Insomnia Disorder
Conditions
Keywords
insomnia, elderly, Polysomnography
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.
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.
Interventions
DRUGACT-541468
Capsules for oral administration containing ACT-541468 at a strength of 5 mg, 10 mg or 25 mg
DRUGPlacebo
Capsules for oral administration matching the ACT-541468 capsules
Sponsors
Idorsia Pharmaceuticals Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
Germany, United States
Participant flow
Recruitment details
Conducted at 10 centers in 2 countries (USA and Germany)
Pre-assignment details
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).
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants 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 | 58 |
| Total | 58 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| 5th Intervention | Adverse Event | 2 | 0 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 57 Participants |
| Age, Continuous | 69 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 57 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Insomnia Severity Index | 20 units on a scale |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 54 Participants |
| Sex: Female, Male Female | 39 Participants |
| Sex: Female, Male Male | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 58 | 0 / 54 | 0 / 56 | 0 / 54 | 0 / 55 | 0 / 56 |
| other Total, other adverse events | 7 / 58 | 11 / 54 | 14 / 56 | 12 / 54 | 10 / 55 | 16 / 56 |
| serious Total, serious adverse events | 0 / 58 | 0 / 54 | 0 / 56 | 0 / 54 | 0 / 55 | 0 / 56 |
Outcome results
Primary
Change in Wake After Sleep Onset (WASO) From Baseline to Days 1 and 2
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
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| ACT-541468 5 mg | Change in Wake After Sleep Onset (WASO) From Baseline to Days 1 and 2 | -18.9 minutes | Standard Error 4.44 |
| ACT-541468 10 mg | Change in Wake After Sleep Onset (WASO) From Baseline to Days 1 and 2 | -32.0 minutes | Standard Error 4.5 |
| ACT-541468 25 mg | Change in Wake After Sleep Onset (WASO) From Baseline to Days 1 and 2 | -45.1 minutes | Standard Error 4.47 |
| ACT-541468 50 mg | Change in Wake After Sleep Onset (WASO) From Baseline to Days 1 and 2 | -61.4 minutes | Standard Error 4.44 |
| Placebo | Change in Wake After Sleep Onset (WASO) From Baseline to Days 1 and 2 | -13.6 minutes | Standard Error 4.5 |
Comparison: 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.)p-value: <0.001Multiple Comparison Procedure-Model
p-value: 0.25895% CI: [-14.7, 4]Linear mixed effects model
p-value: <0.00195% CI: [-27.8, -9]Linear mixed effects model
p-value: <0.00195% CI: [-40.9, -22.2]Linear mixed effects model
p-value: <0.00195% CI: [-57.2, -38.5]Linear mixed effects model
Secondary
Change in Mean Latency to Persistent Sleep (LPS) From Baseline to Days 1 and 2
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ACT-541468 5 mg | Change in Mean Latency to Persistent Sleep (LPS) From Baseline to Days 1 and 2 | -37.92 Minutes | Standard Deviation 48.76 |
| ACT-541468 10 mg | Change in Mean Latency to Persistent Sleep (LPS) From Baseline to Days 1 and 2 | -44.61 Minutes | Standard Deviation 41.28 |
| ACT-541468 25 mg | Change in Mean Latency to Persistent Sleep (LPS) From Baseline to Days 1 and 2 | -44.81 Minutes | Standard Deviation 41.56 |
| ACT-541468 50 mg | Change in Mean Latency to Persistent Sleep (LPS) From Baseline to Days 1 and 2 | -44.88 Minutes | Standard Deviation 44.22 |
| Placebo | Change in Mean Latency to Persistent Sleep (LPS) From Baseline to Days 1 and 2 | -33.88 Minutes | Standard Deviation 41.74 |