A Study to Investigate the Effects of Cortexolone 17α-propionate (and Its Metabolites) on Healthy Volunteers' Heart

NCT03665194 | Completed Phase 1

• 1 other identifier: CB-03-01/33
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

Brief Summary

This is a randomised, double blind placebo controlled Phase I study which will assess the safety, tolerability and PK of Cortexolone 17α-propionate (and its metabolites), and its effects on the QTc interval when administered as multiple doses to healthy adult volunteers. Volunteers will receive a morning and evening dose (12 hours apart) of 225 mg (3 mL Cortexolone 17α-propionate applied topically as a 7.5 % solution (75 mg in 1 mL), giving a total daily dose of 450 mg (6 mL) per individual.

Conditions

Healthy Volunteers

Keywords

QT/QTc Interval

Outcome Measures

Primary Outcomes (12)

• PK parameters of Cortexolone 17α-propionate and the two main metabolites Cortexolone 21-propionate (M1) and Cortexolone (M2)

  Cmax: Maximum observed plasma concentration Days 1 and 4

  Samples will be collected 1hour pre IMP administration and at 2, 3, 4, 5, 6, 7, 8, 9, 10,12 hours post IMP administration on Day1 and Day4. Further samples will be collected at 24 hours (Day 5) and 48 hours (Day 6) after the final dose on Day 4.

• PK parameters of Cortexolone 17α-propionate and the two main metabolites Cortexolone 21-propionate (M1) and Cortexolone (M2)

  tmax: Time of maximum observed plasma concentration

  Samples will be collected 1hour pre IMP administration and at 2, 3, 4, 5, 6, 7, 8, 9, 10,12 hours post IMP administration on Day1 and Day4. Further samples will be collected at 24 hours (Day 5) and 48 hours (Day 6) after the final dose on Day 4.

• PK parameters of Cortexolone 17α-propionate and the two main metabolites Cortexolone 21-propionate (M1) and Cortexolone (M2)

  t½: Apparent plasma terminal elimination half-life

  Samples will be collected 1hour pre IMP administration and at 2, 3, 4, 5, 6, 7, 8, 9, 10,12 hours post IMP administration on Day1 and Day4. Further samples will be collected at 24 hours (Day 5) and 48 hours (Day 6) after the final dose on Day 4.

• PK parameters of Cortexolone 17α-propionate and the two main metabolites Cortexolone 21-propionate (M1) and Cortexolone (M2)

  AUC0-24h: Area under the plasma concentration-time curve from time zero to 24 hours, calculated by the linear/log trapezoidal rule

  Samples will be collected 1hour pre IMP administration and at 2, 3, 4, 5, 6, 7, 8, 9, 10,12 hours post IMP administration on Day1 and Day4. Further samples will be collected at 24 hours (Day 5) and 48 hours (Day 6) after the final dose on Day 4.

• PK parameters of Cortexolone 17α-propionate and the two main metabolites Cortexolone 21-propionate (M1) and Cortexolone (M2)

  AUC0-t: Area under the plasma concentration-time curve from time zero up to the last quantifiable concentration

  Samples will be collected 1hour pre IMP administration and at 2, 3, 4, 5, 6, 7, 8, 9, 10,12 hours post IMP administration on Day1 and Day4. Further samples will be collected at 24 hours (Day 5) and 48 hours (Day 6) after the final dose on Day 4.

• PK parameters of Cortexolone 17α-propionate and the two main metabolites Cortexolone 21-propionate (M1) and Cortexolone (M2)

  AUC0-inf: Area under the plasma concentration-time curve from time zero to infinity

  Samples will be collected 1hour pre IMP administration and at 2, 3, 4, 5, 6, 7, 8, 9, 10,12 hours post IMP administration on Day1 and Day4. Further samples will be collected at 24 hours (Day 5) and 48 hours (Day 6) after the final dose on Day 4.

• PK parameters of Cortexolone 17α-propionate and the two main metabolites Cortexolone 21-propionate (M1) and Cortexolone (M2)

  CL: Blood clearance

  Samples will be collected 1hour pre IMP administration and at 2, 3, 4, 5, 6, 7, 8, 9, 10,12 hours post IMP administration on Day1 and Day4. Further samples will be collected at 24 hours (Day 5) and 48 hours (Day 6) after the final dose on Day 4.

• PK parameters of Cortexolone 17α-propionate and the two main metabolites Cortexolone 21-propionate (M1) and Cortexolone (M2)

  λz: Terminal elimination rate constant

  Samples will be collected 1hour pre IMP administration and at 2, 3, 4, 5, 6, 7, 8, 9, 10,12 hours post IMP administration on Day1 and Day4. Further samples will be collected at 24 hours (Day 5) and 48 hours (Day 6) after the final dose on Day 4.

• PK parameters of Cortexolone 17α-propionate and the two main metabolites Cortexolone 21-propionate (M1) and Cortexolone (M2)

  CLr: Renal clearance

  Samples will be collected 1hour pre IMP administration and at 2, 3, 4, 5, 6, 7, 8, 9, 10,12 hours post IMP administration on Day1 and Day4. Further samples will be collected at 24 hours (Day 5) and 48 hours (Day 6) after the final dose on Day 4.

• PK parameters of Cortexolone 17α-propionate and the two main metabolites Cortexolone 21-propionate (M1) and Cortexolone (M2)

  Vz: Volume of distribution

  Samples will be collected 1hour pre IMP administration and at 2, 3, 4, 5, 6, 7, 8, 9, 10,12 hours post IMP administration on Day1 and Day4. Further samples will be collected at 24 hours (Day 5) and 48 hours (Day 6) after the final dose on Day 4.

• PK parameters of Cortexolone 17α-propionate and the two main metabolites Cortexolone 21-propionate (M1) and Cortexolone (M2)

  MRT: Mean residence time

  Samples will be collected 1hour pre IMP administration and at 2, 3, 4, 5, 6, 7, 8, 9, 10,12 hours post IMP administration on Day1 and Day4. Further samples will be collected at 24 hours (Day 5) and 48 hours (Day 6) after the final dose on Day 4.

• QT interval changes

  QT intervals will be assessed using triplicate 12-lead ECGs electronically recorded at each time point and evaluated by a blinded select cardiologist

  Day1 (each hour starting from 2 till 12 hours post IMP administration), Day 4 (each hour starting from 2 till 12 hours post IMP administration), Day 5 (24 hs post last IMP administration) and Day 6 (48 hs post last IMP administration).

Secondary Outcomes (5)

• Incidence of treatment-emergent adverse event

  Day1, 2, 3, 4, 5, 6 and 14

• Proportion of subjects with skin reaction

  Day1, 2, 3, 4, 5, 6 and 14 (if applicable)

• Proportion of subjects with clinically significant changes in laboratory safety tests (haematology, chemistry, coagulation and urinalysis)

  Haematology, chemistry and coagulation: Day-1/1, 3, 5 and 14. Urinalysis: Day-1 and Day 14

• Proportion of subjects with abnormalities on electrocardiogram (ECG)

  Day1, 4, 6 and 14

• Proportion of subjects with clinically significant changes in vital signs (systolic blood pressure, diastolic blood pressure, pulse rate and temperature)

  Day1, 2, 3, 4, 5 and 14

Study Arms (2)

Cortexolone 17α-propionate 7.5% solution

EXPERIMENTAL

Drug: Cortexolone 17α-propionate solution

Vehicle solution

PLACEBO COMPARATOR

Drug: Placebo

Interventions

Cortexolone 17α-propionate solution DRUG

Single topical application to be applied twice daily (0 hour and 12 hour) on Days 1-3 and Once Daily (0 hour) on Day 4.

Cortexolone 17α-propionate 7.5% solution

Placebo DRUG

matching placebo

Vehicle solution

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Male or female subjects ≥18 and ≤40 years at the date of signing informed consent which is defined as the beginning of the Screening Period.
• Subjects must have a body mass index (BMI) between 18.0-25.0 kg/m² inclusive.
• Subjects must be bald, have a shaved head, or be willing to have their head shaved.
• Female subjects who are either: (a) Non-childbearing potential, e.g. post-menopausal (as defined as amenorrhoea for at least 12 months with no alternative medical cause) or permanently sterile (permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy) OR (b) Childbearing potential AND (if heterosexually active) agree to use at least one form of highly effective contraception as defined below, starting at least one menstrual cycle before first study drug administration and continuing until at least 3 months after the end of the systemic exposure of the study drug.
• Highly effective contraceptive methods for females are as follows:
• Combined (oestrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation as follows:
• Oral
• Intravaginal
• Transdermal
• Progestogen-only hormonal contraception associated with inhibition of ovulation as follows: o Oral
• Injectable
• Implantable
• Intrauterine device (IUD)
• Intrauterine hormone-releasing system (IUS)
• Bilateral tubal occlusion

You may not qualify if:

• Current or recurrent disease (e.g., cardiovascular, haematological, neurological, endocrine, renal, liver, gastrointestinal, hepatic or other conditions) that could affect the action, absorption, or disposition of Cortexolone 17α-propionate, or could affect clinical assessments or clinical laboratory evaluations.
• Current or relevant history of any physical or psychiatric illness that may require treatment or make the subject unlikely to fully comply with the requirements of the study or complete the study, or any condition that presents undue risk from the investigational product or study procedures.
• Any other significant disease or disorder which, in the opinion of the investigator, may put the subject at unacceptable risk because of participation in the study, may influence the result of the study, or may affect the subject's ability to participate in the study.
• History of any pathology affecting the skin such as eczema, psoriasis or any skin hypersensitivity.
• Have tattoos on the scalp or thigh which would affect the area for topical application of the trial drug.
• The history or presence of any of the following cardiac conditions: known structural cardiac abnormalities; family history of long QT syndrome; cardiac syncope or recurrent, idiopathic syncope; exercise related clinically significant cardiac events.
• Any clinically significant abnormalities in rhythm, conduction or morphology of resting ECG or clinically important abnormalities that may interfere with the interpretation of QTc interval changes. This includes subjects with any of the following (at screening, Day -1 or pre-dose of Day 1):
• Sinus node dysfunction.
• Clinically significant PR (PQ) interval prolongation.
• Intermittent second or third degree AV block.
• Complete bundle branch block.
• Sustained cardiac arrhythmia's including (but not limited to) atrial fibrillation or supraventricular tachycardia; any symptomatic arrhythmia with the exception of isolated extra systoles.
• More than 200 ventricular ectopic beats in 24 hours.
• Ventricular tachycardia (ventricular tachycardia defined as ≥ 3 successive ventricular ectopic beats at a rate of \> 120 bpm).
• Abnormal T wave morphology.

Sponsors & Collaborators

• Cassiopea SpA: lead

Study Sites (1)

Richmond Pharmacology Ltd

London, SW17 0RE, United Kingdom

Location

Study Officials

• Jorg Taubel, MD FFPM

  Richmond Pharmacology Limited

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Thirty-two volunteers will be enrolled and evaluated (i.e. complete the study). Subjects will be dosed in four groups of eight (purely for logistical reasons relating to the procedure times expected with dosing and ECG). Volunteers will receive either the active drug or matching placebo in a 3:1 ratio. Therefore within each cohort, six volunteers will receive the active drug and two will receive matching placebo.

Study Record Dates

• First Submitted: June 18, 2018
• First Posted: September 11, 2018
• Study Start: June 6, 2018
• Primary Completion: September 12, 2018
• Study Completion: September 12, 2018
• Last Updated: February 4, 2019

Record last verified: 2019-02

Locations

GB (1)