Primary objective- To evaluate the effects of ACT-541468 on objective simulated driving performance, i.e., the standard deviation of the lateral position (SDLP), after single- and multiple dose administrations (i.e., on Day 1 and Day 4) in the…
ID
Source
Brief title
Condition
- Sleep disorders and disturbances
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Driving performance as measured by the SDLP (difference from placebo, cm) on
Day 2 and 5 at 9 h post dose following administration of ACT-541468.
Secondary outcome
Effects of ACT-541468 on Days 2 and 5 on other driving performance parameters 9
h post dose:
- Mean lateral position (MLP).
- Mean speed (MS).
- SD of the mean speed (SDMS).
- Number of lapses (lapses are short periods of inattention and reduced
alertness which may be a risk factor for car crashes. A lapse is defined as
change from the steady lateral position of * 100 cm for * 4 s.)
- Drive safety score (DSS), a 24-item composite safety score.
- Subjective driving performance and effort scale.
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 WHO has identified motor vehicle accidents (MVAs) as one of the major
causes of injury and death around the world [who.int]. An important factor
contributing to traffic accidents is inattention of the driver due to reduced
alertness or increased sleepiness. It has been estimated that
fatigue/sleepiness plays a role in 10*30 % of traffic accidents [Horne 1995,
Maycock 1996, Verster 2003]. In the US, the FDA considers the reduction of the
incidence of MVAs that occur because of drug-impaired driving a public health
priority [FDA 2017]. Assessing the ability to operate a motor vehicle following
drug intake is a critical component of the FDA-guided assessment of drug risks
and related strategies to reduce these risks.
Drugs that have pronounced CNS impairing effects and are intended to be
administered primarily at night are of concern because residual daytime effects
can impair driving ability [FDA 2017].Driving studies that included the dual
orexin receptor antagonist suvorexant have been performed in non-elderly
[Vermeeren 2015] and elderly subjects [Vermeeren 2016], with no clinically
meaningful residual effects as assessed by overall mean changes of the SDLP.
However, some individuals in the non-elderly study who were treated with
suvorexant had to stop the next-day driving test due to drowsiness [Vermeeren
2015].
Following oral administration, ACT-541468 has been shown to cause distinct
adverse effects on the CNS due to the drug*s expected pharmacological effects
[Section 1.2.2]. Therefore, the next level of evaluation in this tiered
approach [FDA 2017] is the application of various driving tasks to assess the
potential effects of ACT-541468 on the ability to drive a car in the morning
after evening administration.
Study objective
Primary objective
- To evaluate the effects of ACT-541468 on objective simulated driving
performance, i.e., the standard deviation of the lateral position (SDLP), after
single- and multiple dose administrations (i.e., on Day 1 and Day 4) in the
evening.
Secondary and exploratory objectives
- To evaluate the effects of ACT-541468 on other objective simulated driving
performance parameters.
- To evaluate the effects of ACT-541468 on subjective simulated driving
performance.
- To evaluate the potential relationship between driving performance parameters
and plasma concentrations of ACT-541468.
- To evaluate tolerability and safety of multiple oral doses of ACT-541468
(multiple oral doses) and zopiclone (two separate doses).
Study design
This is a single-center, randomized, double-blind, double-dummy, placebo- and
active-controlled, 4-way cross-over study.
Intervention
Subject will be randomized into any of the four treatment sequences (A, B, C,
D) in a cross-over fashion.
A: ACT-541468 50 mg, zopiclone 7.5 mg, Placebo, ACT-541468 100 mg
B: ACT-541468 100 mg, Placebo, zopiclone 7.5 mg, ACT-541468 50 mg
C: zopiclone 7.5 mg, ACT-541468 100 mg, ACT-541468 50 mg, Placebo
D: Placebo, ACT-541468 50 mg, ACT-541468 100 mg, zopiclone 7.5 mg
Study burden and risks
Administration of ACT-541468 has been evaluated in several preclinical
toxicology and pharmacology studies and in phase I and phase 2 studies.
ACT-541468 was found to be generally safe and well tolerated. lt is however,
unsure what the effect on next-day driving ability is. This study will provide
valuable human data on driving ability, both objectively as well as
subjectively. 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 CHD-4123
CH
Hegenheimermattweg 91
Allschwil CHD-4123
CH
Listed location countries
Age
Inclusion criteria
1. Be male or female (of nonchildbearing potential) aged 50 to 80 years, inclusive, at the Screening Visit.
2. Have a body mass index *18.5 and *30.0 kg/m2 at the Screening Visit.
3. Be judged to be in good health by the investigator, based on clinical evaluations including laboratory safety
tests, medical history, physical examination and vital sign measurements performed at the
screening visit and before the first dose of study drug.
Exclusion criteria
1. Pregnant or lactating women.
2. Known hypersensitivity to ACT-541468, zopiclone, or treatments of the same class, or any of their excipients.
3. Unstable medical condition, significant medical disorder, or acute illness within 2 months prior to Screening.
4. Current heavy tobacco user (* 15 cigarettes per day) or smoker with an urge to wake up during the night to smoke.
5. No history of narcolepsy, cataplexy or fainting.
6. Mini Mental State Examination (MMSE) score < 25 at Screening.
7. Current or previous diagnosis of insomnia-related disorder according to the Diagnostic and Statistical Manual of Mental Disorders version 5 (DSM-5) criteria.
8. Modified Swiss Narcolepsy Scale total score < 0 at Screening.
9. Activities that disturb the circadian rhythm (e.g., working night shift, travelling across 3 time zones) within 2 weeks before (each) study treatment.
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 | EUCTR2018-003773-97-NL |
| CCMO | NL68520.056.19 |