• To evaluate the tolerability and safety of ascending single oral doses of ACT-541468 in healthy male subjects.• To investigate the single oral dose pharmacokinetic (PK) and PD of ACT-541468 in healthy male subjects.• To investigate dose…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
Sleep disorders
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Concentrations of ACT-541468 and its metabolites and radioactivity in whole
blood and plasma per time point will be summarized by dose presenting number of
observations, arithmetic mean, minimum, median, maximum, standard deviation
(SD), standard error (SE), and 95% confidence interval (CI) of the mean.
Dose proportionality will be assessed across ACT-541468 doses (formulation A)
using the power model described by Gough et al., [Gough 1995] which will be
applied to the loge AUC0-* and Cmax data. A point estimate and 90% CI will be
determined for the population mean slope.
Differences between formulation A (reference) and formulation B (test) for
AUC0-8, AUC0-24, AUC0-t, AUC0-*, Cmax, Cu/C, and t* will be explored using the
ratio of geometric means (absolute) and its 90% CI. Differences between
formulation A and formulation B for tmax will be explored using the median
difference and its 90% CI.
• Individual absolute bioavailability will be listed by subject number and
summarized overall presenting number of observations, arithmetic mean and its
95% CI, minimum, median, maximum, SD, and CV(%).
• Absolute bioavailability (F) will be calculated using the geometric means of
AUC0-*
All PK parameters of 14C-labeled ACT-541468 (including CL, Vss, and cumulative
excretion in urine and feces) will be presented as described above.
If applicable, individual concentrations of ACT-541468 in urine will be listed
per collection interval by dose and subject and summarized by dose presenting
number of observations, arithmetic mean, minimum, median, maximum, SD, SE,
CVb(%), and 95% CI of the means. Percentage of total dose excreted (unchanged
and metabolized) in urine and CLR will be similarly listed and summarized with
the exception that also the geometric mean and 95% CI will be provided.
Individual PD data will be listed by dose, formulation, and subject. At each
time point, absolute values and change from baseline of PD variables will be
summarized with arithmetic mean, median, SD, SE, 95% CI, minimum, and maximum.
The All-treated set will be used to perform all safety analyses.
All AEs and SAEs are to be coded using the MedDRA dictionary (Version 17.1 or a
more recent version, if available).
ECG abnormalities will be coded using the clinical data interchange standards
consortium terminology.
Safety and tolerability data will be listed and summarized descriptively.
Secondary outcome
NA
Background summary
The neuropeptides orexin-A and orexin-B are synthesized by a discrete number of
neurons (~3500 in rat, ~70,000 in man) in lateral hypothalamic areas (LHA) and
act at the interface of sleep, energy homeostasis, and reward/aversion systems
of the brain. Endogenous orexins activate two closely related G protein-coupled
receptors, the orexin-1 (OX1) and the orexin-2 (OX2) receptors, leading to
transient increases in intracellular calcium levels in projection neurons
expressing orexin receptors. In insomnia patients, the dual orexin receptor
antagonist almorexant dose-dependently increased sleep efficiency and total
sleep time by decreasing latency to persistent sleep and wake after sleep
onset. Repeat-dose animal studies showed no loss of efficacy over time. The
dual orexin receptor antagonist suvorexant is approved for the treatment of
insomnia characterized by difficulties with sleep onset and/or sleep
maintenance. Insomnia (as inappropriate nocturnal wakefulness) affects 10-15%
of the US population chronically, with up to a third suffering from it
occasionally. Insomnia has a wide range of effects on quality of life and is
associated with increased accident risk and chronic health problems. Currently,
standard insomnia treatments are mainly γ-aminobutyric acid-A receptor
modulators, which evoke sleep by increasing non-REM sleep but decreasing REM
sleep. They can also impair cognitive performance, locomotor skills, and
balance when waking. The latter is of particular concern for older adults as
falls are a primary cause of injury in this population. Orexin receptor
antagonists are expected to minimize these side effects, as orexin receptors
are not present in the cerebellum or in the vestibular nuclei, where balance
and locomotor activity are controlled. ACT-541468 is a potent and selective
orexin receptor antagonist that blocks the actions of the orexin neuropeptides
at both OX1 and OX2 receptors. The orexin system is involved in the regulation
of sleep and arousal by the central nervous system and is currently being
targeted in the development of new therapies for sleep disorders. ACT-541468
decreases wakefulness while maintaining natural sleep patterns in rat and dog
and, thus, is a potential candidate for the treatment of insomnia.
Study objective
• To evaluate the tolerability and safety of ascending single oral doses of
ACT-541468 in healthy male subjects.
• To investigate the single oral dose pharmacokinetic (PK) and PD of ACT-541468
in healthy male subjects.
• To investigate dose proportionality across different doses of ACT-541468.
• To evaluate the relative PK properties of two oral formulations of ACT-541468
after single-dose treatment in healthy male subjects.
• To investigate the absolute bioavailability of a single oral dose of
ACT-541468 compared to an i.v. 14C-labeled ACT-541468 tracer.
• To investigate the rate and routes of elimination of a single oral dose of a
14C-labeled ACT-541468 tracer and the mass balance in urine and feces.
• To investigate the PK of total radioactivity (tracer) in whole blood and in
plasma following oral administration of 14C-labeled ACT-541468.
• To identify and quantify ACT-541468 metabolites in plasma, urine, and feces.
Study design
This is a single-center, double-blind, randomized, placebo-controlled,
ascending single oral dose Phase 1 study. In addition, the study includes a
biocomparison part, an absolute bioavailability part, and a mass balance and
metabolism part. Each dose group will be investigated in a new group of eight
healthy male subjects (six on active drug and two on placebo). If seven dose
groups will be performed, 56 healthy male subjects will be enrolled.
Intervention
At each dose level, six subjects will receive a single oral dose of ACT-541468
(formulation A) and two subjects will receive a single oral dose of matching
placebo.
For the biocomparison part in the second dose group subjects will participate
in two different treatment periods, separated by a washout period of 10-14 days
between study drug administrations. In a double-blind, randomized, crossover
design six subjects will receive a single oral dose of ACT-541468 formulation A
and a single oral dose of ACT-541468 formulation B. Subjects on placebo (two)
will receive the matching placebos in both treatment periods.
Subjects in the absolute bioavailability part in the fourth dose group will
receive a single oral dose of ACT-541468 (formulation A) followed by 2.3 µg
(250 nCi) of the 14C-labeled ACT-541468 tracer as a short i.v. infusion.
Subjects in the mass balance part in the third dose group will receive a single
oral dose of ACT-541468 (formulation A) followed by 15 mL of 2.3 µg (250 nCi)
of the 14C-labeled ACT-541468 tracer orally.
Formulation A:
ACT-541468 as the hydrochloride salt, as hard capsules for oral administration
formulated at strengths of 5 mg, 25 mg, and 100 mg.
Formulation B:
ACT-541468 as the free base, lipid-based liquid-filled soft capsules for oral
administration formulated at the strength of 25 mg.
Study burden and risks
Burden:
-The subjects will remain fasted from at least 10 h prior to (each) study drug
administration until 3.5 h thereafter.
-The intake of liquids is not allowed from 1 h before until 1 h after oral
study drug administration.
-Smoking and consumption of any grapefruit or grapefruit juice is not permitted
from screening until the EOS. Drinking of alcoholic beverages and xanthine
containing beverages (e.g., coffee, tea, cola, cocoa, Red Bull) or food is not
permitted from at least 48 h prior to clinic admission and during the treatment
period(s).
-From screening until the EOS, the subjects must refrain from strenuous
physical exercise, physical work, strenuous sports activities (endurance
sports), and activities disturbing the circadian rhythm.
-On the day(s) of the study drug administration, the subjects must remain in a
sitting position from approximately 5 min before and until 4 h after intake of
study drug, except for the body sway measurement (conducted in standing
position), measurement of vital signs (two pre-dose measurements, conducted in
supine position), ECG and EEG (conducted in supine position), or going to the
toilet.
-Subjects will have to perform different pharmacodynamic tests and
questionnaires.
Risk:
-In animal studies with ACT-541468 at very high doses (much higher than used in
this study) a drop in body temperature and heart rate was seen. We will measure
your heart rate, body temperature and blood pressure regularly during the study.
-At these high doses there were also some effects observed on the liver. As a
result of this, the liver increased in size. We will measure liver function by
analyzing blood samples during the study.
-As ACT-541468 has not been tested in humans so far, not all side effects are
known yet. Based on the fact that it is being developed as a sleeping agent,
effects associated with this could be: drowsiness, dizziness, fatigue and
decreased alertness. More severe effects could be narcolepsy like symptoms,
cataplexy, or weak muscle tone. There may also be unexpected side effects.
-The radioactive exposure risk is minimal in this study because of the very
small planned radioactive dose (a tracer) of 9.25 kilobecquerel (kBq),
corresponding to 250 nanocurie (nCi) to be administered. As the average adult
human body contains as natural 14C background around 100 nCi [Turteltaub 2000,
Lappin 2010], a transient exposure to 250 nCi of a 14C-labeled compound is
considered very safe - essentially comprising a negligible level of radiation.
Therefore, regulatory authorities do not require a formal application with
animal dosimetry data to allow such low level of 14C-study in human subjects
[Lappin 2010, Sarapa 2005, ICH guideline M3 2009].
Gewerbestrasse 16
Allschwil CH-4123
CH
Gewerbestrasse 16
Allschwil CH-4123
CH
Listed location countries
Age
Inclusion criteria
• Signed informed consent in the local language prior to any study-mandated procedure.
• 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 (BMI) between 18.0 and 30.0 kg/m2 (inclusive) at screening.
• Systolic blood pressure 100-145 mmHg, diastolic blood pressure 50-90 mmHg, and pulse rate 45-90 bpm (inclusive) measured at screening on the dominant arm after 5 min in supine position.
• 12-lead ECG without clinically relevant abnormalities in supine position at screening.
• Negative results from alcohol breath test and urine drug screen at screening and at Day 1.
• Ability to communicate well with the investigator in the local language, and to understand and comply with the requirements of the study.
• Only for subjects in the mass balance and metabolism part (third dose group): subjects must have a regular (daily) defecation pattern.
Exclusion criteria
• Previous history of fainting, collapse, syncope, orthostatic hypotension, or vasovagal reactions.
• Veins unsuitable for i.v. 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 (OTC) 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 (appendectomy and herniotomy allowed; cholecystectomy not allowed).
• Excessive caffeine consumption, defined as >= 800 mg per day at screening.
• Smoking within 3 months prior to screening and inability to refrain from smoking during the course of the study (from screening to EOS).
• 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 HIV serology at screening.
• Known hypersensitivity to any excipients of the drug formulations.
• Modified Swiss Narcolepsy Scale total score < 0 at screening or history of narcolepsy or cataplexy.
• 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 at screening.
• Only for subjects in the mass balance and metabolism part (third dose group) or the absolute bioavailability part (fourth dose group): Radiation exposure, including that from the present study, excluding background radiation but including diagnostic rays and other medical exposures, exceeding 5 mSv in the last 12 months or 10 mSv in the last 5 years. Occupationally exposed workers, as defined in the relevant Ionisation Radiation Regulations, must not participate in the study.
• Participation in any study involving administration of any 14C-labeled compound within 12 months prior to screening.
• For subjects in the mass balance and metabolism part (third dose group): Clinically relevant constipation (defined as lasting more than 3 days) in the 4-week period before screening.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-003129-16-NL |
| CCMO | NL51750.056.14 |