Insomnia Disorder
Conditions
Keywords
Insomnia, Polysomnography
Brief summary
This study evaluates the dose response of ACT-541468 on the change of WASO from baseline to Days 1 and 2, assessed by PSG.
Detailed description
This study consists of the following phases: screening phase; double-blind treatment phase; safety follow-up phase. Safety is monitored throughout the study.
Interventions
DRUGACT-541468 5 mg
Capsule for oral administration containing ACT-541468 at a strength of 5 mg
DRUGACT-541468 10 mg
Capsule for oral administration containing ACT-541468 at a strength of 10 mg
DRUGACT-541468 25 mg
Capsule for oral administration containing ACT-541468 at a strength of 25 mg
DRUGZolpidem
Over-encapsulated zolpidem tablet at a strength of 10 mg
DRUGPlacebo 1
Placebo capsules matching ACT-541468 capsules
DRUGPlacebo 2
Placebo capsules matching over-encapsulated zolpidem
Sponsors
Idorsia Pharmaceuticals Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 64 Years
Healthy volunteers
No
Inclusion criteria
Principal inclusion Criteria: * Signed informed consent prior to any study-mandated procedure. * Male or female aged 18-64 years (inclusive). * Women of childbearing potential must have negative pregnancy tests and use reliable methods of contraception up to 30 days after EOT. * Body mass index (BMI): 18.5 ≤ BMI (kg/m2) \< 32.0. * Insomnia disorder according to DSM-5 criteria. * Insufficient sleep quantity as collected subjectively in the sleep diary and validated objectively by polysomnography. * Insomnia Severity Index score ≥ 15. Principal
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 \> or= 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 direct 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 and Days 1&2 | 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 Latency to Persistent Sleep (LPS) From Baseline to Days 1 and 2 | Baseline and Days 1&2 | LPS is the duration of time in minutes from lights off to persistent sleep onset as determined by PSG |
| Change in Subjective Latency to Sleep Onset (sLSO) From Baseline to Week 4 | Baseline and Week 4 | sLSO is the self-reported time to fall asleep, as reported in the sleep diary |
| Change in Subjective Wake After Sleep Onset (sWASO) From Baseline to Week 4 | Baseline and Week 4 | sWASO is the self-reported time spent awake after sleep onset as reported in the sleep diary. |
Countries
Germany, Hungary, Israel, Spain, Sweden, United States
Participant flow
Recruitment details
Conducted at 38 sites in 6 countries (Germany, Hungary, Israel, Spain, Sweden, and the USA)
Pre-assignment details
Screening details: screening period (screening visit followed by at least 7 days at home) and a run-in period (2 PSG nights on single-blind placebo, followed by 5-12 days with no treatment), and lasting a max. of 28 days. N = 360 subjects were randomized; N = 359 subjects were treated; N = 1 subject discontinued due to randomization error.
Participants by arm
| Arm | Count |
|---|---|
| ACT-541468 5 mg Each subject received one 5-mg ACT-541468 capusle (+ one placebo capsule), once daily in the evening for 4 weeks
ACT-541468 5 mg: Capsule for oral administration containing ACT-541468 at a strength of 5 mg
Placebo 1: Placebo capsules matching ACT-541468 capsules | 60 |
| ACT-541468 10 mg Each subject received one 10-mg ACT-541468 capusle (+ one placebo capsule), once daily in the evening for 4 weeks
ACT-541468 10 mg: Capsule for oral administration containing ACT-541468 at a strength of 10 mg
Placebo 1: Placebo capsules matching ACT-541468 capsules | 58 |
| ACT-541468 25 mg Each subject received one 25-mg ACT-541468 capsule (+ one placebo capsule), once daily in the evening) for 4 weeks
ACT-541468 25 mg: Capsule for oral administration containing ACT-541468 at a strength of 25 mg
Placebo 1: Placebo capsules matching ACT-541468 capsules | 60 |
| ACT-541468 50 mg Each subject received two 25-mg ACT-541468 capsules, once daily in the evening for 4 weeks
ACT-541468 25 mg: Capsule for oral administration containing ACT-541468 at a strength of 25 mg | 61 |
| Zolpidem Each subject received one 10-mg zolpidem capsule (+ one placebo capusle), once daily in the evening for 4 weeks
Zolpidem: Over-encapsulated zolpidem tablet at a strength of 10 mg
Placebo 2: Placebo capsules matching over-encapsulated zolpidem | 60 |
| Placebo Each subject received two placebo capsules, once daily in the evening for 4 weeks
Placebo 1: Placebo capsules matching ACT-541468 capsules | 60 |
| Total | 359 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 2 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Randomized in error | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 0 | 1 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total | ACT-541468 5 mg | ACT-541468 10 mg | ACT-541468 25 mg | ACT-541468 50 mg | Zolpidem |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 48 years | 47 years | 41 years | 48 years | 48 years | 46 years | 43 years |
| Age, Customized Adults (18-64 years) | 60 Participants | 359 Participants | 60 Participants | 58 Participants | 60 Participants | 61 Participants | 60 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 39 Participants | 9 Participants | 3 Participants | 9 Participants | 5 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 51 Participants | 319 Participants | 51 Participants | 54 Participants | 51 Participants | 56 Participants | 56 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 35 Participants | 5 Participants | 8 Participants | 4 Participants | 5 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 52 Participants | 321 Participants | 54 Participants | 49 Participants | 56 Participants | 56 Participants | 54 Participants |
| Sex: Female, Male Female | 38 Participants | 230 Participants | 38 Participants | 38 Participants | 39 Participants | 39 Participants | 38 Participants |
| Sex: Female, Male Male | 22 Participants | 129 Participants | 22 Participants | 20 Participants | 21 Participants | 22 Participants | 22 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 / 60 | 0 / 58 | 0 / 60 | 0 / 61 | 0 / 60 | 0 / 60 |
| other Total, other adverse events | 21 / 60 | 22 / 58 | 23 / 60 | 21 / 61 | 24 / 60 | 18 / 60 |
| serious Total, serious adverse events | 0 / 60 | 2 / 58 | 0 / 60 | 1 / 61 | 0 / 60 | 0 / 60 |
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 and Days 1&2
| 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 | -28.4 minutes | Standard Error 4.24 |
| ACT-541468 10 mg | Change in Wake After Sleep Onset (WASO) From Baseline to Days 1 and 2 | -32.3 minutes | Standard Error 4.32 |
| ACT-541468 25 mg | Change in Wake After Sleep Onset (WASO) From Baseline to Days 1 and 2 | -37.7 minutes | Standard Error 4.25 |
| ACT-541468 50 mg | Change in Wake After Sleep Onset (WASO) From Baseline to Days 1 and 2 | -47.1 minutes | Standard Error 4.21 |
| Zolpidem | Change in Wake After Sleep Onset (WASO) From Baseline to Days 1 and 2 | -29.9 minutes | Standard Error 4.3 |
| Placebo | Change in Wake After Sleep Onset (WASO) From Baseline to Days 1 and 2 | -21.4 minutes | Standard Error 4.24 |
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: 0.24195% CI: [-18.7, 4.7]ANCOVA
p-value: 0.07295% CI: [-22.6, 1]ANCOVA
p-value: 0.00795% CI: [-27.9, -4.5]ANCOVA
p-value: <0.00195% CI: [-37.3, -13.9]ANCOVA
p-value: 0.15595% CI: [-20.4, 3.3]ANCOVA
Secondary
Change in 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 and Days 1&2
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ACT-541468 5 mg | Change in Latency to Persistent Sleep (LPS) From Baseline to Days 1 and 2 | -26.88 Minutes | Standard Deviation 45.42 |
| ACT-541468 10 mg | Change in Latency to Persistent Sleep (LPS) From Baseline to Days 1 and 2 | -29.31 Minutes | Standard Deviation 26.79 |
| ACT-541468 25 mg | Change in Latency to Persistent Sleep (LPS) From Baseline to Days 1 and 2 | -36.14 Minutes | Standard Deviation 34.34 |
| ACT-541468 50 mg | Change in Latency to Persistent Sleep (LPS) From Baseline to Days 1 and 2 | -36.41 Minutes | Standard Deviation 26.71 |
| Zolpidem | Change in Latency to Persistent Sleep (LPS) From Baseline to Days 1 and 2 | -45.14 Minutes | Standard Deviation 32.82 |
| Placebo | Change in Latency to Persistent Sleep (LPS) From Baseline to Days 1 and 2 | -22.02 Minutes | Standard Deviation 46.63 |
Secondary
Change in Subjective Latency to Sleep Onset (sLSO) From Baseline to Week 4
sLSO is the self-reported time to fall asleep, as reported in the sleep diary
Time frame: Baseline and Week 4
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ACT-541468 5 mg | Change in Subjective Latency to Sleep Onset (sLSO) From Baseline to Week 4 | -13.38 Minutes | Standard Deviation 27.79 |
| ACT-541468 10 mg | Change in Subjective Latency to Sleep Onset (sLSO) From Baseline to Week 4 | -21.07 Minutes | Standard Deviation 24.26 |
| ACT-541468 25 mg | Change in Subjective Latency to Sleep Onset (sLSO) From Baseline to Week 4 | -15.50 Minutes | Standard Deviation 25.51 |
| ACT-541468 50 mg | Change in Subjective Latency to Sleep Onset (sLSO) From Baseline to Week 4 | -23.65 Minutes | Standard Deviation 24.12 |
| Zolpidem | Change in Subjective Latency to Sleep Onset (sLSO) From Baseline to Week 4 | -19.98 Minutes | Standard Deviation 19.28 |
| Placebo | Change in Subjective Latency to Sleep Onset (sLSO) From Baseline to Week 4 | -16.32 Minutes | Standard Deviation 21.16 |
Secondary
Change in Subjective Wake After Sleep Onset (sWASO) From Baseline to Week 4
sWASO is the self-reported time spent awake after sleep onset as reported in the sleep diary.
Time frame: Baseline and Week 4
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ACT-541468 5 mg | Change in Subjective Wake After Sleep Onset (sWASO) From Baseline to Week 4 | -31.32 Minutes | Standard Deviation 33.32 |
| ACT-541468 10 mg | Change in Subjective Wake After Sleep Onset (sWASO) From Baseline to Week 4 | -24.35 Minutes | Standard Deviation 33.4 |
| ACT-541468 25 mg | Change in Subjective Wake After Sleep Onset (sWASO) From Baseline to Week 4 | -29.8 Minutes | Standard Deviation 39.88 |
| ACT-541468 50 mg | Change in Subjective Wake After Sleep Onset (sWASO) From Baseline to Week 4 | -35.45 Minutes | Standard Deviation 37.53 |
| Zolpidem | Change in Subjective Wake After Sleep Onset (sWASO) From Baseline to Week 4 | -29.08 Minutes | Standard Deviation 27.28 |
| Placebo | Change in Subjective Wake After Sleep Onset (sWASO) From Baseline to Week 4 | -23.61 Minutes | Standard Deviation 32.62 |