- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03315338
First-in-human Study in Healthy Subjects
A Phase I Adaptive Dose, Double-blind, Placebo-controlled, Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacological Effects of Orally Administered CORT118335 in Healthy Subjects
Study Overview
Status
Conditions
Intervention / Treatment
- Drug: CORT118335, 25 mg
- Drug: Placebo oral capsule
- Drug: CORT118335, 75mg
- Drug: CORT118335, 225mg
- Drug: CORT118335, 675mg
- Drug: CORT118335, 600mg
- Drug: Prednisone Oral Tablet
- Drug: Glucose
- Drug: CORT118335, 630mg
- Drug: CORT118335, 375mg
- Drug: CORT118335, 100mg
- Drug: Placebo oral suspension
- Drug: CORT118335, 300mg
- Drug: CORT118335, 900mg
- Drug: CORT118335, 1500mg
- Drug: CORT118335, 150mg
- Drug: CORT118335, dose to be determined
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.
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
-
-
Nottinghamshire
-
Nottingham, Nottinghamshire, United Kingdom, NG11 6JS
- Quotient Clinical
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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:
- 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 Plan
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Triple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: SAD Part 1 Active Cohort A
CORT118335, 25 mg
|
CORT118335 is supplied as capsules for oral dosing
|
Placebo Comparator: SAD Part 1 Placebo oral capsule Cohort A
|
Placebo capsules, orally administered
|
Experimental: SAD Part 1 Active Cohort B
CORT118335, 75mg
|
CORT118335 is supplied as capsules for oral dosing
|
Placebo Comparator: SAD Part 1 Placebo Cohort B
|
Placebo capsules, orally administered
|
Experimental: SAD Part 1 Active Cohort C
CORT118335, 225mg
|
CORT118335 is supplied as capsules for oral dosing
|
Placebo Comparator: SAD Part 1 Placebo Cohort C
|
Placebo capsules, orally administered
|
Experimental: SAD Part 1 Active Cohort D
CORT118335, 675mg
|
CORT118335 is supplied as capsules for oral dosing
|
Placebo Comparator: SAD Part 1 Placebo Cohort D
|
Placebo capsules, orally administered
|
Experimental: SAD Part 2 Active Cohort A, Fasting
CORT118335, 600mg, is supplied as capsules for oral dosing given after an overnight fast
|
CORT118335 is supplied as capsules for oral dosing
|
Experimental: SAD Part 2 Active Cohort A, Fed
CORT118335, 600mg, is supplied as capsules for oral dosing given after a high-fat breakfast
|
CORT118335 is supplied as capsules for oral dosing
|
Placebo Comparator: SAD Part 2 Placebo PD Effect Cohort B
|
Placebo capsules, orally administered
Challenge Agent, Dose and Route of Administration: Standard release 1x20mg and 1x5mg (25mg total) dose, orally administered.
75 g in 300 mL solution, orally administered
|
Experimental: SAD Part 2 Active PD Effect Cohort B: 630mg of CORT118335
|
Challenge Agent, Dose and Route of Administration: Standard release 1x20mg and 1x5mg (25mg total) dose, orally administered.
75 g in 300 mL solution, orally administered
CORT118335 is supplied as capsules for oral dosing
|
Experimental: SAD Part 2 Active PD Effect Cohort B: 675mg of CORT118335
|
CORT118335 is supplied as capsules for oral dosing
Challenge Agent, Dose and Route of Administration: Standard release 1x20mg and 1x5mg (25mg total) dose, orally administered.
75 g in 300 mL solution, orally administered
|
Experimental: MAD Part 3 Active Cohort A
CORT118335, 375mg qd for 14 days
|
CORT118335 is supplied as capsules for oral dosing
|
Placebo Comparator: MAD Part 3 Placebo Cohort A
Placebo qd for 14 days
|
Placebo capsules, orally administered
|
Experimental: SAD Part 4 Active Cohort A
CORT118335, 100mg
|
CORT118335 is supplied as a suspension for oral dosing
|
Placebo Comparator: SAD Part 4 Placebo Cohort A
|
Reference Therapy, Dose and Route of Administration: Placebo suspension, orally administered. |
Experimental: SAD Part 4 Active Cohort B
CORT118335, 300mg
|
CORT118335 is supplied as a suspension for oral dosing
|
Placebo Comparator: SAD Part 4 Placebo Cohort B
|
Reference Therapy, Dose and Route of Administration: Placebo suspension, orally administered. |
Experimental: SAD Part 4 Active Cohort C, Fasting
CORT118335, 900mg is supplied as suspension for oral dosing given after an overnight fast
|
CORT118335 is supplied as a suspension for oral dosing
|
Experimental: SAD Part 4 Active Cohort C, Fed
CORT118335, 900mg is supplied as suspension for oral dosing given after a high-fat breakfast
|
CORT118335 is supplied as a suspension for oral dosing
|
Placebo Comparator: SAD Part 4 Placebo Cohort C, Fasting
Supplied as suspension for oral dosing given after an overnight fast
|
Reference Therapy, Dose and Route of Administration: Placebo suspension, orally administered. |
Placebo Comparator: SAD Part 4 Placebo Cohort C, Fed
Supplied as suspension for oral dosing given after a high-fat breakfast
|
Reference Therapy, Dose and Route of Administration: Placebo suspension, orally administered. |
Experimental: SAD Part 4 Active Cohort Part D
CORT118335, 1500mg
|
CORT118335 is supplied as a suspension for oral dosing
|
Placebo Comparator: SAD Part 4 Placebo Cohort D
|
Reference Therapy, Dose and Route of Administration: Placebo suspension, orally administered. |
Experimental: MAD Part 5 Active Cohort A
CORT118335, 150mg
|
CORT118335 is supplied as a suspension for oral dosing
|
Placebo Comparator: MAD Part 5 Placebo Cohort A
|
Reference Therapy, Dose and Route of Administration: Placebo suspension, orally administered. |
Experimental: MAD Part 5 Active Cohort B
CORT118335, dose to be determined
|
CORT118335 is supplied as suspension for oral dosing
|
Placebo Comparator: MAD Part 5 Placebo Cohort B
|
Reference Therapy, Dose and Route of Administration: Placebo suspension, orally administered. |
Experimental: MAD Part 5 Active Cohort C
CORT118335, dose to be determined
|
CORT118335 is supplied as suspension for oral dosing
|
Placebo Comparator: MAD Part 5 Placebo Cohort C
|
Reference Therapy, Dose and Route of Administration: Placebo suspension, orally administered. |
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
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
|
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 Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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
|
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
Time Frame: SAD parts: Pre dose through 96 hours post dose; MAD parts: Pre first dose through 96 hours post final dose of IMP
|
The elapsed time from dosing at which analyte was first quantifiable in a concentration vs time profile (tlag)
|
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
Time Frame: SAD parts: Pre dose through 96 hours post dose; MAD parts: Pre first dose through 96 hours post final dose of IMP
|
The time from dosing at which Cmax was apparent (tmax)
|
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
Time Frame: SAD parts: Pre dose through 96 hours post dose; MAD parts: Pre first dose through 96 hours post final dose of IMP
|
Maximum observed concentration (Cmax)
|
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 Frame: MAD parts: Pre first dose through 96 hours post final dose of IMP
|
Time from dosing of the minimum plasma drug concentration (tmin)
|
MAD parts: Pre first dose through 96 hours post final dose of IMP
|
Cmin (MAD only) PK parameter
Time Frame: MAD parts: Pre first dose through 96 hours post final dose of IMP
|
Minimum plasma drug concentration (Cmin)
|
MAD parts: Pre first dose through 96 hours post final dose of IMP
|
Clast PK parameter
Time Frame: SAD parts: Pre dose through 96 hours post dose; MAD parts: Pre first dose through 96 hours post final dose of IMP
|
Last measurable concentration (Clast)
|
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 Frame: SAD parts: Pre dose through 96 hours post dose; MAD parts: Pre first dose through 96 hours post final dose of IMP
|
Time from dosing of the last measurable concentration (tlast)
|
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
Time Frame: SAD parts: Pre dose through 96 hours post dose; MAD parts: Pre first dose through 96 hours post final dose of IMP
|
The apparent elimination half-life (t1/2)
|
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
Time Frame: SAD parts: Pre dose through 96 hours post dose; MAD parts: Pre first dose through 96 hours post final dose of IMP
|
The slope of the apparent elimination phase (lambda-z)
|
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
Time Frame: SAD parts: Pre dose through 96h post dose; MAD parts: Pre first dose through 96h post final dose of IMP
|
Area under the plasma concentration-time curve from time zero to infinity (AUCinf)
|
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
Time Frame: SAD parts: Pre dose through 96 hours post dose; MAD parts: Pre first dose through 96 hours post final dose of IMP
|
Area under the curve from 0 time to last measurable concentration [AUC(0-last)]
|
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
Time Frame: SAD parts: Pre dose through 24 hours post dose; MAD parts: Pre first dose through 24 hours post final dose of IMP
|
Area under the curve from 0 time to 24 h post dose [AUC(0-24)]
|
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
|
Pre first dose through 96 hours post final dose
|
|
Food effect: AUC(0-inf) PK parameter
Time Frame: Pre first dose through 96 hours post final dose
|
Area under the curve from 0 time extrapolated to infinity [AUC(0-inf)]
|
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
|
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
|
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
|
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
|
Pre first dose through 24 hours post final dose
|
|
PD: glucose tolerance
Time Frame: Pre first dose through 24 hours post final dose
|
Pre first dose through 24 hours post final dose
|
|
Homeostatic model assessment of insulin-resistance (HOMA-IR)
Time Frame: Pre-dose through Day 14
|
Pre-dose through Day 14
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Stuart Mair, MBChB, MFPM, Quotient Clinical
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- CORT118335-850
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Healthy
-
Prevent Age Resort "Pervaya Liniya"RecruitingHealthy Aging | Healthy Diet | Healthy LifestyleRussian Federation
-
Maastricht University Medical CenterCompletedHealthy Volunteers | Healthy Subjects | Healthy AdultsNetherlands
-
Yale UniversityNot yet recruitingHealth-related Benefits of Introducing Table Olives Into the Diet of Young Adults: Olives For HealthHealthy Diet | Healthy Lifestyle | Healthy Nutrition | CholesterolUnited States
-
Hasselt UniversityRecruitingHealthy | Healthy AgingBelgium
-
Galera Therapeutics, Inc.Syneos HealthCompleted
-
Galera Therapeutics, Inc.Syneos HealthCompletedHealthy | Healthy VolunteersAustralia
-
University of PennsylvaniaActive, not recruitingHealthy | Healthy AgingUnited States
-
Chalmers University of TechnologyGöteborg UniversityCompletedHealthy | Nutrition, HealthySweden
-
University of ManitobaNot yet recruitingHealthy | Healthy Diet
Clinical Trials on CORT118335, 25 mg
-
Corcept TherapeuticsRecruitingNon-alcoholic Steatohepatitis (NASH)United States
-
Corcept TherapeuticsRecruitingNonalcoholic Steatohepatitis (NASH)United States
-
Corcept TherapeuticsCompletedHealthyUnited Kingdom
-
Zydus Lifesciences LimitedRecruitingAmyotrophic Lateral SclerosisIndia
-
Corcept TherapeuticsCompleted
-
ViiV HealthcareGlaxoSmithKline; Janssen PharmaceuticalsCompletedInfection, Human Immunodeficiency VirusUnited States
-
Idorsia Pharmaceuticals Ltd.CompletedHepatic ImpairmentSwitzerland
-
Idorsia Pharmaceuticals Ltd.Completed
-
Repros Therapeutics Inc.Completed