Cushing's Syndrome
Conditions
Keywords
Primary Pigmented Nodular Adrenal Disease (PPNAD), Moon Facies, Dorsocervical Fat Pad, Adrenal Adenoma, Adrenal Carcinoma, Adrenal Autonomy, Cortisol, Cushing's Syndrome, Cushing's Disease, Cushing's, Hypercortisolemia, Cushingoid, Type 2 Diabetes, Impaired Glucose Intolerance, Hypertension, Adrenal Corticotrophic Hormone (ACTH), Adrenocortical Carcinoma
Brief summary
Cushing's syndrome is a relatively rare disorder caused by prolonged exposure to high levels of the glucocorticoid hormone cortisol. Cushing's syndrome may result from elevated endogenous or exogenous sources of cortisol. Endogenous Cushing's syndrome resulting from cortisol overproduction by the adrenal glands is the subject of this protocol. Patients with exogenous Cushing's syndrome, which develops as a side effect of chronic administration of high doses of glucocorticoids, were not eligible for enrollment in this study. The purpose of this study was to evaluate the safety and efficacy of CORT125134 for treatment of endogenous Cushing's syndrome. The multicenter study was conducted in the United States and in Europe.
Detailed description
This was a Phase 2, open-label study with two dose groups, each with a two-step dose escalation, designed to evaluate the safety and efficacy of CORT125134 for the treatment of endogenous Cushing's syndrome. CORT125134 was administered orally once daily for 16 weeks with dose escalations occurring every 4 weeks. Pharmacokinetics (PK) profiles were generated at every dose level. A data review committee reviewed PK and safety data and recommended the final plan for dose escalation in Group 2.
Interventions
DRUGCORT125134
Sponsors
Corcept Therapeutics
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Has a confirmed diagnosis of endogenous Cushing's syndrome. 2. Requires medical treatment of hypercortisolemia. 3. Meets at least one of the following criteria: 1. Has type 2 diabetes mellitus. 2. Has impaired glucose tolerance. 3. Has hypertension.
Exclusion criteria
1. Has non-endogenous source of hypercortisolemia 2. Has uncontrolled, clinically significant hypothyroidism or hyperthyroidism 3. Has poorly controlled hypertension 4. Has Stage ≥ 4 renal failure
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With One or More Adverse Events | Group 1: up to Week 16; Group 2: up to Week 20 | All treatment-emergent adverse events were recorded and summarized. |
| Percentage of Participants With One or More Severe (≥Grade 3) Adverse Events | Group 1: up to Week 16; Group 2: up to Week 20 | All treatment-emergent adverse events with Common Terminology Criteria for Adverse Events (CTCAE) ≥Grade 3 (severe) were recorded and summarized. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Hypertension Who Experience Improvement in Blood Pressure Following Treatment With CORT125134 | Group 1: Week 12 or last observation; Group 2: Week 16 or last observation | Improvement in blood pressure was defined as a participant who experiences at least a 5 mmHg decrease in mean diastolic or systolic BP from baseline who has not taken an additional antihypertensive medication during the treatment period or increased the dosage of a concurrent antihypertensive medication. |
| Percentage of Participants With IGT / T2DM Who Experienced a ≥25% Reduction in AUCglucose Following Treatment With CORT125134 | Before and 0.5, 1, 1.5, and 2 hours after a glucose drink at Week 12 or last observation (Group 1) or Week 16 or last observation (Group 2) | Improvement in glucose control was defined as a participant who experiences at least a 25% decrease from baseline in area under the concentration-time curve for blood glucose (AUCglucose) who has not taken an additional diabetes medication during the treatment period or increased the dosage of a concurrent diabetes medication. |
Countries
Hungary, Italy, Netherlands, United Kingdom, United States
Participant flow
Recruitment details
All enrolled participants who received at least 1 dose of study drug
Participants by arm
| Arm | Count |
|---|---|
| Group 1: Low-dose Group 100 mg/day for 4 weeks in Period 1, then 150 mg/day for 4 weeks in Period 2, then 200 mg/day for 4 weeks in Period 3. Period 3 was followed by a 4-week follow-up period. | 17 |
| Group 2: High-dose Group 250 mg/day for 4 weeks in Period 1, then 300 mg/day for 4 weeks in Period 2, then 350 mg/day for 4 weeks in Period 3, then 400 mg/day for 4 weeks in Period 4. Period 4 was followed by a 4-week follow-up period. | 18 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 | Adverse Event | 0 | 2 |
| Period 1 | Withdrawal by Subject | 0 | 1 |
| Period 2 | Adverse Event | 1 | 0 |
| Period 3 | Adverse Event | 0 | 2 |
| Period 4 | Adverse Event | 0 | 5 |
Baseline characteristics
| Characteristic | Group 2: High-dose Group | Total | Group 1: Low-dose Group |
|---|---|---|---|
| Age, Continuous | 49.5 years STANDARD_DEVIATION 13.46 | 48.6 years STANDARD_DEVIATION 13.37 | 47.6 years STANDARD_DEVIATION 13.62 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 3 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 32 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Hypertension | 11 Participants | 23 Participants | 12 Participants |
| Impaired Glucose Tolerance (IGT) / Type-2 Diabetes Mellitus (T2DM) | 15 Participants | 28 Participants | 13 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 18 Participants | 35 Participants | 17 Participants |
| Region of Enrollment Hungary | 2 Participants | 5 Participants | 3 Participants |
| Region of Enrollment Italy | 7 Participants | 14 Participants | 7 Participants |
| Region of Enrollment Netherlands | 0 Participants | 2 Participants | 2 Participants |
| Region of Enrollment United Kingdom | 0 Participants | 2 Participants | 2 Participants |
| Region of Enrollment United States | 9 Participants | 12 Participants | 3 Participants |
| Sex: Female, Male Female | 16 Participants | 25 Participants | 9 Participants |
| Sex: Female, Male Male | 2 Participants | 10 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 17 | 0 / 18 |
| other Total, other adverse events | 15 / 17 | 18 / 18 |
| serious Total, serious adverse events | 0 / 17 | 4 / 18 |
Outcome results
Primary
Percentage of Participants With One or More Adverse Events
All treatment-emergent adverse events were recorded and summarized.
Time frame: Group 1: up to Week 16; Group 2: up to Week 20
Population: All enrolled participants who received at least 1 dose of study drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 1: Low-dose Group | Percentage of Participants With One or More Adverse Events | 15 Participants |
| Group 2: High-dose Group | Percentage of Participants With One or More Adverse Events | 18 Participants |
Primary
Percentage of Participants With One or More Severe (≥Grade 3) Adverse Events
All treatment-emergent adverse events with Common Terminology Criteria for Adverse Events (CTCAE) ≥Grade 3 (severe) were recorded and summarized.
Time frame: Group 1: up to Week 16; Group 2: up to Week 20
Population: All enrolled participants who received at least 1 dose of study drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 1: Low-dose Group | Percentage of Participants With One or More Severe (≥Grade 3) Adverse Events | 3 Participants |
| Group 2: High-dose Group | Percentage of Participants With One or More Severe (≥Grade 3) Adverse Events | 7 Participants |
Secondary
Percentage of Participants With Hypertension Who Experience Improvement in Blood Pressure Following Treatment With CORT125134
Improvement in blood pressure was defined as a participant who experiences at least a 5 mmHg decrease in mean diastolic or systolic BP from baseline who has not taken an additional antihypertensive medication during the treatment period or increased the dosage of a concurrent antihypertensive medication.
Time frame: Group 1: Week 12 or last observation; Group 2: Week 16 or last observation
Population: All enrolled participants with hypertension at Baseline who received at least one dose of study drug and had at least one post-baseline assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1: Low-dose Group | Percentage of Participants With Hypertension Who Experience Improvement in Blood Pressure Following Treatment With CORT125134 | 41.67 Percentage of participants |
| Group 2: High-dose Group | Percentage of Participants With Hypertension Who Experience Improvement in Blood Pressure Following Treatment With CORT125134 | 63.64 Percentage of participants |
Secondary
Percentage of Participants With IGT / T2DM Who Experienced a ≥25% Reduction in AUCglucose Following Treatment With CORT125134
Improvement in glucose control was defined as a participant who experiences at least a 25% decrease from baseline in area under the concentration-time curve for blood glucose (AUCglucose) who has not taken an additional diabetes medication during the treatment period or increased the dosage of a concurrent diabetes medication.
Time frame: Before and 0.5, 1, 1.5, and 2 hours after a glucose drink at Week 12 or last observation (Group 1) or Week 16 or last observation (Group 2)
Population: All enrolled participants with IGT / T2DM at Baseline who received at least one dose of study drug and had at least one post-baseline assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1: Low-dose Group | Percentage of Participants With IGT / T2DM Who Experienced a ≥25% Reduction in AUCglucose Following Treatment With CORT125134 | 23.08 Percentage of participants |
| Group 2: High-dose Group | Percentage of Participants With IGT / T2DM Who Experienced a ≥25% Reduction in AUCglucose Following Treatment With CORT125134 | 0 Percentage of participants |
Post Hoc
Percentage of Participants With IGT / T2DM Who Experienced Improvement in Glucose Control Following Treatment With CORT125134: Responder Definition Based on Response Criteria for Phase 3 Study NCT03697109
Improvement in glucose control was defined based on response criteria for Phase 3 study NCT03697109: a participant who experiences 1) a hemoglobin A1c (HbA1c) that is decreased by ≥ 0.5% from baseline, 2) a 2-hour oGTT plasma glucose that is normalized (\< 7.8 mmol/L) or decreased by ≥ 2.8 mmol/L from baseline, or 3) a total daily insulin dose that has decreased by ≥ 25% or total daily sulfonylurea dose that has decreased by ≥ 50% and an HbA1c that is unchanged or decreased from baseline.
Time frame: Before and 0.5, 1, 1.5, and 2 hours after a glucose drink at Week 12 or last observation (Group 1) or Week 16 or last observation (Group 2)
Population: All enrolled participants with IGT / T2DM at Baseline who received at least one dose of study drug and had non-missing post-baseline data collected, with exclusions based on clinical judgment and/or important protocol deviations applied on a visit and outcome level rather than a participant level.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1: Low-dose Group | Percentage of Participants With IGT / T2DM Who Experienced Improvement in Glucose Control Following Treatment With CORT125134: Responder Definition Based on Response Criteria for Phase 3 Study NCT03697109 | 15.38 Percentage of participants |
| Group 2: High-dose Group | Percentage of Participants With IGT / T2DM Who Experienced Improvement in Glucose Control Following Treatment With CORT125134: Responder Definition Based on Response Criteria for Phase 3 Study NCT03697109 | 50.00 Percentage of participants |