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CompletedNCT03335956Updated Jul 26, 2018

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

A Phase 1 interventional study of CORT125281, 40mg, fasted and Prednisone 25mg, fasted in Healthy, sponsored by Corcept Therapeutics. Completed at 1 site in United Kingdom. Open to participants aged 18 Years to 65 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2018-07-26.

Sponsored by Corcept Therapeutics · Phase 1, Interventional, and Basic science

Phase
Phase 1
Study type
Interventional
Enrollment
48
Allocation
Randomized
Ages
18 Years to 65 Years
Sex
All
01

Study 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.

Read the 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.

02

Conditions studied

  • Healthy

Keywords

  • Glucocorticoid receptor; antagonist
03

Who can participate

Ages eligible
18 Years to 65 Years
Sexes eligible
All
Accepts healthy volunteers
Yes

Inclusion criteria

  1. Give written informed consent
  2. If male, have undergone vasectomy, with no wish to have the procedure reversed

  3. 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.
  4. Be aged 18 to 65 years inclusive
  5. Have a BMI of 19 to 30 kg/m2, inclusive
  6. Be willing to comply with study restrictions as described in Section 4.6
  7. Be able to comply with the requirements of the entire study
  8. 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
  9. For multiple dose cohorts, have a morning serum cortisol within the local reference range at screening and/or Day -1
  10. Have suitable veins for multiple venepunctures/cannulation
  11. Be able to swallow size 0 capsules whole

Exclusion criteria

Exclusion Criteria:

  1. Be an employee or immediate family member of the CRU or Corcept
  2. Have been previously enrolled in this study
  3. 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)
  4. 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

  5. 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

  6. 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
  7. Have a positive test for alcohol, smoking or drugs of abuse at screening or admission to any of the dosing sessions

  8. 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.
  9. Have any medical or social reasons for not participating in the study raised by their General Practitioner/primary care physician
  10. 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
  11. Taken any prohibited prior medication, as described in Section 4.6.3
04

Study design

Phase
Phase 1
Primary purpose
Basic science
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Triple (Participant, Care provider, Investigator)
Enrollment
48 participants (actual)

Study arms

  • Placebo comparator
    SAD Part 1 Placebo Cohort 1 Period 1

    Drug: Prednisone 25mg, fasted · Drug: Placebo oral capsule, fasted

  • Experimental
    SAD Part 1 Active Cohort Period 1

    Drug: CORT125281, 40mg, fasted · Drug: Prednisone 25mg, fasted

  • Placebo comparator
    SAD Part 1 Placebo Cohort 1 Period 2

    Drug: Prednisone 25mg, fasted · Drug: Placebo oral capsule, fasted

  • Experimental
    SAD Part 1 Active Cohort 1 Period 2

    Drug: Prednisone 25mg, fasted · Drug: CORT125281, 120mg, fasted

  • Placebo comparator
    SAD Part 1 Placebo Cohort 1 Period 3

    Drug: Prednisone 25mg, fasted · Drug: Placebo oral capsule, fasted

  • Experimental
    SAD Part 1 Active Cohort 1 Period 3

    Drug: Prednisone 25mg, fasted · Drug: CORT125281, 360mg, fasted

  • Placebo comparator
    SAD Part 2 Placebo Cohort 2 Period 4

    Drug: Prednisone 25mg, fasted · Drug: Placebo oral capsule, fasted

  • Experimental
    SAD Part 2 Active Cohort 2 Period 4

    Drug: Prednisone 25mg, fasted · Drug: CORT125281, 720mg, fasted

  • Placebo comparator
    SAD Part 2 Placebo Cohort 2 Period 5

    Drug: Placebo oral capsule, fed · Drug: Prednisone 25mg, fed

  • Experimental
    SAD Part 2 Active Cohort 2 Period 5

    Drug: Prednisone 25mg, fed · Drug: CORT125281, 360mg, fed

  • Placebo comparator
    SAD Part 2 Placebo Cohort 2 Period 6

    Drug: Prednisone 25mg, fasted · Drug: Placebo oral capsule

  • Experimental
    SAD Part 2 Active Cohort 2 Period 6

    Drug: Prednisone 25mg, fasted · Drug: CORT125281, 360mg

  • Placebo comparator
    MAD Placebo Cohort 1

    Drug: Pioglitazone 15mg Tablet · Drug: Placebo oral capsule

  • Experimental
    MAD Active Cohort 1

    Drug: Pioglitazone 15mg Tablet · Drug: CORT125281, 120mg

  • Placebo comparator
    MAD Placebo Cohort 2

    Drug: Pioglitazone 15mg Tablet · Drug: Placebo oral capsule

  • Experimental
    MAD Active Cohort 2

    Drug: Pioglitazone 15mg Tablet · Drug: CORT125281, 180mg

  • Placebo comparator
    MAD Placebo Cohort 3

    Drug: Pioglitazone 15mg Tablet · Drug: Placebo oral capsule

  • Experimental
    MAD Active Cohort 3

    Drug: Pioglitazone 15mg Tablet · Drug: CORT125281, 240mg

  • Placebo comparator
    MAD Placebo Cohort 4

    Drug: Pioglitazone 15mg Tablet · Drug: Placebo oral capsule

  • Experimental
    MAD Active Cohort 4

    Drug: Pioglitazone 15mg Tablet · Drug: CORT125281, 360mg

Interventions

  • DrugCORT125281, 40mg, fasted

    CORT125281 is supplied as capsules for oral dosing

  • DrugPrednisone 25mg, fasted

    Challenge Agent, Dose and Route of Administration: Standard release 25 mg tablets, orally administered

  • DrugPlacebo oral capsule, fasted

    Reference Therapy, Dose and Route of Administration: Placebo capsule, orally administered

  • DrugPioglitazone 15mg Tablet

    Probe Substrate, Dose and Route of Administration: 15 Mg tablet, orally administered

  • DrugPlacebo oral capsule, fed

    Reference Therapy, Dose and Route of Administration: Placebo capsule, orally administered

  • DrugPrednisone 25mg, fed

    Challenge Agent, Dose and Route of Administration: Standard release 25 mg tablets, orally administered

  • DrugCORT125281, 120mg, fasted

    CORT125281 is supplied as capsules for oral dosing

  • DrugCORT125281, 360mg, fasted

    CORT125281 is supplied as capsules for oral dosing

  • DrugCORT125281, 720mg, fasted

    CORT125281 is supplied as capsules for oral dosing

  • DrugCORT125281, 360mg, fed

    CORT125281 is supplied as capsules for oral dosing

  • DrugCORT125281, 360mg

    CORT125281 is supplied as capsules for oral dosing twice, 12 hours apart, fasted (morning) and after evening meal

  • DrugCORT125281, 120mg

    CORT125281 is supplied as capsules for oral dosing once daily

  • DrugCORT125281, 180mg

    CORT125281 is supplied as capsules for oral dosing twice daily

  • DrugCORT125281, 240mg

    CORT125281 is supplied as capsules for oral dosing twice daily

  • DrugCORT125281, 360mg

    CORT125281 is supplied as capsules for oral dosing once daily

  • DrugPlacebo oral capsule

    Reference Therapy, Dose and Route of Administration: Placebo capsule, orally administered twice, 12 hours apart, fasted (morning) and after evening meal

  • DrugPlacebo oral capsule

    Reference Therapy, Dose and Route of Administration: Placebo capsule, orally administered, twice daily

  • DrugPlacebo oral capsule

    Reference Therapy, Dose and Route of Administration: Placebo capsule, orally administered, once daily

05

What researchers measure

Primary outcomes

  1. Adverse Events (AEs)

    Time frame: SAD Cohorts Day 1 to Day 14; MAD Cohorts Day 1 to Day 30

Secondary outcomes

  1. AUCtau Pharmacokinetic (PK) parameter

    Area under the curve over a dose-interval (AUCtau)

    Time frame: MAD Cohorts Day 3 to 19

  2. AUC 0-tz PK parameter

    Area under the curve from the time of dosing until the last quantifiable concentration (AUC 0-tz)

    Time frame: CORT125281/CORT125324 - SAD Cohorts Day 1 to 4; MAD Cohorts Day 3 to 19; Pioglitizone - MAD Cohort Day 1 to 15

  3. AUC 0-infinity PK parameter

    Area under the curve from the time of dosing extrapolated to infinity (AUC 0-infinity)

    Time frame: CORT125281/CORT125324 - SAD Cohorts Day 1 to 4; MAD Cohorts Day 3 to 19; Pioglitizone - MAD Cohort Day 1 to 15

  4. Cmax PK parameter

    Maximum concentration (Cmax)

    Time frame: CORT125281/CORT125324 - SAD Cohorts Day 1 to 4; MAD Cohorts Day 3 to 19; Pioglitizone - MAD Cohort Day 1 to 15

  5. Cmin PK parameter

    Minimum concentration within a dose interval (Cmin)

    Time frame: MAD Cohorts Day 3 to 19

  6. Tmax PK parameter

    Time to maximum concentration (Tmax)

    Time frame: SAD Cohorts Day 1 to 4; MAD Cohorts Day 3 to 19

  7. tlag PK parameter

    Latest time after dosing before the first quantifiable concentration (tlag)

    Time frame: SAD Cohorts Day 1 to 4; MAD Cohorts Day 3 to 19

  8. apparent terminal rate constant PK parameter

    Time frame: SAD Cohorts Day 1 to 4; MAD Cohorts Day 3 to 19

  9. t1/2 PK parameter

    Apparent terminal elimination half-life (t1/2)

    Time frame: SAD Cohorts Day 1 to 4; MAD Cohorts Day 3 to 19

  10. MRT PK parameter

    Mean residence time (MRT)

    Time frame: SAD Cohorts Day 1 to 4; MAD Cohorts Day 3 to 19

  11. Vz/F PK parameter

    Apparent oral volume of distribution during the terminal elimination phase (Vz/F)

    Time frame: SAD Cohorts Day 1 to 4; MAD Cohorts Day 3 to 19

  12. CL/F PK parameter

    Apparent oral clearance (CL/F)

    Time frame: SAD Cohorts Day 1 to 4; MAD Cohorts Day 3 to 19

  13. Observed accumulation ratio PK parameter

    Time frame: MAD Cohorts Day 3 to 19

  14. 4β-OH cholesterol PK parameter

    4β-Hydroxycholesterol (4β-OH)

    Time frame: MAD Cohorts Day 1 to Day 17

  15. Pharmacodynamics (PD) Peripheral blood neutrophil, eosinophil and lymphocyte counts

    Time frame: SAD Cohorts pre-dose through 24 hours post dose

  16. PD Serum osteocalcin

    Time frame: SAD Cohorts pre-dose through 24 hours post dose

  17. PD Pre- and postprandial blood glucose

    Time frame: SAD Cohorts Day 1, pre-dose to 6 hours post dose

  18. PD Cytokines

    Time frame: SAD Cohorts Day 1, pre-dose to 24 hours post dose; MAD Cohorts Day 3 to Day 10

  19. PD T cell profiling by flow cytometry

    Time frame: SAD Cohorts Day 1, pre-dose to 24 hours post dose; MAD Cohorts Day 3 to Day 10

  20. PD Gene expression for glucocorticoid-modulated genes

    Time frame: SAD Cohorts Day 1, pre-dose to 4 hours post dose

  21. PD Cortisol

    Time frame: MAD Cohorts pre-dose to Day 16

  22. PD ACTH

    Adrenocorticotropic hormone (ACTH)

    Time frame: MAD Cohorts pre-dose to Day 16

  23. PD DHEA S

    Dehydroepiandrosterone sulphate (DHEA-S)

    Time frame: MAD Cohorts Day 3 to Day 16

  24. PD androstenedione

    Time frame: MAD Cohorts Day 3 to Day 16

  25. PD Fasting glucose

    Time frame: MAD Cohorts Day 1 to Day 13

  26. PD insulin

    Time frame: MAD Cohorts Day 1 to Day 13

  27. PD HOMA-IR

    Homeostatic model assessment of insulin-resistance (HOMA-IR)

    Time frame: MAD Cohorts Day 1 to Day 13

06

Study locations

1 site
  • Hammersmith Medicines Research
    London, United Kingdom
07

References and documents

Individual participant data

Plan to share: Undecided

No publications or documents are linked to this record.

08

Registry details

Key details

Study ID
NCT03335956
Lead sponsor
Corcept Therapeutics
Responsible party
Sponsor
First posted
Nov 8, 2017
Start date
Sep 21, 2017
Primary completion
May 31, 2018
Completion
Jun 25, 2018
Last update
Jul 26, 2018

Study contacts

Stacie Shepherd, M.D., Ph.D.
study director · Corcept Therapeutics

Oversight

Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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