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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03335956
Recruitment Status : Completed
First Posted : November 8, 2017
Last Update Posted : July 26, 2018
Sponsor:
Information provided by (Responsible Party):
Corcept Therapeutics

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: 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.

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Study Type : Interventional  (Clinical Trial)
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 : September 21, 2017
Actual Primary Completion Date : May 31, 2018
Actual Study Completion Date : June 25, 2018

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




Primary Outcome Measures :
  1. Adverse Events (AEs) [ Time Frame: SAD Cohorts Day 1 to Day 14; MAD Cohorts Day 1 to Day 30 ]

Secondary Outcome Measures :
  1. AUCtau Pharmacokinetic (PK) parameter [ Time Frame: MAD Cohorts Day 3 to 19 ]
    Area under the curve over a dose-interval (AUCtau)

  2. AUC 0-tz PK parameter [ Time Frame: 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)

  3. AUC 0-infinity PK parameter [ Time Frame: 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)

  4. Cmax PK parameter [ Time Frame: CORT125281/CORT125324 - SAD Cohorts Day 1 to 4; MAD Cohorts Day 3 to 19; Pioglitizone - MAD Cohort Day 1 to 15 ]
    Maximum concentration (Cmax)

  5. Cmin PK parameter [ Time Frame: MAD Cohorts Day 3 to 19 ]
    Minimum concentration within a dose interval (Cmin)

  6. Tmax PK parameter [ Time Frame: SAD Cohorts Day 1 to 4; MAD Cohorts Day 3 to 19 ]
    Time to maximum concentration (Tmax)

  7. tlag PK parameter [ Time Frame: SAD Cohorts Day 1 to 4; MAD Cohorts Day 3 to 19 ]
    Latest time after dosing before the first quantifiable concentration (tlag)

  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 [ Time Frame: SAD Cohorts Day 1 to 4; MAD Cohorts Day 3 to 19 ]
    Apparent terminal elimination half-life (t1/2)

  10. MRT PK parameter [ Time Frame: SAD Cohorts Day 1 to 4; MAD Cohorts Day 3 to 19 ]
    Mean residence time (MRT)

  11. Vz/F PK parameter [ Time Frame: SAD Cohorts Day 1 to 4; MAD Cohorts Day 3 to 19 ]
    Apparent oral volume of distribution during the terminal elimination phase (Vz/F)

  12. CL/F PK parameter [ Time Frame: SAD Cohorts Day 1 to 4; MAD Cohorts Day 3 to 19 ]
    Apparent oral clearance (CL/F)

  13. Observed accumulation ratio PK parameter [ Time Frame: MAD Cohorts Day 3 to 19 ]
  14. 4β-OH cholesterol PK parameter [ Time Frame: MAD Cohorts Day 1 to Day 17 ]
    4β-Hydroxycholesterol (4β-OH)

  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 [ Time Frame: MAD Cohorts pre-dose to Day 16 ]
    Adrenocorticotropic hormone (ACTH)

  23. PD DHEA S [ Time Frame: MAD Cohorts Day 3 to Day 16 ]
    Dehydroepiandrosterone sulphate (DHEA-S)

  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 [ Time Frame: MAD Cohorts Day 1 to Day 13 ]
    Homeostatic model assessment of insulin-resistance (HOMA-IR)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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:

  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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03335956


Locations
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United Kingdom
Hammersmith Medicines Research
London, United Kingdom
Sponsors and Collaborators
Corcept Therapeutics
Investigators
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Study Director: Stacie Shepherd, M.D., Ph.D. Corcept Therapeutics
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Responsible Party: Corcept Therapeutics
ClinicalTrials.gov Identifier: NCT03335956    
Other Study ID Numbers: CORT125281-600
First Posted: November 8, 2017    Key Record Dates
Last Update Posted: July 26, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Corcept Therapeutics:
Glucocorticoid receptor; antagonist
Additional relevant MeSH terms:
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Pioglitazone
Prednisone
Cortisone
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Hypoglycemic Agents