CORT125134 Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the dose-related safety, tolerability, pharmacokinetics (PK) and pharmacological effects (PD) of CORT125134 and its active metabolite CORT125201 after single and multiple ascending oral doses of CORT125134 in healthy participants.

Detailed Description
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This is a 3-part, single-center study of single and multiple ascending doses of CORT125134 in healthy participants. Part I is a single dose study. Initially, participants will be enrolled sequentially into 1 of up to 6 cohorts, each containing 10 participants, in a double-blind, randomized, placebo-controlled assessment of single-ascending doses (SAD) of CORT125134. Within each cohort, 8 participants will be randomly assigned to receive a single dose of CORT125134, and 2 participants will be randomly assigned to receive a single dose of matching placebo. Thereafter, Cohort 7 will be a food-effect cohort, in which all 8 participants will receive a single dose of CORT125134 after a high-fat breakfast (open label). Cohorts 8 and 9 will be pharmacological effect cohorts, in each of which 10 participants will receive a challenge agent (prednisone, 25 mg) alone on Day -19; with an active comparator (mifepristone, 600 mg) on Day -12, and with CORT125134 on Day 1 in an open-label single sequence crossover design. Pharmacological effects will be explored by measuring effects on peripheral blood eosinophil, lymphocyte and neutrophil counts, serum osteocalcin, assay of messenger ribonucleic acid (mRNA) expression of FK506 Binding Protein 5 (FKBP5) and Glucocorticoid-induced Leucine Zipper (GILZ) in whole blood (proof of pharmacological effect Cohort 8) and by measuring effects on oral glucose tolerance (proof of concept Cohort 9). Part 2 and 3 will be double-blind, randomized, placebo-controlled assessments of multiple oral ascending doses (MAD) of CORT125134. Participants will be enrolled sequentially into 1 of up to 4 cohorts (Cohorts 10-13), each containing 12 participants. Within each cohort, 9 participants will be randomly assigned to receive CORT125134 and 3 participants to receive matching placebo daily for 14 days (Days 1-14). The effects of CORT125134 on response to prednisone challenge will be additionally explored in Cohorts 12 and 13 in a single sequence crossover, with prednisone being given alone on Day -5 and in combination with CORT125134 or placebo on Day 14. Throughout the study, routine safety tests and assessments of PK (CORT125134 and CORT125201) will be performed, and changes in serum cortisol and plasma adrenocorticotrophic hormone (ACTH) measured.

Official Title
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A Phase I Adaptive Dose, Double-Blind, Placebo-Controlled, SAD and MAD Study to Measure the Safety, Tolerability, Pharmacokinetics and Pharmacological Effects of Orally Administered CORT125134 in Healthy Subjects

Conditions
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Healthy

Intervention / Treatment
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* Drug: CORT125134
* Drug: Matching Placebo of CORT125134
* Drug: Mifepristone
* Drug: Prednisone
* Drug: Glucose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provide written informed consent Weight <= 102 kilogram (kg); body mass index (BMI) 18-30 kg/meter squared Morning serum cortisol in reference range Willing and able to communicate, participate in the whole study and to abide by study restrictions including use of contraception Exclusion Criteria: Participation in any clinical research study, received treatment with any investigational drug or device, or donated blood within the previous 3 months Has a history of alcoholism, substance abuse, or drug abuse within 1 year; positive screen for alcohol or drugs of abuse Current smokers, smoked and/or used tobacco and/or nicotine-containing products within 6 months, or positive screen for carbon monoxide Females of childbearing potential, pregnant or breastfeeding, and/or with a positive pregnancy test Has a condition that could be aggravated by glucocorticoid blockade or activation Has clinically relevant abnormal findings on vital signs, physical examination, laboratory screening tests, or 12-lead electrocardiogram (ECG) Has history of clinically significant cardiovascular, renal, hepatic, endocrine, metabolic, chronic respiratory, gastrointestinal or neurological disease Has used systemic glucocorticoids within 12 months

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SAD Cohorts 1 through 6<br>Participants will receive single doses of 5 mg up to 400 mg of CORT125134 (capsule) in a dose escalation format. The doses selected will be subject to amendment based on emerging data. | Drug: CORT125134<br>* Oral capsules<br>|
| Placebo Comparator: SAD Cohorts 1 through 6 Placebo<br>Participants will receive single doses of Matching Placebo of CORT125134 (capsule). | Drug: Matching Placebo of CORT125134<br>* Placebo<br>|
| Experimental: Food Effect Cohort 7<br>Participants will receive a single dose of CORT125134 (capsule) with a standard high fat breakfast. The dose will be chosen such that it has been previously administered in a prior SAD cohort. | Drug: CORT125134<br>* Oral capsules<br>|
| Experimental: Pharmacological Effect Cohort 8<br>Participants will receive a single dose of 25 mg of prednisone on Day -19; a single dose of 25 mg prednisone and 600 mg of mifepristone on Day -12; and a single dose of 25 mg prednisone and a single dose of CORT125134 on Day 1. The dose of CORT125134 will be chosen such that it has been previously administered in a prior SAD cohort. | Drug: CORT125134<br>* Oral capsules<br>Drug: Mifepristone<br>* Active comparator<br>Drug: Prednisone<br>* Challenge agent<br>|
| Experimental: Proof of Concept (POC) Cohort 9<br>Participants will receive a single dose of 25 mg of prednisone on Day -19; a single dose of 25 mg of prednisone and 600 mg of mifepristone on Day -12; and a single dose of 25 mg prednisone and a single dose of CORT125134 on Day 1. An oral glucose tolerance test will be administered on each study day. The dose of CORT125134 will be chosen such that it has been previously administered in a prior SAD cohort. | Drug: CORT125134<br>* Oral capsules<br>Drug: Mifepristone<br>* Active comparator<br>Drug: Prednisone<br>* Challenge agent<br>Drug: Glucose<br> <br> |
| Experimental: MAD Cohorts 10 and 11<br>Participants will receive the selected dose of CORT125134 (capsule) following receipt of data from Cohorts 1-9 up to a maximum frequency of twice a day for a total of 14 days. | Drug: CORT125134<br>* Oral capsules<br>|
| Placebo Comparator: MAD Cohorts 10 and 11 Placebo<br>Participants will receive Matching Placebo of CORT125134 (capsule) up to a maximum frequency of twice a day for a total of 14 days. | Drug: Matching Placebo of CORT125134<br>* Placebo<br>|
| Experimental: MAD of PoPE Cohorts 12 and 13<br>Proof of Pharmacological Effect (PoPE+POC). Participants will receive 25 mg of prednisone (both cohorts) and an oral glucose tolerance test (Cohort 13 only) on Day -5. Participants will then receive the selected dose of CORT125134 (capsule) for a total of 13 days. Participants may either receive a higher dose level than previously administered or a repeat of a dose level given in 1 of the previous 2 MAD Cohorts. Participants will then receive 25 mg of prednisone (both cohorts) and an oral glucose tolerance test (Cohort 13 only) on Day 14. | Drug: CORT125134<br>* Oral capsules<br>Drug: Prednisone<br>* Challenge agent<br>Drug: Glucose<br> <br> |
| Placebo Comparator: MAD of PoPE Cohort 12 and 13 Placebo<br>Participants will receive 25 mg of prednisone (both cohorts) and an oral glucose tolerance test (Cohort 13 only) on Day -5. Participants will then receive the Matching Placebo of CORT125134 (capsule) for a total of 13 days. Participants will then receive 25 mg of prednisone (both cohorts) and an oral glucose tolerance test (Cohort 13 only) on Day 14. | Drug: Matching Placebo of CORT125134<br>* Placebo<br>Drug: Prednisone<br>* Challenge agent<br>Drug: Glucose<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events (AEs) (Safety and Tolerability) of CORT125134 |  | Single dose Cohorts 1-9 Day 1 to Day 15; MAD Cohorts 10-13 Day 1 to Day 28/Day 24 (Cohort 13) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| QT internal corrected for heart rate using Fridericia's formula (QTcF) exposure-response analysis |  | SAD Cohorts 1-6: Pre dose through 24 hours post dose; MAD Cohorts: Pre first dose through 24 hours post final dose of Investigational Medicinal Product (IMP) | 
| CORT125134 Pharmacokinetic (PK) of total lag time (Tlag) |  | Single dose Cohorts Day 1 to Day 15; MAD Cohorts Day 1 to Day 28/24 (Cohort 13) | 
| CORT125134 PK of peak plasma concentration (Cmax) |  | Single dose Cohorts Day 1 to Day 15; MAD Cohorts Day 1 to Day 28/24 (Cohort 13) | 
| CORT125134 PK of time to reach maximum observed concentration (Tmax) |  | Single dose Cohorts Day 1 to Day 15; MAD Cohorts 10-12 Day 1 to Day 28/24 (Cohort 13) | 
| CORT125134 PK of area under the plasma concentration-time curve from time zero to time of last measurable concentration (AUClast) |  | Single dose Cohorts Day 1 to Day 15; MAD Cohorts Day 1 to Day 28/24 (Cohort 13) | 
| CORT125201 PK of peak plasma concentration (Cmax) |  | Single dose Cohorts Day 1 to Day 15; MAD Cohorts Day 1 to Day 28/24 (Cohort 13) | 
| CORT125201 PK time Lag (Tlag) |  | Single dose Cohorts Day 1 to Day 15; MAD Cohorts Day 1 to Day 28/24 (Cohort 13) | 
| CORT125201 PK of time to reach maximum observed concentration (Tmax) |  | Single dose Cohorts Day 1 to Day 15; MAD Cohorts Day 1 to Day 28/24 (Cohort 13) | 
| CORT125201 PK of area under the plasma concentration-time curve from time zero to time of last measurable concentration (AUClast) |  | Single dose Cohorts Day 1 to Day 15; MAD Cohorts Day 1 to Say 28/24 (Cohort 13) | 
| Eosinophil count |  | Single dose Cohort 8 Days -19 to Day 2; MAD Cohorts 12 and 13 Days -5 to Day 15 | 
| Lymphocyte count |  | Single dose Cohort 8 Days -19 to Day 2; MAD Cohorts 12 and 13 Days -5 to Day 15 | 
| Neutrophil count |  | Single dose Cohort 8 Days -19 to Day 2; MAD Cohorts 12 and 13 Days -5 to Day 15 | 
| Osteocalcin |  | Single dose Cohort 8 Days -19 to Day 2; MAD Cohorts 12 and 13 Days -5 to Day 15 | 
| FKBP5 expression |  | Single dose Cohort 8 Days -19 to Day 2; MAD Cohorts 12 and 13 Days -5 to Day 15 | 
| Glucocorticoid-induced leucine zipper (GILZ) expression |  | Single dose Cohort 8 Days -19 to Day 2; MAD Cohorts 12 and 13 Days -5 to Day 15 | 
| Glucose tolerance |  | Single dose Cohort 9 Days -19 to Day 2; MAD Cohort 13 Days -5 to Day 15 | 
| Serum cortisol |  | SAD Cohorts 1-6: Pre dose to Day 15; MAD Cohorts 10-11: Pre dose to Day 28 | 
| Plasma adrenocorticotrophic hormone (ACTH) |  | SAD Cohorts 1-6: Pre dose to Day 15; MAD Cohorts 10-11: Pre dose to Day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glucocorticoid receptor; antagonist