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

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

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

Study Overview

• Status: Active, not recruiting
• Conditions: Cushing Syndrome
• Intervention / Treatment: Drug: Relacorilant; Other: Placebo

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.

• Study Type: Interventional
• Enrollment (Estimated): 152
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Clinical Trial Lead; Phone Number: 650-327-3270; Email: CorceptStudy455@corcept.com

Study Locations

• Austria
  • Graz, Austria, 8036
    • Site 60
  • Vienna, Austria, 1090
    • Site 47
• Bulgaria
  • Sofia, Bulgaria, 1431
    • Site 27
• Canada
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H-2Y9
      • Site 70
• Germany
  • München, Germany, 80336
    • Site 54
  • Würzburg, Germany, 97080
    • Site 49
• Israel
  • Kfar Saba, Israel, 4428164
    • Site 29
  • Petach Tikva, Israel, 4941480
    • Site 28
  • Tel Aviv, Israel
    • Site 69
• Italy
  • Ancona, Italy, 60030
    • Site 43
  • Messina, Italy, 98125
    • Site 15
  • Milano, Italy, 20149
    • Site 26
  • Napoli, Italy, 80131
    • Site 12
  • Orbassano, Italy, 10043
    • Site 38
  • Roma, Italy, 00161
    • Site 40
  • Roma, Italy, 00189
    • Site 16
  • Torino, Italy, 10126
    • Site 48
• Netherlands
  • Rotterdam, Netherlands, 3015 AA
    • Site 34
• Poland
  • Kraków, Poland, 31- 501
    • Site 59
  • Lublin, Poland, 20-412
    • Site 33
• Romania
  • Bucharest, Romania, 010825
    • Site 66
  • Bucharest, Romania, 011863
    • Site 63
  • Bucharest, Romania, 011863
    • Site 64
  • Iaşi, Romania, 700106
    • Site 73
• Spain
  • Alicante, Spain, 03010
    • Site 75
  • Barcelona, Spain, 08916
    • Site 74
  • Girona, Spain, 17007
    • Site 25
  • Madrid, Spain, 28007
    • Site 24
  • Málaga, Spain, 29006
    • Site 22
  • Sevilla, Spain, 41013
    • Site 23
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • Site 21
  • California
    • Los Angeles, California, United States, 90095
      • Site 36
    • Torrance, California, United States, 90502
      • Site 68
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Site 32
  • Florida
    • Miami, Florida, United States, 33136
      • Site 10
  • Georgia
    • Atlanta, Georgia, United States, 30318
      • Site 14
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Site 7
  • Louisiana
    • Metairie, Louisiana, United States, 70006
      • Site 2
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Site 45
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Site 20
  • Mississippi
    • Jackson, Mississippi, United States, 39202
      • Site 4
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • Site 53
  • New York
    • Albany, New York, United States, 12203
      • Site 8
    • New York, New York, United States, 10021
      • Site 57
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Site 17
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Site 11
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Site 62
    • Pittsburgh, Pennsylvania, United States, 15213
      • Site 71
  • Texas
    • Dallas, Texas, United States, 75390
      • Site 51
    • El Paso, Texas, United States, 79935
      • Site 3
    • Houston, Texas, United States, 77079
      • Site 65

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Relacorilant (open-label phase); The dose of relacorilant will be increased sequentially from 100 mg orally once daily to a target dose of 400 mg once daily.	Drug: Relacorilant; Relacorilant is supplied as 100 mg capsules for oral dosing.; Other Names: CORT125134
Experimental: Relacorilant (randomized-withdrawal phase); 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.	Drug: Relacorilant; Relacorilant is supplied as 100 mg capsules for oral dosing.; Other Names: CORT125134
Placebo Comparator: Placebo (randomized-withdrawal phase); Placebo matched to study drug	Other: Placebo; Placebo matched to study drug

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Week OL22 to Week RW12
In all patients, assessment of safety based on treatment-emergent adverse events (TEAEs) as graded by CTCAE v5.0.		Screening through Post Treatment Follow-up (up to 48 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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		Week Open label 22 (OL22) to Week Randomized withdraw 12 (RW12)
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.		Open Label week 22 (OL22) to Randomized Withdraw week 12 (RW12)
In patients with IGT at Baseline, the mean change from Visit OL22 to RW12 in the 2 hour glucose value of the oGTT		Week OL22 to week RW12
In patients with hypertension the mean change in SBP or DBP as compared between relacorilant and placebo		Week OL22 to week RW12
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.	Week OL22 to week RW12
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		Week OL22 to week RW12
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	Week OL22 to Week RW12
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)		Baseline to week OL22 or End of Treatment (ET)
In patients with IGT, the mean change in 2-hour oGTT glucose from Baseline to Visit OL22/ET		Baseline to week OL22 or ET
In patients with DM (HbA1c ≥6.5% at Baseline), the mean change in HbA1c from Baseline to Visit OL22/ET		Baseline to week OL22 or 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	Baseline to week OL22 or ET

Collaborators and Investigators

• Sponsor: Corcept Therapeutics
• Investigators: Study Director: Andreas Moraitis, MD, Corcept Therapeutics

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): November 15, 2018
• Primary Completion (Estimated): April 1, 2024
• Study Completion (Estimated): April 1, 2024

Study Registration Dates

• First Submitted: September 27, 2018
• First Submitted That Met QC Criteria: October 3, 2018
• First Posted (Actual): October 5, 2018

Study Record Updates

• Last Update Posted (Actual): March 8, 2024
• Last Update Submitted That Met QC Criteria: March 6, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Hypertension; Type 2 Diabetes; Cortisol; Cushing syndrome; Cushing disease; Hypercortisolemia; Cushingoid; Impaired Glucose Intolerance; Adrenocorticotropic hormone; Primary Pigmented Nodular Adrenal Disease; Moon Facies; Dorsocervical Fat Pad; Adrenal Adenoma; Adrenal Autonomy; Cushing
• Additional Relevant MeSH Terms: Pathologic Processes; Endocrine System Diseases; Disease; Adrenocortical Hyperfunction; Adrenal Gland Diseases; Syndrome; Cushing Syndrome
• Other Study ID Numbers: CORT125134-455

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No