Efficacy and Safety of ACT-541468 in Elderly Subjects With Insomnia Disorder

• Sponsor: Idorsia Pharmaceuticals Ltd. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02841709
• Collaborator: (none)
• Enrollment: 58
• Locations: 10
• Arms: 5
• Actual Duration (Months): 7
• Patients Per Site: 5.8
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

This study evaluates the dose response of ACT-541468 on the change of wake after sleep onset (WASO) assessed by polysomnography (PSG) on the first 2 days of each treatment period.

Condition or Disease	Intervention/Treatment	Phase
Insomnia Disorder	Drug: ACT-541468; Drug: Placebo	Phase 2

Detailed Description

The study consists of 3 phases: a screening phase, a double-blind treatment phase consisting of 5 periods, and a safety follow-up phase. Safety is monitored throughout the study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 58 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Multi-center, Double-blind, Randomized, Placebo-controlled, 5-period, 5-treatment Crossover, Polysomnography Dose-response Study to Assess the Efficacy and Safety of ACT-541468 in Elderly Subjects With Insomnia Disorder
• Actual Study Start Date: Nov 28, 2016
• Actual Primary Completion Date: May 31, 2017
• Actual Study Completion Date: Jun 29, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sequence 1 Each subject participates in 5 treatment periods. On the evening of the first 2 days of each period they receive one dose (D) of ACT-541468 or placebo orally in the following order: D4, D2, D3, D1 and P, with D4 = the highest dose (50 mg) and D1 the lowest dose (5 mg). Each treatment period is separated from the next one by a 5- to 12-day washout.	Drug: ACT-541468; Capsules for oral administration containing ACT-541468 at a strength of 5 mg, 10 mg or 25 mg; Drug: Placebo; Capsules for oral administration matching the ACT-541468 capsules
Experimental: Sequence 2 Each subject participates in 5 treatment periods. On the evening of the first 2 days of each period they receive one dose (D) of ACT-541468 or placebo orally in the following order: D2, P, D4, D3 and D1, with D4 = the highest dose (50 mg) and D1 the lowest dose (5 mg). Each treatment period is separated from the next one by a 5- to 12-day washout.	Drug: ACT-541468; Capsules for oral administration containing ACT-541468 at a strength of 5 mg, 10 mg or 25 mg; Drug: Placebo; Capsules for oral administration matching the ACT-541468 capsules
Experimental: Sequence 3 Each subject participates in 5 treatment periods. On the evening of the first 2 days of each period they receive one dose (D) of ACT-541468 or placebo orally in the following order: D3, D1, D2, P and D4, with D4 = the highest dose (50 mg) and D1 the lowest dose (5 mg). Each treatment period is separated from the next one by a 5- to 12-day washout.	Drug: ACT-541468; Capsules for oral administration containing ACT-541468 at a strength of 5 mg, 10 mg or 25 mg; Drug: Placebo; Capsules for oral administration matching the ACT-541468 capsules
Experimental: Sequence 4 Each subject participates in 5 treatment periods. On the evening of the first 2 days of each period they receive one dose (D) of ACT-541468 or placebo orally in the following order: P, D4, D1, D2, D3, with D4 = the highest dose (50 mg) and D1 the lowest dose (5 mg). Each treatment period is separated from the next one by a 5- to 12-day washout.	Drug: ACT-541468; Capsules for oral administration containing ACT-541468 at a strength of 5 mg, 10 mg or 25 mg; Drug: Placebo; Capsules for oral administration matching the ACT-541468 capsules
Experimental: Sequence 5 Each subject participates in 5 treatment periods. On the evening of the first 2 days of each period they receive one dose (D) of ACT-541468 or placebo orally in the following order: D1, D3, P, D4 and D2 with D4 = the highest dose (50 mg) and D1 the lowest dose (5 mg). Each treatment period is separated from the next one by a 5- to 12-day washout.	Drug: ACT-541468; Capsules for oral administration containing ACT-541468 at a strength of 5 mg, 10 mg or 25 mg; Drug: Placebo; Capsules for oral administration matching the ACT-541468 capsules

Outcome Measures

Primary Outcome Measures

1. Change in Wake After Sleep Onset (WASO) From Baseline to Days 1 and 2 [Baseline to Day 1 and Day 2 of each treatment period]

   WASO is the time in minutes spent awake after onset of persistent sleep until lights on as determined by polysomnography (PSG)

Secondary Outcome Measures

1. Change in Mean Latency to Persistent Sleep (LPS) From Baseline to Days 1 and 2 [Baseline to Day 1 and Day 2 of each treatment period]

   LPS is the duration of time in minutes from lights off to persistent sleep onset as determined by PSG

Eligibility Criteria

Criteria

• Ages Eligible for Study: 65 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Signed informed consent prior to any study-mandated procedure.

• Male or female aged ≥ 65 years.

• Body mass index (BMI): 18.5 ≤ BMI (kg/m2 ) < 32.0

• Insomnia disorder according to DSM-5 criteria.

• Self-reported history of insufficient sleep quantity.

• Insufficient sleep quantity as collected subjectively in the sleep diary and validated objectively by polysomnography.

• Insomnia Severity Index score ≥ 15.

Exclusion Criteria:

• Any current history of sleep disorder other than insomnia, or any lifetime history of related breathing disorder, periodic limb movement disorder, restless legs syndrome, circadian rhythm disorder, rapid eye movement (REM) behavior disorder, or narcolepsy.

• Self-reported usual daytime napping ≥ 1 hour per day, and ≥ 3 days per week.

• Caffeine consumption ≥ 600 mg per day.

• Shift work within 2 weeks prior to the screening visit, or planned shift work during study.

• Travel ≥ 3 time zones within 1 week prior to the screening visit, or planned travel ≥ 3 time zones during study.

• Hematology or biochemistry test results deviating from the normal range to a clinically relevant extent as per judgment of the Investigator.

• AST and/or ALT > 2 × ULN and/or bilirubin > 1.5 × ULN (except known history of Gilbert's syndrome);

• Severe renal impairment (known or defined as estimated creatinine clearance < 30 mL/min);

• History or clinical evidence of any disease or medical condition or treatment, which may put the subject at risk of participation in the study or may interfere with the study assessments.

• Any circumstances or conditions, which, in the opinion of the investigator, may affect the subject's full participation in the study or compliance with the protocol.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Investigator Site	Brandon	Florida	United States	33511
2	Investigator Site	Chicago	Illinois	United States	60634
3	Investigator Site	Las Vegas	Nevada	United States	89104
4	Investigator Site	New York	New York	United States	10019
5	Investigator Site	Cincinnati	Ohio	United States	45255
6	Investigator Site	Berlin		Germany	10115
7	Investigator Site	Berlin		Germany	10117
8	Investigator Site	Hamburg		Germany	20253
9	Investigator Site	Hannover		Germany	30159
10	Investigator Site	Schwerin		Germany	19053

Sponsors and Collaborators

• Idorsia Pharmaceuticals Ltd.

Investigators

• Study Director: Clinical Trials, Idorsia Pharmaceuticals Ltd.

Study Documents (Full-Text)

• Study Protocol - Aug 10, 2016
• Statistical Analysis Plan - Jul 12, 2017

More Information

Publications

None provided.

• Responsible Party: Idorsia Pharmaceuticals Ltd.
• ClinicalTrials.gov Identifier: NCT02841709
• Other Study ID Numbers: AC-078A202
• First Posted: Jul 22, 2016
• Last Update Posted: Apr 24, 2020
• Last Verified: Apr 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Idorsia Pharmaceuticals Ltd.: insomnia; elderly; Polysomnography
• Additional relevant MeSH terms: Sleep Initiation and Maintenance Disorders

Study Results

Participant Flow

Recruitment Details	Conducted at 10 centers in 2 countries (USA and Germany)
Pre-assignment Detail	Screening phase: From informed consent to randomization, lasting a max. of 28 days and comprising a screening period (screening visit + at least 7 days at home) and a run-in period (2 consecutive PSG nights on SB placebo, + 5-12 days at home with no treatment). Note: More subjects were randomized (n = 58) than originally planned (n = 50).

Arm/Group Title	Sequence 1 (D4, D2, D3, D1 and P)	Sequence 2 (D2, P, D4, D3 and D1)	Sequence 3 (D3, D1, D2, P and D4)	Sequence 4 (P, D4, D1, D2 and D3)	Sequence 5 (D1, D3, P, D4 and D2)
Arm/Group Description	Each subject participated in 5 treatment periods. On the evening of the first 2 days of each period they received one dose (D) of ACT-541468 or placebo orally in the following order: D4, D2, D3, D1 and P, with D4 = the highest dose (50 mg) and D1 the lowest dose (5 mg). Each treatment period was separated from the next one by a 5- to 12-day washout.	Each subject participated in 5 treatment periods. On the evening of the first 2 days of each period they received one dose (D) of ACT-541468 or placebo orally in the following order: D2, P, D4, D3 and D1, with D4 = the highest dose (50 mg) and D1 the lowest dose (5 mg). Each treatment period was separated from the next one by a 5- to 12-day washout.	Each subject participated in 5 treatment periods. On the evening of the first 2 days of each period they received one dose (D) of ACT-541468 or placebo orally in the following order: D3, D1, D2, P and D4, with D4 = the highest dose (50 mg) and D1 the lowest dose (5 mg). Each treatment period was separated from the next one by a 5- to 12-day washout.	Each subject participated in 5 treatment periods. On the evening of the first 2 days of each period they received one dose (D) of ACT-541468 or placebo orally in the following order: P, D4, D1, D2, and D3, with D4 = the highest dose (50 mg) and D1 the lowest dose (5 mg). Each treatment period was separated from the next one by a 5- to 12-day washout.	Each subject participated in 5 treatment periods. On the evening of the first 2 days of each period they received one dose (D) of ACT-541468 or placebo orally in the following order: D1, D3, P, D4 and D2 with D4 = the highest dose (50 mg) and D1 the lowest dose (5 mg). Each treatment period was separated from the next one by a 5- to 12-day washout.
Period Title: 1st Intervention
STARTED	12	11	12	12	11
COMPLETED	12	11	12	12	11
NOT COMPLETED	0	0	0	0	0
Period Title: 1st Intervention
STARTED	12	11	12	12	11
COMPLETED	12	11	12	12	11
NOT COMPLETED	0	0	0	0	0
Period Title: 1st Intervention
STARTED	12	11	12	12	11
COMPLETED	12	11	12	12	11
NOT COMPLETED	0	0	0	0	0
Period Title: 1st Intervention
STARTED	12	11	12	12	11
COMPLETED	12	11	12	12	11
NOT COMPLETED	0	0	0	0	0
Period Title: 1st Intervention
STARTED	12	11	12	12	11
COMPLETED	12	11	12	12	11
NOT COMPLETED	0	0	0	0	0
Period Title: 1st Intervention
STARTED	12	11	12	12	11
COMPLETED	12	11	12	12	11
NOT COMPLETED	0	0	0	0	0
Period Title: 1st Intervention
STARTED	12	11	12	12	11
COMPLETED	12	11	12	12	11
NOT COMPLETED	0	0	0	0	0
Period Title: 1st Intervention
STARTED	12	11	12	12	11
COMPLETED	12	11	12	12	11
NOT COMPLETED	0	0	0	0	0
Period Title: 1st Intervention
STARTED	12	11	12	12	11
COMPLETED	10	11	12	12	9
NOT COMPLETED	2	0	0	0	2

Baseline Characteristics

Arm/Group Title	All Study Participants
Arm/Group Description	Each subject participated in 5 treatment periods. On the evening of the first 2 days of each period they received one dose (D) of ACT-541468 or placebo orally in the following order: D4, D2, D3, D1 and P, with D4 = the highest dose (50 mg) and D1 the lowest dose (5 mg). Each treatment period was separated from the next one by a 5- to 12- day washout. ACT-541468: Capsules for oral administration containing ACT-541468 at a strength of 5 mg, 10 mg or 25 mg Placebo: Capsules for oral administration matching the ACT-541468 capsules
Overall Participants	58
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	57 98.3%
>=65 years	1 1.7%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	69
Sex: Female, Male (Count of Participants)
Female	39 67.2%
Male	19 32.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 1.7%
Not Hispanic or Latino	57 98.3%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 1.7%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	3 5.2%
White	54 93.1%
More than one race	0 0%
Unknown or Not Reported	0 0%
Insomnia Severity Index (units on a scale) [Mean (Full Range) ]
Mean (Full Range) [units on a scale]	20

Outcome Measures

1. Primary Outcome

Title	Change in Wake After Sleep Onset (WASO) From Baseline to Days 1 and 2
Description	WASO is the time in minutes spent awake after onset of persistent sleep until lights on as determined by polysomnography (PSG)
Time Frame	Baseline to Day 1 and Day 2 of each treatment period

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ACT-541468 5 mg	ACT-541468 10 mg	ACT-541468 25 mg	ACT-541468 50 mg	Placebo
Arm/Group Description	Each subject participated in 5 treatment periods. On the evening of the first 2 days of each period they received one dose (D) of ACT-541468 or placebo orally in the following order: D4, D2, D3, D1 and P, with D4 = the highest dose (50 mg) and D1 the lowest dose (5 mg). Each treatment period was separated from the next one by a 5- to 12- day washout. ACT-541468: Capsules for oral administration containing ACT-541468 at a strength of 5 mg, 10 mg or 25 mg Placebo: Capsules for oral administration matching the ACT-541468 capsules	Each subject participated in 5 treatment periods. On the evening of the first 2 days of each period they received one dose (D) of ACT-541468 or placebo orally in the following order: D4, D2, D3, D1 and P, with D4 = the highest dose (50 mg) and D1 the lowest dose (5 mg). Each treatment period was separated from the next one by a 5- to 12- day washout. ACT-541468: Capsules for oral administration containing ACT-541468 at a strength of 5 mg, 10 mg or 25 mg Placebo: Capsules for oral administration matching the ACT-541468 capsules	Each subject participated in 5 treatment periods. On the evening of the first 2 days of each period they received one dose (D) of ACT-541468 or placebo orally in the following order: D4, D2, D3, D1 and P, with D4 = the highest dose (50 mg) and D1 the lowest dose (5 mg). Each treatment period was separated from the next one by a 5- to 12- day washout. ACT-541468: Capsules for oral administration containing ACT-541468 at a strength of 5 mg, 10 mg or 25 mg Placebo: Capsules for oral administration matching the ACT-541468 capsules	Each subject participated in 5 treatment periods. On the evening of the first 2 days of each period they received one dose (D) of ACT-541468 or placebo orally in the following order: D4, D2, D3, D1 and P, with D4 = the highest dose (50 mg) and D1 the lowest dose (5 mg). Each treatment period was separated from the next one by a 5- to 12- day washout. ACT-541468: Capsules for oral administration containing ACT-541468 at a strength of 5 mg, 10 mg or 25 mg Placebo: Capsules for oral administration matching the ACT-541468 capsules	Each subject participated in 5 treatment periods. On the evening of the first 2 days of each period they received one dose (D) of ACT-541468 or placebo orally in the following order: D4, D2, D3, D1 and P, with D4 = the highest dose (50 mg) and D1 the lowest dose (5 mg). Each treatment period was separated from the next one by a 5- to 12- day washout. ACT-541468: Capsules for oral administration containing ACT-541468 at a strength of 5 mg, 10 mg or 25 mg Placebo: Capsules for oral administration matching the ACT-541468 capsules
Measure Participants	56	54	55	56	54
Least Squares Mean (Standard Error) [minutes]	-18.9 (4.44)	-32.0 (4.50)	-45.1 (4.47)	-61.4 (4.44)	-13.6 (4.50)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ACT-541468 5 mg, ACT-541468 10 mg, ACT-541468 25 mg, ACT-541468 50 mg, Placebo
	Comments	Multiple Comparison Procedure-Modeling (MCP-Mod) was used to assess a dose response across placebo and all ACT-541468 doses. The null hypothesis of "no dose response" was rejected if at least one of the six Multiple Contrasts Tests (MCTs) had a multiplicity adjusted p-value <0.05. The analysis was performed using the R-package "DoseFinding" (Bornkamp B, Pinheiro J, Bretz F. Planning and analyzing dose finding experiments. 2016. Available from: cranrprojects.org/web/packages/DoseFinding.)
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Multiple Comparison Procedure-Model
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	ACT-541468 5 mg, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.258
	Comments
	Method	Linear mixed effects model
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-5.4
	Confidence Interval	(2-Sided) 95%; -14.7 to 4.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.73
	Estimation Comments	Parameter Dispersion Type: Standard Error of the LS Mean

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	ACT-541468 10 mg, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Linear mixed effects model
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-18.4
	Confidence Interval	(2-Sided) 95%; -27.8 to -9.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.76
	Estimation Comments	Parameter Dispersion Type: Standard Error of the LS Mean

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	ACT-541468 25 mg, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Linear mixed effects model
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-31.5
	Confidence Interval	(2-Sided) 95%; -40.9 to -22.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.74
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	ACT-541468 50 mg, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Linear mixed effects model
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-47.8
	Confidence Interval	(2-Sided) 95%; -57.2 to -38.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.74
	Estimation Comments

2. Secondary Outcome

Title	Change in Mean Latency to Persistent Sleep (LPS) From Baseline to Days 1 and 2
Description	LPS is the duration of time in minutes from lights off to persistent sleep onset as determined by PSG
Time Frame	Baseline to Day 1 and Day 2 of each treatment period

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ACT-541468 5 mg	ACT-541468 10 mg	ACT-541468 25 mg	ACT-541468 50 mg	Placebo
Arm/Group Description	Each subject participated in 5 treatment periods. On the evening of the first 2 days of each period they received one dose (D) of ACT-541468 or placebo orally in the following order: D4, D2, D3, D1 and P, with D4 = the highest dose (50 mg) and D1 the lowest dose (5 mg). Each treatment period was separated from the next one by a 5- to 12- day washout. ACT-541468: Capsules for oral administration containing ACT-541468 at a strength of 5 mg, 10 mg or 25 mg Placebo: Capsules for oral administration matching the ACT-541468 capsules	Each subject participated in 5 treatment periods. On the evening of the first 2 days of each period they received one dose (D) of ACT-541468 or placebo orally in the following order: D4, D2, D3, D1 and P, with D4 = the highest dose (50 mg) and D1 the lowest dose (5 mg). Each treatment period was separated from the next one by a 5- to 12- day washout. ACT-541468: Capsules for oral administration containing ACT-541468 at a strength of 5 mg, 10 mg or 25 mg Placebo: Capsules for oral administration matching the ACT-541468 capsules	Each subject participated in 5 treatment periods. On the evening of the first 2 days of each period they received one dose (D) of ACT-541468 or placebo orally in the following order: D4, D2, D3, D1 and P, with D4 = the highest dose (50 mg) and D1 the lowest dose (5 mg). Each treatment period was separated from the next one by a 5- to 12- day washout. ACT-541468: Capsules for oral administration containing ACT-541468 at a strength of 5 mg, 10 mg or 25 mg Placebo: Capsules for oral administration matching the ACT-541468 capsules	Each subject participated in 5 treatment periods. On the evening of the first 2 days of each period they received one dose (D) of ACT-541468 or placebo orally in the following order: D4, D2, D3, D1 and P, with D4 = the highest dose (50 mg) and D1 the lowest dose (5 mg). Each treatment period was separated from the next one by a 5- to 12- day washout. ACT-541468: Capsules for oral administration containing ACT-541468 at a strength of 5 mg, 10 mg or 25 mg Placebo: Capsules for oral administration matching the ACT-541468 capsules	Each subject participated in 5 treatment periods. On the evening of the first 2 days of each period they received one dose (D) of ACT-541468 or placebo orally in the following order: D4, D2, D3, D1 and P, with D4 = the highest dose (50 mg) and D1 the lowest dose (5 mg). Each treatment period was separated from the next one by a 5- to 12- day washout. ACT-541468: Capsules for oral administration containing ACT-541468 at a strength of 5 mg, 10 mg or 25 mg Placebo: Capsules for oral administration matching the ACT-541468 capsules
Measure Participants	56	54	55	56	54
Mean (Standard Deviation) [Minutes]	-37.92 (48.76)	-44.61 (41.28)	-44.81 (41.56)	-44.88 (44.22)	-33.88 (41.74)

Adverse Events

Time Frame	Start of screening until the end of the safety follow-up period.
Arm/Group Title	Single-blind Placebo (Run-in Period)		Placebo		ACT-541468 5 mg		ACT-541468 10 mg		ACT-541468 25 mg		ACT-541468 50 mg
Arm/Group Description	Single-blind placebo was administered during the run-in period. Placebo: Capsules for oral administration matching the ACT-541468 capsules		Each subject participated in 5 treatment periods. On the evening of the first 2 days of each period they received one dose (D) of ACT-541468 or placebo orally in the following order: D1, D3, P, D4 and D2 with D4 = the highest dose (50 mg) and D1 the lowest dose (5 mg). Each treatment period was separated from the next one by a 5- to 12- day washout. ACT-541468: Capsules for oral administration containing ACT-541468 at a strength of 5 mg, 10 mg or 25 mg Placebo: Capsules for oral administration matching the ACT-541468 capsules		Each subject participated in 5 treatment periods. On the evening of the first 2 days of each period they received one dose (D) of ACT-541468 or placebo orally in the following order: D1, D3, P, D4 and D2 with D4 = the highest dose (50 mg) and D1 the lowest dose (5 mg). Each treatment period was separated from the next one by a 5- to 12- day washout. ACT-541468: Capsules for oral administration containing ACT-541468 at a strength of 5 mg, 10 mg or 25 mg Placebo: Capsules for oral administration matching the ACT-541468 capsules		Each subject participated in 5 treatment periods. On the evening of the first 2 days of each period they received one dose (D) of ACT-541468 or placebo orally in the following order: D1, D3, P, D4 and D2 with D4 = the highest dose (50 mg) and D1 the lowest dose (5 mg). Each treatment period was separated from the next one by a 5- to 12- day washout. ACT-541468: Capsules for oral administration containing ACT-541468 at a strength of 5 mg, 10 mg or 25 mg Placebo: Capsules for oral administration matching the ACT-541468 capsules		Each subject participated in 5 treatment periods. On the evening of the first 2 days of each period they received one dose (D) of ACT-541468 or placebo orally in the following order: D1, D3, P, D4 and D2 with D4 = the highest dose (50 mg) and D1 the lowest dose (5 mg). Each treatment period was separated from the next one by a 5- to 12- day washout. ACT-541468: Capsules for oral administration containing ACT-541468 at a strength of 5 mg, 10 mg or 25 mg Placebo: Capsules for oral administration matching the ACT-541468 capsules		Each subject participated in 5 treatment periods. On the evening of the first 2 days of each period they received one dose (D) of ACT-541468 or placebo orally in the following order: D1, D3, P, D4 and D2 with D4 = the highest dose (50 mg) and D1 the lowest dose (5 mg). Each treatment period was separated from the next one by a 5- to 12- day washout. ACT-541468: Capsules for oral administration containing ACT-541468 at a strength of 5 mg, 10 mg or 25 mg Placebo: Capsules for oral administration matching the ACT-541468 capsules
All Cause Mortality
	Single-blind Placebo (Run-in Period)		Placebo		ACT-541468 5 mg		ACT-541468 10 mg		ACT-541468 25 mg		ACT-541468 50 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/58 (0%)		0/54 (0%)		0/56 (0%)		0/54 (0%)		0/55 (0%)		0/56 (0%)
Serious Adverse Events
	Single-blind Placebo (Run-in Period)		Placebo		ACT-541468 5 mg		ACT-541468 10 mg		ACT-541468 25 mg		ACT-541468 50 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/58 (0%)		0/54 (0%)		0/56 (0%)		0/54 (0%)		0/55 (0%)		0/56 (0%)
Other (Not Including Serious) Adverse Events
	Single-blind Placebo (Run-in Period)		Placebo		ACT-541468 5 mg		ACT-541468 10 mg		ACT-541468 25 mg		ACT-541468 50 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/58 (12.1%)		11/54 (20.4%)		14/56 (25%)		12/54 (22.2%)		10/55 (18.2%)		16/56 (28.6%)
Cardiac disorders
Bundle branch block left	0/58 (0%)	0	1/54 (1.9%)	1	0/56 (0%)	0	0/54 (0%)	0	0/55 (0%)	0	0/56 (0%)	0
Supraventricular extrasystoles	0/58 (0%)	0	0/54 (0%)	0	0/56 (0%)	0	0/54 (0%)	0	0/55 (0%)	0	1/56 (1.8%)	1
Ventricular extrasystoles	0/58 (0%)	0	0/54 (0%)	0	0/56 (0%)	0	0/54 (0%)	0	0/55 (0%)	0	1/56 (1.8%)	1
Ear and labyrinth disorders
Cerumen impaction	0/58 (0%)	0	1/54 (1.9%)	1	0/56 (0%)	0	0/54 (0%)	0	0/55 (0%)	0	0/56 (0%)	0
Eye disorders
Photophobia	1/58 (1.7%)	1	0/54 (0%)	0	0/56 (0%)	0	0/54 (0%)	0	0/55 (0%)	0	0/56 (0%)	0
Gastrointestinal disorders
Abdominal discomfort	0/58 (0%)	0	1/54 (1.9%)	1	0/56 (0%)	0	0/54 (0%)	0	0/55 (0%)	0	0/56 (0%)	0
Abdominal pain upper	0/58 (0%)	0	0/54 (0%)	0	0/56 (0%)	0	0/54 (0%)	0	1/55 (1.8%)	1	0/56 (0%)	0
Defaecation urgency	0/58 (0%)	0	0/54 (0%)	0	1/56 (1.8%)	1	1/54 (1.9%)	1	1/55 (1.8%)	1	0/56 (0%)	0
Diarrhoea	0/58 (0%)	0	1/54 (1.9%)	1	1/56 (1.8%)	1	1/54 (1.9%)	1	0/55 (0%)	0	0/56 (0%)	0
Dry mouth	0/58 (0%)	0	0/54 (0%)	0	1/56 (1.8%)	1	0/54 (0%)	0	0/55 (0%)	0	0/56 (0%)	0
Dyspepsia	0/58 (0%)	0	0/54 (0%)	0	1/56 (1.8%)	1	0/54 (0%)	0	0/55 (0%)	0	0/56 (0%)	0
Frequent bowel movements	0/58 (0%)	0	0/54 (0%)	0	1/56 (1.8%)	1	1/54 (1.9%)	1	1/55 (1.8%)	1	0/56 (0%)	0
Gastrooesophageal reflux disease	0/58 (0%)	0	0/54 (0%)	0	0/56 (0%)	0	0/54 (0%)	0	1/55 (1.8%)	1	0/56 (0%)	0
Nausea	0/58 (0%)	0	0/54 (0%)	0	0/56 (0%)	0	0/54 (0%)	0	1/55 (1.8%)	1	0/56 (0%)	0
Vomiting	0/58 (0%)	0	0/54 (0%)	0	0/56 (0%)	0	0/54 (0%)	0	0/55 (0%)	0	1/56 (1.8%)	1
General disorders
Fatigue	0/58 (0%)	0	2/54 (3.7%)	2	0/56 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0	4/56 (7.1%)	4
Feeling abnormal	0/58 (0%)	0	0/54 (0%)	0	0/56 (0%)	0	0/54 (0%)	0	0/55 (0%)	0	1/56 (1.8%)	1
Gait disturbance	1/58 (1.7%)	1	0/54 (0%)	0	2/56 (3.6%)	3	1/54 (1.9%)	1	1/55 (1.8%)	1	1/56 (1.8%)	1
Infections and infestations
Cystitis	0/58 (0%)	0	0/54 (0%)	0	0/56 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0	0/56 (0%)	0
Nasopharyngitis	0/58 (0%)	0	1/54 (1.9%)	1	1/56 (1.8%)	1	1/54 (1.9%)	1	0/55 (0%)	0	2/56 (3.6%)	2
Upper respiratory tract infection	0/58 (0%)	0	0/54 (0%)	0	1/56 (1.8%)	1	0/54 (0%)	0	0/55 (0%)	0	0/56 (0%)	0
Injury, poisoning and procedural complications
Contusion	0/58 (0%)	0	0/54 (0%)	0	1/56 (1.8%)	1	0/54 (0%)	0	0/55 (0%)	0	0/56 (0%)	0
Fall	0/58 (0%)	0	0/54 (0%)	0	1/56 (1.8%)	1	0/54 (0%)	0	0/55 (0%)	0	0/56 (0%)	0
Investigations
Alanine aminotransferase increased	0/58 (0%)	0	0/54 (0%)	0	0/56 (0%)	0	0/54 (0%)	0	1/55 (1.8%)	1	0/56 (0%)	0
Blood pressure increased	0/58 (0%)	0	0/54 (0%)	0	0/56 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0	0/56 (0%)	0
Blood pressure systolic increased	0/58 (0%)	0	0/54 (0%)	0	1/56 (1.8%)	1	0/54 (0%)	0	0/55 (0%)	0	0/56 (0%)	0
Blood thyroid stimulating hormone increased	1/58 (1.7%)	1	0/54 (0%)	0	0/56 (0%)	0	0/54 (0%)	0	0/55 (0%)	0	0/56 (0%)	0
Blood triglycerides increased	0/58 (0%)	0	0/54 (0%)	0	0/56 (0%)	0	0/54 (0%)	0	0/55 (0%)	0	1/56 (1.8%)	1
Gamma-glutamyltransferase increased	0/58 (0%)	0	0/54 (0%)	0	0/56 (0%)	0	0/54 (0%)	0	0/55 (0%)	0	1/56 (1.8%)	1
Metabolism and nutrition disorders
Hypochloraemia	0/58 (0%)	0	0/54 (0%)	0	0/56 (0%)	0	0/54 (0%)	0	0/55 (0%)	0	1/56 (1.8%)	1
Musculoskeletal and connective tissue disorders
Back pain	0/58 (0%)	0	2/54 (3.7%)	2	0/56 (0%)	0	0/54 (0%)	0	1/55 (1.8%)	1	0/56 (0%)	0
Muscle spasms	0/58 (0%)	0	0/54 (0%)	0	0/56 (0%)	0	0/54 (0%)	0	1/55 (1.8%)	1	0/56 (0%)	0
Pain in extremity	0/58 (0%)	0	0/54 (0%)	0	1/56 (1.8%)	1	0/54 (0%)	0	0/55 (0%)	0	0/56 (0%)	0
Nervous system disorders
Cerebellar ataxia	0/58 (0%)	0	1/54 (1.9%)	1	0/56 (0%)	0	0/54 (0%)	0	0/55 (0%)	0	0/56 (0%)	0
Dizziness	0/58 (0%)	0	0/54 (0%)	0	2/56 (3.6%)	2	1/54 (1.9%)	1	0/55 (0%)	0	0/56 (0%)	0
Dysgeusia	0/58 (0%)	0	1/54 (1.9%)	1	0/56 (0%)	0	0/54 (0%)	0	0/55 (0%)	0	0/56 (0%)	0
Headache	2/58 (3.4%)	2	1/54 (1.9%)	1	2/56 (3.6%)	2	0/54 (0%)	0	1/55 (1.8%)	1	1/56 (1.8%)	1
Hyporeflexia	0/58 (0%)	0	0/54 (0%)	0	1/56 (1.8%)	1	0/54 (0%)	0	0/55 (0%)	0	0/56 (0%)	0
Migraine	1/58 (1.7%)	1	0/54 (0%)	0	0/56 (0%)	0	0/54 (0%)	0	0/55 (0%)	0	1/56 (1.8%)	1
Somnolence	0/58 (0%)	0	0/54 (0%)	0	1/56 (1.8%)	1	0/54 (0%)	0	0/55 (0%)	0	0/56 (0%)	0
Tension headache	0/58 (0%)	0	0/54 (0%)	0	0/56 (0%)	0	0/54 (0%)	0	1/55 (1.8%)	1	0/56 (0%)	0
Tremor	0/58 (0%)	0	1/54 (1.9%)	1	0/56 (0%)	0	0/54 (0%)	0	0/55 (0%)	0	0/56 (0%)	0
Psychiatric disorders
Anxiety	0/58 (0%)	0	0/54 (0%)	0	1/56 (1.8%)	2	0/54 (0%)	0	0/55 (0%)	0	0/56 (0%)	0
Delusional disorder, unspecified type	0/58 (0%)	0	0/54 (0%)	0	0/56 (0%)	0	0/54 (0%)	0	0/55 (0%)	0	1/56 (1.8%)	1
Hallucination, visual	0/58 (0%)	0	1/54 (1.9%)	1	0/56 (0%)	0	0/54 (0%)	0	0/55 (0%)	0	0/56 (0%)	0
Renal and urinary disorders
Pollakiuria	0/58 (0%)	0	0/54 (0%)	0	0/56 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0	0/56 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	1/58 (1.7%)	1	0/54 (0%)	0	0/56 (0%)	0	0/54 (0%)	0	0/55 (0%)	0	1/56 (1.8%)	1
Dyspnoea	0/58 (0%)	0	0/54 (0%)	0	0/56 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0	0/56 (0%)	0
Dyspnoea exertional	0/58 (0%)	0	0/54 (0%)	0	1/56 (1.8%)	2	0/54 (0%)	0	0/55 (0%)	0	0/56 (0%)	0
Nasal oedema	0/58 (0%)	0	0/54 (0%)	0	0/56 (0%)	0	0/54 (0%)	0	0/55 (0%)	0	1/56 (1.8%)	1
Skin and subcutaneous tissue disorders
Acne	0/58 (0%)	0	0/54 (0%)	0	0/56 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0	0/56 (0%)	0
Dermatitis contact	0/58 (0%)	0	1/54 (1.9%)	1	0/56 (0%)	0	0/54 (0%)	0	0/55 (0%)	0	0/56 (0%)	0
Erythema	0/58 (0%)	0	0/54 (0%)	0	0/56 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0	0/56 (0%)	0
Night sweats	0/58 (0%)	0	0/54 (0%)	0	1/56 (1.8%)	1	0/54 (0%)	0	0/55 (0%)	0	0/56 (0%)	0
Rash pruritic	0/58 (0%)	0	0/54 (0%)	0	1/56 (1.8%)	1	0/54 (0%)	0	0/55 (0%)	0	0/56 (0%)	0
Vascular disorders
Hot flush	0/58 (0%)	0	0/54 (0%)	0	0/56 (0%)	0	1/54 (1.9%)	1	0/55 (0%)	0	0/56 (0%)	0
Hypertension	0/58 (0%)	0	0/54 (0%)	0	1/56 (1.8%)	1	1/54 (1.9%)	1	1/55 (1.8%)	1	0/56 (0%)	0
Thrombophlebitis	0/58 (0%)	0	0/54 (0%)	0	1/56 (1.8%)	1	0/54 (0%)	0	0/55 (0%)	0	0/56 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.