A Double-blind, Randomised, Placebo-controlled Study of the Safety, Tolerability, Pharmacokinetics (PK), and Pharmacodynamics (PD) of SAD and MAD of CORT125281 in Healthy Subjects
Overview
- Phase
- Phase 1
- Intervention
- Placebo oral capsule, fasted
- Conditions
- Healthy
- Sponsor
- Corcept Therapeutics
- Enrollment
- 48
- Locations
- 1
- Primary Endpoint
- Adverse Events (AEs)
- Status
- Completed
- Last Updated
- 7 years ago
Overview
Brief Summary
This initial Phase I study will evaluate the dose-related safety and tolerability pharmacokinetics (PK) of CORT125281, and CORT125324 (active metabolite), and pharmacodynamics (PD) after single and multiple ascending oral doses of CORT125281 in healthy subjects.
Detailed Description
Separate single-and multiple-ascending dose (SAD and MAD) parts will be conducted. Throughout each part of the study, safety, pharmacological (PD) and PK effects will be assessed. Safety and tolerability will be assessed using adverse event (AE) monitoring, measurement of vital signs, recording 12-lead electrocardiogram (ECG), physical examination and clinical laboratory safety tests. Blood samples will be collected at intervals for assay of plasma concentration of CORT125281 and CORT125324. The SAD part of the study is double-blind, randomized and placebo-controlled with respect to CORT125281. Two cohorts, each of 9 subjects, will receive three sequential single doses of the investigational medicinal product (IMP), either CORT125281 at the assigned dose level or placebo, in a partial within-subject crossover manner. The starting dose is CORT125281, 40 mg; the rules for determining later doses are detailed within the protocol. The PD effects of CORT125281 will be examined by testing its ability to ameliorate the pharmacological effects of a concomitantly administered dose of prednisone. The MAD part of the study will be double-blind, randomized, placebo-controlled and parallel-group with respect to CORT125281. Up to four cohorts of 8 subjects, randomized so that 6 receive CORT125281 and 2 receive placebo, will participate in the study, so that up to four dose levels of CORT125281 are studied in total. An exploratory assessment will be made of the effect of repeated doses of CORT125281 on exposure to pioglitazone, probe substrate for CYP2C8. Each subject will be admitted on Day-1 for baseline assessments. On Day1, subjects will receive a single oral dose of pioglitazone, 15mg. From Day3 to Day16 (14 days), subjects will be dosed daily with IMP (CORT125281 at the selected dose or placebo). On Day13, subjects will receive a second dose of pioglitazone, 15 mg.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Give written informed consent
- •If male, have undergone vasectomy, with no wish to have the procedure reversed
- •If female, using appropriate precautions to avoid pregnancy, defined as of nonchildbearing potential (ie, postmenopausal or permanently sterilised) or using highly effective contraception with low user-dependency
- •A woman is postmenopausal if it is more than 12 months since her last menstruation, without an alternative medical cause. A concentration of FSH in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy.
- •Accepted methods of permanent sterilization methods are hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
- •An IUD is the only acceptable method of highly effective contraception with low user-dependency, provided that the subject has tolerated its use for at least 3 months before the first dose of study medication and undertakes not to have it removed for 1 month after the last dose.
- •Be aged 18 to 65 years inclusive
- •Have a BMI of 19 to 30 kg/m2, inclusive
- •Be willing to comply with study restrictions as described in Section 4.6
- •Be able to comply with the requirements of the entire study
Exclusion Criteria
- •Be an employee or immediate family member of the CRU or Corcept
- •Have been previously enrolled in this study
- •Have multiple drug allergies, or be allergic to any of the components of study medication, its matching placebo, challenge agents or probe substrates (see Section 5.1)
- •Have a condition that could be aggravated by glucocorticoid blockade (eg, asthma, any chronic inflammatory condition) or activation (eg, immunodeficiency, active infection) Subjects with inactive seasonal hay fever may be included. Subjects with childhood (aged less than 18 years) asthma may be included provided they have had no symptoms and required no treatment for at least 5 years
- •In the 6 calendar months before study drug administration, on average
- •Have smoked more than 5 cigarettes/day
- •Have consumed more than 14 units (female) or 21 units (male) of alcohol/week
- •Consumed liquorice or other glycyrrhetic acid derivatives regularly, in the judgement of the Investigator
- •In the 3 calendar months before study drug administration
- •Have donated blood or plasma in excess of 400 mL
Arms & Interventions
SAD Part 2 Placebo Cohort 2 Period 4
Intervention: Placebo oral capsule, fasted
SAD Part 1 Placebo Cohort 1 Period 1
Intervention: Placebo oral capsule, fasted
SAD Part 1 Active Cohort Period 1
Intervention: CORT125281, 40mg, fasted
SAD Part 1 Placebo Cohort 1 Period 1
Intervention: Prednisone 25mg, fasted
SAD Part 1 Active Cohort Period 1
Intervention: Prednisone 25mg, fasted
SAD Part 1 Placebo Cohort 1 Period 2
Intervention: Prednisone 25mg, fasted
SAD Part 1 Placebo Cohort 1 Period 2
Intervention: Placebo oral capsule, fasted
SAD Part 1 Active Cohort 1 Period 2
Intervention: Prednisone 25mg, fasted
SAD Part 2 Placebo Cohort 2 Period 4
Intervention: Prednisone 25mg, fasted
SAD Part 1 Active Cohort 1 Period 2
Intervention: CORT125281, 120mg, fasted
SAD Part 1 Placebo Cohort 1 Period 3
Intervention: Prednisone 25mg, fasted
SAD Part 1 Placebo Cohort 1 Period 3
Intervention: Placebo oral capsule, fasted
SAD Part 1 Active Cohort 1 Period 3
Intervention: Prednisone 25mg, fasted
SAD Part 1 Active Cohort 1 Period 3
Intervention: CORT125281, 360mg, fasted
SAD Part 2 Active Cohort 2 Period 4
Intervention: Prednisone 25mg, fasted
SAD Part 2 Active Cohort 2 Period 4
Intervention: CORT125281, 720mg, fasted
SAD Part 2 Placebo Cohort 2 Period 5
Intervention: Placebo oral capsule, fed
SAD Part 2 Placebo Cohort 2 Period 5
Intervention: Prednisone 25mg, fed
SAD Part 2 Active Cohort 2 Period 5
Intervention: Prednisone 25mg, fed
SAD Part 2 Active Cohort 2 Period 5
Intervention: CORT125281, 360mg, fed
SAD Part 2 Placebo Cohort 2 Period 6
Intervention: Prednisone 25mg, fasted
SAD Part 2 Placebo Cohort 2 Period 6
Intervention: Placebo oral capsule
SAD Part 2 Active Cohort 2 Period 6
Intervention: Prednisone 25mg, fasted
SAD Part 2 Active Cohort 2 Period 6
Intervention: CORT125281, 360mg
MAD Placebo Cohort 1
Intervention: Pioglitazone 15mg Tablet
MAD Placebo Cohort 1
Intervention: Placebo oral capsule
MAD Active Cohort 1
Intervention: Pioglitazone 15mg Tablet
MAD Active Cohort 1
Intervention: CORT125281, 120mg
MAD Placebo Cohort 2
Intervention: Pioglitazone 15mg Tablet
MAD Placebo Cohort 2
Intervention: Placebo oral capsule
MAD Active Cohort 2
Intervention: Pioglitazone 15mg Tablet
MAD Active Cohort 2
Intervention: CORT125281, 180mg
MAD Placebo Cohort 3
Intervention: Pioglitazone 15mg Tablet
MAD Placebo Cohort 3
Intervention: Placebo oral capsule
MAD Active Cohort 3
Intervention: Pioglitazone 15mg Tablet
MAD Active Cohort 3
Intervention: CORT125281, 240mg
MAD Placebo Cohort 4
Intervention: Pioglitazone 15mg Tablet
MAD Placebo Cohort 4
Intervention: Placebo oral capsule
MAD Active Cohort 4
Intervention: Pioglitazone 15mg Tablet
MAD Active Cohort 4
Intervention: CORT125281, 360mg
Outcomes
Primary Outcomes
Adverse Events (AEs)
Time Frame: SAD Cohorts Day 1 to Day 14; MAD Cohorts Day 1 to Day 30
Secondary Outcomes
- AUC 0-infinity PK parameter(CORT125281/CORT125324 - SAD Cohorts Day 1 to 4; MAD Cohorts Day 3 to 19; Pioglitizone - MAD Cohort Day 1 to 15)
- AUC 0-tz PK parameter(CORT125281/CORT125324 - SAD Cohorts Day 1 to 4; MAD Cohorts Day 3 to 19; Pioglitizone - MAD Cohort Day 1 to 15)
- tlag PK parameter(SAD Cohorts Day 1 to 4; MAD Cohorts Day 3 to 19)
- apparent terminal rate constant PK parameter(SAD Cohorts Day 1 to 4; MAD Cohorts Day 3 to 19)
- MRT PK parameter(SAD Cohorts Day 1 to 4; MAD Cohorts Day 3 to 19)
- CL/F PK parameter(SAD Cohorts Day 1 to 4; MAD Cohorts Day 3 to 19)
- Cmin PK parameter(MAD Cohorts Day 3 to 19)
- Pharmacodynamics (PD) Peripheral blood neutrophil, eosinophil and lymphocyte counts(SAD Cohorts pre-dose through 24 hours post dose)
- PD Serum osteocalcin(SAD Cohorts pre-dose through 24 hours post dose)
- PD T cell profiling by flow cytometry(SAD Cohorts Day 1, pre-dose to 24 hours post dose; MAD Cohorts Day 3 to Day 10)
- Tmax PK parameter(SAD Cohorts Day 1 to 4; MAD Cohorts Day 3 to 19)
- t1/2 PK parameter(SAD Cohorts Day 1 to 4; MAD Cohorts Day 3 to 19)
- PD Pre- and postprandial blood glucose(SAD Cohorts Day 1, pre-dose to 6 hours post dose)
- PD Fasting glucose(MAD Cohorts Day 1 to Day 13)
- PD insulin(MAD Cohorts Day 1 to Day 13)
- PD Cytokines(SAD Cohorts Day 1, pre-dose to 24 hours post dose; MAD Cohorts Day 3 to Day 10)
- AUCtau Pharmacokinetic (PK) parameter(MAD Cohorts Day 3 to 19)
- Cmax PK parameter(CORT125281/CORT125324 - SAD Cohorts Day 1 to 4; MAD Cohorts Day 3 to 19; Pioglitizone - MAD Cohort Day 1 to 15)
- PD Gene expression for glucocorticoid-modulated genes(SAD Cohorts Day 1, pre-dose to 4 hours post dose)
- PD Cortisol(MAD Cohorts pre-dose to Day 16)
- PD ACTH(MAD Cohorts pre-dose to Day 16)
- PD DHEA S(MAD Cohorts Day 3 to Day 16)
- PD HOMA-IR(MAD Cohorts Day 1 to Day 13)
- Observed accumulation ratio PK parameter(MAD Cohorts Day 3 to 19)
- PD androstenedione(MAD Cohorts Day 3 to Day 16)
- Vz/F PK parameter(SAD Cohorts Day 1 to 4; MAD Cohorts Day 3 to 19)
- 4β-OH cholesterol PK parameter(MAD Cohorts Day 1 to Day 17)