Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ACT-451840 in Healthy Subjects (Part A)

NCT02186002 | Completed Phase 1

• 1 other identifier: AC-071-101
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

The primary objective of the study was to evaluate the safety and tolerability of ACT-451840 in healthy male subjects.Secondary objectives were : to investigate the pharmacokinetics (PK) of ACT-451840; to investigate the effect of food on the PK of ACT-451840; to evaluate the urinary excretion of ACT-451840 and to investigate the antimalarial activity of ACT-451840.

Conditions

Healthy

Keywords

ACT-451840; Safety; Tolerability; Pharmacokinetics

Outcome Measures

Primary Outcomes (10)

• Change in systolic blood pressure from baseline up to end of study

  Blood pressure (systolic and diastolic) and pulse rate will be measured using an automatic oscillometric device, always on the dominant/same arm (i.e., dominant arm right = writing with right hand). Measurements should be recorded from the subject in the supine position after having rested for a 5-minute period.

  4 days

• Change in diastolic blood pressure from baseline up to end of study

  Blood pressure (systolic and diastolic) and pulse rate will be measured using an automatic oscillometric device, always on the dominant/same arm (i.e., dominant arm right = writing with right hand). Measurements should be recorded from the subject in the supine position after having rested for a 5-minute period.

  4 days

• Change in pulse rate from baseline up to end of study

  Blood pressure (systolic and diastolic) and pulse rate will be measured using an automatic oscillometric device, always on the dominant/same arm (i.e., dominant arm right = writing with right hand). Measurements should be recorded from the subject in the supine position after having rested for a 5-minute period.

  4 days

• Change in body weight from baseline up to end of study

  Body weight will be measured using the same weighing scale for all subjects and throughout the study. The weighing scale should have a precision of at least 0.5 kg.

  4 days

• Change in heart rate from baseline up to end of study

  Heart rate will be measured using a standard 12-lead electrocardiogram recorded at rest with the subject in the supine position for a 5-minute period. Electrocardiograms will be performed immediately prior to dosing and at 1, 2, 4, 6, 8, 12, 24, 48, and 96 hours post dosing.

  4 days

• Change in PQ/PR interval from baseline up to end of study

  PQ/PR interval (time interval from the beginning of the P wave to the beginning of the QRS complex) will be measured using a standard 12-lead electrocardiogram recorded at rest with the subject in the supine position for a 5-minute period. Electrocardiograms will be performed immediately prior to dosing and at 1, 2, 4, 6, 8, 12, 24, 48, and 96 hours post dosing.

  4 days

• Change in QRS interval from baseline up to end of study

  QRS interval (time interval from the beginning of the Q wave to the end of the S wave) will be measured using a standard 12-lead electrocardiogram recorded at rest with the subject in the supine position for a 5-minute period. Electrocardiograms will be performed immediately prior to dosing and at 1, 2, 4, 6, 8, 12, 24, 48, and 96 hours post dosing.

  4 days

• Change in QTc interval (time interval from beginning of the Q wave until end of the T wave) according to Fridericia's correction (QTcF interval) from baseline up to end of study

  QTcF interval will be measured using a standard 12-lead electrocardiogram recorded at rest with the subject in the supine position for a 5-minute period. Electrocardiograms will be performed immediately prior to dosing and at 1, 2, 4, 6, 8, 12, 24, 48, and 96 hours post dosing. The QTcF interval is the QTc interval corrected for heart rate with Fridericia's formula (QTcB = QT/RR\^0.33 where RR is 60/heart rate)

  4 days

• Change in QTc interval (time interval from beginning of the Q wave until end of the T wave) according to Bazett's correction (QTcB interval) from baseline up to end of study

  QTcB interval will be measured using a standard 12-lead electrocardiogram recorded at rest with the subject in the supine position for a 5-minute period. Electrocardiograms will be performed immediately prior to dosing and at 1, 2, 4, 6, 8, 12, 24, 48, and 96 hours post dosing. The QTcB interval is the QTc interval corrected for heart rate with Bazett's formula (QTcB = QT/RR\^0.5 where RR is 60/heart rate).

  4 days

• Number of treatment-emergent electrocardiogram abnormalities from baseline up to end of study

  Treatment-emergent electrocardiogram abnormalities will be identified using a standard 12-lead electrocardiogram recorded at rest with the subject in the supine position for a 5-minute period. Electrocardiograms will be performed immediately prior to dosing and at 1, 2, 4, 6, 8, 12, 24, 48, and 96 hours post dosing.

  4 days

Secondary Outcomes (8)

• Maximum plasma concentration (Cmax) of ACT-451840

  4 days

• Time to maximum plasma concentration (tmax) of ACT-451840

  4 days

• Area under the plasma concentration-time curve (AUC(0-t)) of ACT-451840

  4 days

• Area under the plasma concentration-time curve (AUC(0-infinity)) of ACT-451840

  4 days

• Plasma half life (t1/2) of ACT-451840

  4 days

Study Arms (6)

Group 1

EXPERIMENTAL

A single oral dose of 10 mg ACT-451840 or placebo to be administered to subjects in the fasted state. Six subjects are to receive ACT-451840 and 2 subjects to receive matching placebo.

Drug: ACT-451840 10 mg; Drug: Placebo

Group 2

EXPERIMENTAL

A single oral dose of 50 mg ACT-451840 or placebo to be administered to subjects in the fasted state. Six subjects are to receive ACT-451840 and 2 subjects to receive matching placebo. If indicated by the pharmacokinetic data obtained in the preceding groups and if not previously performed, a food effect investigation will be conducted after a washout period of at least 7 days. A dose of 50 mg ACT-451840 or placebo is to be administered to subjects in the fed state, followed by the second observation period of 4 days. Six subjects who received ACT-451810 in the fasted state are to receive ACT-451840 in the fed state and 2 subjects who received placebo in the fasted state to receive matching placebo in the fed state.

Drug: ACT-451840 50 mg; Drug: Placebo

Group 3

EXPERIMENTAL

A single oral dose of 200 mg ACT-451840 or placebo to be administered to subjects in the fasted state. Six subjects are to receive ACT-451840 and 2 subjects to receive matching placebo. If indicated by the pharmacokinetic data obtained in the preceding groups and if not previously performed, a food effect investigation will be conducted after a washout period of at least 7 days. A dose of 200 mg ACT-451840 or placebo is to be administered to subjects in the fed state, followed by the second observation period of 4 days. Six subjects who received ACT-451810 in the fasted state are to receive ACT-451840 in the fed state and 2 subjects who received placebo in the fasted state to receive matching placebo in the fed state.

Drug: ACT-451840 200 mg; Drug: Placebo

Group 4

EXPERIMENTAL

A single dose of 500 mg ACT-451840 or placebo to be administered to subjects in the fasted state, followed by an observation period of 4 days. If indicated by the pharmacokinetic data obtained in the preceding groups and if not previously performed, a food effect investigation will be conducted after a washout period of at least 7 days. A dose of 500 mg ACT-451840 or placebo is to be administered to subjects in the fed state, followed by the second observation period of 4 days. Six subjects who received ACT-451810 in the fasted state are to receive ACT-451840 in the fed state and 2 subjects who received placebo in the fasted state to receive matching placebo in the fed state.

Drug: ACT-451840 500 mg; Drug: Placebo

Group 5

EXPERIMENTAL

A single oral dose of 1000 mg ACT-451840 or placebo to be administered to subjects in the fasted state. Six subjects are to receive ACT-451840 and 2 subjects to receive matching placebo. If indicated by the pharmacokinetic data obtained in the preceding groups and if not previously performed, a food effect investigation will be conducted after a washout period of at least 7 days. A dose of 1000 mg ACT-451840 or placebo is to be administered to subjects in the fed state, followed by the second observation period of 4 days. Six subjects who received ACT-451810 in the fasted state are to receive ACT-451840 in the fed state and 2 subjects who received placebo in the fasted state to receive matching placebo in the fed state.

Drug: ACT-451840 1000 mg; Drug: Placebo

Group 6

EXPERIMENTAL

A single oral dose of ACT-451840 or placebo to be administered to subjects in the fed state. Six subjects are to receive ACT-451840 and 2 subjects to receive matching placebo. The dose of ACT-451840 to be determined on the basis of the pharmacokinetic results for the previous groups

Drug: ACT-451840 (Dose to be determined); Drug: Placebo

Interventions

ACT-451840 10 mg DRUG

ACT-451840 was provided as dry powder, which was reconstituted as a suspension with 25 mL of tap water

Group 1

ACT-451840 50 mg DRUG

ACT-451840 was provided as dry powder, which was reconstituted as a suspension with 25 mL of tap water

Group 2

ACT-451840 200 mg DRUG

ACT-451840 was provided as dry powder, which was reconstituted as a suspension with 25 mL of tap water

Group 3

ACT-451840 500 mg DRUG

ACT-451840 was provided as dry powder, which was reconstituted as a suspension with 25 mL of tap water

Group 4

ACT-451840 1000 mg DRUG

ACT-451840 was provided as dry powder, which was reconstituted as a suspension with 25 mL of tap water

Group 5

ACT-451840 (Dose to be determined) DRUG

ACT-451840 was provided as dry powder, which was reconstituted as a suspension with 25 mL of tap water

Group 6

Placebo DRUG

Group 1; Group 2; Group 3; Group 4; Group 5; Group 6

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Signed informed consent in the local language prior to any study-mandated procedure.
• Body mass index (BMI) of 18.0 to 28.0 kg/m2 (inclusive) at screening.
• Systolic blood pressure 100-145 mmHg, diastolic blood pressure 50-90 mmHg, and pulse rate 45-90 beats per minute (inclusive), measured on the dominant arm, after 5 min in the supine position at screening.
• lead electrocardiogram without clinically relevant abnormalities, measured after 5 min in the supine position at screening.
• Hematology, coagulation, clinical chemistry, and urinalysis test results not deviating from the normal range to a clinically relevant extent at screening.
• No clinically significant findings on the physical examination at screening.
• Negative results from urine drug screen at screening.
• Ability to communicate well with the investigator, in the local language, and to understand and comply with the requirements of the study.
• Subject covered by Health Insurance system and/or in compliance with the recommendations of the National Law in force relating to biomedical research.
• If the subject's partner could become pregnant, reliable methods of contraception must be used from the time of the first administration of study medication until 3 months following administration of the last dose of study medication.

You may not qualify if:

• Known allergic reactions or hypersensitivity to any excipient of the drug formulation(s).
• 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 drug.
• Previous history of fainting, collapse, syncope, orthostatic hypotension, or vasovagal reactions.
• Documented history of chronic liver or gall bladder disease.
• Documented history of hemolytic anemia.
• Veins unsuitable for intravenous puncture on either arm (e.g., veins that are difficult to locate, access, or puncture, veins with a tendency to rupture during or after puncture).
• Previous exposure to the study medication.
• Treatment with another investigational drug within 3 months prior to screening or participation in more than four investigational drug studies within the 12 months prior to screening.
• Subject who had received more than 4,500 Euros as indemnities for his participation in a biomedical research within the 12 last months, including the indemnities for the present study.
• History or clinical evidence of alcoholism or drug abuse within the 3-year period prior to screening.
• Excessive caffeine consumption, defined as 800 mg or more per day at screening.
• Smoking within 3 months prior to screening and inability to refrain from smoking during the course of the study.
• Previous treatment with any prescribed or over-the-counter medications (including herbal medicines such as St. John's Wort) within 2 weeks prior to first study drug administration.
• Loss of 250 mL or more of blood within 3 months prior to screening.
• Positive results from the hepatitis (hepatitis B and C) serology, except for vaccinated subjects.

Sponsors & Collaborators

• Idorsia Pharmaceuticals Ltd.: lead

Study Sites (1)

OPTIMED Clinical Research

Gières, 38610, France

Location

Related Publications (1)

• Bruderer S, Hurst N, de Kanter R, Miraval T, Pfeifer T, Donazzolo Y, Dingemanse J. First-in-humans study of the safety, tolerability, and pharmacokinetics of ACT-451840, a new chemical entity with antimalarial activity. Antimicrob Agents Chemother. 2015 Feb;59(2):935-42. doi: 10.1128/AAC.04125-14. Epub 2014 Nov 24.

  PMID: 25421475 DERIVED

MeSH Terms

Interventions

ACT-451840

Study Officials

• Clinical Trials

  Idorsia Pharmaceuticals Ltd.

  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: July 8, 2014
• First Posted: July 10, 2014
• Study Start: December 1, 2011
• Primary Completion: April 1, 2012
• Study Completion: April 1, 2012
• Last Updated: August 9, 2019

Record last verified: 2019-08

Locations

FR (1)