A Study to Assess the Tolerability, Safety, Pharmacodynamics, and Pharmacokinetics of Ascending Single Doses (Including Food Interaction) and Ascending Multiple Doses of ACT-453859, and Multiple Doses of Setipiprant (ACT-129968)

NCT02381496 | Completed Phase 1

• 1 other identifier: AC-072-101
• Study Type: interventional
• Target: 88
• Locations: 0 countries
• Sites: N/A

Brief Summary

This is a three-part study to assess the tolerability, safety, pharmacodynamics, and pharmacokinetics of ascending single doses (including food interaction) of ACT-453859 in healthy male subjects, of ascending multiple doses of ACT-453859 in healthy male and female subjects, and of multiple doses of setipiprant (ACT-129968) in healthy male and female subjects.

Conditions

Healthy

Keywords

ACT-453859; ACT-463036; Setipiprant; Tolerability; safety; pharmacodynamics; pharmacokinetics

Outcome Measures

Primary Outcomes (14)

• Area under the plasma concentration-time curve (AUC(0-t)) for single doses of ACT-453859

  Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. AUC(0-t) will be calculated according to the linear trapezoidal rule using the measured concentration-time values above the limit of quantification (LOQ).

  72 hours

• AUC(0-t) for the active metabolite ACT-463036 after single doses of ACT-453859

  Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. AUC(0-t) will be calculated according to the linear trapezoidal rule using the measured concentration-time values above the LOQ.

  72 hours

• Area under the plasma concentration-time curve (AUC(0-infinity)) for single doses of ACT-453859

  Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. AUC(0-infinity) will be calculated by combining AUC(0-t) and AUC(extra). AUC(extra) represents an extrapolated value obtained by Ct/λz, where Ct is the last plasma concentration measured above the LOQ and λZ represents the terminal elimination rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal elimination phase.

  72 hours

• AUC(0-infinity) for the active metabolite ACT-463036 after single doses of ACT-453859

  Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. AUC(0-infinity) will be calculated by combining AUC(0-t) and AUC(extra). AUC(extra) represents an extrapolated value obtained by Ct/λz, where Ct is the last plasma concentration measured above the LOQ and λZ represents the terminal elimination rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal elimination phase.

  72 hours

• Time to reach maximum plasma concentration (tmax) for single doses of ACT-453859

  Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. The measured individual plasma concentrations of ACT-453859 will be used to directly obtain tmax.

  72 hours

• tmax for the active metabolite ACT-463036 after single doses of ACT-453859

  Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. The measured individual plasma concentrations of ACT-463036 will be used to directly obtain tmax.

  72 hours

• Terminal elimination rate constant (λZ) for single doses of ACT-453859

  Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. λZ will be determined by log-linear regression analysis of the measured plasma concentrations of the terminal elimination phase.

  72 hours

• λZ for the active metabolite ACT-463036 after single doses of ACT-453859

  Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. λZ will be determined by log-linear regression analysis of the measured plasma concentrations of the terminal elimination phase.

  72 hours

• Plasma half life (t1/2) for single doses of ACT-453859

  Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. t1/2 will be calculated as follows: t½ = ln 2/λZ.

  72 hours

• t1/2 for the active metabolite ACT-463036 after single doses of ACT-453859

  Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. t1/2 will be calculated as follows: t½ = ln 2/λZ.

  72 hours

• Maximum plasma concentration (Cmax) for single doses of ACT-453859

  Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. The measured individual plasma concentrations of ACT-453859 will be used to directly obtain Cmax.

  72 hours

• Cmax for the active metabolite ACT-463036 after single doses of ACT-453859

  Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. The measured individual plasma concentrations of ACT-463036 will be used to directly obtain Cmax.

  72 hours

• Renal clearance (CLR) following single dose of ACT-453859 100 mg

  Urine samples for pharmacokinetic assessments will be collected at various time points over the study period. CLR will be calculated by dividing the total amount of unchanged ACT-453859 excreted in urine during the collection interval by AUC(0-t).

  72 hours

• Percentage of ACT-453859 excreted unchanged in the urine following single dose of ACT-453859 100 mg

  Urine samples for pharmacokinetic assessments will be collected at various time points over the study period.The percentage of total dose excreted unchanged in urine will be calculated by the total amount excreted, divided by the dose administered, multiplied by 100.

  72 hours

Secondary Outcomes (27)

• Area under the plasma concentration-time curve (AUCτ) for multiple doses of ACT-453859 (Day 1 & Day 7)

  11 days

• AUCτ for the active metabolite ACT-463036 after multiple doses of ACT-453859 (Day 1 & Day 7)

  11 days

• Cmax for multiple doses of ACT-453859 (Day 1 & Day 7)

  11 days

• Cmax for the active metabolite ACT-463036 after multiple doses of ACT-453859 (Day 1 & Day 7)

  11 days

• tmax for multiple doses of ACT-453859 (Day 1 & Day 7)

  11 days

Study Arms (11)

Part A: Cohort A1: ACT-453859 1 mg

EXPERIMENTAL

ACT-453859 1 mg or placebo, single dose, administered orally in the fasted state * Six male subjects will receive ACT-453859 * Two male subjects will receive matching placebo

Drug: ACT-453859 1 mg; Other: Placebo

Part A: Cohort A2: ACT-453859 3 mg

EXPERIMENTAL

ACT-453859 3 mg or placebo, single dose, administered orally in the fasted state * Six male subjects will receive ACT-453859 * Two male subjects will receive matching placebo

Drug: ACT-453859 3 mg; Other: Placebo

Part A: Cohort A3: ACT-453859 10 mg

EXPERIMENTAL

ACT-453859 10 mg or placebo, single dose, administered orally in the fasted state * Six male subjects will receive ACT-453859 * Two male subjects will receive matching placebo

Drug: ACT-453859 10 mg; Other: Placebo

Part A: Cohort A4: ACT-453859 30 mg

EXPERIMENTAL

ACT-453859 30 mg or placebo, single dose, administered orally in the fasted state * Six male subjects will receive ACT-453859 * Two male subjects will receive matching placebo

Drug: ACT-453859 30mg; Other: Placebo

Part A: Cohort A5: ACT-453859 100 mg

EXPERIMENTAL

ACT-453859 100 mg or placebo, single dose, administered orally in the fasted state * Six male subjects will receive ACT-453859 * Two male subjects will receive matching placebo After a washout period of 10-20 days subjects will return for a second study period to receive the same treatment received in the first session but under fed conditions

Drug: ACT-453859 100 mg; Other: Placebo

Part A: Cohort A6: ACT-453859 300 mg

EXPERIMENTAL

ACT-453859 300 mg or placebo, single dose, administered orally in the fasted state * Six male subjects will receive ACT-453859 * Two male subjects will receive matching placebo

Drug: ACT-453859 300 mg; Other: Placebo

Part A: Cohort A7: ACT-453859 800 mg

EXPERIMENTAL

ACT-453859 800 mg or placebo, single dose, administered orally in the fasted state * Six male subjects will receive ACT-453859 * Two male subjects will receive matching placebo

Drug: ACT-453859 800 mg; Other: Placebo

Part B: Cohort B1: ACT-453859 10 mg

EXPERIMENTAL

ACT-453859 10 mg or placebo, once a day for 7 days, administered orally in the fasted state * Three male subjects will receive ACT-453859 * Three female subjects will receive ACT-453859 * One male subject will receive matching placebo * One female subject will receive matching placebo

Drug: ACT-453859 10 mg; Other: Placebo

Part B: Cohort B2: ACT-453859 100 mg

EXPERIMENTAL

ACT-453859 100 mg or placebo, once a day for 7 days, administered orally in the fasted state * Three male subjects will receive ACT-453859 * Three female subjects will receive ACT-453859 * One male subject will receive matching placebo * One female subject will receive matching placebo

Drug: ACT-453859 100 mg; Other: Placebo

Part B: Cohort B3: ACT-453859 800 mg

EXPERIMENTAL

ACT-453859 800 mg, once a day for 7 days, administered orally in the fasted state * Three male subjects will receive ACT-453859 * Three female subjects will receive ACT-453859 * One male subject will receive matching placebo * One female subject will receive matching placebo

Drug: ACT-453859 800 mg; Other: Placebo

Part C: Treatment Periods I & II: Setipiprant

EXPERIMENTAL

Setipiprant 500 mg, twice daily for 7 days, administered orally in Treatment Period I (TPI) and setipiprant 1000 mg, twice daily for 7 days, administered orally in Treatment Period II (TPII) * Four male subjects will receive setipiprant 500 mg twice a day in TPI and 1000 mg twice a day in TPII. * Four female subjects will receive setipiprant 500 mg twice a day in TPI and 1000 mg twice a day in TPII. There will be a washout period of 10 days between TPI and TPII

Drug: Setipiprant 500 mg; Drug: Setipiprant 1000 mg

Interventions

ACT-453859 1 mg DRUG

Capsule

Part A: Cohort A1: ACT-453859 1 mg

ACT-453859 3 mg DRUG

Capsule

Part A: Cohort A2: ACT-453859 3 mg

ACT-453859 10 mg DRUG

Capsule

Part A: Cohort A3: ACT-453859 10 mg; Part B: Cohort B1: ACT-453859 10 mg

ACT-453859 30mg DRUG

Capsule

Part A: Cohort A4: ACT-453859 30 mg

ACT-453859 100 mg DRUG

Capsule

Part A: Cohort A5: ACT-453859 100 mg; Part B: Cohort B2: ACT-453859 100 mg

ACT-453859 300 mg DRUG

Capsule

Part A: Cohort A6: ACT-453859 300 mg

ACT-453859 800 mg DRUG

Capsule

Part A: Cohort A7: ACT-453859 800 mg; Part B: Cohort B3: ACT-453859 800 mg

Placebo OTHER

Matching ACT-453859 placebo capsule

Part A: Cohort A1: ACT-453859 1 mg; Part A: Cohort A2: ACT-453859 3 mg; Part A: Cohort A3: ACT-453859 10 mg; Part A: Cohort A4: ACT-453859 30 mg; Part A: Cohort A5: ACT-453859 100 mg; Part A: Cohort A6: ACT-453859 300 mg; Part A: Cohort A7: ACT-453859 800 mg; Part B: Cohort B1: ACT-453859 10 mg; Part B: Cohort B2: ACT-453859 100 mg; Part B: Cohort B3: ACT-453859 800 mg

Setipiprant 500 mg DRUG

Capsule

Part C: Treatment Periods I & II: Setipiprant

Setipiprant 1000 mg DRUG

Capsule

Part C: Treatment Periods I & II: Setipiprant

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Signed informed consent.
• Healthy male subjects (Part A), healthy male and female subjects for Parts B \& C.
• Hematology, coagulation (Part A and Part B only), clinical chemistry, and urinalysis test results not deviating from the normal range to a clinically relevant extent.
• No clinically significant findings on physical examination.
• Body mass index between 18.0 and 28.0 kg/m\^2.
• Systolic blood pressure 100-145 mmHg, diastolic blood pressure 50-90 mmHg, and heart rate 45-90 beats per minute.
• lead electrocardiogram without clinically relevant abnormalities.
• Negative results from urine drug screen and alcohol breath test.
• Able and willing to refrain from sunbathing, prolonged sun exposure, and artificial sunlight exposure such as solarium, and to limit skin and eye exposure to sunlight using appropriate precautions from the first dose until safety follow-up visit for Parts A and B.
• Ability to communicate well with the investigator in the local language, and to understand and comply with the requirements of the study.
• For male subjects: consent that the female partner uses a medically acceptable method of contraception throughout the entire study period and for 90 days after the study is completed.
• For male subjects: agree not to donate sperm from the first drug administration until 90 days after completion of the study.
• For Part C, women of childbearing potential must have a negative serum pregnancy test and a negative urine pregnancy test pre-dose on Day 1 (of each treatment period for Part C). Women of childbearing potential must consistently and correctly use a reliable method of contraception, be sexually inactive or have a vasectomized partner.
• Willing to adhere to the prohibitions and restrictions specified in this protocol.

You may not qualify if:

• Previous history of fainting, collapses, syncope, orthostatic hypotension, or vasovagal reactions.
• Veins unsuitable for intravenous puncture on either arm.
• Treatment with any prescribed or over-the-counter medications within 2 weeks prior to first study drug administration.
• Treatment or substances known to inhibit cytochrome P (CYP) enzyme drug metabolism .
• Treatment or substances known to induce CYP enzyme drug metabolism.
• Treatment with another investigational drug within 3 months prior or participated in more than four investigational drug studies within 1 year prior to Screening. Subjects will not participate in more than one part of the study.
• History or clinical evidence of alcoholism or drug abuse within the 3-year period prior to Screening.
• History or clinical evidence of any disease, and/or existence of any surgical or medical condition, which might interfere with the absorption, distribution, metabolism or excretion of the study drugs.
• Excessive caffeine consumption.
• Smoking, tobacco use, or use of nicotine products within 3 months and inability to refrain from smoking during the course of the study.
• Loss of 250 mL or more of blood, or an equivalent amount of plasma, within 3 months prior to Screening.
• Positive results from the hepatitis serology, except for vaccinated subjects or subjects with past but resolved hepatitis.
• Positive results from human immunodeficiency virus serology.
• Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol.
• Legal incapacity or limited legal capacity.

Sponsors & Collaborators

• Idorsia Pharmaceuticals Ltd.: lead

MeSH Terms

Interventions

ACT-453859; 2-(2-(1-naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido(4,3-b)indol-5(2H)-yl)acetic acid

Study Officials

• Martine Géhin, PhD

  Actelion

  STUDY DIRECTOR

Study Design

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

Study Record Dates

• First Submitted: March 3, 2015
• First Posted: March 6, 2015
• Study Start: December 1, 2011
• Primary Completion: April 1, 2012
• Study Completion: April 1, 2012
• Last Updated: July 10, 2018

Record last verified: 2018-07