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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Cushing Syndrome

Intervention / Treatment
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* Drug: Relacorilant
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Relacorilant (open-label phase)<br>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<br>* Relacorilant is supplied as 100 mg capsules for oral dosing.<br>* Other names: CORT125134;|
| Experimental: Relacorilant (randomized-withdrawal phase)<br>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<br>* Relacorilant is supplied as 100 mg capsules for oral dosing.<br>* Other names: CORT125134;|
| Placebo Comparator: Placebo (randomized-withdrawal phase)<br>Placebo matched to study drug | Other: Placebo<br>* Placebo matched to study drug<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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