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

• ClinicalTrials.gov Identifier: NCT03697109
• Recruitment Status: Completed
• First Posted: October 5, 2018
• Last Update Posted: May 2, 2024
• Sponsor: Corcept Therapeutics
• Information provided by (Responsible Party): Corcept Therapeutics

Tracking Information

• First Submitted Date: September 27, 2018
• First Posted Date: October 5, 2018
• Last Update Posted Date: May 2, 2024
• Actual Study Start Date: November 15, 2018
• Actual Primary Completion Date: April 8, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 7, 2023)

• In patients with hypertension, the proportion of patients with a loss of response with respect to hypertension from visit OL22 to RW12 [ Time Frame: Week OL22 to Week 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. [ Time Frame: Screening through Post Treatment Follow-up (up to 48 weeks) ]

Original Primary Outcome Measures (submitted: October 3, 2018)

• In patients with diabetes mellitus/impaired glucose tolerance (DM/IGT), the mean change from Week OL22 to Week RW12 or Early Termination (ET) in the 2-hour oGTT glucose (mg/dL) as compared between relacorilant and placebo [ Time Frame: Week OL22 to Week RW12 ]
• In patients with hypertension, the proportion of patients with 1) an increase in systolic or diastolic blood pressure of at least 5 mmHg or 2) any increase in antihypertensive medication from OL22 to RW12/ET as compared between relacorilant and placebo [ Time Frame: Week OL22 to Week RW12 ]
• 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) ]

Current Secondary Outcome Measures (submitted: August 7, 2023)

• 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) ]
• 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) ]
• 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 ]
• In patients with hypertension the mean change in SBP or DBP as compared between relacorilant and placebo [ Time Frame: 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 [ Time Frame: Week OL22 to week RW12 ]
  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 [ Time Frame: 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 [ Time Frame: Week OL22 to Week RW12 ]
  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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Baseline to week OL22 or ET ]
• In patients with uncontrolled hypertension the mean change in SBP or DBP from Baseline to visit OL22/ET [ Time Frame: Baseline to week OL22 or ET ]
  Blood pressure will be measured by 24 hour ABPM readings

Original Secondary Outcome Measures (submitted: October 3, 2018)

• In patients with DM/IGT, the proportion of patients who meet any of the DM/IGT response criteria at the end of the OL phase (Week OL22). [ Time Frame: Open Label Phase (Baseline to Week OL22) ]
  - The DM/IGT response criteria for the Open-Label Phase (assessed at Week OL22) are:

  • HbA1c has decreased by ≥0.5% from Baseline
  • The 2-hour oGTT glucose is normalized (<140 mg/dL) or decreased by ≥50 mg/dL from Baseline
  • Total daily insulin dose has decreased by ≥25% or daily sulfonylurea dose has decreased from Baseline by ≥50% and HbA1c is unchanged or decreased compared with Baseline
• In patients with hypertension, the proportion of patients who meet any of the hypertension response criteria at the end of the OL phase (Week OL22) [ Time Frame: Open Label Phase (Baseline to Week OL22) ]
  • The hypertension response criteria for the Open-Label Phase (assessed at Week OL22) are:
  • ≥5 mm Hg decrease in SBP and/or DBP from Baseline without worsening of either, based on 24-hour ABPM
  • A reduction in the number or dose of BP medications, and SBP and DBP by ABPM are no worse than at Baseline.
• The mean change from Baseline to Week OL22 in Cushing Quality-of-Life (QoL) score [ Time Frame: Open Label Phase (Baseline to Week OL22) ]
  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.
• Proportion of patients who worsened, as assessed by the Global Clinical Response, from Week OL22 to Week RW12/ET [ Time Frame: Week OL22 to Week RW12 ]
  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

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of the Efficacy and Safety of Relacorilant in Patients With Endogenous Cushing Syndrome
• 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
• 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.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Cushing Syndrome

Intervention

• Drug: Relacorilant
  Relacorilant is supplied as 100 mg capsules for oral dosing.
  Other Name: CORT125134
• Other: Placebo
  Placebo matched to study drug

Study Arms

• 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.
  Intervention: Drug: Relacorilant
• 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.
  Intervention: Drug: Relacorilant
• Placebo Comparator: Placebo (randomized-withdrawal phase)
  Placebo matched to study drug
  Intervention: Other: Placebo

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 7, 2023): 152
• Original Estimated Enrollment (submitted: October 3, 2018): 130
• Actual Study Completion Date: April 15, 2024
• Actual Primary Completion Date: April 8, 2024 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Austria, Bulgaria, Canada, Germany, Israel, Italy, Netherlands, Poland, Romania, Spain, United States

Administrative Information

• NCT Number: NCT03697109
• Other Study ID Numbers: CORT125134-455
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Corcept Therapeutics
• Original Responsible Party: Same as current
• Current Study Sponsor: Corcept Therapeutics
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Andreas Moraitis, MD; Corcept Therapeutics

• PRS Account: Corcept Therapeutics
• Verification Date: May 2024