Single-ascending Dose Study to Investigate the Tolerability, Safety, Pharmacokinetics, and Pharmacodynamics of ACT-462206

NCT01954589 | Completed Phase 1

• 1 other identifier: AC-074-101
• Study Type: interventional
• Target: 56
• Locations: 1 country
• Sites: 1

Brief Summary

A study of ACT-462206 to evaluate the tolerability, safety, pharmacokinetics, and pharmacodynamic of ascending single doses of ACT-462206, a novel dual orexin receptor antagonist in healthy male subjects.

Conditions

Safety; Tolerability; Pharmacodynamics; Pharmacokinetics

Keywords

ACT-462206; Selective dual orexin receptor antagonist

Outcome Measures

Primary Outcomes (14)

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

  Blood pressure was measured on the dominant arm using an automatic oscillometric device. Measurements were taken with the subject in the supine position after a resting period of at least 5 min. The dominant (writing) arm was used for all measurements. Measurements were taken at 1, 3, 5, 8, 24, 48, 72 and 96 hours post-dose.

  96 hours

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

  Blood pressure was measured on the dominant arm using an automatic oscillometric device. Measurements were taken with the subject in the supine position after a resting period of at least 5 min. The dominant (writing) arm was used for all measurements. Measurements were taken at 1, 3, 5, 8, 24, 48, 72 and 96 hours post-dose.

  96 hours

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

  Heart rate was measured on the dominant arm using an automatic oscillometric device. The dominant (writing) arm was used for all measurements. Measurements were taken at 1, 3, 5, 8, and 96 hours post-dose.

  96 hours

• Change in body weight from baseline up to the 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.

  96 hours

• Change in PR Interval from baseline up to the end of study

  A standard 12-lead electrocardiogram (ECG) was recorded in supine position after a 5-min rest period. The PR interval is the time interval from the beginning of the P wave to the beginning of the QRS complex. Measurements were taken at 1, 3, 5, 8, and 96 hours post-dose.

  96 hours

• Change in QRS Interval from baseline up to the end of study

  A standard 12-lead ECG was recorded in supine position after a 5-min rest period. The QRS interval is the time interval from the beginning of the Q wave to the end of the S wave. Measurements were taken at 1, 3, 5, 8, and 96 hours post-dose.

  96 hours

• Change in QTcB Interval from baseline up to the end of study

  A standard 12-lead ECG was recorded in supine position after a 5-min rest period. The QTcB interval is the QT interval (interval from beginning of the Q wave until end of the T wave) corrected for heart rate with Bazett's formula (QTcB = QT/RR\^0.5 where RR is 60/heart rate). Measurements were taken at 1, 3, 5, 8, and 96 hours post-dose.

  96 hours

• Change in QTcF Interval from baseline up to the end of study

  A standard 12-lead ECG was recorded in supine position after a 5-min rest period. The QTcF interval is the QT interval (interval from beginning of the Q wave until end of the T wave) corrected for heart rate with Fridericia's formula (QTcF = QT/RR\^0.33 where RR is 60/heart rate). Measurements were taken at 1, 3, 5, 8, and 96 hours post-dose.

  96 hours

• Change in saccadic peak velocity from baseline up to the end of study

  Recording of eye movements was performed in a quiet room with ambient illumination, with only 1 subject present. A microcomputer system was used for recording \& analysis. Disposable electrodes were applied on the forehead \& beside the lateral canthi of both eyes for registration of the electro-oculographic signals. Head movements were restricted using a fixed head support. The target consisted of a moving dot displayed on a computer screen, fixed in front of the head support. Saccadic eye movements were recorded for stimulus amplitudes of approximately 15 degrees to either side. Fifteen saccades were recorded with inter-stimulus intervals varying randomly between 3 and 6 s. Average values of saccadic peak velocity of all correct saccades were used as variables.Measurements were taken at 20 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, and 10 hours post-dose.

  10 hours

• Change in performance on adaptive tracking from baseline up to the end of study

  The adaptive tracking test was performed using customized equipment and software, following a standard protocol. Adaptive tracking is a pursuit-tracking task. The subject was asked to keep a dot inside a randomly moving circle by operating a joystick. If successful, the speed of the moving circle was increased. Conversely, the velocity was reduced if the subject could not maintain the dot inside the circle. The average performance (%) and the standard deviation of scores during a 3.5-min assessment period were used for analysis. The assessment period included a run-in time of 0.5 min, during which data were not recorded.Measurements were taken at 20 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, and 10 hours post-dose.

  10 hours

• Change in body sway from baseline up to the end of study

  Body sway was assessed using a body sway meter. All body movements during a 2-min period of time were integrated and expressed as mm sway on a digital display. Measurements of body sway were made in the sagittal (forward/backward) planes by positioning of the subject relative to the apparatus, with a string attached to the waist. The contribution of vision to postural control was eliminated by asking subjects to close their eyes. Subjects were instructed to wear the same pair of comfortable, low-heeled shoes in each session. Before starting a measurement, subjects were asked to stand still and comfortable, with their feet approximately 10 cm apart and their hands in a relaxed position alongside the body. Measurements were taken at 20 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, and 10 hours post-dose.

  10 hours

• Change in visual analogue scale (VAS) score to assess alertness from baseline up to the end of study

  Dutch versions of the VAS according to Bond and Lader (British Journal of Medical Psychology 1974;47:211-18) were used to assess subjective alertness. At each time point of assessment, the subject indicated (with a mouse click on the computer screen) how he felt, on sixteen dimension horizontal VAS. Measurements were taken at 20 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, and 10 hours post-dose.

  10 hours

• Change in VAS score to assess mood from baseline up to the end of study

  Dutch versions of the VAS according to Bond and Lader (British Journal of Medical Psychology 1974;47:211-18) were used to assess subjective mood. At each time point of assessment, the subject indicated (with a mouse click on the computer screen) how he felt, on sixteen dimension horizontal VAS. Measurements were taken at 20 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, and 10 hours post-dose.

  10 hours

• Change in VAS score to assess calmness from baseline up to the end of study

  Dutch versions of the VAS according to Bond and Lader (British Journal of Medical Psychology 1974;47:211-18) were used to assess subjective calmness. At each time point of assessment, the subject indicated (with a mouse click on the computer screen) how he felt, on sixteen dimension horizontal VAS. Measurements were taken at 20 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, and 10 hours post-dose.

  10 hours

Secondary Outcomes (6)

• Maximum plasma concentration (Cmax) of ACT-462206

  96 hours

• Time to reach maximum plasma concentration (tmax) of ACT-462206

  96 hours

• Area under the plasma concentration-time curve (AUC) from time zero to time t of the last measured concentration above the limit of quantification (AUC0-t) of ACT-462206

  96 hours

• AUC from time zero to infinity (AUC0-∞) of ACT-462206

  96 hours

• AUC from time zero to 8 hours after administration (AUC0-8) of ACT-462206

  8 hours

Study Arms (7)

ACT-462206 5 mg/Placebo

EXPERIMENTAL

6 subjects received a single, 5 mg, oral dose of ACT-462206 and 2 subjects received a single, oral dose of placebo

Drug: ACT-462206 5 mg; Drug: Placebo

ACT-462206 25 mg/Placebo

EXPERIMENTAL

6 subjects received a single, 25 mg, oral dose of ACT-462206 and 2 subjects received a single, oral dose of placebo

Drug: ACT-462206 25 mg; Drug: Placebo

ACT-462206 100mg/Placebo

EXPERIMENTAL

6 subjects received a single, 100 mg, oral dose of ACT-462206 and 2 subjects received a single, oral dose of placebo

Drug: ACT-462206 100mg; Drug: Placebo

ACT-462206 200mg/Almorexant 400mg/Placebo

EXPERIMENTAL

Subjects were assigned to one of two possible treatment sequences: A/B or B/A with a washout period of 14 days between treatment periods. Treatment A: Single oral dose of ACT-462206 200 mg or placebo. Treatment B: Single oral dose of almorexant 400 mg or placebo. In each sequence 6 subjects received ACT-462206 or almorexant \& 2 subjects received placebo

Drug: ACT-462206 200mg; Drug: Almorexant 400mg; Drug: Placebo

Experimental: ACT-462206 400mg/Placebo

EXPERIMENTAL

6 subjects received a single, 400 mg, oral dose of ACT-462206 and 2 subjects received a single, oral dose of placebo

Drug: ACT-462206 400mg; Drug: Placebo

ACT-462206 1000 mg

EXPERIMENTAL

6 subjects received a single, 1000 mg, oral dose of ACT-462206 and 2 subjects received a single, oral dose of placebo

Drug: ACT-462206 1000 mg; Drug: Placebo

ACT-462206 1500mg/Placebo

EXPERIMENTAL

6 subjects received a single, 1500 mg, oral dose of ACT-462206 and 2 subjects received a single, oral dose of placebo

Drug: ACT-462206 1500mg; Drug: Placebo

Interventions

ACT-462206 5 mg DRUG

ACT-462206 5 mg/Placebo

ACT-462206 25 mg DRUG

ACT-462206 25 mg/Placebo

ACT-462206 100mg DRUG

ACT-462206 100mg/Placebo

ACT-462206 200mg DRUG

ACT-462206 200mg/Almorexant 400mg/Placebo

ACT-462206 400mg DRUG

Experimental: ACT-462206 400mg/Placebo

ACT-462206 1000 mg DRUG

ACT-462206 1000 mg

ACT-462206 1500mg DRUG

ACT-462206 1500mg/Placebo

Almorexant 400mg DRUG

ACT-462206 200mg/Almorexant 400mg/Placebo

Placebo DRUG

ACT-462206 1000 mg; ACT-462206 100mg/Placebo; ACT-462206 1500mg/Placebo; ACT-462206 200mg/Almorexant 400mg/Placebo; ACT-462206 25 mg/Placebo; ACT-462206 5 mg/Placebo; Experimental: ACT-462206 400mg/Placebo

Eligibility Criteria

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

You may qualify if:

• Healthy male subjects aged between 18 and 45 years (inclusive) at screening
• Hematology, clinical chemistry, and urinalysis results not deviating from the normal range to a clinically relevant extent at screening
• No clinically significant findings on physical examination at screening
• Body mass index between 18.0 and 28.0 kg/m\^2 (inclusive) at screening
• Systolic blood pressure 100-145 mmHg, diastolic blood pressure 50-90 mmHg, and heart rate 45-90 beats per minute (inclusive) measured at screening on the dominant arm (dominant arm is the writing arm) after 5 min in supine position
• lead electrocardiogram without clinically relevant abnormalities in the supine position 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.

You may not qualify if:

• Previous history of fainting, collapse, syncope, orthostatic hypotension, or vasovagal reactions
• 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)
• Treatment with any prescribed medications (including vaccines) or over-the-counter medications (including herbal medicines such as St John's Wort) within 2 weeks prior to (first) study drug administration
• Treatment with another investigational drug within 3 months prior to screening or having participated in more than four investigational drug studies within 1 year prior to screening
• 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, defined as ≥ 800 mg per day at screening of caffeine)
• Smoking within 3 months prior to screening 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, at screening
• Positive results from the human immunodeficiency virus serology at screening
• Known hypersensitivity to any excipients of the drug formulations
• Modified Swiss Narcolepsy Scale total score \< 0 or history of narcolepsy or cataplexy
• Any circumstances or conditions, which, in the opinion of the investigator, might affect full participation in the study or compliance with the protocol
• Legal incapacity or limited legal capacity at screening

Sponsors & Collaborators

• Idorsia Pharmaceuticals Ltd.: lead

Study Sites (1)

Centre for Human Drug Research

Leiden, 2333 CL, Netherlands

Location

MeSH Terms

Interventions

ACT-462206; almorexant

Study Officials

• Petra Baecker, MD

  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: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 27, 2013
• First Posted: October 7, 2013
• Study Start: November 1, 2011
• Primary Completion: January 1, 2012
• Study Completion: January 1, 2012
• Last Updated: July 10, 2018

Record last verified: 2018-07

Locations

NL (1)