To evaluate the pharmacodynamic (PD) effects of the study treatments (ACT-541468 50 mg, ethanol at a blood level of 0.6 g/L for 5 h) as co-administration in 4 different combinations (ACT-541468 plus ethanol, ACT-541468 alone, ethanol alone, and…
ID
Source
Brief title
Condition
- Sleep disorders and disturbances
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Change from baseline for:
* Saccadic peak velocity (degrees/sec) to assess sedation.
* Smooth pursuit (%) to assess eye movement coordination and attention.
* Adaptive tracking (%) to assess visuo-motor control and vigilance.
* Body sway (antero-posterior in mm / 2 min) to assess postural stability.
* Visual analog scales (VAS) Bond & Lader to assess subjective alertness, mood,
and calmness.
* VAS for alcohol intoxication to assess subjective effects of ethanol.
Secondary outcome
ACT-541468 PK endpoints for treatments A and B:
* The area under the plasma concentration-time curve (AUC) from time zero to 24
h (AUC0*24).
* The AUC from zero to infinity (AUC0**).
* The maximum plasma concentration (Cmax).
* The time to reach Cmax (tmax).
* The terminal elimination half-life (t*).
Ethanol PK endpoints for treatments A and C:
* Breath ethanol concentrations (BrEC).
* Total ethanol dose (in grams) required to maintain the 0.6 g/L ethanol clamp.
Safety endpoints:
* Treatment-emergent AEs from study treatment administration up to EOT in each
treatment period.
* Treatment-emergent SAEs from study treatment administration up to EOT in each
treatment period.
Background summary
The neuropeptides orexin-A and orexin-B are synthesized in the lateral
hypothalamic areas [De Lecea 1998] and activate the orexin-1 and orexin-2
receptors [Kilduff 2000]. Nerve fibers from orexin neurons make projections to
the basal forebrain, corticolimbic structures, and brainstem, particularly to
those regions related to waking and regulation of sleep [Hagan 1999, Sakurai
2007]. Infusing exogenous orexins into cerebral ventricles in rats leads to
enhanced behavioral activity, arousal, delayed onset of sleep, and maintenance
of cortical activation
ACT-541468 is a new potent and selective compound that blocks the actions of
the orexin neuropeptides at both orexin-1 and orexin-2 receptors. Due to the
wide connections of the orexin system with brain areas involved in
sleep/arousal regulation, ACT-541468 is being evaluated for the treatment of
insomnia disorders. In humans, ACT-541468 has a dose-dependent effect on wake
after sleep onset (WASO) and shows pharmacodynamic effects on a battery of CNS
tests, including adaptive tracking, VAS alertness and body sway. In contrast to
the commonly used drugs (e.g. benzodiazepines) for the treatment of insomnia,
ACT-541468 preserves a normal sleep architecture.
Ethanol is often used by insomnia patients as self-medication to help them
falling asleep. It is currently unknown if there is an interaction between
ACT-541468 and ethanol. And in case there is an interaction, whether this
results in additive or synergistic effects. Therefore, a clinical study to
investigate the possible interaction of ACT-541468 and ethanol on PK and PD has
strong relevance.
Study objective
To evaluate the pharmacodynamic (PD) effects of the study treatments
(ACT-541468 50 mg, ethanol at a blood level of 0.6 g/L for 5 h) as
co-administration in 4 different combinations (ACT-541468 plus ethanol,
ACT-541468 alone, ethanol alone, and placebo) in healthy subjects.
To explore the magnitude of interaction effect between ACT-541468 and ethanol
on PD variables.
To evaluate the potential pharmacokinetic (PK) interactions between a single
dose of ACT-541468 (50 mg) and ethanol (at a blood level of 0.6 g/L for 5h) in
healthy subjects.
To evaluate the safety and tolerability of the co-administration of a single
dose of ACT-541468 (50 mg) and ethanol (at a blood level of 0.6 g/L for 5 h) in
healthy subjects.
Study design
Single-center, double-blind, randomized, placebo-controlled, double-dummy, 2x2
factorial design, four-way crossover Phase 1 study.
Intervention
There will be 4 study treatments (A, B, C, and D) and each subject will receive
all 4 treatments in a blinded crossover fashion. Each subject will be
randomized to one of the sequences defined using a Williams square design
balanced for first order carry-over effects.
Treatment A (ethanol + ACT-541468) will consist of a 5 h i.v. ethanol clamp at
a level of 0.6 g/L in combination with a single oral dose of ACT-541468 (50 mg).
Treatment B (ethanol placebo + ACT-541468) will consist of a 5 h i.v. placebo
clamp in combination with a single oral dose of ACT-541468 (50 mg).
Treatment C (ethanol + ACT-541468 placebo) will consist of a 5 h i.v. ethanol
clamp at a level of 0.6 g/L in combination with a single oral dose of matching
ACT-541468 placebo.
Treatment D (ethanol placebo + ACT-541468 placebo) will consist of a 5 h i.v.
placebo clamp in combination with a single oral dose of matching ACT-541468
placebo.
Study burden and risks
Administration of ACT-541468 has been evaluated in several preclinical
toxicology and pharmacology studies and in phase 1 and phase 2 studies.
ACT-541468 was found to be generally safe and well tolerated. It is however,
unsure how it will interact with ethanol, a substance that is often used as
self-medication by insomnia patients.
This study will provide valuable human data on the safety, tolerability,
pharmacokinetics and pharmacodynamis of ACT-541468 when given in combination
with ethanol. This data will be of critical importance for further development
of this compound for treatment of insomnia. Thus, it is felt that the potential
benefits of the study as part of the development plan for insomnia exceed the
risks. Subjects will be carefully screened and monitored.
Hegenheimermattweg 91
Allschwil CH-4123
CH
Hegenheimermattweg 91
Allschwil CH-4123
CH
Listed location countries
Age
Inclusion criteria
1. Signed informed consent in a language understandable to the subject prior to any study-mandated procedure.
2. Healthy male and female subjects aged between 18 and 45 years (inclusive) at screening.
3. Women of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test on Day 1 pre-dose of each treatment period. They must consistently and correctly use (from screening, during the entire study, and for at least 90 days after last study treatment intake) a reliable method of contraception with a failure rate of <1% per year, be sexually inactive, or have a vasectomized partner. If a hormonal contraceptive is used, it must be initiated at least 1 month before first treatment administration.
4. Women of non-childbearing potential (i.e., postmenopausal [defined as 12 consecutive months with no menses without an alternative medical cause, confirmed by a follicle-stimulating hormone test], with previous bilateral salpingectomy, bilateral salpingo-oophorectomy or hysterectomy, or with premature ovarian failure [confirmed by a specialist], XY genotype, Turner syndrome, uterine agenesis).
5. Body mass index of 18.0 to 32.0 kg/m2 (inclusive) at screening.
6. No clinically relevant findings on the physical examination at screening.
7. Systolic blood pressure 100-145 mmHg, diastolic blood pressure 50-90 mmHg, and pulse rate 45-90 bpm (inclusive), measured on either arm, after 5 min in the supine position at screening.
8. 12-lead ECG without clinically relevant abnormalities, measured after 5 min in the supine position at screening.
9. No clinically relevant findings in clinical laboratory tests (hematology, clinical chemistry, and urinalysis) at screening.
10. Negative results from urine drug screen and breath alcohol test at screening and on Day 1 pre-dose.
11. Ability to communicate well with the investigator, in a language understandable to the subject, and to understand and comply with the requirements of the study.
12. Previous experience with alcohol consumption and, therefore, familiar with the effects of alcohol.
Exclusion criteria
1. Pregnant or lactating women.
2. Known hypersensitivity to ACT-541468 or treatments of the same class, or any of its excipients.
3. History of major medical or surgical disorders, which in the opinion of the investigator, are likely to interfere with the absorption, distribution, metabolism, or excretion of the study treatment(s) (appendectomy and herniotomy allowed, cholecystectomy not allowed).
4. Acute, ongoing, recurrent, or chronic systemic disease able to interfere with the evaluation of the study.
5. Previous history of fainting, collapse, syncope, orthostatic hypotension, or vasovagal reactions.
6. Veins unsuitable for intravenous (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).
7. Participation in a clinical study involving study treatment administration within 3 months prior to screening or in more than 4 clinical studies within 1 year prior to screening.
8. Excessive caffeine consumption, defined as 800 mg per day at screening
9. Nicotine intake (e.g., smoking, nicotine patch, nicotine chewing gum, or electronic cigarettes) within 3 months prior to screening and inability to refrain from nicotine intake from screening until End-of-Study (EOS).
10. Previous treatment with any prescribed medications (including vaccines) or over-the-counter (OTC) medications (including herbal medicines such as St John*s Wort, homeopathic preparations, vitamins, and minerals) within 2 weeks prior to first study treatment administration.
11. Loss of 250 mL or more of blood within 3 months prior to screening.
12. Positive results from the hepatitis serology, except for vaccinated subjects or subjects with past but resolved hepatitis, at screening.
13. Positive results from the HIV serology at screening.
14. Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol.
15. Legal incapacity or limited legal capacity at screening.
16. History or clinical evidence of alcoholism or drug abuse.
17. History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of more than 21 units or an average daily intake of more than 3 units (males), or defined as an average weekly intake of more than 14 units or an average daily intake of more than 2 units (females). One unit is equivalent to a half-pint (220 mL) of beer or 1 measure (25 mL) of spirits or 1 glass (125 mL) of wine.
18. Individuals of Asian descent or other individuals reporting ethanol intolerance (Asian descent defined as 1 or more parents or grandparents of Asian origin).
19. Modified Swiss Narcolepsy Scale total score < 0 at screening or history of narcolepsy or cataplexy.
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 | EUCTR2018-001871-19-NL |
| CCMO | NL66145.056.18 |