a significant change compared with baseline 
at each visit in cases where departures from MMRM assumptions are noted. SAS statement that 
implements PROC MIXED will be used and the sample SAS code is presented in Appendix 3 
and can be modified as needed. 


 
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For all endpoints in the OL phase that are described as proportions, the point estimate and the 
two-sided 95% CI will be calculated.  
9.8.4.2.1 24-Hour Ambulatory Blood Pressure in OL Phase 
24-hour systolic and diastolic ambulatory blood pressure will be obtained by the patient at home 
using an ambulatory BP monitor. The mean change in the mean 24-hour SBP and DBP from 
Baseline OL to OL22 will be analyzed using an MMRM analysis for the subgroup of systolic 
hypertension and diastolic hypertension patients in the mITT-OL population. A REML‒based 
linear MMRM analysis will be used. 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. The Kenward-Roger approximation will be used to estimate denominator degrees 
of freedom. Least-squares means will be used to estimate the change from baseline treatment 
effect at each visit, including Visit OL22.  
Mean 24-hour SBP and DBP, will be summarized using descriptive statistics including two-sided 
95% CI of the mean by visit, to include the change from baseline for the mITT-OL population. 
Mean 24-hour SBP and DBP will also be analyzed by a Wilcoxon signed-rank test to evaluate if 
there is a significant change from Baseline OL by visit up to Visit OL22/ET for the mITT-OL 
population.  
The protocol has been amended to collect ABPM assessments at Visit OL2. Since this was added 
only in protocol Amendment 4 (17 December 2020), there may be a sizable number of patients 
with missing values. A sensitivity analysis for the mITT-OL population will be conducted using 
the method defined in Section 9.8.3 with one model that includes OL2 and one without OL2 to 
evaluate if there is any difference.  
A plot of mean 24-hour SBP and DBP values over time will be presented.  
Analysis will be performed separately for patients with uncontrolled hypertension at Baseline OL 
in the mITT-OL population, patients without uncontrolled hypertension (i.e. patients with only 
DM/IGT) at Baseline OL in the mITT-OL population, patients with uncontrolled hypertension at 
Baseline OL in the mITT-OL population and treated with antihypertensive medications, patients 
with uncontrolled hypertension at Baseline OL in the mITT-OL population and not treated with 
antihypertensive medications, patients with controlled hypertension at Baseline OL in the mITT-
OL population and treated with antihypertensive medications, patients without uncontrolled 
hypertension at Baseline OL in the mITT-OL population and not treated with antihypertensive 
medications. 
9.8.4.2.2 Cushing QoL in OL Phase 
The mean change in the standardized Cushing QoL total score, physical problems subscale, and 
psychosocial issues subscale (Section 9.8.4.1.4) from Baseline OL to OL22 will be analyzed 
using a REML‒based linear MMRM analysis. The model will use visit as a fixed effect, and 
patient as a random effect. A compound symmetry covariance structure will be used to model the 
within-patient errors. The Kenward-Roger approximation will be used to estimate denominator 


 
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degrees of freedom. Least-squares means will be used to estimate the change from baseline 
treatment effect at each visit, including Visit OL22.  
In all patients in the mITT-OL population, Cushing QoL will be summarized using descriptive 
statistics including two-sided 95% CI of the mean by visit, to include the change from baseline. 
Cushing QoL assessments will also be analyzed by a Wilcoxon signed-rank test to evaluate if 
there is a significant change compared with Baseline OL by visit up to Visit OL22/ET.  
A plot of the mean standardized Cushing QoL total score, physical problems subscale, and 
psychosocial issues subscale over time will be presented. 
In addition, the null hypothesis that the mean change from baseline in the Cushing QoL total 
score (original scale) is less or equal to 10 points (versus the alternative hypothesis that it is >10 
points) will be rejected if the lower bound of the two-sided 95% CI (or, equivalently, 1-sided 
97.5% CI) exceeds 10. The change of 10 points in Cushing’s QoL is considered clinically 
meaningful.  
9.8.4.2.3 Body-fat Composition by DXA in OL Phase 
In all patients in the mITT-OL population, changes in the percent and absolute amounts of total 
mass, lean mass and fat mass as measured by DXA scan will be summarized using descriptive 
statistics including two-sided 95% CI of the mean by visit, to include the change from baseline. 
A REML‒based linear MMRM analysis will be used to evaluate the change in each parameter 
from Baseline OL to OL22. 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. The Kenward-Roger approximation will be used to estimate denominator degrees of 
freedom. Least-squares means will be used to estimate the change from baseline treatment effect 
at each visit, including Visit OL22.  
The absolute amounts of total mass, lean mass and fat mass will also be analyzed by a Wilcoxon 
signed-rank test to evaluate if there is a significant change compared with Baseline OL at each 
visit up to Visit OL22/ET.  
9.8.4.2.4 Beck Depression Inventory®-II (BDI-II) in OL Phase 
In all patients in the mITT-OL population, the total BDI-II score, which is based on a 21-
question self-report inventory that measures depression (Beck et al. 1996), will be summarized 
using descriptive statistics including two-sided 95% CI of the mean by visit, to include the 
change from baseline. A REML‒based linear MMRM analysis will be used. 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. The Kenward-Roger approximation will 
be used to estimate denominator degrees of freedom. Least-squares means will be used to 
estimate the change from baseline treatment effect at each visit, including Visit OL22.  
The total BDI-II score will also be analyzed by a Wilcoxon signed-rank test to evaluate if there is 
a significant change compared with Baseline OL at each visit up to Visit OL22/ET for the mITT-
OL population.  


 
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9.8.4.2.5 Body Weight in OL Phase 
The mean change in body weight from Baseline OL to OL22 will be analyzed using a REML‒
based linear MMRM analysis for the mITT-OL population. 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. The Kenward-Roger approximation will be used to estimate 
denominator degrees of freedom. Least-squares means will be used to estimate the change from 
baseline treatment effect at each visit, including Visit OL22.  
In all patients in the mITT-OL population, body weight will be summarized using descriptive 
statistics including two-sided 95% CI of the mean by visit, to include the change from baseline. 
Body weight will also be analyzed by a Wilcoxon signed-rank test to evaluate if there is a 
significant change compared with Baseline OL at each visit up to Visit OL22/ET.  
A plot of mean body weight values over time will be presented. 
9.8.4.2.6 oGTT Plasma Glucose in OL Phase 
Plasma glucose (mmol/L) from the 2-hour oGTT test will be summarized using descriptive 
statistics including two-sided 95% CI of the mean by visit and time point (pre-glucose drink and 
0.5, 1, 1.5, and 2 hours post glucose drink), to include the change from baseline for the mITT-OL 
population. A REML-based linear MMRM will be used to analyze the mean change in the 
plasma glucose from Baseline OL to Visit OL22 for the mITT-OL population. 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. The Kenward-Roger approximation will 
be used to estimate denominator degrees of freedom. Least-squares means will be used to 
estimate the change from baseline treatment effect at each visit, including Visit OL22.  
In addition, plasma glucose (mmol/L) will also be analyzed by a Wilcoxon signed-rank test to 
evaluate if there is a significant change compared with Baseline OL at each time point (pre-
glucose drink and 0.5, 1, 1.5, and 2 hours post glucose drink) for the change from baseline by 
visit up to Visit OL22/ET. A column summarizing change from pre-glucose drink values will 
also be included.  
A plot of mean plasma glucose (mmol/L) values over time will be presented. 
Analysis will be performed separately for the subgroup of patients with DM at Baseline OL in 
the mITT-OL population, patients with IGT at Baseline OL in the mITT-OL population, and 
patients with normal blood glucose at Screening in the mITT-OL population.  
9.8.4.2.7 HbA1c in OL Phase 
REML-based MMRM analysis will be performed on the mITT-OL population to analyze the 
change in HbA1c from Baseline OL to Visit OL22. 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. The Kenward-Roger approximation will be used to estimate denominator 
degrees of freedom. Least-squares means will be used to estimate the change from baseline 
treatment effect at each visit, including Visit OL22.  


 
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HbA1c will be summarized using descriptive statistics including two-sided 95% CI of the 
mean by visit, to include the change from baseline. HbA1c will be analyzed by a Wilcoxon 
signed-rank test to evaluate if there is a significant change compared with Baseline OL at each 
visit up to Visit OL22/ET for the mITT-OL population.  
A plot of mean HbA1c values over time will be presented. 
Analysis will be performed separately for patients with DM at Baseline OL in the mITT-OL 
population, patients with DM at Baseline OL in the mITT-OL population with HbA1c ≥6.5% at 
Baseline OL, patients with IGT at Baseline OL in the mITT-OL population, and patients with 
normal blood glucose at Screening in the mITT-OL population. 
9.8.4.2.8 Change in AUCglucose from Baseline to Visit OL22 in Patients with DM/IGT 
The change in AUCglucose from Baseline OL to Visit OL22 will also be analyzed using a REML-
based linear MMRM for the mITT-OL population. 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. The Kenward-Roger approximation will be used to estimate denominator 
degrees of freedom. Least-squares means will be used to estimate the change from baseline 
treatment effect at each visit, including Visit OL22.  
Additionally, AUCglucose will be summarized using descriptive statistics including two-sided 95% 
CI of the mean, and the change in AUCglucose from Baseline OL up to Visit OL22/ET will be 
analyzed by a Wilcoxon signed-rank test to evaluate if there is a significant change compared 
with Baseline OL at each visit for the mITT-OL population. 
The analysis will be performed separately for patients with DM at Baseline OL in the mITT-OL 
population, patients with IGT at Baseline OL in the mITT-OL population, and patients with 
normal blood glucose at Screening in the mITT-OL population.  
9.8.4.2.9 Analysis of Other Continuous Exploratory Efficacy Endpoints in OL Phase 
The continuous exploratory efficacy endpoints include waist circumference; serum osteocalcin; 
sit-to-stand test score; trail-making test score; sex-hormone levels (estradiol, total and free 
testosterone, sex-hormone‒binding globulin, follicle-stimulating hormone, and luteinizing 
hormone) separately for male and female patients; urinary free cortisol (UFC), late-night salivary 
cortisol and plasma adrenocorticotropic hormone (ACTH); and daytime and nighttime average 
blood pressure.  
In patients in the mITT-OL population, all continuous exploratory efficacy endpoints will be 
summarized using descriptive statistics including two-sided 95% CI of the mean by visit, to 
include the change from baseline. Fasting serum cortisol, UFC, late-night salivary cortisol, 
osteocalcin, and plasma ACTH levels will be presented separately for patients with ACTH 
independent and ACTH dependent Cushing syndrome. 
Continuous exploratory efficacy endpoints in the OL phase of the study may be analyzed using a 
similar approach as described above in Section 9.8.4. A REML‒based linear MMRM analysis 
will be used. The MMRM model will use visit as a fixed effect, and patient as a random effect. 


 
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An unstructured covariance structure will be used to model the within-patient errors. The 
Kenward-Roger approximation will be used to estimate denominator degrees of freedom. Least-
squares means will be used to estimate the change from baseline treatment effect at each visit, 
including Visit OL22.  
A plot of the mean UFC and ACTH values over time will be presented separately for patients 
with ACTH independent and ACTH dependent Cushing syndrome. Additionally, A plot of mean 
24-hour average daytime and nighttime values over time will be presented. 
9.8.4.2.10 ACTH in Patients with Adrenal Cushing Syndrome (ACTH Independent) in OL 
Phase 
In all patients with adrenal Cushing syndrome (ACTH independent) in the mITT-OL population, 
ACTH will be summarized using descriptive statistics including two-sided 95% CI of the mean 
by visit, to include the change from baseline. A REML‒based linear MMRM analysis will be 
used. 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. The Kenward-
Roger approximation will be used to estimate denominator degrees of freedom. Least-squares 
means will be used to estimate the change from baseline treatment effect at each visit, including 
Visit OL22. ACTH will also be analyzed by a Wilcoxon signed-rank test to evaluate if there is a 
significant change compared with baseline at Visit OL22/ET.  
A plot of mean ACTH values over time will be presented.  
In patient with Adrenal Cushing syndrome (ACTH independent), the ACTH in OL phase of the 
study will be analyzed using a similar approach as described above in Section 9.8.4. A REML‒
based linear MMRM analysis will be used. The MMRM model will use visit as a fixed effect, 
and patient as a random effect. An unstructured covariance structure will be used to model the 
within-patient errors. The Kenward-Roger approximation will be used to estimate denominator 
degrees of freedom. Least-squares means will be used to estimate the change from baseline 
treatment effect at each visit, including Visit OL22.  
9.8.4.2.11 Responder Analysis in OL Phase in Patients with Hypertension  
In patients with uncontrolled hypertension at Baseline OL in the mITT-OL population, mean 24-
hour SBP and DBP per patient per visit will be included in the analysis. A responder will be 
defined as a patient who experiences at least a 5 mm Hg decrease in mean DBP or SBP from 
Baseline OL to Visit OL22, without worsening of either (defined as increase in mean SBP or 
DBP by at least 5 mm Hg). The number and percentage of patients who are responders will be 
presented along with a 95% exact binomial two-sided CI (Clopper-Pearson).  
9.8.4.2.12 Antidiabetic Medication and Antihypertensive Medication in OL Phase 
In patients with uncontrolled hypertension at Baseline OL in the mITT-OL population, the 
number and proportion of patients whose dose of antihypertensive medication decreased, 
discontinued, stayed the same, or increased from Baseline OL to Visit OL22 will be summarized, 
among those patients taking such medications at Baseline OL. In patients with DM/IGT at 


 
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Baseline OL in the mITT-OL population, the number and proportion of patients whose dose of 
diabetes medication decreased, discontinued, stayed the same, or increased from Baseline OL to 
Visit OL22 will be summarized, among those patients taking such medications at Baseline OL. 
Separately, in patients with DM at Baseline OL in the mITT-OL population with HbA1c ≥6.5% 
at Baseline OL, the number and proportion of patients whose dose of diabetes medication 
decreased, discontinued, stayed the same, or increased from Baseline OL to Visit OL22 will be 
summarized, among those patients taking such medications at Baseline OL. 
9.8.4.2.13 Global Clinical Response Score in OL Phase 
In all patients, the DRB (Data Review Board) will evaluate Global Clinical Response 
(Katznelson et al. 2014) at each visit. Each of 3 members of the DRB will review the 
7 categories of clinical parameters evaluate whether a patient’s signs and symptoms of Cushing 
syndrome have changed and will rate the patient’s overall response based on the totality of signs 
and symptoms as +1 (improved), 0 (unchanged), or −1 (worsened) at every visit after Baseline 
OL. Each patient’s final score will be the median of the 3 ratings. The change from baseline to 
Visit OL22 will be summarized using frequency table including proportions of patients that 
improve (with overall response category +1 (improved)) and patients that did not improve (with 
overall response categories 0 [unchanged], or −1 [worsened]) by visit for the mITT-OL 
population. Confidence intervals (95% exact binomial two-sided CI using Clopper-Pearson 
method) will also be presented. 
9.8.4.2.14 Responder Analysis in OL Phase in Patients with DM/IGT  
In patients with DM at Baseline OL in the mITT-OL population, HbA1c, 2-hour plasma oGTT 
glucose and total daily insulin dose per patient per visit will be included in the analysis. A 
responder will be defined as a patient who experiences at least 0.5% decrease in HbA1c from 
Baseline OL to Visit OL22, or 2-hour plasma oGTT glucose is normalized (<140 mg/dL) or 
decreased at least 50 mg/dL from Baseline OL to Visit OL22 or total daily insulin dose has 
decreased by at least 25% with HbA1c unchanged or decreased compared with Baseline OL. In 
patients with IGT at Baseline OL in the mITT-OL population, 2-hour plasma oGTT glucose per 
patient per visit will be included in the analysis. A responder will be defined as a patient whose 
2-hour plasma oGTT glucose is normalized (<140 mg/dL) from Baseline OL to Visit OL22. The 
number and percentage of patients who are responders will be presented along with a 95% exact 
binomial two-sided CI (Clopper-Pearson).  
9.8.4.2.15 Responder Analysis in OL Phase in Patients with Both DM/IGT and 
Hypertension  
In patients in the mITT-OL population, HbA1c (DM only), 2-hour plasma oGTT glucose, total 
daily insulin dose (DM only), mean 24-hour SBP and DBP per patient per visit will be included 
in the analysis. A responder will be defined as a patient who meets the above-mentioned 
response criteria (Section 9.8.4.2.11 and Section 9.8.4.2.14) for both conditions, or meets one of 
the DM or IGT response criteria with no worsening in hypertension (defined as increase in mean 
SBP or DBP by at least 5 mm Hg), or meet one of the uncontrolled hypertension response 


 
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criteria with no worsening in DM (defined as increase of the HbA1c by at least 0.5%) or IGT 
(defined as 2-hour plasma oGTT glucose >200 mg/dL). The number and percentage of patients 
who are responders will be presented along with a 95% exact binomial two-sided CI (Clopper-
Pearson). 
9.8.4.2.16 Responder Analysis by Dose in OL Phase  
Responder analysis described above in Section 9.8.4.2.11, Section 9.8.4.2.14, and Section 
9.8.4.2.15 will be performed for the mITT-OL population by dose at which response was first 
reached. Percentage of patients with response at each dose level and 95% CI will be calculated. 
Denominator will be the total number of all responders at OL22 and numerator will be the 
number of patients at each dose level when their response was first reached. Additionally, 
percentage of patients with response and 95% CI will be calculated for each dose level at each 
scheduled visit (ratio of patients with response at dose level and visit to total number of patients 
who reached the dose level and visit).  
In patients in the mITT-OL population with hypertension at Baseline OL, the number and 
percentage of patients whose blood pressure normalized (SBP<130 mm Hg and DBP <80 mm 
Hg) at Visit OL22 will be presented along with a 95% exact binomial two-sided CI (Clopper-
Pearson).  
9.8.4.2.17 Response Analysis (AUCglucose) from Baseline OL to OL22  
For patients in the DM/IGT subgroup in the mITT-OL population, the proportion of patients who 
achieve ≥25% reduction in AUCglucose from Baseline OL to Visit OL22 will be summarized. The 
number and percentage of patients who are responders will be presented along with a 95% exact 
binomial two-sided CI (Clopper-Pearson). The response will be summarized separately for 
patients with DM/IGT, DM only, and IGT only.  
9.8.4.2.18 Response Analysis (HbA1c) from Baseline OL to OL22  
For patients in the DM/IGT subgroup in the mITT-OL population, the proportion of patients who 
achieve ≥0.5% reduction in HbA1c from Baseline OL to Visit OL22 will be summarized. The 
number and percentage of patients who are responders will be presented along with a 95% exact 
binomial two-sided CI (Clopper-Pearson). The response will be summarized separately for 
patients with DM/IGT, DM only, and IGT only.  
9.8.5 Multicenter Studies 
This is a multicenter study with sites across different regions expected to participate. A subgroup 
analysis is planned by region (North America vs. ROW).  
9.9 
Subgroup Analyses  
For primary efficacy and key secondary efficacy endpoints, the following subgroups will be 
considered if 10 or more patients are in each category in RW Phase: 


 
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 Intrinsic factors: Age (<45 vs. [45, 65) vs. ≥65); race; ethnicity; sex, and menopausal 
status (post-menopausal vs. pre-menopausal). Post-menopausal is defined as females 50 
years of age or older. Pre-menopausal is defined as females less than 50 years of age. 
 Extrinsic factors: (Geographic Region: North America vs. ROW). 
Cushing syndrome comorbidity as described above in Section 6.10 are key subgroups of interest 
for subgroup analysis. Additional subgroups to be considered are: 
 For secondary efficacy endpoints in RW phase, subgroup analysis will be performed by 
last dose received in OL phase (100 mg, 200 mg, 300 mg, and 400 mg).  
 For analysis of Change from Baseline in AUCglucose and plasma glucose in OL phase, 
subgroup analysis will be performed by DM or IGT for patients with DM/IGT and also 
for DM/IGT patients who met response criteria and are randomized.  
 For analysis of Change from Baseline in ABPM in OL phase, subgroup analysis will be 
performed for hypertension patients who met response criteria and are randomized.  
9.10 
Pharmacodynamic Analysis  
Samples for PD assessments will be collected from all patients at the scheduled time points. 
During the RW phase, the results for all PD assessments will remain blinded.  
PD measurements on fasting serum cortisol, UFC, late-night salivary cortisol, and plasma 
ACTH levels will be summarized. Descriptive statistics will be presented for results and change 
from baseline to Visit OL22 where PD blood samples were scheduled to be collected. Wilcoxon 
signed-rank test will also be performed to evaluate if there is a significant change from baseline 
to Visit OL22. Fasting serum cortisol, UFC, late-night salivary cortisol, and plasma ACTH levels 
will be presented separately for patients with ACTH-independent and ACTH-dependent Cushing 
syndrome. UFC, late-night salivary cortisol, and plasma ACTH levels are also protocol defined 
exploratory efficacy endpoints in Section 9.8.4. 
9.11 
Pharmacokinetic Analysis  
Pharmacokinetic (PK) endpoints and analysis methods will be described in a separate 
PK Analysis Plan that will be finalized before the database lock. 
9.12 
Safety Analyses  
Safety Population was defined as all patients who received at least 1 dose of study drug. All 
safety analyses will be performed in the OL phase Safety-OL population and the RW phase 
Safety-RW population.  
All safety data will appear in by-patient data listings. 
9.12.1 Adverse Events 
Treatment-emergent adverse events (TEAEs) are defined as those AEs with onset after the first 
dose of study drug or existing events that worsened after the first dose during the study and up to 


 
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28 days after the last dose of study drug. In the OL phase, TEAEs will be summarized by dose 
level at AE onset, and overall, unless otherwise specified. Percentages are based on the number 
of patients who have been dosed at each dose level. In the RW phase, TEAEs will be 
summarized by treatment arm, and overall. Percentages are based on the number of patients in 
each treatment arm. Treatment emergent period for OL phase and RW phase are defined in 
(Section 7.1). 
Events reported with a partial onset date (e.g., 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 26.0.  
TEAEs assigned to CTCAE Grade 4 or 5 will be considered serious (i.e., treatment-emergent 
serious adverse events [TESAEs]) whether or not they are considered serious by the investigator. 
Summaries that are displayed by system organ class (SOC) and preferred terms (PT) will be 
ordered by descending incidence of SOC and PT within each system organ class. Summaries 
displayed by PT only will be ordered by descending incidence of PT.  
Tabular summaries with numbers and percentages of patients that have the following adverse 
events will be provided: 
 Overview of TEAEs in OL phase 
 Overview of TEAEs by treatment arm and overall, in RW phase  
 Summary of TEAEs in OL phase: 
- By SOC and PT 
- By decreasing incidence of PT 
- By SOC, PT, and maximum severity 
- By cumulative dose prior to the onset of the AE 
- EAIR by SOC and PT 
 Summary of TEAEs in RW phase by treatment arm and overall: 
- By SOC and PT 
- By decreasing incidence of PT 
- By SOC, PT, and maximum severity 
- By cumulative dose prior to the onset of the AE 
- EAIR by SOC and PT 
 Summary of TEAEs related to study drug by investigator assessment in OL phase: 
o By SOC and PT 
o By decreasing incidence of PT 
o By SOC, PT, and maximum severity 
 Summary of TEAEs related to study drug by investigator assessment by treatment arm 
and overall in the RW phase: 
o By SOC and PT 


 
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o By decreasing incidence of PT 
o By SOC, PT, and maximum severity 
 Summary of treatment-emergent serious adverse events in OL phase: 
o By SOC and PT 
o By decreasing incidence of PT 
o By SOC, PT, and maximum severity 
o Related to study drug per investigator by SOC and PT 
o Related to study drug per investigator by decreasing frequency of PT 
o With action taken of permanent discontinuation of study drug by SOC and PT 
o With action taken of permanent discontinuation of study drug by SOC, PT, and 
maximum severity 
o With action taken of permanent discontinuation of study by SOC and PT 
o With action taken of permanent discontinuation of study by SOC, PT, and 
maximum severity 
o Leading to study drug dose change by SOC and PT (based on exposure CRF) 
o EAIR by SOC and PT 
 Summary of treatment-emergent serious adverse events by treatment arm and overall, in 
the RW phase: 
o By SOC and PT 
o By decreasing incidence of PT 
o By SOC, PT, and maximum severity 
o Related to study drug per investigator by SOC and PT 
o Related to study drug per investigator by decreasing frequency of PT 
o With action taken of permanent discontinuation of study drug by SOC and PT 
o With action taken of permanent discontinuation of study drug by SOC, PT, and 
maximum severity 
o With action taken of permanent discontinuation of study by SOC and PT 
o With action taken of permanent discontinuation of study by SOC, PT, and 
maximum severity 
o Leading to study drug dose change by SOC and PT 
o EAIR by SOC and PT 
 Summary of TEAEs with action taken of permanent discontinuation of study drug in 
OL phase: 
o By SOC and PT 
o By decreasing incidence of PT 
o By SOC, PT, and maximum severity 
 Summary of TEAEs with action taken of permanent discontinuation of study drug by 
treatment arm and overall in the RW phase: 
o By SOC and PT 


 
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o By decreasing incidence of PT 
o By SOC, PT, and maximum severity 
 Summary of TEAEs with action taken of permanent discontinuation of study in 
OL phase: 
o By SOC and PT 
o By decreasing incidence of PT 
o By SOC, PT, and maximum severity 
 Summary of TEAEs with action taken of permanent discontinuation of study by 
treatment arm and overall in the RW phase: 
o By SOC and PT 
o By decreasing incidence of PT 
o By SOC, PT, and maximum severity 
 Summary of TEAEs by SOC and PT by comorbidity type (DM/IGT or hypertension) in 
OL phase as well as by treatment arm in RW phase 
 TEAEs by PT occurring in at least 10% of the Safety Population in OL phase, overall and 
by comorbidity type 
 TEAEs by PT occurring in at least 10% of the Safety Population by treatment arm and 
overall in RW phase, and by comorbidity type 
 TEAEs by PT for PT with ≥5% difference between treatment arms in RW phase 
 TEAEs with fatal outcome in OL phase 
 TEAEs with fatal outcome in RW phase by treatment arm and overall 
 Grade 3 or higher TEAE by SOC and PT in OL phase and RW phase 
 Grade 3 or higher TEAEs related to study drug by investigator assessment, by SOC and 
PT in OL phase and RW phase 
 TEAEs leading to dose reductions in OL phase, by SOC and PT 
 TEAEs leading to dose interruptions in OL phase, by SOC and PT 
 TEAEs leading to dose reductions in RW phase by treatment arm and overall, by SOC 
and PT  
 TEAEs leading to dose interruptions in RW phase by treatment arm and overall, by SOC 
and PT 
 Shift in CTCAE grade of TEAEs that are ongoing at the initiation of RW phase 
Summaries with number of patients and percentages based on the number of patients in the 
Safety population that have the following adverse events will be provided: 
 Overview of TEAEs in OL phase 
 Summary of TEAEs in OL phase: 
- By SOC and PT 
- By decreasing incidence of PT 
 Summary of treatment-emergent serious adverse events in OL phase: 


 
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- By SOC and PT 
- By decreasing incidence of PT 
 Summary of treatment-emergent serious adverse events by treatment arm and overall, in 
the RW phase: 
- By SOC and PT 
- By decreasing incidence of PT 
At each level of summarization (e.g., any AE, SOC, and PT), patients experiencing more than 
one AE will be counted only once within each dose level. 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 plot of patient incidence of TEAEs occurring in at least 10% of the population by CTCAE 
grade and MedDRA PT will be presented. 
Adverse event data will be presented in data listings by OL/RW phase. TEAEs, Serious TEAEs, 
TEAEs with action taken of permanent discontinuation of the study drug, TEAEs with action 
taken of permanent discontinuation of the study, TEAEs leading to dose reductions, TEAEs 
leading to dose interruptions, Grade 3 or higher TEAEs and TEAEs with fatal outcome will be 
presented in separate data listings, also separating OL and RW phase. 
The Exposure Adjusted Incidence Rate (EAIR) for a TEAE is defined as:  
𝐸𝑣𝑒𝑛𝑡 𝐼𝑛𝑐𝑖𝑑𝑒𝑛𝑐𝑒 𝑟𝑎𝑡𝑒 𝑝𝑒𝑟 100 𝑃𝑌𝐸= 𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑠𝑢𝑏𝑗𝑒𝑐𝑡𝑠 𝑤𝑖𝑡ℎ 𝑎 𝑒𝑣𝑒𝑛𝑡
𝑇𝑜𝑡𝑎𝑙 𝑃𝑌𝐸
 × 100 
The total patient-years-exposure (PYE) to a treatment is the sum of individual patient’s PYE 
within the treatment exposure period (OL and RW phase, separately) and is defined as:  
 For patients with an event within the exposure period:  
𝑃𝑌𝐸= (𝐹𝑖𝑟𝑠𝑡 𝑒𝑣𝑒𝑛𝑡 𝑠𝑡𝑎𝑟𝑡 𝑑𝑎𝑡𝑒−𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 𝑑𝑎𝑡𝑒+ 1)/365.25 
 For patients with no event within the exposure period:   
𝑃𝑌𝐸= (𝑠𝑡𝑢𝑑𝑦 𝑝𝑎𝑟𝑡𝑖𝑐𝑖𝑝𝑎𝑡𝑖𝑜𝑛 𝑒𝑛𝑑 𝑑𝑎𝑡𝑒− 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 𝑑𝑎𝑡𝑒 )/365.25 
Study participation end date is defined as the minimum of (the last dose date + 28 of the study 
phase, the start dose of RW phase (for OL Phase only), the end of study date and death date).   
The exact 95% CI based on Poisson distribution (Ulm 1990) for EAIR is defined as:  
(
𝜒2(𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑠𝑢𝑏𝑗𝑒𝑐𝑡𝑠 𝑤𝑖𝑡ℎ 𝑎𝑛 𝑒𝑣𝑒𝑛𝑡),0.025)
2
2 × 𝑇𝑜𝑡𝑎𝑙 𝑃𝑌𝐸
,
𝜒2(1+𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑠𝑢𝑏𝑗𝑒𝑐𝑡𝑠 𝑤𝑖𝑡ℎ 𝑎𝑛 𝑒𝑣𝑒𝑛𝑡),0.975)
2
2 × 𝑇𝑜𝑡𝑎𝑙 𝑃𝑌𝐸
 ) × 100 
where χ2ν,a is the chi-square quantile for upper tail probability on ν degrees of freedom.  For the 
RW phase, the crude risk difference and EAIR risk difference in relacorilant and placebo along 
with the 95% confidence interval will be provided for TEAEs and TESAEs.  


 
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9.12.2 Special Safety Topics 
A set of special safety topics were defined to identify and characterize events possibly associated 
with the use of relacorilant based on the mechanism of action, observed during the relacorilant 
pre-clinical and clinical development program, or are of clinical importance to the treated 
population. Summaries of these special safety topics will be produced to enhance the 
understanding of safety data.  
Each special safety topic is a grouped clinical term comprising a broad set of AEs that are related 
patho-physiologically. The search methods used to identify the AEs grouped within each topic 
vary and may utilize an algorithmic approach or include one or more of the following: 
standardized MedDRA queries (SMQs), keyword searches of MedDRA PTs, and predefined lists 
of relevant PTs/SOCs. The search strategies used in analyses are specified in Appendix 5.  
The special safety topics for this analysis include: 
 Excessive GR antagonism 
 Adrenal insufficiency 
 Irregular vaginal bleeding associated with endometrial hypertrophy 
 Peripheral edema 
 Renal failure 
 Arterial thromboembolism 
 Venous thromboembolism 
 Skin neoplasms 
 Neoplasms (all) 
 Cardiotoxicity 
 Hepatotoxicity 
 Anemia 
 Thrombocytopenia 
 Hemorrhage 
 Peripheral neuropathy 
 Hyperkalemia 
 Hypokalemia 
 Hyperpigmentation 
 New onset or exacerbation of pre-existing hypertension 
 Acne 
 Hyperandrogenism in females 
 Hypogonadism in males 


 
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9.12.3 Deaths  
All deaths during the study, including the post-treatment follow-up period, will be summarized 
including the primary cause of death, in OL phase and in RW phase, respectively. A listing of all 
deaths reported in OL and RW phase will be provided. 
9.12.4 Clinical Laboratory Tests  
All descriptive summaries of laboratory results will be based on data analyzed by the central 
laboratory and presented in Système International (SI) and conventional 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 (FDA Position Statement 2013). All data will 
be included in by-patient data listings. Laboratory measurements identified as abnormal (i.e., 
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, hematology, and lipid panel, will 
be summarized for both SI and conventional units, separately. Descriptive statistics will be 
presented for observed values and changes from baseline to the last post-baseline value in the OL 
phase and within treatment arm in the RW phase.  
Where applicable, laboratory results will be classified as “low,” “normal,” or “high” with 
respect to the parameter-specific reference ranges (i.e., below the lower limit of the normal 
range, within the normal range, or above the upper limit of the normal range). The classification 
will be re-derived using the normal ranges provided by the laboratory. 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 selected 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 5.0 (NCI-CTCAE 2017), where applicable. Grades will be 
presented as Grade 0, Grade 1, Grade 2, Grade 3 and Grade 4. Summary tables will be presented 
for each laboratory parameter to summarize the following: 
 The worst observed post-baseline severity grade within each dose level in OL phase 
 The last observed post-baseline CTCAE grade within each dose level in the OL phase 
 The worst observed severity grade by treatment arm and overall in RW phase.  


 
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Summary results will include the count and percentage of patients within each dose level in 
OL phase and by treatment arm in RW phase. 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. 
9.12.5 Vital Signs  
Vital sign parameter measurements, including BP, heart rate, respiratory rate, and oral body 
temperature, will be presented in listings and summarized. Descriptive statistics will be presented 
for results and change from baseline to the last post-baseline value in OL phase and RW phase. 
9.12.6 Electrocardiograms  
Twelve-lead electrocardiograms (ECG) interval parameters will be presented in listings and 
summarized. Descriptive statistics will be presented for results and change from baseline to the 
last post-baseline visit within OL phase and within treatment arm in RW phase using the average 
of the duplicate readings per patient per visit. The average of the triplicate readings at Screening 
will be used as baseline. 
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. 
9.12.7 Physical Examination 
Results of the physical examination will be presented in patient data listings by study visit, dose 
at time of study visit, and body system in the OL and RW phase. A listing of abnormal physical 
exam findings by visit and body system will be provided. The description of the abnormal 
finding and indication if the finding was clinically significant or not will be displayed. 
9.12.8 Pituitary MRI  
Magnetic resonance imaging (MRI) tumor measurements (tumor volume and summation of the 3 
tumor dimensions) will be summarized using descriptive statistics, to include the change from 
baseline to post-baseline. Change from baseline to post-baseline MRI 
(Increased/Decreased/Unchanged) will be summarized by frequency counts and percentages. A 
clinically significant volume change is defined as a change of at least 20%. A listing of MRI 
results by visit will be provided for each patient. Results will include tumor size categories (non-
visible, microadenoma, macroadenoma), longest vertical diameter, tumor volume and change 
from previous MRI (Increased/Decreased/Unchanged).  
9.12.9 Pregnancy Tests 
Results of the pregnancy tests will be presented in patient data listings by study visit, and dose at 
time of study visit for OL phase and RW phase.  


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


 
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11 
REFERENCES 
Beck AT, Steer RA, Brown GK. 1996. Beck Depression Inventory®-II(BDI®-II) Manual. 
Pearson Publishing Company, London, UK. 
Clinical Data Interchange Standards Consortium. Standardized Lab Units, SI and the Regulatory 
Environment Accessed August 14, 2020 at: 
https://www.cdisc.org/kb/articles/standardized-lab-units and U.S Food and Drug 
Administration Position Statement: Position on Use of SI Units for Lab Tests, 25 October 
2013. Accessed August 14, 2020 at: https://www.fda.gov/media/109533/download 
Hochberg Y. 1988. A sharper Bonferroni procedure for multiple tests of significance. 
Biometrika. 75:800–802. 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH). 1998. Guidance for Industry: E9 Statistical 
principles for clinical trials. U.S Food and Drug Administration; Accessed August 14, 
2020 at: https://www.fda.gov/media/71336/download 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH). 2003. Guidance for Industry: M2 eCTD: 
Electronic Common Technical Document Specification, Appendix 7. U.S Food and Drug 
Administration; Accessed December 22, 2023 at: 
https://www.fda.gov/media/71513/download 
International Council for Harmonization of Technical Requirements of Pharmaceuticals for 
Human Use (ICH). 2021. ICH Harmonized Guideline: E9(R1) Statistical Principles for 
Clinical Trials: Addendum: Estimands and Sensitivity Analysis in Clinical Trials. U.S 
Food and Drug Administration; Accessed January 31, 2022 at: 
https://www.fda.gov/media/148473/download 
International Council from Harmonization of Pharmaceuticals for Human Use (ICH). 2018. 
Guidance for Industry: ICH E6 (R2) Good Clinical Practice Integrated Addendum to ICH 
E6(R1). U.S Food and Drug Administration; Accessed August 14, 2020 at: 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/e6r2-good-
clinical-practice-integrated-addendum-ich-e6r1 
Katznelson L, Loriaux DL, Feldman D, et al. 2014. Global clinical response in Cushing’s 
syndrome patients treated with mifepristone. Clin Endocrinol. 80:562–569. doi: 
10.1111/cen.12332.  
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. 
Mehrotra DV, Liu F, Permutt T. Missing data in clinical trials: control-based mean imputation 
and sensitivity analysis. Pharmaceutical Statistics. 2017;16:378-392. 
https://doi.org/10.1002/pst.1817 


 
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National Cancer Institute-Common Terminology Criteria for Adverse Events, version 5.0, dated 
27 November 2017. US Department of Health and Human Services, National Institutes of 
Health, Accessed August 14, 2020 at: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
National Research Council (US) Panel on Handling Missing Data in Clinical Trials. 2010. The 
Prevention and Treatment of Missing Data in Clinical Trials. Washington (DC): National 
Academies Press (US). ISBN-13: 978-0-309-15814-5ISBN-10: 0-309-15814-1 
Steingrimsson, Jon Arni, Hanley Daniel F, Rosenblum Michael. Improving precision by 
adjusting for prognostic baseline variables in randomized trials with binary outcomes, 
without regression model assumptions. Contemporary Clinical Trials. 2017 54:18-24. 
Ulm, K. A simple method to calculate the confidence interval of a standardized mortality ratio 
(SMR). Am J Epidemiol. 1990;131 (2):373-5. 
 


 
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12 
APPENDIX 


 
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APPENDIX 1 
Propensity score approach will be used to impute missing data of SBP/DBP at Visit RW12 for 
patients who do not take rescue medication. The step-by-step methods are described below:  
– Analysis will be performed for patients in the Hypertension subgroup of the ITT-RW 
population. 
– All values for SBP/DBP up to the Visit RW12, will be used in the analysis regardless 
if they discontinue treatment (including values from retrieved dropouts). 
– Within the same treatment arm, obtain the set of propensity scores from a logistic 
regression model, in which patient’s status (Yes/No) of coming back for Visit RW12 
assessment is regressed on observed baseline characteristics including comorbidity 
type (response to DM/IGT criteria, yes vs no), height*, weight, body mass index 
(BMI)**, waist circumference, plasma ACTH, 24-hr UFC, late-night salivary 
cortisol, osteocalcin and mean 24-hour SBP and DBP from ABPM. Time on study 
treatment during the RW phase will also be a covariate in the model.  
– One-to-one or pair matching will be implemented, and patients will be matched with 
quartiles of the propensity score within the same treatment arm. 
– Impute missing values of SBP/DBP at Visit RW12 for patients who discontinue early, 
but do not come back for Visit RW12 measurement with the SBP/DBP values at Visit 
RW12 from matched pair of patients.  
 
* Height will not be assessed at Visit OL22. Data from Baseline OL will be used instead.  
**BMI at Visit OL22 will be calculated using Height at Baseline OL and weight at Visit OL22. 
 
 


 
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APPENDIX 2 
Propensity score approach will be used to impute missing data of AUCglucose at Visit RW12 for 
patients who do not take rescue medication. The step-by-step methods are described below:  
– Analysis will be performed using the patients in the DM/IGT subgroup from the 
ITT-RW population. 
– All values for AUCglucose up to the Visit RW12, will be used in the analysis regardless 
of if they discontinue treatment (including values from retrieved dropouts). 
– Within the same treatment arm, obtain the set of propensity scores from a logistic 
regression model, in which patient’s status (Yes/No) of coming back for Visit RW12 
assessment is regressed on observed RW baseline characteristics from Visit OL22 
including comorbidity type (response to hypertension criteria, yes vs no), 
Comorbidity Subgroup (DM vs. IGT), height*, weight, body mass index (BMI)**, 
waist circumference, plasma ACTH, 24-hr UFC, late-night salivary cortisol, oGTT 
plasma glucose, AUCglucose, HbA1c and osteocalcin. Time on study treatment during 
the RW phase will also be a covariate in the model.  
– One-to-one or pair matching will be implemented, and patients will be matched 
within quartiles of the propensity score within the same treatment arm. 
– Impute missing values of AUCglucose at Visit RW12 for patients who discontinue but 
do not come back for Visit RW12 measurement with the AUCglucose at Visit RW12 
from the matched pair of patients.  
 
* Height will not be assessed at Visit OL22. Data from Baseline OL will be used instead.  
**BMI at Visit OL22 will be calculated using Height at Baseline OL and weight at Visit OL22. 
–  
 


 
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APPENDIX 3 
Example SAS code below will be used to conduct MMRM analyses. 
 
ods output tests3=tests3 estimates=dsestimates lsmeans=dslsmeans convergencestatus=cstatus  
                  FitStatistics=cfit modelinfo=cinfo; 
ods graphics on;  
proc mixed data=mixed method=reml; 
 class trt (ref= "0") visit (ref= "BL") sfactor usubjid; 
 model aucchg = trt visit  trt*visit sfactor auc_ol22/ ddfm=kenwardroger; 
 repeated visit / type=un# subject=usubjid; 
 estimate "Trt diff at BL"      trt 1 -1  trt*visit 1  0  0  0  -1   0   0   0/ cl;  
 estimate "Trt diff at RW4"   trt 1 -1  trt*visit 0  1  0  0   0  -1   0   0/ cl;  
 estimate "Trt diff at RW8"   trt 1 -1  trt*visit 0  0  1  0   0   0  -1   0/ cl; 
 estimate "Trt diff at RW12" trt 1 -1  trt*visit 0  0  0  1   0   0   0  -1/ cl; 
 lsmeans trt*visit / cl; 
run; 
 
# Go through the sequence of covariance structure as described in Section 9.8.3.2.2 if 
convergence criteria not met by using “un” option.  
Example of SAS code for monotone regression:  
proc mi data=bpmi out=bpmi2 nimpute=100 seed=876453 minmaxiter=200; 
 
class trt01pn patstype; 
 
var trt01pn patstype base rw4 rw8 rw12; 
 
monotone regression; 
run; 
 
 
 


 
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APPENDIX 4 
The list of medications (WHO drug preferred terms) that are considered BP medications include 
all terms classified under the ATC level 3 code (‘C02A’, ‘C02C’, ‘C02D’, ‘C03A’, ‘C03B’, 
‘C03C’, ‘C03D’, ‘C07A’, ‘C08C’, ‘C09A’, ‘C09B’, ‘C09C’ and ‘C10A’), among which ATC 
level 3 code ‘C03D’ refers to mineralocorticoid antagonists medications. 
 


 
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APPENDIX 5 
Special Safety Topics 
Topic 
Definition 
Search Methodology 
Search Strategy 
Excessive GR antagonism  
A syndrome with severe (Grade 3 
or higher) symptoms which is 
caused by excessive antagonism 
of the glucocorticoid receptor 
after treatment with a competitive 
antagonist. 
Algorithm 
Two or more of the following specified adverse events with 
temporal association (event onset +/- 2 days) and at least 1 has 
severity=Grade 3 or higher: 
 Fatigue 
 Decreased appetite 
 Nausea 
 Vomiting 
 Abdominal pain 
Adrenal insufficiency 
Deficiency of cortisol produced 
by the adrenal cortex that leads to 
under-stimulation of both the 
glucocorticoid receptor AND the 
mineralocorticoid receptor. 
MedDRA HLT 
(Predefined PT list) 
Adrenal cortical hypofunctions (HLT) 
Irregular vaginal bleeding 
associated with 
endometrial hypertrophy 
Vaginal bleeding in females, 
including menstruation, which is 
considered unusual for the patient 
and associated with endometrial 
thickening or hypertrophy. 
Sponsor-defined PT list 
One or more AE of the following specified AEs: 
Abnormal uterine bleeding, Dysmenorrhoea, Heavy menstrual 
bleeding, Menometrorrhagia, Polymenorrhagia, 
Polymenorrhoea, Intermenstrual bleeding, Abnormal menstrual 
clots  
AND 
One or more AE of the following specified AEs: 
Endometrial hypertrophy, Endometrial thickening 
Peripheral edema  
Fluid accumulation in the 
interstitial space. 
Sponsor-defined PT list 
Generalised oedema, Gravitational oedema, Localised oedema, 
Non-pitting oedema, Oedema, Oedema peripheral, Peripheral 
swelling, Fluid retention, Skin oedema, Swelling, Skin swelling 


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


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


 
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Topic 
Definition 
Search Methodology 
Search Strategy 
Acne  
An inflammatory skin condition 
in which the pores of the skin are 
blocked.  
Keyword search 
Any PT containing: %acne%, %folliculitis% 
Hyperandrogenism  
The presence of an excess amount 
of androgens in females 
Sponsor-defined PT list 
Adrenal androgen excess, Hyperandrogenism, Hirsutism, Blood 
testosterone increased, Androgens increased, Blood 
androstenedione increased, Dihydrotestosterone increased, 
Amenorrhoea, Hypomenorrhoea, Menstruation delayed, 
Menstruation irregular  
Hypogonadism 
Deficiency of androgens in males 
Sponsor-defined PT list 
Adrenal androgen deficiency, Androgen deficiency, 
Feminisation acquired, Hypogonadism male, Blood testosterone 
decreased, Androgens decreased, Blood androstenedione 
decreased, Dihydrotestosterone decreased