Efficacy and Safety of Tasimelteon Compared With Placebo in Totally Blind Subjects With Non-24-Hour Sleep-Wake Disorder

• Sponsor: Vanda Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01163032
• Collaborator: (none)
• Enrollment: 136
• Locations: 28
• Arms: 2
• Duration (Months): 27
• Patients Per Site: 4.9
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy and safety of a six month double-mask treatment of tasimelteon or placebo in male and female subjects with Non-24-Hour Sleep-Wake Disorder

Condition or Disease	Intervention/Treatment	Phase
Non-24-Hour Sleep-Wake Disorder	Drug: tasimelteon; Drug: Placebo	Phase 3

Detailed Description

Non-24-Hour Sleep-Wake Disorder (N24HSWD) occurs when individuals, primarily those without light perception, are unable to synchronize their endogenous circadian pacemaker to the 24-hour light-dark cycle, and the timing of their circadian rhythm instead reflects the intrinsic period of their endogenous circadian pacemaker. As a result, the circadian rhythm of sleep-wake propensity in these individuals moves gradually later and later each day if there circadian period is > 24 hours and earlier and earlier if < 24 hours. These individuals will be able to sleep well at night when their sleep-wake propensity rhythm is approximately aligned with the 24-hour light-dark and social cycle. However, after a short time, the endogenous sleep-wake propensity rhythm and the 24-hour light-dark cycle will move out of synchrony with each other, and they may have difficulty falling asleep until well into the night. In addition to problems sleeping at the desired time, the subjects experience daytime sleepiness and daytime napping.

This will be a multicenter, randomized, double-masked, placebo-controlled, parallel study. The study has two phases: the pre-randomization phase followed by either the randomization phase or the open-label extension (OLE). The pre-randomization phase comprises a screening visit where subject's initial eligibility will be evaluated, a circadian period (τ) estimation segment, and a variable-length in-phase transition segment in which subjects will wait to start treatment until their circadian phase is aligned with their target bedtime. Subjects that meet all entry criteria for the study will enter the randomization phase. During the randomization phase, subjects will be asked to take either 20 mg tasimelteon or placebo approximately 1 hour prior to their target bedtime for 26 weeks in a double-masked fashion. Subjects who have a τ greater than 24.0 and meet all entry criteria but that are ineligible for the randomization phase due to their τ estimate may be given the opportunity to participate in the OLE phase. During the OLE phase, subjects will take open-label 20mg tasimelteon for 26 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 136 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-Mask, Placebo-Controlled, Parallel Study to Investigate the Efficacy and Safety of 20 mg Tasimelteon Versus Placebo in Totally Blind Subjects With N24HSWD Followed by an OLE Phase
• Study Start Date: Aug 1, 2010
• Actual Primary Completion Date: Nov 1, 2012
• Actual Study Completion Date: Nov 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: tasimelteon 20 mg tasimelteon capsules, PO daily for 6 months	Drug: tasimelteon; 20 mg tasimelteon capsules, PO daily for 6 months; Other Names: VEC-162
Placebo Comparator: placebo Placebo capsules, PO daily for 6 months	Drug: Placebo; Placebo capsules, PO daily for 6 months

Outcome Measures

Primary Outcome Measures

1. Proportion of Patients Entrained as Assessed by Urinary aMT6 [1 month]

   Entrainment is a measure of synchronization of the master body clock to the 24-hour day. The circadian period (τ) was calculated using urinary aMT6s collected over four 48 hour periods , collected approximately 1 week apart for 4 separate weeks, during the screening and month 1 of the randomization phase of the trial. Entrainment was defined as having a post-baseline τ value less than 24.1 and a 95% CI that included 24.0.

2. Proportion of Patients With a Clinical Response: Entrainment of aMT6 and Score of ≥ 3 on N24CRS [6 months]

   Clinical response is defined as the coincident demonstration of entrainment (aMT6) and a score ≥ 3 on the Non-24 Clinical Response Scale (N24CRS). N24CRS measures improvement in sleep-wake measures and overall functioning (LQ-nTST, UQ-dTSD, MoST and CGI-C). Each assessment is scored as a 1 or 0 depending on the pre-specified threshold (see below). LQ-nTST: >45 minutes increase in average nighttime sleep duration; UQ-dTSD: >45 minutes decrease in average daytime sleep duration; MoST: >30 minutes increase and a standard deviation <2 hours during double-masked phase (6 months); CGI-C: <2.0 from the average of D112 and Day 183 compared to baseline For patients randomized to tasimelteon 20 mg and who also participated in the screening phase of Study 3203 (month 7 of treatment), the screening τ from Study 3203 was used if the patient did not become entrained in Study 3201 but did become entrained during the screening phase of Study 3203.

Secondary Outcome Measures

1. Proportion of Patients Entrained as Assessed by Urinary Cortisol [1 month]

   Entrainment is a measure of synchronization of the master body clock to the 24-hour day. The circadian period (τ) was calculated using urinary cortisol collected over four 48 hour periods, approximately 1 week apart for 4 separate weeks, during the screening and month 1 of the randomization phase of the trial. Entrainment was defined as having a post-baseline τ value less than 24.1 and a 95% CI that included 24.0.

2. Average Clinical Global Impression of Change (CGI-C) [Day 112 and 183]

   CGI-C scores range from 1 (very much improved) to 7 (very much worse). The average post-randomization score was obtained for each patient by averaging the last 2 scheduled assessments (Day D112 and Day D183). Lower number indicates improvement.

3. Proportion of Responders With a Combined Sleep/Wake Response for LQ-nTST (≥ 90 Minutes) and UQ-dTSD (≤ 90 Minutes) [6 months]

   The sleep/wake response represents measurement of the combined improvement in the nighttime sleep duration and daytime sleep duration. Individuals that have an improvement in nighttime sleep and daytime sleep, defined as an increase of 90 minutes or more in the lower quartile of subjective nighttime total sleep time (LQ-nTST) and a decrease of 90 minutes or more in the upper quartile of daytime total sleep duration (UQ-dTSD) are considered to be a responder.

4. Average Lower Quartile of Nights of Nighttime Total Sleep Time (LQ-nTST) [6 months]

   LQ-nTST measures the difference in average nighttime sleep during the patient's worst 25% of nights (shortest total nighttime sleep) between the randomized phase (6 months)and the screening phase (~ 6 weeks). The higher number indicates improvement.

5. Average Upper Quartile of Days of Subjective Daytime Sleep Duration (UQ-dTSD) [6 months]

   UQ-dTSD measures the difference in average daytime sleep during the patient's worst 25% of days (longest total daytime sleep) between the randomized phase (6 months) and the screening phase (~ 6 weeks). Lower number indicates improvement.

6. Average Midpoint of Sleep (MoST) [6 months]

   Midpoint of Sleep Timing (MoST) is the measurement of the average midpoint of sleep time relative to bedtime. The average MoST value will trend to 0 as an individual's sleep becomes more fragmented. Improvement is defined as an increase in the average.

7. Number of Patients With a Treatment Emergent Adverse Event (Open Label Extension Phase Only) [6 months]

   Adverse events were recorded in the source documents from the time of the patient's informed consent signature until the end of the patient's study participation. An AE was defined as any untoward medical occurrence in a clinical investigation patient who does not necessarily have causal relationship with treatment.

Other Outcome Measures

1. Proportion of Patients With a Clinical Response: Entrainment of aMT6 and Score of ≥ 2 on N24CRS [6 months]

   Clinical response is defined as the coincident demonstration of entrainment (aMT6) and a score ≥ 2 on the Non-24 Clinical Response Scale (N24CRS) which includes LQ-nTST, UQ-dTSD, MoST and CGI-C assessments. Each assessment is scored as a 1 or 0 depending on the pre-specified threshold (see below). LQ-nTST: >45 minutes increase in average nighttime sleep duration; UQ-dTSD: >45 minutes decrease in average daytime sleep duration; MoST: >30 minutes increase and a standard deviation <2 hours during double-masked phase (6 months); CGI-C: <2.0 from the average of D112 and Day 183 compared to baseline For patients randomized to tasimelteon 20 mg and who also participated in the screening phase of Study 3203 (month 7 of treatment), the screening τ from Study 3203 was used if the patient did not become entrained in Study 3201 but did become entrained during the screening phase of Study 3203.

2. Proportion of Patients With a Clinical Response (Score of ≥ 3 on N24CRS) [6 months]

   Non-24 Clinical Response Scale (N24CRS) was a 4-item scale which includes LQ-nTST, UQ-dTSD, MoST and CGI-C assessments. Each assessment is scored as a 1 or 0 depending on the pre-specified threshold (see below). LQ-nTST: >45 minutes increase in average nighttime sleep duration; UQ-dTSD: >45 minutes decrease in average daytime sleep duration; MoST: >30 minutes increase and a standard deviation <2 hours during double-masked phase (6 months); CGI-C: <2.0 from the average of D112 and Day 183 compared to baseline

3. Proportion of Patients With a Clinical Response (Score of ≥ 2 on N24CRS) [6 months]

   Non-24 Clinical Response Scale (N24CRS) was a 4-item scale which includes LQ-nTST, UQ-dTSD, MoST and CGI-C assessments. Each assessment is scored as a 1 or 0 depending on the pre-specified threshold (see below). LQ-nTST: >45 minutes increase in average nighttime sleep duration; UQ-dTSD: >45 minutes decrease in average daytime sleep duration; MoST: >30 minutes increase and a standard deviation <2 hours during double-masked phase (6 months); CGI-C: <2.0 from the average of D112 and Day 183 compared to baseline

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Ability and acceptance to provide informed consent;

• No perception of light by the subject's own report;

• Diagnosis of N24HSWD as determined by:

1. History (within the last 3 months) of trouble sleeping at night difficulty initiating sleep or staying asleep), difficulty awakening in the morning, or daytime sleepiness as determined by answering yes to at least one question in the Sleep Complaint Questionnaire and

2. Urinary aMT6s demonstrates a progressive delay of the aMT6 acrophase time.

• Willing and able to comply with study requirements and restrictions including a commitment to a fixed 9-hour sleep opportunity during the study;

• Fluent in English;

Exclusion Criteria:

• Have a probable diagnosis of a current sleep disorder other than N24HSWD that is the primary cause of the sleep disturbance based on clinical investigator medical judgment;

• Current clinically significant cardiovascular, respiratory, neurologic, hepatic, hematopoietic, renal, gastrointestinal or metabolic dysfunction unless currently controlled and stable;

• History (within the 12 months prior to screening) of psychiatric disorders including Major Depressive Disorder, Generalized Anxiety Disorder, Axis II Disorders, delirium or any other psychiatric disorder that in the opinion of the clinical investigator would affect participation in the study or full compliance with study procedures;

• History of intolerance and/or hypersensitivity to melatonin or melatonin agonists;

• Worked night, rotating, or split (period of work, followed by break, and then return to work) shift work within 1 month of the screening visit or plan to work these shifts during the study;

• Unable to perform calls to the study IVR system to report questionnaire results;

• Exposure to any investigational drug, including placebo, within 30 days or 5 half lives (whichever was longer) of screening;

• Use of central nervous system prescription or OTC medications, other than melatonin, that affects the sleep-wake cycle

• Use of melatonin or melatonin agonist

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pulmonary Associates, PA	Phoenix	Arizona	United States	85006
2	SDS Clinical Trials Inc.	Orange	California	United States	92868
3	VA Palo Alto Health Care System/PAIRE (San Fransisco Bay Area)	Palo Alto	California	United States	94304
4	St. Johns Sleep Disorder Center - St. Johns Medical Plaza	Santa Monica	California	United States	90404
5	Radiant Research - Denver	Denver	Colorado	United States	80239
6	PAB Clinical Research Inc.	Brandon	Florida	United States	33511
7	Kendall South Medical Center, Inc.	Miami	Florida	United States	33175
8	Ocean Sleep Disorders Center - Ormond Beach	Ormond Beach	Florida	United States	32174
9	Sleep Disorders Center Of Georgia	Atlanta	Georgia	United States	30342
10	Suburban Lung Associates SC (Chicago Metropolitan Area)	Elk Grove Village	Illinois	United States	60007
11	The Center for Sleep and Wake Disorders (Washington, D.C. Metropolitan Area)	Chevy Chase	Maryland	United States	20815
12	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
13	Michigan Head-Pain Neurological Institute	Ann Arbor	Michigan	United States	48104
14	St. Luke's Sleep Medicine and Research Center (St. Louis Metropolitan Area)	Chesterfield	Missouri	United States	63017
15	New York Eye and Ear Infirmary	New York	New York	United States	10003
16	Tri-State Sleep Disorders Center	Cincinnati	Ohio	United States	45246
17	Ohio Sleep Medicine Institute (Columbus Metropolitan Area)	Dublin	Ohio	United States	43017
18	Lynn Health Science Institute	Oklahoma city	Oklahoma	United States	73112
19	Columbia Research Group Inc.	Portland	Oregon	United States	97239
20	Center For Sleep Medicine at Chestnut Hill Hospital	Philadelphia	Pennsylvania	United States	19118
21	Consolidated Clinical trials	Pittsburgh	Pennsylvania	United States	15221
22	SleepMed, Inc. - Columbia	Columbia	South Carolina	United States	29201
23	Todd J. Swick, M.D., P.A.	Houston	Texas	United States	77063
24	Advanced Sleep Research GmbH	Berlin		Germany	10117
25	Bergmannsheil University Hospital - Medical Clinic III	Bochum		Germany	44789
26	Klinische-Forschung Hannover Mitte	Hannover		Germany	30159
27	Universitaetsklinikum Glesen and Marburg gmbH/Schlaflabor - Sleep Lab University Marburg	Marburg		Germany	35043
28	Bonomed Studiezentrum	Munich		Germany	80331

Sponsors and Collaborators

• Vanda Pharmaceuticals

Investigators

• Study Director: Vanda Pharmaceuticals, Vanda Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Vanda Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01163032
• Other Study ID Numbers: VP-VEC-162-3201
• First Posted: Jul 15, 2010
• Last Update Posted: Oct 16, 2014
• Last Verified: Oct 1, 2014

• Keywords provided by Vanda Pharmaceuticals: Blindness; Eye Diseases; Nap Disorders; Circadian Rhythm Disorders; Sleep disorders; Circadian Rhythm Sleep Disorders; Dyssomnias; Nervous System Diseases
• Additional relevant MeSH terms: Sleep Wake Disorders; Sleep Disorders, Circadian Rhythm; Disease

Study Results

Participant Flow

Recruitment Details	*Various category for the Randomization Phase: 4 patients in each treatment group discontinued due to study termination by the sponsor and 1 patient in the tasimelteon group discontinued due to travel across multiple time zones

Arm/Group Title	Tasimelteon (Randomized)	Placebo (Randomized)	Open Label Tasimelteon
Arm/Group Description	20 mg tasimelteon capsules, PO daily for 6 months tasimelteon: 20 mg tasimelteon capsules, PO daily for 6 months	Placebo capsules, PO daily for 6 months Placebo: Placebo capsules, PO daily for 6 months	20 mg tasimelteon capsules, PO daily for 6 months tasimelteon: 20 mg tasimelteon capsules, PO daily for 6 months
Period Title: Randomization Phase
STARTED	42	42	0
COMPLETED	32	30	0
NOT COMPLETED	10	12	0
Period Title: Randomization Phase
STARTED	0	0	55
COMPLETED	0	0	39
NOT COMPLETED	0	0	16

Baseline Characteristics

Arm/Group Title	Tasimelteon (Randomized)	Placebo (Randomized)	Open Label Tasimelteon	Total
Arm/Group Description	20 mg tasimelteon capsules, PO daily for 6 months tasimelteon: 20 mg tasimelteon capsules, PO daily for 6 months	Placebo capsules, PO daily for 6 months Placebo: Placebo capsules, PO daily for 6 months	20 mg tasimelteon capsules, PO daily for 6 months tasimelteon: 20 mg tasimelteon capsules, PO daily for 6 months	Total of all reporting groups
Overall Participants	42	42	52	136
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.8 (12.63)	50.7 (13.15)	50.37 (13.17)	50.6 (12.91)
Age, Customized (years) [Mean (Standard Deviation) ]
Rand to OLE	42.00 (5.66)	54.00 (NA)	NA (NA)	46.00 (8.00)
Sex/Gender, Customized (participants) [Number]
Rand to OLE (Female)	0 0%	0 0%	0 0%	0 0%
Rand to OLE (Male)	2 4.8%	1 2.4%	0 0%	3 2.2%
Sex: Female, Male (Count of Participants)
Female	18 42.9%	17 40.5%	25 48.1%	60 44.1%
Male	24 57.1%	25 59.5%	27 51.9%	76 55.9%

Outcome Measures

1. Primary Outcome

Title	Proportion of Patients Entrained as Assessed by Urinary aMT6
Description	Entrainment is a measure of synchronization of the master body clock to the 24-hour day. The circadian period (τ) was calculated using urinary aMT6s collected over four 48 hour periods , collected approximately 1 week apart for 4 separate weeks, during the screening and month 1 of the randomization phase of the trial. Entrainment was defined as having a post-baseline τ value less than 24.1 and a 95% CI that included 24.0.
Time Frame	1 month

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population: all subjects randomized into the study that have τ calculated post-randomization.

Arm/Group Title	Tasimelteon (Randomized)	Placebo (Randomized)
Arm/Group Description	20 mg tasimelteon capsules, PO daily for 6 months tasimelteon: 20 mg tasimelteon capsules, PO daily for 6 months	Placebo capsules, PO daily for 6 months Placebo: Placebo capsules, PO daily for 6 months
Measure Participants	40	38
Number [percentage of patients]	20	2.6

2. Primary Outcome

Title	Proportion of Patients With a Clinical Response: Entrainment of aMT6 and Score of ≥ 3 on N24CRS
Description	Clinical response is defined as the coincident demonstration of entrainment (aMT6) and a score ≥ 3 on the Non-24 Clinical Response Scale (N24CRS). N24CRS measures improvement in sleep-wake measures and overall functioning (LQ-nTST, UQ-dTSD, MoST and CGI-C). Each assessment is scored as a 1 or 0 depending on the pre-specified threshold (see below). LQ-nTST: >45 minutes increase in average nighttime sleep duration; UQ-dTSD: >45 minutes decrease in average daytime sleep duration; MoST: >30 minutes increase and a standard deviation <2 hours during double-masked phase (6 months); CGI-C: <2.0 from the average of D112 and Day 183 compared to baseline For patients randomized to tasimelteon 20 mg and who also participated in the screening phase of Study 3203 (month 7 of treatment), the screening τ from Study 3203 was used if the patient did not become entrained in Study 3201 but did become entrained during the screening phase of Study 3203.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Analysis Population: all patients in the ITT population that had at least 70% of 1 circadian cycle of nighttime total sleep data reported during each phase (screening and post-randomization)

Arm/Group Title	Tasimelteon (Randomized)	Placebo (Randomized)
Arm/Group Description	20 mg tasimelteon capsules, PO daily for 6 months tasimelteon: 20 mg tasimelteon capsules, PO daily for 6 months	Placebo capsules, PO daily for 6 months Placebo: Placebo capsules, PO daily for 6 months
Measure Participants	38	34
Number [percentage of patients]	23.7	0

3. Other Pre-specified Outcome

Title	Proportion of Patients With a Clinical Response: Entrainment of aMT6 and Score of ≥ 2 on N24CRS
Description	Clinical response is defined as the coincident demonstration of entrainment (aMT6) and a score ≥ 2 on the Non-24 Clinical Response Scale (N24CRS) which includes LQ-nTST, UQ-dTSD, MoST and CGI-C assessments. Each assessment is scored as a 1 or 0 depending on the pre-specified threshold (see below). LQ-nTST: >45 minutes increase in average nighttime sleep duration; UQ-dTSD: >45 minutes decrease in average daytime sleep duration; MoST: >30 minutes increase and a standard deviation <2 hours during double-masked phase (6 months); CGI-C: <2.0 from the average of D112 and Day 183 compared to baseline For patients randomized to tasimelteon 20 mg and who also participated in the screening phase of Study 3203 (month 7 of treatment), the screening τ from Study 3203 was used if the patient did not become entrained in Study 3201 but did become entrained during the screening phase of Study 3203.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Analysis Population: all patients in the ITT population that had at least 70% of 1 circadian cycle of nighttime total sleep data reported during each phase (screening and post-randomization)

Arm/Group Title	Tasimelteon (Randomized)	Placebo (Randomized)
Arm/Group Description	20 mg tasimelteon capsules, PO daily for 6 months tasimelteon: 20 mg tasimelteon capsules, PO daily for 6 months	Placebo capsules, PO daily for 6 months Placebo: Placebo capsules, PO daily for 6 months
Measure Participants	38	34
Number [percentage of patients]	28.9	0

4. Other Pre-specified Outcome

Title	Proportion of Patients With a Clinical Response (Score of ≥ 3 on N24CRS)
Description	Non-24 Clinical Response Scale (N24CRS) was a 4-item scale which includes LQ-nTST, UQ-dTSD, MoST and CGI-C assessments. Each assessment is scored as a 1 or 0 depending on the pre-specified threshold (see below). LQ-nTST: >45 minutes increase in average nighttime sleep duration; UQ-dTSD: >45 minutes decrease in average daytime sleep duration; MoST: >30 minutes increase and a standard deviation <2 hours during double-masked phase (6 months); CGI-C: <2.0 from the average of D112 and Day 183 compared to baseline
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Analysis Population: all patients in the ITT population that had at least 70% of 1 circadian cycle of nighttime total sleep data reported during each phase (screening and post-randomization)

Arm/Group Title	Tasimelteon (Randomized)	Placebo (Randomized)
Arm/Group Description	20 mg tasimelteon capsules, PO daily for 6 months tasimelteon: 20 mg tasimelteon capsules, PO daily for 6 months	Placebo capsules, PO daily for 6 months Placebo: Placebo capsules, PO daily for 6 months
Measure Participants	38	34
Number [percentage of patients]	28.9	2.9

5. Secondary Outcome

Title	Proportion of Patients Entrained as Assessed by Urinary Cortisol
Description	Entrainment is a measure of synchronization of the master body clock to the 24-hour day. The circadian period (τ) was calculated using urinary cortisol collected over four 48 hour periods, approximately 1 week apart for 4 separate weeks, during the screening and month 1 of the randomization phase of the trial. Entrainment was defined as having a post-baseline τ value less than 24.1 and a 95% CI that included 24.0.
Time Frame	1 month

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population: all subjects randomized into the study that have τ calculated post-randomization.

Arm/Group Title	Tasimelteon (Randomized)	Placebo (Randomized)
Arm/Group Description	20 mg tasimelteon capsules, PO daily for 6 months tasimelteon: 20 mg tasimelteon capsules, PO daily for 6 months	Placebo capsules, PO daily for 6 months Placebo: Placebo capsules, PO daily for 6 months
Measure Participants	40	38
Number [percentage of patients]	17.5	2.6

6. Secondary Outcome

Title	Average Clinical Global Impression of Change (CGI-C)
Description	CGI-C scores range from 1 (very much improved) to 7 (very much worse). The average post-randomization score was obtained for each patient by averaging the last 2 scheduled assessments (Day D112 and Day D183). Lower number indicates improvement.
Time Frame	Day 112 and 183

Outcome Measure Data

Analysis Population Description

Analysis Population: all patients in the ITT population that had at least 70% of 1 circadian cycle of nighttime total sleep data reported during each phase (screening and post-randomization)

Arm/Group Title	Tasimelteon (Randomized)	Placebo (Randomized)
Arm/Group Description	20 mg tasimelteon capsules, PO daily for 6 months tasimelteon: 20 mg tasimelteon capsules, PO daily for 6 months	Placebo capsules, PO daily for 6 months Placebo: Placebo capsules, PO daily for 6 months
Measure Participants	38	34
Mean (Standard Error) [score]	2.6 (0.20)	3.4 (0.21)

7. Secondary Outcome

Title	Proportion of Responders With a Combined Sleep/Wake Response for LQ-nTST (≥ 90 Minutes) and UQ-dTSD (≤ 90 Minutes)
Description	The sleep/wake response represents measurement of the combined improvement in the nighttime sleep duration and daytime sleep duration. Individuals that have an improvement in nighttime sleep and daytime sleep, defined as an increase of 90 minutes or more in the lower quartile of subjective nighttime total sleep time (LQ-nTST) and a decrease of 90 minutes or more in the upper quartile of daytime total sleep duration (UQ-dTSD) are considered to be a responder.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Analysis Population: all patients in the ITT population that had at least 70% of 1 circadian cycle of nighttime total sleep data reported during each phase (screening and post-randomization)

Arm/Group Title	Tasimelteon (Randomized)	Placebo (Randomized)
Arm/Group Description	20 mg tasimelteon capsules, PO daily for 6 months tasimelteon: 20 mg tasimelteon capsules, PO daily for 6 months	Placebo capsules, PO daily for 6 months Placebo: Placebo capsules, PO daily for 6 months
Measure Participants	38	34
Number [percentage of patients]	13.2	2.9

8. Secondary Outcome

Title	Average Lower Quartile of Nights of Nighttime Total Sleep Time (LQ-nTST)
Description	LQ-nTST measures the difference in average nighttime sleep during the patient's worst 25% of nights (shortest total nighttime sleep) between the randomized phase (6 months)and the screening phase (~ 6 weeks). The higher number indicates improvement.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Analysis Population: all patients in the ITT population that had at least 70% of 1 circadian cycle of nighttime total sleep data reported during each phase (screening and post-randomization)

Arm/Group Title	Tasimelteon (Randomized)	Placebo (Randomized)
Arm/Group Description	20 mg tasimelteon capsules, PO daily for 6 months tasimelteon: 20 mg tasimelteon capsules, PO daily for 6 months	Placebo capsules, PO daily for 6 months Placebo: Placebo capsules, PO daily for 6 months
Measure Participants	38	34
Mean (Standard Error) [minutes]	56.80 (9.305)	17.08 (9.702)

9. Secondary Outcome

Title	Average Upper Quartile of Days of Subjective Daytime Sleep Duration (UQ-dTSD)
Description	UQ-dTSD measures the difference in average daytime sleep during the patient's worst 25% of days (longest total daytime sleep) between the randomized phase (6 months) and the screening phase (~ 6 weeks). Lower number indicates improvement.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Analysis Population: all patients in the ITT population that had at least 70% of 1 circadian cycle of nighttime total sleep data reported during each phase (screening and post-randomization)

Arm/Group Title	Tasimelteon (Randomized)	Placebo (Randomized)
Arm/Group Description	20 mg tasimelteon capsules, PO daily for 6 months tasimelteon: 20 mg tasimelteon capsules, PO daily for 6 months	Placebo capsules, PO daily for 6 months Placebo: Placebo capsules, PO daily for 6 months
Measure Participants	38	34
Mean (Standard Error) [minutes]	-46.48 (6.595)	-17.87 (6.889)

10. Secondary Outcome

Title	Average Midpoint of Sleep (MoST)
Description	Midpoint of Sleep Timing (MoST) is the measurement of the average midpoint of sleep time relative to bedtime. The average MoST value will trend to 0 as an individual's sleep becomes more fragmented. Improvement is defined as an increase in the average.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Analysis Population: all patients in the ITT population that had at least 70% of 1 circadian cycle of nighttime total sleep data reported during each phase (screening and post-randomization)

Arm/Group Title	Tasimelteon (Randomized)	Placebo (Randomized)
Arm/Group Description	20 mg tasimelteon capsules, PO daily for 6 months tasimelteon: 20 mg tasimelteon capsules, PO daily for 6 months	Placebo capsules, PO daily for 6 months Placebo: Placebo capsules, PO daily for 6 months
Measure Participants	38	34
Mean (Standard Error) [minutes]	35.00 (5.313)	14.48 (5.547)

11. Post-Hoc Outcome

Title	Proportion of Responders With a Combined Sleep/Wake Response for LQ-nTST (≥ 45 Minutes) and UQ-dTSD (≤ 45 Minutes)
Description	Responder analysis with responder defined as an increase of 45 minutes or more in (LQ-nTST) and a decrease of 45 minutes or more in (UQ-dTSD).
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Analysis Population: all patients in the ITT population that had at least 70% of 1 circadian cycle of nighttime total sleep data reported during each phase (screening and post-randomization)

Arm/Group Title	Tasimelteon (Randomized)	Placebo (Randomized)
Arm/Group Description	20 mg tasimelteon capsules, PO daily for 6 months tasimelteon: 20 mg tasimelteon capsules, PO daily for 6 months	Placebo capsules, PO daily for 6 months Placebo: Placebo capsules, PO daily for 6 months
Measure Participants	38	34
Number [percentage of patients]	31.6	8.8

12. Other Pre-specified Outcome

Title	Proportion of Patients With a Clinical Response (Score of ≥ 2 on N24CRS)
Description	Non-24 Clinical Response Scale (N24CRS) was a 4-item scale which includes LQ-nTST, UQ-dTSD, MoST and CGI-C assessments. Each assessment is scored as a 1 or 0 depending on the pre-specified threshold (see below). LQ-nTST: >45 minutes increase in average nighttime sleep duration; UQ-dTSD: >45 minutes decrease in average daytime sleep duration; MoST: >30 minutes increase and a standard deviation <2 hours during double-masked phase (6 months); CGI-C: <2.0 from the average of D112 and Day 183 compared to baseline
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Analysis Population: all patients in the ITT population that had at least 70% of 1 circadian cycle of nighttime total sleep data reported during each phase (screening and post-randomization)

Arm/Group Title	Tasimelteon (Randomized)	Placebo (Randomized)
Arm/Group Description	20 mg tasimelteon capsules, PO daily for 6 months tasimelteon: 20 mg tasimelteon capsules, PO daily for 6 months	Placebo capsules, PO daily for 6 months Placebo: Placebo capsules, PO daily for 6 months
Measure Participants	38	34
Number [percentage of patients]	57.9	20.6

13. Secondary Outcome

Title	Number of Patients With a Treatment Emergent Adverse Event (Open Label Extension Phase Only)
Description	Adverse events were recorded in the source documents from the time of the patient's informed consent signature until the end of the patient's study participation. An AE was defined as any untoward medical occurrence in a clinical investigation patient who does not necessarily have causal relationship with treatment.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

One subject who rolled into the OLE from the randomized phase (tasimelteon) experienced an unrelated TEAE during the OLE phase.

Arm/Group Title	Open Label Tasimelteon
Arm/Group Description	20 mg tasimelteon capsules, PO daily for 6 months tasimelteon: 20 mg tasimelteon capsules, PO daily for 6 months
Measure Participants	54
Number [participants]	37 88.1%

Adverse Events

Time Frame	1st dose to 30 days following last administration of study treatment
Adverse Event Reporting Description	55 subjects enrolled into the Open Label phase (including 3 randomized subjects who rolled into the OLE). One subject enrolled in the Open Label phase but did not take any study drug.
Arm/Group Title	Tasimelteon (Randomized)		Placebo (Randomized)		Open Label Tasimelteon
Arm/Group Description	20 mg tasimelteon capsules, PO daily for 6 months tasimelteon: 20 mg tasimelteon capsules, PO daily for 6 months		Placebo capsules, PO daily for 6 months Placebo: Placebo capsules, PO daily for 6 months		20 mg tasimelteon capsules, PO daily for 6 months tasimelteon: 20 mg tasimelteon capsules, PO daily for 6 months
All Cause Mortality
	Tasimelteon (Randomized)		Placebo (Randomized)		Open Label Tasimelteon
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Tasimelteon (Randomized)		Placebo (Randomized)		Open Label Tasimelteon
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/42 (9.5%)		2/42 (4.8%)		2/54 (3.7%)
Gastrointestinal disorders
Small Intestinal Obstruction	0/42 (0%)	0	1/42 (2.4%)	1	0/54 (0%)	0
Hepatobiliary disorders
Cholecystitis	1/42 (2.4%)	1	0/42 (0%)	0	0/54 (0%)	0
Infections and infestations
Diverticulitis	1/42 (2.4%)	1	0/42 (0%)	0	0/54 (0%)	0
Injury, poisoning and procedural complications
Procedural Pain	0/42 (0%)	0	1/42 (2.4%)	1	0/54 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute Lymphocytic Leukaemia	1/42 (2.4%)	1	0/42 (0%)	0	0/54 (0%)	0
Nervous system disorders
Syncope	1/42 (2.4%)	1	0/42 (0%)	0	0/54 (0%)	0
Serotonin Syndrome	0/42 (0%)	0	0/42 (0%)	0	1/54 (1.9%)	1
Transient Ischaemic Attack	0/42 (0%)	0	0/42 (0%)	0	1/54 (1.9%)	1
Other (Not Including Serious) Adverse Events
	Tasimelteon (Randomized)		Placebo (Randomized)		Open Label Tasimelteon
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/42 (47.6%)		13/42 (31%)		21/54 (38.9%)
Gastrointestinal disorders
Nausea	1/42 (2.4%)	1	3/42 (7.1%)	3	0/54 (0%)	0
General disorders
Oedema peripheral	3/42 (7.1%)	3	2/42 (4.8%)	2	0/54 (0%)	0
Infections and infestations
Nasopharyngitis	3/42 (7.1%)	3	4/42 (9.5%)	4	5/54 (9.3%)	6
Urinary tract infection	3/42 (7.1%)	3	1/42 (2.4%)	1	5/54 (9.3%)	6
Upper respiratory tract infection	3/42 (7.1%)	3	0/42 (0%)	0	2/54 (3.7%)	2
Investigations
Alanine aminotransferase increased	4/42 (9.5%)	4	2/42 (4.8%)	2	2/54 (3.7%)	2
Asparate aminotransferase increased	3/42 (7.1%)	3	2/42 (4.8%)	2	3/54 (5.6%)	3
Gamma-glutamyltransferase increased	0/42 (0%)	0	2/42 (4.8%)	2	3/54 (5.6%)	3
Nervous system disorders
Headache	7/42 (16.7%)	11	3/42 (7.1%)	3	4/54 (7.4%)	4
Psychiatric disorders
Abnormal dreams	2/42 (4.8%)	2	0/42 (0%)	0	3/54 (5.6%)	3

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.