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A Study of the Efficacy and Safety of Relacorilant in Patients With Endogenous Cushing Syndrome (GRACE)

Primary Purpose

Cushing Syndrome

Status
Active
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Relacorilant
Placebo
Sponsored by
Corcept Therapeutics
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cushing Syndrome focused on measuring 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

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Has a confirmed diagnosis of endogenous Cushing syndrome
  • Meets at least one of the following criteria:
  • Has Type 2 diabetes mellitus
  • Has impaired glucose tolerance
  • Has hypertension

Exclusion Criteria:

  • Has non-endogenous source of hypercortisolemia
  • Has uncontrolled, clinically significant hypothyroidism or hyperthyroidism
  • Has poorly controlled hypertension
  • Has poorly controlled diabetes mellitus
  • Has severe renal insufficiency

Sites / Locations

  • Site 21
  • Site 36
  • Site 68
  • Site 32
  • Site 10
  • Site 14
  • Site 7
  • Site 2
  • Site 45
  • Site 20
  • Site 4
  • Site 53
  • Site 72
  • Site 8
  • Site 57
  • Site 17
  • Site 11
  • Site 62
  • Site 71
  • Site 51
  • Site 3
  • Site 65
  • Site 76
  • Site 60
  • Site 47
  • Site 27
  • Site 70
  • Site 58
  • Site 50
  • Site 54
  • Site 49
  • Site 29
  • Site 28
  • Site 69
  • Site 43
  • Site 15
  • Site 26
  • Site 12
  • Site 38
  • Site 67
  • Site 40
  • Site 16
  • Site 48
  • Site 34
  • Site 59
  • Site 33
  • Site 66
  • Site 63
  • Site 64
  • Site 73
  • Site 75
  • Site 74
  • Site 25
  • Site 24
  • Site 22
  • Site 23

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Placebo Comparator

Arm Label

Relacorilant (open-label phase)

Relacorilant (randomized-withdrawal phase)

Placebo (randomized-withdrawal phase)

Arm Description

The dose of relacorilant will be increased sequentially from 100 mg orally once daily to a target dose of 400 mg once daily.

Patients who meet any of the response criteria will advance to the randomized-withdrawal phase of the study and receive the same highest dose as in the open-label phase.

Placebo matched to study drug

Outcomes

Primary Outcome Measures

In patients with hypertension, the proportion of patients with a loss of response with respect to hypertension from visit OL22 to RW12
Based on 24hour ABPM defined as 1) an increase in systolic and/or diastolic blood pressure of at least 5 mmHg or 2) any increase or modification in antihypertensive medication from Week OL22 to Week RW12/Early Termination as compared between relacorilant and placebo
In all patients, assessment of safety based on treatment-emergent adverse events (TEAEs) as graded by CTCAE v5.0.

Secondary Outcome Measures

In patients with diabetes mellitus/impaired glucose tolerance (DM/IGT), the mean change in area under the curve for glucose from Week OL22 to Week RW12 as compared between relacorilant and placebo
In patients with DM (HbA1c at Baseline >6.5%), the mean change from Visit OL22 to RW12 in HbA1c as compared between relacorilant and placebo.
In patients with IGT at Baseline, the mean change from Visit OL22 to RW12 in the 2 hour glucose value of the oGTT
In patients with hypertension the mean change in SBP or DBP as compared between relacorilant and placebo
The mean change in body weight, body fat measured with DXA scan and Cushing Quality-of-Life (QoL) score as compared between relacorilant and placebo
The Cushing Quality of Life (QoL) patient questionnaire, which evaluates the health-related QoL in patients with Cushing syndrome (Webb et al. 2008), will be administered to all patients. 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.
For patients in either subgroup (DM/IGT or hypertension) the proportion of patients with any increase or modification in diabetes or antihypertensive medication as compared between relacorilant and placebo
Proportion of patients who worsened, as assessed by the Global Clinical Response, from Week OL22 to Week RW12/ET as compared between relacorilant and placebo
Global Clinical Response will be scored in 7 categories: glucose, blood pressure, body composition, clinical appearance, strength, psychiatric health/ cognitive function, Cushing QoL score. An independent Data Review Board (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 each 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
Mean change in QoL, body fat composition as determined by DXA, Beck Depression inventory-II (BDI-II) and body weight from Baseline to visit OL22 or end of treatment (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 uncontrolled hypertension the mean change in SBP or DBP from Baseline to visit OL22/ET
Blood pressure will be measured by 24 hour ABPM readings

Full Information

First Posted
September 27, 2018
Last Updated
August 7, 2023
Sponsor
Corcept Therapeutics
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1. Study Identification

Unique Protocol Identification Number
NCT03697109
Brief Title
A Study of the Efficacy and Safety of Relacorilant in Patients With Endogenous Cushing Syndrome
Acronym
GRACE
Official 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 Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
October 16, 2018 (Actual)
Primary Completion Date
March 2024 (Anticipated)
Study Completion Date
March 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Corcept Therapeutics

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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 and/or uncontrolled hypertension
Detailed Description
This Phase 3 study involves two phases, an open-label (OL) phase and a randomized-withdrawal (RW) phase. Patients will dose-escalate in 100 mg increments to a target dose of 400 mg orally once daily during the open-label phase. Patients will remain on open-label treatment until week 22 at which time they will be evaluated for the randomized-withdrawal phase based on pre-defined 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 randomization will end treatment and may be eligible to roll over into an extension safety study. Patients who complete the randomized-withdrawal phase of the study may also be eligible to roll over into an extension study.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
152 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Relacorilant (open-label phase)
Arm Type
Experimental
Arm Description
The dose of relacorilant will be increased sequentially from 100 mg orally once daily to a target dose of 400 mg once daily.
Arm Title
Relacorilant (randomized-withdrawal phase)
Arm Type
Experimental
Arm Description
Patients who meet any of the response criteria will advance to the randomized-withdrawal phase of the study and receive the same highest dose as in the open-label phase.
Arm Title
Placebo (randomized-withdrawal phase)
Arm Type
Placebo Comparator
Arm Description
Placebo matched to study drug
Intervention Type
Drug
Intervention Name(s)
Relacorilant
Other Intervention Name(s)
CORT125134
Intervention Description
Relacorilant is supplied as 100 mg capsules for oral dosing.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Placebo matched to study drug
Primary Outcome Measure Information:
Title
In patients with hypertension, the proportion of patients with a loss of response with respect to hypertension from visit OL22 to RW12
Description
Based on 24hour ABPM defined as 1) an increase in systolic and/or diastolic blood pressure of at least 5 mmHg or 2) any increase or modification in antihypertensive medication from Week OL22 to Week RW12/Early Termination as compared between relacorilant and placebo
Time Frame
Week OL22 to Week RW12
Title
In all patients, assessment of safety based on treatment-emergent adverse events (TEAEs) as graded by CTCAE v5.0.
Time Frame
Screening through Post Treatment Follow-up (up to 48 weeks)
Secondary Outcome Measure Information:
Title
In patients with diabetes mellitus/impaired glucose tolerance (DM/IGT), the mean change in area under the curve for glucose from Week OL22 to Week RW12 as compared between relacorilant and placebo
Time Frame
Week Open label 22 (OL22) to Week Randomized withdraw 12 (RW12)
Title
In patients with DM (HbA1c at Baseline >6.5%), the mean change from Visit OL22 to RW12 in HbA1c as compared between relacorilant and placebo.
Time Frame
Open Label week 22 (OL22) to Randomized Withdraw week 12 (RW12)
Title
In patients with IGT at Baseline, the mean change from Visit OL22 to RW12 in the 2 hour glucose value of the oGTT
Time Frame
Week OL22 to week RW12
Title
In patients with hypertension the mean change in SBP or DBP as compared between relacorilant and placebo
Time Frame
Week OL22 to week RW12
Title
The mean change in body weight, body fat measured with DXA scan and Cushing Quality-of-Life (QoL) score as compared between relacorilant and placebo
Description
The Cushing Quality of Life (QoL) patient questionnaire, which evaluates the health-related QoL in patients with Cushing syndrome (Webb et al. 2008), will be administered to all patients. 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.
Time Frame
Week OL22 to week RW12
Title
For patients in either subgroup (DM/IGT or hypertension) the proportion of patients with any increase or modification in diabetes or antihypertensive medication as compared between relacorilant and placebo
Time Frame
Week OL22 to week RW12
Title
Proportion of patients who worsened, as assessed by the Global Clinical Response, from Week OL22 to Week RW12/ET as compared between relacorilant and placebo
Description
Global Clinical Response will be scored in 7 categories: glucose, blood pressure, body composition, clinical appearance, strength, psychiatric health/ cognitive function, Cushing QoL score. An independent Data Review Board (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 each 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
Time Frame
Week OL22 to Week RW12
Title
Mean change in QoL, body fat composition as determined by DXA, Beck Depression inventory-II (BDI-II) and body weight from Baseline to visit OL22 or end of treatment (ET)
Time Frame
Baseline to week OL22 or End of Treatment (ET)
Title
In patients with IGT, the mean change in 2-hour oGTT glucose from Baseline to Visit OL22/ET
Time Frame
Baseline to week OL22 or ET
Title
In patients with DM (HbA1c ≥6.5% at Baseline), the mean change in HbA1c from Baseline to Visit OL22/ET
Time Frame
Baseline to week OL22 or ET
Title
In patients with uncontrolled hypertension the mean change in SBP or DBP from Baseline to visit OL22/ET
Description
Blood pressure will be measured by 24 hour ABPM readings
Time Frame
Baseline to week OL22 or ET

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Has a confirmed diagnosis of endogenous Cushing syndrome Meets at least one of the following criteria: Has Type 2 diabetes mellitus Has impaired glucose tolerance Has hypertension Exclusion Criteria: Has non-endogenous source of hypercortisolemia Has uncontrolled, clinically significant hypothyroidism or hyperthyroidism Has poorly controlled hypertension Has poorly controlled diabetes mellitus Has severe renal insufficiency
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Andreas Moraitis, MD
Organizational Affiliation
Corcept Therapeutics
Official's Role
Study Director
Facility Information:
Facility Name
Site 21
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85013
Country
United States
Facility Name
Site 36
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
Site 68
City
Torrance
State/Province
California
ZIP/Postal Code
90502
Country
United States
Facility Name
Site 32
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States
Facility Name
Site 10
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
Site 14
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30318
Country
United States
Facility Name
Site 7
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Facility Name
Site 2
City
Metairie
State/Province
Louisiana
ZIP/Postal Code
70006
Country
United States
Facility Name
Site 45
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21205
Country
United States
Facility Name
Site 20
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
Site 4
City
Jackson
State/Province
Mississippi
ZIP/Postal Code
39202
Country
United States
Facility Name
Site 53
City
Omaha
State/Province
Nebraska
ZIP/Postal Code
68198
Country
United States
Facility Name
Site 72
City
Reno
State/Province
Nevada
ZIP/Postal Code
89511
Country
United States
Facility Name
Site 8
City
Albany
State/Province
New York
ZIP/Postal Code
12203
Country
United States
Facility Name
Site 57
City
New York
State/Province
New York
ZIP/Postal Code
10021
Country
United States
Facility Name
Site 17
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Facility Name
Site 11
City
Oklahoma City
State/Province
Oklahoma
ZIP/Postal Code
73104
Country
United States
Facility Name
Site 62
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19107
Country
United States
Facility Name
Site 71
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15213
Country
United States
Facility Name
Site 51
City
Dallas
State/Province
Texas
ZIP/Postal Code
75390
Country
United States
Facility Name
Site 3
City
El Paso
State/Province
Texas
ZIP/Postal Code
79935
Country
United States
Facility Name
Site 65
City
Houston
State/Province
Texas
ZIP/Postal Code
77079
Country
United States
Facility Name
Site 76
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53226
Country
United States
Facility Name
Site 60
City
Graz
ZIP/Postal Code
8036
Country
Austria
Facility Name
Site 47
City
Vienna
ZIP/Postal Code
1090
Country
Austria
Facility Name
Site 27
City
Sofia
ZIP/Postal Code
1431
Country
Bulgaria
Facility Name
Site 70
City
Halifax
State/Province
Nova Scotia
ZIP/Postal Code
B3H-2Y9
Country
Canada
Facility Name
Site 58
City
Montréal
ZIP/Postal Code
H2X 0A9
Country
Canada
Facility Name
Site 50
City
Leipzig
ZIP/Postal Code
04103
Country
Germany
Facility Name
Site 54
City
München
ZIP/Postal Code
80336
Country
Germany
Facility Name
Site 49
City
Würzburg
ZIP/Postal Code
97080
Country
Germany
Facility Name
Site 29
City
Kfar Saba
ZIP/Postal Code
4428164
Country
Israel
Facility Name
Site 28
City
Petach Tikva
ZIP/Postal Code
4941480
Country
Israel
Facility Name
Site 69
City
Tel Aviv
Country
Israel
Facility Name
Site 43
City
Ancona
ZIP/Postal Code
60030
Country
Italy
Facility Name
Site 15
City
Messina
ZIP/Postal Code
98125
Country
Italy
Facility Name
Site 26
City
Milano
ZIP/Postal Code
20149
Country
Italy
Facility Name
Site 12
City
Napoli
ZIP/Postal Code
80131
Country
Italy
Facility Name
Site 38
City
Orbassano
ZIP/Postal Code
10043
Country
Italy
Facility Name
Site 67
City
Padova
ZIP/Postal Code
35128
Country
Italy
Facility Name
Site 40
City
Roma
ZIP/Postal Code
00161
Country
Italy
Facility Name
Site 16
City
Roma
ZIP/Postal Code
00189
Country
Italy
Facility Name
Site 48
City
Torino
ZIP/Postal Code
10126
Country
Italy
Facility Name
Site 34
City
Rotterdam
ZIP/Postal Code
3015 AA
Country
Netherlands
Facility Name
Site 59
City
Kraków
ZIP/Postal Code
31- 501
Country
Poland
Facility Name
Site 33
City
Lublin
ZIP/Postal Code
20-412
Country
Poland
Facility Name
Site 66
City
Bucharest
ZIP/Postal Code
010825
Country
Romania
Facility Name
Site 63
City
Bucharest
ZIP/Postal Code
011863
Country
Romania
Facility Name
Site 64
City
Bucharest
ZIP/Postal Code
011863
Country
Romania
Facility Name
Site 73
City
Iaşi
ZIP/Postal Code
700106
Country
Romania
Facility Name
Site 75
City
Alicante
ZIP/Postal Code
03010
Country
Spain
Facility Name
Site 74
City
Barcelona
ZIP/Postal Code
08916
Country
Spain
Facility Name
Site 25
City
Girona
ZIP/Postal Code
17007
Country
Spain
Facility Name
Site 24
City
Madrid
ZIP/Postal Code
28007
Country
Spain
Facility Name
Site 22
City
Málaga
ZIP/Postal Code
29006
Country
Spain
Facility Name
Site 23
City
Sevilla
ZIP/Postal Code
41013
Country
Spain

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
35058882
Citation
Pivonello R, Munster PN, Terzolo M, Ferrigno R, Simeoli C, Puglisi S, Bali U, Moraitis AG. Glucocorticoid Receptor Antagonism Upregulates Somatostatin Receptor Subtype 2 Expression in ACTH-Producing Neuroendocrine Tumors: New Insight Based on the Selective Glucocorticoid Receptor Modulator Relacorilant. Front Endocrinol (Lausanne). 2022 Jan 4;12:793262. doi: 10.3389/fendo.2021.793262. eCollection 2021.
Results Reference
derived

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A Study of the Efficacy and Safety of Relacorilant in Patients With Endogenous Cushing Syndrome

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