CompletedNCT03315338Updated May 24, 2019

First-in-human Study in Healthy Subjects

A Phase 1 interventional study of CORT118335, 25 mg and Prednisone Oral Tablet in Healthy, sponsored by Corcept Therapeutics. Completed at 1 site in United Kingdom. Open to participants aged 18 Years to 60 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2019-05-24.

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

Phase: Phase 1
Study type: Interventional
Enrollment: 143
Allocation: Randomized
Ages: 18 Years to 60 Years
Sex: All

Study summary

This initial Phase I study will evaluate the safety, tolerability, and pharmacokinetics (PK) of single and multiple ascending doses of CORT118335, the effect of concomitant administration with food on exposure to CORT118335, and its pharmacological effect in healthy subjects.

Read the detailed description

This is a 5-part, single-center study of single and multiple ascending doses of CORT118335 in healthy subjects.

Parts I and 4 of the study are double-blind, randomized, placebo-controlled assessments of single-ascending doses (SAD) of CORT118335. Subjects will be enrolled sequentially into 1 of up 8 cohorts (Part 1, Cohorts A to D [Cohorts E to G have been cancelled]; Part 4, Cohorts A to D), each containing 8 subjects. Within each cohort, 6 subjects will be randomly assigned to receive a single dose of CORT118335 and 2 subjects will be randomly assigned to receive a single dose of matching placebo.

Part 2 Cohort A, food-effect, will be an open-label 2-way crossover study in one cohort of 12 subjects, randomized in a 1:1 ratio to receive a single dose of CORT118335 once after an overnight fast and once after a high-fat breakfast or the alternate sequence, over 2 study periods separated by a washout of at least 7 days/5 half-lives.

Part 2 Cohort B, PD cohort, will be a double-blind, randomized, placebo-controlled, 3-way cross-over study and will serve as proof of pharmacological effect (GR modulation) for CORT118335. Subjects will be randomized in a 1:1:1 ratio to receive placebo, and two dose levels of CORT118335 in one of three treatment sequences across 3 study periods separated by washouts of at least 7 days/5 half-lives. On each occasion, the ability of CORT118335 to ameliorate the pharmacological effects of a single dose of prednisone will be measured.

Parts 3 and 5 are double-blind, randomized, placebo-controlled assessments of multiple oral ascending doses of CORT118335. Subjects will be enrolled sequentially into 1 of up to 4 cohorts (Part 1 Cohort A [Cohorts B to D have been cancelled; Part 5 Cohorts A to C), each containing 12 subjects. Within each cohort, 9 subjects will be randomly assigned to receive CORT118335 and 3 subjects to receive matching placebo daily for 14 days.

Different formulations of CORT118335 will be used in Parts 1, 2 and 3, and in Parts 4 and 5.

Conditions studied

Healthy

Who can participate

Ages eligible: 18 Years to 60 Years
Sexes eligible: All
Accepts healthy volunteers: Yes

Inclusion criteria

Healthy male subjects or non-pregnant, non-lactating healthy female subjects of non-childbearing potential
Age 18 to 60 years
Body mass index (BMI) of 18.0 to 30.0 kg/m2
Weight of ≤102 kg
Must be willing and able to communicate and participate in the whole study
Morning serum cortisol of 5 μg/dL to 23 μg/dL (138 nmol/L to 635 nmol/L) at screening and/or Day -1 for multiple dose cohorts
Must provide written informed consent
Must agree to use an adequate method of contraception
Must agree to adhere to study restrictions

Exclusion criteria

Exclusion Criteria:

Subjects who have received any IMP in a clinical research study within the 3 months before the first dose in this study
Subjects who are study site or Sponsor employees, or immediate family members of a study site or Sponsor employee
Subjects who have previously been enrolled in this study
Males who have a pregnant partner
History of any drug or alcohol abuse in the year before the first dose in this study
Regular alcohol consumption in male subjects >21 units per week and female subjects >14 units per week (1 unit = ½ pint beer, 25 mL of 40% spirit or a 125 mL glass of wine)
Current smokers and those who have smoked within the 6 months before the first dose in this study. A breath carbon monoxide reading of greater than 10 ppm at screening or on admission
Current users of e-cigarettes and nicotine replacement products and those who have used these products within the 6 months before the first dose in this study
Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the Investigator at screening
Clinically significant abnormal biochemistry, hematology or urinalysis as judged by the Investigator
Positive drugs of abuse test result at screening or on admission (amphetamines, barbiturates, benzodiazepines, cocaine, marijuana/cannabis, methadone, methamphetamine/ecstasy, morphine/opiates, phencyclidine, tricyclic antidepressants)
Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) results
Subject has active renal and/or hepatic disease, as evidenced by:
- an estimated glomerular filtration rate (eGFR) of \<60 mL/min/1.73m2 using Modification of Diet in Renal Disease (MDRD) equation at screening
- ALT and/or AST >1.5 times the upper limit of normal at screening or on admission
- subjects with borderline results can have these tests repeated once.
History of clinically significant cardiovascular, renal, hepatic, endocrine, metabolic, respiratory, gastrointestinal or neurological disease as judged by the Investigator
Subject had any form of cancer within the 2 years before first dose in this study*, with the exception of basal cell and/or squamous cell cancer of the skin that has been treated completely and is without evidence of local recurrence or metastasis
Subject has a history and/or symptoms of adrenal insufficiency
Subject has consumed liquorice or other glycyrrhetic acid derivatives regularly, in the judgement of the Investigator, in the 6 months before the first dose of study medication
Subject has a history of jaundice and/or subject has had a cholecystectomy
Subject has a history of clinically significant gastrointestinal disease including gastroesophageal reflux disease, malabsorption syndrome, colon cancer, chronic colitis, Crohn's disease, inflammatory bowel disease, gastroparesis, constipation, chronic diarrhoea, obstruction, gastrointestinal bleeding, and/or peptic ulcers
Subject has a condition that could be aggravated by glucocorticoid and/or mineralocorticoid blockade (e.g., asthma, any chronic inflammatory condition) or activation (e.g., 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
Subjects with a QTcF interval of >450 msec at screening or pre-dose, based on the mean of three ECGs
History of additional risk factors for torsades de pointes (e.g., heart failure, hypokalaemia, family history of long QT syndrome)
Supine heart rate at rest of \<40 bpm or >100 bpm. BP out with the following ranges: diastolic BP 40-90; systolic BP 90-140 (subjects aged 18-45 year) and 90-160 (subjects aged >45 year). Heart rate and blood pressure can be retested twice in the supine position at intervals of 5 min on a given day at screening and admission.
Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients including glucose/fructose intolerance for the standard oral glucose tolerance test (OGTT)
Presence or history of clinically significant allergy requiring treatment, as judged by the Investigator.
Donation or loss of greater than 400 mL of blood within the 3 months before first study dose
Subjects who are taking, or have taken, any prescribed, over-the-counter drug (other than 4 g per day paracetamol) or herbal remedies within 14 days, or for which 5 times the medication's elimination half-life will not be completed if longer, before the first dose of study medication. Exceptions may apply on a case by case basis, if considered not to interfere with the objectives of the study, as agreed by the Investigator and Sponsor's medical monitor. Standard dose multivitamins are permitted throughout the study period
Subjects who are currently using glucocorticoids or have a history of systemic glucocorticoid use at any dose within the last 12 months or 3 months for inhaled products
Subjects who are taking, or have taken enzyme inducers within 30 days before the first dose of study medication
Subject is expected to require use of any medication (with the exception of standard dose multivitamins) during the study period
Subject has a history or presence of any medical condition or disease which, in the opinion of the Investigator, could interfere with the conduct of the study or could put the subject at unacceptable risk. This specifically includes any subject with flu or flu-like symptoms
Failure to satisfy the Investigator of fitness to participate for any other reason

Study design

Phase: Phase 1
Primary purpose: Basic science
Allocation: Randomized
Intervention model: Parallel assignment
Masking: Triple (Participant, Care provider, Investigator)
Enrollment: 143 participants (actual)

Study arms

Experimental
SAD Part 1 Active Cohort A
CORT118335, 25 mg
Drug: CORT118335, 25 mg
Placebo comparator
SAD Part 1 Placebo oral capsule Cohort A
Drug: Placebo oral capsule
Experimental
SAD Part 1 Active Cohort B
CORT118335, 75mg
Drug: CORT118335, 75mg
Placebo comparator
SAD Part 1 Placebo Cohort B
Drug: Placebo oral capsule
Experimental
SAD Part 1 Active Cohort C
CORT118335, 225mg
Drug: CORT118335, 225mg
Placebo comparator
SAD Part 1 Placebo Cohort C
Drug: Placebo oral capsule
Experimental
SAD Part 1 Active Cohort D
CORT118335, 675mg
Drug: CORT118335, 675mg
Placebo comparator
SAD Part 1 Placebo Cohort D
Drug: Placebo oral capsule
Experimental
SAD Part 2 Active Cohort A, Fasting
CORT118335, 600mg, is supplied as capsules for oral dosing given after an overnight fast
Drug: CORT118335, 600mg
Experimental
SAD Part 2 Active Cohort A, Fed
CORT118335, 600mg, is supplied as capsules for oral dosing given after a high-fat breakfast
Drug: CORT118335, 600mg
Placebo comparator
SAD Part 2 Placebo PD Effect Cohort B
Drug: Prednisone Oral Tablet · Drug: Glucose · Drug: Placebo oral capsule
Experimental
SAD Part 2 Active PD Effect Cohort B: 630mg of CORT118335
Drug: Prednisone Oral Tablet · Drug: Glucose · Drug: CORT118335, 630mg
Experimental
SAD Part 2 Active PD Effect Cohort B: 675mg of CORT118335
Drug: Prednisone Oral Tablet · Drug: Glucose · Drug: CORT118335, 675mg
Experimental
MAD Part 3 Active Cohort A
CORT118335, 375mg qd for 14 days
Drug: CORT118335, 375mg
Placebo comparator
MAD Part 3 Placebo Cohort A
Placebo qd for 14 days
Drug: Placebo oral capsule
Experimental
SAD Part 4 Active Cohort A
CORT118335, 100mg
Drug: CORT118335, 100mg
Placebo comparator
SAD Part 4 Placebo Cohort A
Drug: Placebo oral suspension
Experimental
SAD Part 4 Active Cohort B
CORT118335, 300mg
Drug: CORT118335, 300mg
Placebo comparator
SAD Part 4 Placebo Cohort B
Drug: Placebo oral suspension
Experimental
SAD Part 4 Active Cohort C, Fasting
CORT118335, 900mg is supplied as suspension for oral dosing given after an overnight fast
Drug: CORT118335, 900mg
Experimental
SAD Part 4 Active Cohort C, Fed
CORT118335, 900mg is supplied as suspension for oral dosing given after a high-fat breakfast
Drug: CORT118335, 900mg
Placebo comparator
SAD Part 4 Placebo Cohort C, Fasting
Supplied as suspension for oral dosing given after an overnight fast
Drug: Placebo oral suspension
Placebo comparator
SAD Part 4 Placebo Cohort C, Fed
Supplied as suspension for oral dosing given after a high-fat breakfast
Drug: Placebo oral suspension
Experimental
SAD Part 4 Active Cohort Part D
CORT118335, 1500mg
Drug: CORT118335, 1500mg
Placebo comparator
SAD Part 4 Placebo Cohort D
Drug: Placebo oral suspension
Experimental
MAD Part 5 Active Cohort A
CORT118335, 150mg
Drug: CORT118335, 150mg
Placebo comparator
MAD Part 5 Placebo Cohort A
Drug: Placebo oral suspension
Experimental
MAD Part 5 Active Cohort B
CORT118335, dose to be determined
Drug: CORT118335, dose to be determined
Placebo comparator
MAD Part 5 Placebo Cohort B
Drug: Placebo oral suspension
Experimental
MAD Part 5 Active Cohort C
CORT118335, dose to be determined
Drug: CORT118335, dose to be determined
Placebo comparator
MAD Part 5 Placebo Cohort C
Drug: Placebo oral suspension

Interventions

DrugCORT118335, 25 mg
CORT118335 is supplied as capsules for oral dosing
DrugPrednisone Oral Tablet
Challenge Agent, Dose and Route of Administration: Standard release 1x20mg and 1x5mg (25mg total) dose, orally administered.
DrugGlucose
75 g in 300 mL solution, orally administered
DrugPlacebo oral suspension
Reference Therapy, Dose and Route of Administration: Placebo suspension, orally administered.
DrugCORT118335, 75mg
CORT118335 is supplied as capsules for oral dosing
DrugCORT118335, 225mg
CORT118335 is supplied as capsules for oral dosing
DrugCORT118335, 675mg
CORT118335 is supplied as capsules for oral dosing
DrugCORT118335, 600mg
CORT118335 is supplied as capsules for oral dosing
DrugCORT118335, 630mg
CORT118335 is supplied as capsules for oral dosing
DrugCORT118335, 375mg
CORT118335 is supplied as capsules for oral dosing
DrugCORT118335, 100mg
CORT118335 is supplied as a suspension for oral dosing
DrugCORT118335, 300mg
CORT118335 is supplied as a suspension for oral dosing
DrugCORT118335, 900mg
CORT118335 is supplied as a suspension for oral dosing
DrugCORT118335, 150mg
CORT118335 is supplied as a suspension for oral dosing
DrugCORT118335, 1500mg
CORT118335 is supplied as a suspension for oral dosing
DrugPlacebo oral capsule
Placebo capsules, orally administered
DrugCORT118335, dose to be determined
CORT118335 is supplied as suspension for oral dosing

What researchers measure

Primary outcomes

Adverse Events (AEs)
Time frame: SAD Cohorts: Day -28 to Day 7; Part 2A Cohorts: Day -28 to Day 14; Part 2B Cohorts: Day -28 to Day 21; MAD Cohorts: Day -28 to Day 21

Secondary outcomes

QT interval corrected for heart rate using Fridericia's formula (QTcF) exposure-response analysis
Time frame: SAD parts: Pre dose through 24 hours post dose. MAD parts: Pre first dose through 24 hours post final dose of Investigational Medicinal Product (IMP
tlag Pharmacokinetic (PK) parameter
The elapsed time from dosing at which analyte was first quantifiable in a concentration vs time profile (tlag)
Time frame: SAD parts: Pre dose through 96 hours post dose; MAD parts: Pre first dose through 96 hours post final dose of IMP
tmax PK parameter
The time from dosing at which Cmax was apparent (tmax)
Time frame: SAD parts: Pre dose through 96 hours post dose; MAD parts: Pre first dose through 96 hours post final dose of IMP
Cmax PK parameter
Maximum observed concentration (Cmax)
Time frame: SAD parts: Pre dose through 96 hours post dose; MAD parts: Pre first dose through 96 hours post final dose of IMP
tmin (MAD only) PK parameter
Time from dosing of the minimum plasma drug concentration (tmin)
Time frame: MAD parts: Pre first dose through 96 hours post final dose of IMP
Cmin (MAD only) PK parameter
Minimum plasma drug concentration (Cmin)
Time frame: MAD parts: Pre first dose through 96 hours post final dose of IMP
Clast PK parameter
Last measurable concentration (Clast)
Time frame: SAD parts: Pre dose through 96 hours post dose; MAD parts: Pre first dose through 96 hours post final dose of IMP
tlast PK parameter
Time from dosing of the last measurable concentration (tlast)
Time frame: SAD parts: Pre dose through 96 hours post dose; MAD parts: Pre first dose through 96 hours post final dose of IMP
t1/2 PK parameter
The apparent elimination half-life (t1/2)
Time frame: SAD parts: Pre dose through 96 hours post dose; MAD parts: Pre first dose through 96 hours post final dose of IMP
lambda-z PK parameter
The slope of the apparent elimination phase (lambda-z)
Time frame: SAD parts: Pre dose through 96 hours post dose; MAD parts: Pre first dose through 96 hours post final dose of IMP
AUCinf PK parameter
Area under the plasma concentration-time curve from time zero to infinity (AUCinf)
Time frame: SAD parts: Pre dose through 96h post dose; MAD parts: Pre first dose through 96h post final dose of IMP
AUC(0-last) PK parameter
Area under the curve from 0 time to last measurable concentration \[AUC(0-last)\]
Time frame: SAD parts: Pre dose through 96 hours post dose; MAD parts: Pre first dose through 96 hours post final dose of IMP
AUC(0-24) PK parameter
Area under the curve from 0 time to 24 h post dose \[AUC(0-24)\]
Time frame: SAD parts: Pre dose through 24 hours post dose; MAD parts: Pre first dose through 24 hours post final dose of IMP
Food effect: AUC(0-last) PK parameter
Time frame: Pre first dose through 96 hours post final dose
Food effect: AUC(0-inf) PK parameter
Area under the curve from 0 time extrapolated to infinity \[AUC(0-inf)\]
Time frame: Pre first dose through 96 hours post final dose
Food effect: Cmax PK parameter
Time frame: Pre first dose through 96 hours post final dose
Pharmacodynamics (PD): peripheral differential white blood cell count
Time frame: Pre first dose through 24 hours post final dose
PD: serum osteocalcin and adiponectin concentrations
Time frame: Pre first dose through 24 hours post final dose
PD: messenger ribonucleic acid (mRNA) expression for selected genes in whole blood
Time frame: Pre first dose through 24 hours post final dose
PD: glucose tolerance
Time frame: Pre first dose through 24 hours post final dose
Homeostatic model assessment of insulin-resistance (HOMA-IR)
Time frame: Pre-dose through Day 14

Study locations

1 site

Quotient Clinical
Nottingham, Nottinghamshire NG11 6JS, United Kingdom

References and documents

Individual participant data

Plan to share: Undecided

No publications or documents are linked to this record.

Registry details

Key details

Study ID: NCT03315338
Lead sponsor: Corcept Therapeutics
Responsible party: Sponsor
First posted: Oct 20, 2017
Start date: Sep 15, 2017
Primary completion: Feb 22, 2019
Completion: Feb 22, 2019
Last update: May 24, 2019

Study contacts

Stuart Mair, MBChB, MFPM

principal investigator · Quotient Clinical

Oversight

Data monitoring committee: No
FDA-regulated drug: No
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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