Clinical trial NCT03508635: CORT125134 Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Keywords: Glucocorticoid receptor; antagonist
Lead sponsor: Corcept Therapeutics
Sponsor class: INDUSTRY
First posted: 2018-04-26
Enrollment: 130
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Incidence of Treatment-Emergent Adverse Events (AEs) (Safety and Tolerability) of CORT125134
timeFrame: Single dose Cohorts 1-9 Day 1 to Day 15; MAD Cohorts 10-13 Day 1 to Day 28/Day 24 (Cohort 13)
Secondary outcomes:
measure: QT internal corrected for heart rate using Fridericia's formula (QTcF) exposure-response analysis
timeFrame: 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)
measure: CORT125134 Pharmacokinetic (PK) of total lag time (Tlag)
timeFrame: Single dose Cohorts Day 1 to Day 15; MAD Cohorts Day 1 to Day 28/24 (Cohort 13)
measure: CORT125134 PK of peak plasma concentration (Cmax)
timeFrame: Single dose Cohorts Day 1 to Day 15; MAD Cohorts Day 1 to Day 28/24 (Cohort 13)
measure: CORT125134 PK of time to reach maximum observed concentration (Tmax)
timeFrame: Single dose Cohorts Day 1 to Day 15; MAD Cohorts 10-12 Day 1 to Day 28/24 (Cohort 13)
measure: CORT125134 PK of area under the plasma concentration-time curve from time zero to time of last measurable concentration (AUClast)
timeFrame: Single dose Cohorts Day 1 to Day 15; MAD Cohorts Day 1 to Day 28/24 (Cohort 13)
measure: CORT125201 PK of peak plasma concentration (Cmax)
timeFrame: Single dose Cohorts Day 1 to Day 15; MAD Cohorts Day 1 to Day 28/24 (Cohort 13)
measure: CORT125201 PK time Lag (Tlag)
timeFrame: Single dose Cohorts Day 1 to Day 15; MAD Cohorts Day 1 to Day 28/24 (Cohort 13)
measure: CORT125201 PK of time to reach maximum observed concentration (Tmax)
timeFrame: Single dose Cohorts Day 1 to Day 15; MAD Cohorts Day 1 to Day 28/24 (Cohort 13)
measure: CORT125201 PK of area under the plasma concentration-time curve from time zero to time of last measurable concentration (AUClast)
timeFrame: Single dose Cohorts Day 1 to Day 15; MAD Cohorts Day 1 to Say 28/24 (Cohort 13)
measure: Eosinophil count
timeFrame: Single dose Cohort 8 Days -19 to Day 2; MAD Cohorts 12 and 13 Days -5 to Day 15
measure: Lymphocyte count
timeFrame: Single dose Cohort 8 Days -19 to Day 2; MAD Cohorts 12 and 13 Days -5 to Day 15
measure: Neutrophil count
timeFrame: Single dose Cohort 8 Days -19 to Day 2; MAD Cohorts 12 and 13 Days -5 to Day 15
measure: Osteocalcin
timeFrame: Single dose Cohort 8 Days -19 to Day 2; MAD Cohorts 12 and 13 Days -5 to Day 15
measure: FKBP5 expression
timeFrame: Single dose Cohort 8 Days -19 to Day 2; MAD Cohorts 12 and 13 Days -5 to Day 15
measure: Glucocorticoid-induced leucine zipper (GILZ) expression
timeFrame: Single dose Cohort 8 Days -19 to Day 2; MAD Cohorts 12 and 13 Days -5 to Day 15
measure: Glucose tolerance
timeFrame: Single dose Cohort 9 Days -19 to Day 2; MAD Cohort 13 Days -5 to Day 15
measure: Serum cortisol
timeFrame: SAD Cohorts 1-6: Pre dose to Day 15; MAD Cohorts 10-11: Pre dose to Day 28
measure: Plasma adrenocorticotrophic hormone (ACTH)
timeFrame: SAD Cohorts 1-6: Pre dose to Day 15; MAD Cohorts 10-11: Pre dose to Day 28
Other outcomes:
Locations:
city: Nottingham
country: United Kingdom
facility: Quotient Clinical
state: Nottinghamshire
Study officials:
affiliation: Quotient Clinical
name: Pui Leung
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hunt H, Donaldson K, Strem M, Zann V, Leung P, Sweet S, Connor A, Combs D, Belanoff J. Assessment of Safety, Tolerability, Pharmacokinetics, and Pharmacological Effect of Orally Administered CORT125134: An Adaptive, Double-Blind, Randomized, Placebo-Controlled Phase 1 Clinical Study. Clin Pharmacol Drug Dev. 2018 May;7(4):408-421. doi: 10.1002/cpdd.389. Epub 2017 Oct 2.