Clinical Trial Results:
Glucocorticoid Receptor Antagonism in the Treatment of Hypercortisolism in Patients with Cortisol-Secreting Adrenal Adenomas or Hyperplasia (GRADIENT): A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy and Safety of Relacorilant
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Summary
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EudraCT number |
2019-004956-12 |
Trial protocol |
DE PL BG IT RO |
Global end of trial date |
19 Sep 2024
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Results information
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Results version number |
v1(current) |
This version publication date |
23 Oct 2025
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First version publication date |
23 Oct 2025
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
CORT125134-456
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04308590 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Corcept Therapeutics Incorporated
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Sponsor organisation address |
101 Redwood Shores Parkway, Redwood City, United States, 94065
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Public contact |
Medical Director, Corcept Therapeutics Incorporated, +1 650 327-3270, GRADIENTstudy@corcept.com
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Scientific contact |
Medical Director, Corcept Therapeutics Incorporated, +1 650 327-3270, GRADIENTstudy@corcept.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
19 Sep 2024
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
19 Sep 2024
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary end points of the study are 1) to assess the efficacy of relacorilant based on blood pressure control at Week 22 compared with placebo, and 2) to assess the safety of relacorilant based on adverse events. Patients will be randomized in a 1:1 ratio to treatment with relacorilant (active drug) or placebo. Patients will receive relacorilant or placebo for 22 weeks. Patients who complete the study may also be eligible to roll over into an extension study.
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Protection of trial subjects |
This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
27 Jul 2020
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Romania: 16
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Country: Number of subjects enrolled |
Spain: 13
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Country: Number of subjects enrolled |
Bulgaria: 1
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Country: Number of subjects enrolled |
Germany: 6
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Country: Number of subjects enrolled |
Italy: 20
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Country: Number of subjects enrolled |
Poland: 15
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Country: Number of subjects enrolled |
United States: 53
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Country: Number of subjects enrolled |
Israel: 9
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Country: Number of subjects enrolled |
Austria: 4
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Worldwide total number of subjects |
137
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EEA total number of subjects |
75
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
72
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From 65 to 84 years |
65
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
A total of 307 patients were screened, and 137 were enrolled. | ||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Carer | ||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Relacorilant | ||||||||||||||||||||||||||||||
Arm description |
Patients will receive relacorilant increased sequentially from 100 mg once daily to a maximum dose of 400 mg once daily. | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Relacorilant
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Investigational medicinal product code |
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Other name |
CORT125134
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Relacorilant is supplied as blister-packed capsules for oral dosing. Relacorilant 400 mg dose consists of 4 relacorilant 100-mg capsules. Relacorilant 100-mg, 200-mg, and 300-mg doses are each given as a combination of 4 capsules containing relacorilant 100-mg and placebo as per the assigned dose.
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Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Placebo is supplied as blister-packed capsules for oral dosing. Each dose consists of 4 capsules containing placebo.
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Arm title
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Placebo | ||||||||||||||||||||||||||||||
Arm description |
Patients will receive placebo matched to study drug once daily. | ||||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Placebo is supplied as blister-packed capsules for oral dosing. Each dose consists of 4 capsules containing placebo.
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Baseline characteristics reporting groups
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Reporting group title |
Relacorilant
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Reporting group description |
Patients will receive relacorilant increased sequentially from 100 mg once daily to a maximum dose of 400 mg once daily. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Patients will receive placebo matched to study drug once daily. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Relacorilant
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Reporting group description |
Patients will receive relacorilant increased sequentially from 100 mg once daily to a maximum dose of 400 mg once daily. | ||
Reporting group title |
Placebo
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Reporting group description |
Patients will receive placebo matched to study drug once daily. | ||
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End point title |
Change in Average 24-hour SBP | ||||||||||||
End point description |
Blood pressure was measured by 24-hour ABPM. The 24-hour average SBP is reported. The analysis population was patients in the ITT Population who had HTN with or without DM/IGT at Baseline.
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End point type |
Primary
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End point timeframe |
Baseline and Week 22
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Statistical analysis title |
Difference in Change in Average 24-hour SBP | ||||||||||||
Statistical analysis description |
The primary analysis will determine whether there is a difference between treatment groups in terms of change from Baseline to Week 22 in 24-hour average SBP. This was performed using a linear mixed-model-for-repeated-measures (MMRM) analysis using a placebo wash-out multiple imputation for treatment discontinuation and for patients that use rescue medication.
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Comparison groups |
Relacorilant v Placebo
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Number of subjects included in analysis |
84
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||
P-value |
= 0.416 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-2.67
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-9.096 | ||||||||||||
upper limit |
3.766 | ||||||||||||
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End point title |
Number of Patients With 1 or More Treatment-emergent Adverse Events (TEAEs) as Graded by CTCAE v5.0. [1] | |||||||||
End point description |
The analysis population was patients in the Safety Population which included all randomized patients who received at least 1 dose of study drug.
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End point type |
Primary
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End point timeframe |
Baseline and up to Week 26
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No between-group statistical analysis was planned or conducted for this end point. |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Change in Area Under the Concentration-time Curve of Blood Glucose (AUCglucose) | ||||||||||||
End point description |
AUCglucose was calculated based on results of the plasma 2-hour oGTT. The analysis population was patients in the ITT Population who had DM/IGT with or without HTN at Baseline and had an available assessment at Week 22.
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End point type |
Secondary
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End point timeframe |
Before and at time intervals up to 2 hours post glucose drink at Baseline and Week 22.
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change in Average Diastolic Blood Pressure (DBP) | |||||||||||||||||||||
End point description |
Blood pressure was measured by 24-hour ABPM. Daytime average DBP was measured from 06:00 to 21:59. Nighttime average DBP was measured from 22:00 to 05:59. The analysis population was patients in the ITT Population who had HTN with or without DM/IGT at Baseline and had an available assessment at Week 22.
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End point type |
Secondary
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End point timeframe |
Baseline and Week 22.
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| No statistical analyses for this end point | ||||||||||||||||||||||
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End point title |
Change in Average Heart Rate (HR) | |||||||||||||||||||||
End point description |
Heart rate was measured by 24-hour ABPM. Daytime average HR was measured from 06:00 to 21:59. Nighttime average HR was measured from 22:00 to 05:59. The analysis population was patients in the ITT Population who had HTN with or without DM/IGT at Baseline and had an available assessment at Week 22.
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End point type |
Secondary
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End point timeframe |
Baseline and Week 22.
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| No statistical analyses for this end point | ||||||||||||||||||||||
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End point title |
Change in Average Daytime and Nighttime SBP | ||||||||||||||||||
End point description |
Blood pressure was measured by 24-hour ABPM. Daytime average SBP was measured from 06:00 to 21:59. Nighttime average SBP was measured from 22:00 to 05:59. The analysis population was patients in the ITT Population who had HTN with or without DM/IGT at Baseline and had an available assessment at Week 22.
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End point type |
Secondary
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End point timeframe |
Baseline and Week 22
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Change in Hemoglobin HbA1c for Patients With HbA1c ≥5.7% at Baseline | ||||||||||||
End point description |
The analysis population was patients in the ITT Population who had DM/IGT with HbA1c ≥5.7% at Baseline and had an available assessment at Week 22.
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End point type |
Secondary
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End point timeframe |
Baseline and Week 22
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change in HbA1c for Patients With HbA1c ≥6.5% at Baseline | ||||||||||||
End point description |
The analysis population was patients in the ITT Population who had DM/IGT with HbA1c ≥6.5% at Baseline and had an available assessment at Week 22.
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End point type |
Secondary
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End point timeframe |
Baseline and Week 22
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of Patients With DM Who Achieved 2-hour oGTT Glucose <140 mg/dL | |||||||||
End point description |
Glucose was measured using the 2 hour timepoint of the 2-hour oGTT. The analysis population was patients in the ITT Population who had DM with or without HTN at Baseline and had an available assessment at Week 22.
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End point type |
Secondary
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End point timeframe |
2 hours post glucose drink at Week 22
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| No statistical analyses for this end point | ||||||||||
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End point title |
Number of Patients With IGT Who Achieved 2-hour oGTT Glucose <140 mg/dL | |||||||||
End point description |
Glucose was measured using the 2 hour timepoint of the 2-hour oGTT. The analysis population was patients in the ITT Population who had IGT with or without HTN at Baseline and had an available assessment at Week 22.
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End point type |
Secondary
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End point timeframe |
2 hours post glucose drink at Week 22
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| No statistical analyses for this end point | ||||||||||
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End point title |
Number of Patients With Any Dose Decrease in Antihypertensive Medication | |||||||||
End point description |
The analysis population was patients in the ITT Population who had HTN with or without DM/IGT at Baseline, received antihypertension medication both at Baseline and postbaseline, and had an available assessment at Week 22.
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End point type |
Secondary
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End point timeframe |
Baseline and Week 22
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| No statistical analyses for this end point | ||||||||||
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End point title |
Number of Patients With Any Dose Decrease in Diabetes Medication | |||||||||
End point description |
The analysis population was patients in the ITT Population who had DM/IGT at Baseline, received diabetes medication both at Baseline and postbaseline, and had an available assessment at Week 22.
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End point type |
Secondary
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End point timeframe |
Baseline and Week 22
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| No statistical analyses for this end point | ||||||||||
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End point title |
Number of Patients With Any Dose Increase or Switch in Antihypertensive Medication | |||||||||
End point description |
The analysis population was patients in the ITT Population who had HTN with or without DM/IGT at Baseline, received antihypertension medication both at Baseline and postbaseline, and had an available assessment at Week 22.
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End point type |
Secondary
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End point timeframe |
Baseline and Week 22
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| No statistical analyses for this end point | ||||||||||
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End point title |
Number of Patients With Any Dose Increase or Switch in Diabetes Medication | |||||||||
End point description |
The analysis population was patients in the ITT Population who had DM/IGT at Baseline, received diabetes medication both at Baseline and postbaseline, and had an available assessment at Week 22.
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End point type |
Secondary
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End point timeframe |
Baseline and Week 22
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| No statistical analyses for this end point | ||||||||||
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End point title |
Number of Patients With HbA1c ≥6.5% at Baseline Who Achieved HbA1c <6.5% | |||||||||
End point description |
The analysis population was patients in the ITT Population who had DM with HbA1c ≥6.5% at Baseline and had an available assessment at Week 22.
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End point type |
Secondary
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End point timeframe |
Baseline and Week 22
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| No statistical analyses for this end point | ||||||||||
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End point title |
Number of Patients With Normalization of the 24-hour Average SBP (<130 mm Hg) | |||||||||
End point description |
Blood pressure was measured by 24-hour ABPM Test. Reported is the number of patients with HTN at Baseline who achieved SBP <130 mm Hg at Week 22. The analysis population was patients in the ITT Population who had HTN with or without DM/IGT at Baseline.
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End point type |
Secondary
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End point timeframe |
Baseline and Week 22
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| No statistical analyses for this end point | ||||||||||
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End point title |
Number of Patients With a Reduction in 24-hour Average SBP by ≥5 mm Hg | |||||||||
End point description |
Blood pressure was measured by 24-hour ABPM. Reported is the number of patients with HTN at Baseline who achieved at least a 5 mm Hg reduction in 24-hour average SBP at Week 22. The analysis population was patients in the ITT Population who had HTN with or without DM/IGT at Baseline.
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End point type |
Secondary
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End point timeframe |
Baseline and Week 22
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| No statistical analyses for this end point | ||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Up to Week 26
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
26.0
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Reporting groups
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Reporting group title |
Relacorilant
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Reporting group description |
Patients will receive relacorilant increased sequentially from 100 mg once daily to a maximum dose of 400 mg once daily. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Patients will receive placebo matched to study drug once daily. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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06 Aug 2021 |
1. Revised the conditions under which dose escalation based on tolerability and improvement in hyperglycemia and/or hypertension will occur. 2. Provided conditions for study procedures due to COVID-19 restrictions. 3. Secondary end points for patients with systolic hypertension were added. 4. Exploratory efficacy end points of insulin resistance indices and hyperglucagonemia were added. 5. Added exclusion criteria to exclude candidates who have DM Type 1 or require inhaled glucocorticoid use and have no alternative option or have a history of cyclic Cushing syndrome with fluctuating clinical manifestations or have used mitotane prior to Baseline. |
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21 Jun 2023 |
1. Food effects study data was updated. 2. Secondary and exploratory objectives and end points were revised. 3. Assessment of PK was moved from a secondary to exploratory objective to align with the unchanged placement of PK as an exploratory end point. 4. Reference to mean SBP was revised to average SBP based on 24-hour ABPM for clarity, including primary and secondary end points and inclusion criterion #5 and exclusion criterion #1. 5. Reference to mean DBP was revised to average DBP based on 24-hour ABPM for clarity, including secondary end points and exclusion criterion #1. 6. Removed assessment of clinical benefit as a determinant for inclusion in the extension study. Investigators cannot be expected to assess clinical benefit while blinded. 7. Added unit for glomerular filtration rate to exclusion criterion #5, which was inadvertently omitted and updated section number for exclusion criterion #18. 8. Typo for dose escalation was corrected (“AND” to “OR”). 9. Conditions for use of rescue antidiabetic and antihypertensive concomitant medications were revised for accuracy. 9. Conditions for use of rescue antidiabetic and antihypertensive concomitant medication were revised. 10. Visit windows were revised for clarity, and procedures for visit assessments during dose escalation and maintenance phase were added. 11. Procedures for collection, documentation, and reporting of AEs and SAEs were revised for clarity. 12. The statistical section was revised for alignment with the statistical analysis plan, including analysis of primary, secondary, and exploratory end points. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| One protocol amendment occurred after the end of trial date and included updates to primary and secondary end points and statistical analyses. This amendment is not included in the Substantial Protocol Amendments (Globally). | |||
