CORT125281 Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD)

Sponsor

Corcept Therapeutics (Industry)

Overall Status

Completed

CT.gov ID

NCT03335956

Collaborator

(none)

Enrollment

Location

Arms

9.1

Actual Duration (Months)

5.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: CORT125281, 40mg, fasted Drug: Prednisone 25mg, fasted Drug: Placebo oral capsule, fasted Drug: Pioglitazone 15mg Tablet Drug: Placebo oral capsule, fed Drug: Prednisone 25mg, fed Drug: CORT125281, 120mg, fasted Drug: CORT125281, 360mg, fasted Drug: CORT125281, 720mg, fasted Drug: CORT125281, 360mg, fed Drug: CORT125281, 360mg Drug: CORT125281, 120mg Drug: CORT125281, 180mg Drug: CORT125281, 240mg Drug: CORT125281, 360mg Drug: Placebo oral capsule Drug: Placebo oral capsule Drug: Placebo oral capsule	Phase 1

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

48 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Basic Science

Official Title:

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

Actual Study Start Date :

Sep 21, 2017

Actual Primary Completion Date :

May 31, 2018

Actual Study Completion Date :

Jun 25, 2018

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: SAD Part 1 Placebo Cohort 1 Period 1	Drug: Prednisone 25mg, fasted Challenge Agent, Dose and Route of Administration: Standard release 25 mg tablets, orally administered Drug: Placebo oral capsule, fasted Reference Therapy, Dose and Route of Administration: Placebo capsule, orally administered
Experimental: SAD Part 1 Active Cohort Period 1	Drug: CORT125281, 40mg, fasted CORT125281 is supplied as capsules for oral dosing Drug: Prednisone 25mg, fasted Challenge Agent, Dose and Route of Administration: Standard release 25 mg tablets, orally administered
Placebo Comparator: SAD Part 1 Placebo Cohort 1 Period 2	Drug: Prednisone 25mg, fasted Challenge Agent, Dose and Route of Administration: Standard release 25 mg tablets, orally administered Drug: Placebo oral capsule, fasted Reference Therapy, Dose and Route of Administration: Placebo capsule, orally administered
Experimental: SAD Part 1 Active Cohort 1 Period 2	Drug: Prednisone 25mg, fasted Challenge Agent, Dose and Route of Administration: Standard release 25 mg tablets, orally administered Drug: CORT125281, 120mg, fasted CORT125281 is supplied as capsules for oral dosing
Placebo Comparator: SAD Part 1 Placebo Cohort 1 Period 3	Drug: Prednisone 25mg, fasted Challenge Agent, Dose and Route of Administration: Standard release 25 mg tablets, orally administered Drug: Placebo oral capsule, fasted Reference Therapy, Dose and Route of Administration: Placebo capsule, orally administered
Experimental: SAD Part 1 Active Cohort 1 Period 3	Drug: Prednisone 25mg, fasted Challenge Agent, Dose and Route of Administration: Standard release 25 mg tablets, orally administered Drug: CORT125281, 360mg, fasted CORT125281 is supplied as capsules for oral dosing
Placebo Comparator: SAD Part 2 Placebo Cohort 2 Period 4	Drug: Prednisone 25mg, fasted Challenge Agent, Dose and Route of Administration: Standard release 25 mg tablets, orally administered Drug: Placebo oral capsule, fasted Reference Therapy, Dose and Route of Administration: Placebo capsule, orally administered
Experimental: SAD Part 2 Active Cohort 2 Period 4	Drug: Prednisone 25mg, fasted Challenge Agent, Dose and Route of Administration: Standard release 25 mg tablets, orally administered Drug: CORT125281, 720mg, fasted CORT125281 is supplied as capsules for oral dosing
Placebo Comparator: SAD Part 2 Placebo Cohort 2 Period 5	Drug: Placebo oral capsule, fed Reference Therapy, Dose and Route of Administration: Placebo capsule, orally administered Drug: Prednisone 25mg, fed Challenge Agent, Dose and Route of Administration: Standard release 25 mg tablets, orally administered
Experimental: SAD Part 2 Active Cohort 2 Period 5	Drug: Prednisone 25mg, fed Challenge Agent, Dose and Route of Administration: Standard release 25 mg tablets, orally administered Drug: CORT125281, 360mg, fed CORT125281 is supplied as capsules for oral dosing
Placebo Comparator: SAD Part 2 Placebo Cohort 2 Period 6	Drug: Prednisone 25mg, fasted Challenge Agent, Dose and Route of Administration: Standard release 25 mg tablets, orally administered Drug: Placebo oral capsule Reference Therapy, Dose and Route of Administration: Placebo capsule, orally administered twice, 12 hours apart, fasted (morning) and after evening meal
Experimental: SAD Part 2 Active Cohort 2 Period 6	Drug: Prednisone 25mg, fasted Challenge Agent, Dose and Route of Administration: Standard release 25 mg tablets, orally administered Drug: CORT125281, 360mg CORT125281 is supplied as capsules for oral dosing twice, 12 hours apart, fasted (morning) and after evening meal
Placebo Comparator: MAD Placebo Cohort 1	Drug: Pioglitazone 15mg Tablet Probe Substrate, Dose and Route of Administration: 15 Mg tablet, orally administered Drug: Placebo oral capsule Reference Therapy, Dose and Route of Administration: Placebo capsule, orally administered, once daily
Experimental: MAD Active Cohort 1	Drug: Pioglitazone 15mg Tablet Probe Substrate, Dose and Route of Administration: 15 Mg tablet, orally administered Drug: CORT125281, 120mg CORT125281 is supplied as capsules for oral dosing once daily
Placebo Comparator: MAD Placebo Cohort 2	Drug: Pioglitazone 15mg Tablet Probe Substrate, Dose and Route of Administration: 15 Mg tablet, orally administered Drug: Placebo oral capsule Reference Therapy, Dose and Route of Administration: Placebo capsule, orally administered, twice daily
Experimental: MAD Active Cohort 2	Drug: Pioglitazone 15mg Tablet Probe Substrate, Dose and Route of Administration: 15 Mg tablet, orally administered Drug: CORT125281, 180mg CORT125281 is supplied as capsules for oral dosing twice daily
Placebo Comparator: MAD Placebo Cohort 3	Drug: Pioglitazone 15mg Tablet Probe Substrate, Dose and Route of Administration: 15 Mg tablet, orally administered Drug: Placebo oral capsule Reference Therapy, Dose and Route of Administration: Placebo capsule, orally administered, twice daily
Experimental: MAD Active Cohort 3	Drug: Pioglitazone 15mg Tablet Probe Substrate, Dose and Route of Administration: 15 Mg tablet, orally administered Drug: CORT125281, 240mg CORT125281 is supplied as capsules for oral dosing twice daily
Placebo Comparator: MAD Placebo Cohort 4	Drug: Pioglitazone 15mg Tablet Probe Substrate, Dose and Route of Administration: 15 Mg tablet, orally administered Drug: Placebo oral capsule Reference Therapy, Dose and Route of Administration: Placebo capsule, orally administered, once daily
Experimental: MAD Active Cohort 4	Drug: Pioglitazone 15mg Tablet Probe Substrate, Dose and Route of Administration: 15 Mg tablet, orally administered Drug: CORT125281, 360mg CORT125281 is supplied as capsules for oral dosing once daily

Outcome Measures

Primary Outcome Measures

Adverse Events (AEs) [SAD Cohorts Day 1 to Day 14; MAD Cohorts Day 1 to Day 30]

Secondary Outcome Measures

AUCtau Pharmacokinetic (PK) parameter [MAD Cohorts Day 3 to 19]
Area under the curve over a dose-interval (AUCtau)
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]
Area under the curve from the time of dosing until the last quantifiable concentration (AUC 0-tz)
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]
Area under the curve from the time of dosing extrapolated to infinity (AUC 0-infinity)
Cmax PK parameter [CORT125281/CORT125324 - SAD Cohorts Day 1 to 4; MAD Cohorts Day 3 to 19; Pioglitizone - MAD Cohort Day 1 to 15]
Maximum concentration (Cmax)
Cmin PK parameter [MAD Cohorts Day 3 to 19]
Minimum concentration within a dose interval (Cmin)
Tmax PK parameter [SAD Cohorts Day 1 to 4; MAD Cohorts Day 3 to 19]
Time to maximum concentration (Tmax)
tlag PK parameter [SAD Cohorts Day 1 to 4; MAD Cohorts Day 3 to 19]
Latest time after dosing before the first quantifiable concentration (tlag)
apparent terminal rate constant 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]
Apparent terminal elimination half-life (t1/2)
MRT PK parameter [SAD Cohorts Day 1 to 4; MAD Cohorts Day 3 to 19]
Mean residence time (MRT)
Vz/F PK parameter [SAD Cohorts Day 1 to 4; MAD Cohorts Day 3 to 19]
Apparent oral volume of distribution during the terminal elimination phase (Vz/F)
CL/F PK parameter [SAD Cohorts Day 1 to 4; MAD Cohorts Day 3 to 19]
Apparent oral clearance (CL/F)
Observed accumulation ratio PK parameter [MAD Cohorts Day 3 to 19]
4β-OH cholesterol PK parameter [MAD Cohorts Day 1 to Day 17]
4β-Hydroxycholesterol (4β-OH)
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 Pre- and postprandial blood glucose [SAD Cohorts Day 1, pre-dose to 6 hours post dose]
PD Cytokines [SAD Cohorts Day 1, pre-dose to 24 hours post dose; MAD Cohorts Day 3 to Day 10]
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]
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]
Adrenocorticotropic hormone (ACTH)
PD DHEA S [MAD Cohorts Day 3 to Day 16]
Dehydroepiandrosterone sulphate (DHEA-S)
PD androstenedione [MAD Cohorts Day 3 to Day 16]
PD Fasting glucose [MAD Cohorts Day 1 to Day 13]
PD insulin [MAD Cohorts Day 1 to Day 13]
PD HOMA-IR [MAD Cohorts Day 1 to Day 13]
Homeostatic model assessment of insulin-resistance (HOMA-IR)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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
Be judged to be in good health, based upon the results of a medical history, physical examination, vital signs, 12-lead ECG, and clinical laboratory findings
For multiple dose cohorts, have a morning serum cortisol within the local reference range at screening and/or Day -1
Have suitable veins for multiple venepunctures/cannulation
Be able to swallow size 0 capsules whole

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
Have participated in another clinical trial of a new chemical entity or a prescription medicine

Have a positive test for alcohol, smoking or drugs of abuse at screening or admission to any of the dosing sessions
Have clinically-relevant abnormal findings on vital signs, physical examination, laboratory screening tests, or 12-lead ECG, at screen and/or before first dose, including but not limited to:

Abnormal ECG waveform morphology that would preclude accurate measurement of the QT interval
QTcF >450 ms (from mean of 3 supine ECGs, performed at least 2 minutes apart)
Stage 2 or higher hypertension (supine/semi-recumbent systolic blood pressure [SBP] >160 mmHg; diastolic blood pressure [DBP] >100 mmHg, based on mean of duplicate values recorded at least 2 minutes apart)
Stage 1 hypertension (supine/semi-recumbent SBP 140-160 mmHg; DBP 90-100 mmHg, based on mean of duplicate values recorded at least 2 minutes apart) associated with indication for treatment ie, evidence of end-organ damage, diabetes or a 10 year cardiovascular risk, estimated using a standard calculator eg, QRisk2 2016

20%

Glomerular filtration rate, estimated using the chronic kidney disease epidemiology (collaboration) (CKD-EPI) method (eGFR; see Section 6.2.5) <60 mL/minute/1.73 m2
Hypokalaemia (potassium below lower limit of normal)
ALT, AST and/or gammaglutamyl transferase (GGT) >1.5 times the upper limit of normal
Seropositive for hepatitis B, hepatitis C or human immunodeficiency viruses.

Have any medical or social reasons for not participating in the study raised by their General Practitioner/primary care physician
Have any other condition that might increase the risk to the individual or decrease the chance of obtaining satisfactory data, as assessed by the Investigator
Taken any prohibited prior medication, as described in Section 4.6.3

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hammersmith Medicines Research	London		United Kingdom

Sponsors and Collaborators

Corcept Therapeutics

Investigators

Study Director: Stacie Shepherd, M.D., Ph.D., Corcept Therapeutics

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Corcept Therapeutics

ClinicalTrials.gov Identifier:

NCT03335956

Other Study ID Numbers:

CORT125281-600

First Posted:

Nov 8, 2017

Last Update Posted:

Jul 26, 2018

Last Verified:

Jul 1, 2018

Individual Participant Data (IPD) Sharing Statement:

Undecided

Plan to Share IPD:

Undecided

Studies a U.S. FDA-regulated Drug Product:

Studies a U.S. FDA-regulated Device Product:

Keywords provided by Corcept Therapeutics

Glucocorticoid receptor; antagonist

Additional relevant MeSH terms:

Pioglitazone

Prednisone

Cortisone

Study Results

No Results Posted as of Jul 26, 2018