Withdrawal Study to Demonstrate the Maintenance Effect in the Treatment of Non-24-Hour Sleep-Wake Disorder
Primary Purpose
Non-24-Hour Sleep-Wake Disorder
Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
tasimelteon
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Non-24-Hour Sleep-Wake Disorder focused on measuring Blindness, Eye Diseases, Nap Disorders, Circadian Rhythm Disorders, Sleep Disorders, Circadian Rhythm Sleep Disorders, Dyssomnias, Nervous System Diseases
Eligibility Criteria
Inclusion Criteria:
- Ability and acceptance to provide informed consent;
- Males, non-fecund females (i.e., surgically sterilized, if procedure was done 6 months before screening or subject is postmenopausal, without menses for 6 months before screening), or females of child-bearing potential using an acceptable method of birth control for a period of 35 days before the first dosing and must have a negative pregnancy test at the screening and baseline visits; Note: Women using hormonal methods of birth control must use an additional method of birth control during the study and for one month after the last dose.
- Willing and able to comply with study requirements and restrictions including a commitment to a fixed 9-hour sleep opportunity during the study;
- Diagnosis of N24HSWD in a previous clinical trial as measured by a tau value of > 24.1 and the lower bound of the 95% CI is > 24.
Exclusion Criteria:
- 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 is not being successfully treated or has not been resolved and 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;
History of drug or alcohol abuse as defined in DSM-IV, Diagnostic Criteria for Drug and Alcohol Abuse, within the 12 months prior to screening and/or regular consumption of alcoholic drinks (> 2 drinks/day or > 14 drinks/week);
a. Note: A standard drink is equal to 13.7 grams (0.6 ounces) of pure alcohol or
- 12-ounces of beer
- 8-ounces of malt liquor
- 5-ounces of wine
- 1.5-ounces or a "shot" of 80-proof distilled spirits or liquor (e.g., gin, rum, vodka, or whiskey);
- Subject is at risk of suicide, in the opinion of the Investigator. Evidence of suicide risk could include any suicide attempt within the past year or any other suicidal behavior within the past year;
- Current clinically significant cardiovascular, respiratory, neurologic, hepatic, hematopoietic, renal, gastrointestinal or metabolic dysfunction unless currently controlled and stable;
- Subjects who have estimated creatinine clearance (CLcr; based on the Cockcroft-Gault equation) ≤ to 55 mL/min;
- Clinically significant deviation from normal in clinical laboratory results, vital signs measurements, or physical examination findings at screening as determined by the clinical investigator;
- Indication of impaired liver function (values for AST, ALT or bilirubin > 2 times Upper Limit of Normal);
- Pregnant or lactating females;
- A positive test for drugs of abuse at the screening visit; Note: A positive drug screen at Visit 1 needs to be discussed with the medical monitor and will be evaluated on a case-by-case basis.
- Smoke more than 10 cigarettes/day;
- 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;
- Unwilling or unable to follow the medication restrictions described in Section 8.2., or unwilling or unable to sufficiently wash-out from use of a restricted medication
- Unable to perform calls to the study IVR system to report questionnaire results;
- Any other sound medical reason as determined by the clinical investigator;
- Legal incompetence or limited legal competence, detainment in an institution for official or legal reasons.
Sites / Locations
- Pulmonary Associates, PA
- SDS Clinical Trials Inc.
- VA Palo Alto Health Care System/PAIRE (San Fransisco Bay Area)
- St. Johns Sleep Disorder Center - St. Johns Medical Plaza
- Radiant Research - Denver
- PAB Clinical Research Inc.
- Kendall South Medical Center, Inc.
- Ocean Sleep Disorders Center - Ormond Beach
- Sleep Disorders Center Of Georgia
- Suburban Lung Associates SC
- The Center for Sleep and Wake Disorders (Washington, D.C. Metropolitan Area)
- Brigham and Women's Hospital
- Michigan Head-Pain Neurological Institute
- St. Luke's Sleep Medicine and Research Center (St. Louis Metropolitan Area)
- New York Eye and Ear Infirmary
- Ohio Sleep Medicine Institute (Columbus Metropolitan Area)
- Lynn Health Science Institute
- Columbia Research Group Inc.
- Mercy Fitzgerald Hospital - Sleep Disorders Center (Philadelphia Metropolitan Area)
- Consolidated Clinical trials
- SleepMed, Inc. - Columbia
- Todd J. Swick, M.D., P.A.
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
tasimelteon
Placebo
Arm Description
20 mg tasimelteon capsules
Placebo capsules
Outcomes
Primary Outcome Measures
Maintenance of Entrainment (aMT6s) in Subjects With N24HSWD.
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 separate 48 hour periods, approximately 1 week apart, during the run-in and randomized phases of the trial. Maintenance of entrainment is defined as the proportion of subjects who become non-entrained to a 24 hour day after randomization to tasimelteon or placebo. Non-entrainment was defined as having a post-baseline τ value ≥ 24.1 or the lower bound of the 95% CI >24.0.
Secondary Outcome Measures
Maintenance of Entrainment (Cortisol) in Subjects With N24HSWD
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 separate 48 hour periods, approximately 1 week apart, during the run-in and randomized phases of the trial. Maintenance of entrainment is defined as the proportion of subjects who become non-entrained to a 24 hour day after randomization to tasimelteon or placebo. Non-entrainment was defined as having a post-baseline τ value ≥ 24.1 or the lower bound of the 95% CI >24.0.
Change From Run-In in Subjective Nighttime Total Sleep Time in Lower Quartile of Days (LQ-nTST) During the Randomized Phase
LQ-nTST measures the average nighttime sleep during the patient's worst 25% of nights (shortest total nighttime sleep) from run-in and randomized phase. The higher number indicates improvement.
Change From Run-In in Total Daytime Sleep Duration in Lower Quartile of Days (UQ-dTSD) During the Randomized Phase
UQ-dTSD measures the average daytime sleep during the patient's worst 25% of days (longest total daytime sleep) from run-in and randomized phase. Lower number indicates improvement.
Change From Run-In in Midpoint of Sleep (MoST) During the Randomized Phase
Midpoint of Sleep Timing (MoST) is the measurement of the average timing of sleep 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.
Change From Run-In in Circadian Time to Relapse During the Randomized Phase
Time to relapse is defined as a 45 minute or greater decrement in the weekly average of subjective nighttime total sleep time (nTST) compared to the Run-in Phase.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01430754
Brief Title
Withdrawal Study to Demonstrate the Maintenance Effect in the Treatment of Non-24-Hour Sleep-Wake Disorder
Official Title
A Randomized Withdrawal Study to Demonstrate the Maintenance of Effect of 20 mg Tasimelteon in the Treatment of N24HSWD
Study Type
Interventional
2. Study Status
Record Verification Date
October 2014
Overall Recruitment Status
Completed
Study Start Date
September 2011 (undefined)
Primary Completion Date
December 2012 (Actual)
Study Completion Date
December 2012 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Vanda Pharmaceuticals
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
The purpose of this study is to evaluate the maintenance effect and safety of 20 mg tasimelteon versus placebo in subjects suffering from Non-24-Hour Sleep-Wake Disorder.
Detailed Description
Non-24-Hour Sleep-Wake Disorder (N24HSWD) occurs when individuals 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 is < 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. As time progresses, the endogenous circadian rhythm of sleep-wake propensity in these individuals moves further and further away from the 24-hour light-dark cycle and gradually, these individuals are unable to sleep at night and as a result experience extreme sleepiness during the daytime hours and more frequent naps with a longer duration. Eventually, the sleep-wake time moves back into alignment with the social time for sleep and the individuals sleep well at night and have decreased daytime napping. The alignment between their endogenous circadian rhythms and the 24-hour day is temporary as they are continually drifting later and later each day.
This will be a multicenter, randomized withdrawal, double-masked, placebo-controlled, parallel study. The study has three phases: the tasimelteon run-in phase, the tau estimation phase, and the randomized withdrawal phase. Subjects who have participated in study VP-VEC-162-3201 that meet the entry criteria for this study will be eligible for the run-in phase The run-in phase comprises a screening visit where subject's initial eligibility will be evaluated. Subjects that meet the inclusion/exclusion criteria at screening will enter the run-in phase and will be dosed with 20 mg of tasimelteon daily for 6 weeks. The tau estimation phase (48 hour urine collection samples to evaluate response to tasimelteon) will follow the run-in phase and will last approximately 6 weeks long. The randomized withdrawal phase comprises approximately eight weeks of treatment with either placebo or tasimelteon 20 mg taken approximately 1 hour prior to their target bedtime in a double-masked fashion.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Non-24-Hour Sleep-Wake Disorder
Keywords
Blindness, Eye Diseases, Nap Disorders, Circadian Rhythm Disorders, Sleep Disorders, Circadian Rhythm Sleep Disorders, Dyssomnias, Nervous System Diseases
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
20 (Actual)
8. Arms, Groups, and Interventions
Arm Title
tasimelteon
Arm Type
Experimental
Arm Description
20 mg tasimelteon capsules
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo capsules
Intervention Type
Drug
Intervention Name(s)
tasimelteon
Other Intervention Name(s)
VEC-162
Intervention Description
20 mg tasimelteon capsules, daily
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo capsules, daily
Primary Outcome Measure Information:
Title
Maintenance of Entrainment (aMT6s) in Subjects With N24HSWD.
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 separate 48 hour periods, approximately 1 week apart, during the run-in and randomized phases of the trial. Maintenance of entrainment is defined as the proportion of subjects who become non-entrained to a 24 hour day after randomization to tasimelteon or placebo. Non-entrainment was defined as having a post-baseline τ value ≥ 24.1 or the lower bound of the 95% CI >24.0.
Time Frame
Approximately 12 weeks
Secondary Outcome Measure Information:
Title
Maintenance of Entrainment (Cortisol) in Subjects With N24HSWD
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 separate 48 hour periods, approximately 1 week apart, during the run-in and randomized phases of the trial. Maintenance of entrainment is defined as the proportion of subjects who become non-entrained to a 24 hour day after randomization to tasimelteon or placebo. Non-entrainment was defined as having a post-baseline τ value ≥ 24.1 or the lower bound of the 95% CI >24.0.
Time Frame
Approximately 12 weeks
Title
Change From Run-In in Subjective Nighttime Total Sleep Time in Lower Quartile of Days (LQ-nTST) During the Randomized Phase
Description
LQ-nTST measures the average nighttime sleep during the patient's worst 25% of nights (shortest total nighttime sleep) from run-in and randomized phase. The higher number indicates improvement.
Time Frame
Approximately 12 weeks
Title
Change From Run-In in Total Daytime Sleep Duration in Lower Quartile of Days (UQ-dTSD) During the Randomized Phase
Description
UQ-dTSD measures the average daytime sleep during the patient's worst 25% of days (longest total daytime sleep) from run-in and randomized phase. Lower number indicates improvement.
Time Frame
Approximately 12 weeks
Title
Change From Run-In in Midpoint of Sleep (MoST) During the Randomized Phase
Description
Midpoint of Sleep Timing (MoST) is the measurement of the average timing of sleep 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
Approximately 12 weeks
Title
Change From Run-In in Circadian Time to Relapse During the Randomized Phase
Description
Time to relapse is defined as a 45 minute or greater decrement in the weekly average of subjective nighttime total sleep time (nTST) compared to the Run-in Phase.
Time Frame
Approximately 8 weeks
10. Eligibility
Sex
All
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Ability and acceptance to provide informed consent;
Males, non-fecund females (i.e., surgically sterilized, if procedure was done 6 months before screening or subject is postmenopausal, without menses for 6 months before screening), or females of child-bearing potential using an acceptable method of birth control for a period of 35 days before the first dosing and must have a negative pregnancy test at the screening and baseline visits; Note: Women using hormonal methods of birth control must use an additional method of birth control during the study and for one month after the last dose.
Willing and able to comply with study requirements and restrictions including a commitment to a fixed 9-hour sleep opportunity during the study;
Diagnosis of N24HSWD in a previous clinical trial as measured by a tau value of > 24.1 and the lower bound of the 95% CI is > 24.
Exclusion Criteria:
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 is not being successfully treated or has not been resolved and 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;
History of drug or alcohol abuse as defined in DSM-IV, Diagnostic Criteria for Drug and Alcohol Abuse, within the 12 months prior to screening and/or regular consumption of alcoholic drinks (> 2 drinks/day or > 14 drinks/week);
a. Note: A standard drink is equal to 13.7 grams (0.6 ounces) of pure alcohol or
12-ounces of beer
8-ounces of malt liquor
5-ounces of wine
1.5-ounces or a "shot" of 80-proof distilled spirits or liquor (e.g., gin, rum, vodka, or whiskey);
Subject is at risk of suicide, in the opinion of the Investigator. Evidence of suicide risk could include any suicide attempt within the past year or any other suicidal behavior within the past year;
Current clinically significant cardiovascular, respiratory, neurologic, hepatic, hematopoietic, renal, gastrointestinal or metabolic dysfunction unless currently controlled and stable;
Subjects who have estimated creatinine clearance (CLcr; based on the Cockcroft-Gault equation) ≤ to 55 mL/min;
Clinically significant deviation from normal in clinical laboratory results, vital signs measurements, or physical examination findings at screening as determined by the clinical investigator;
Indication of impaired liver function (values for AST, ALT or bilirubin > 2 times Upper Limit of Normal);
Pregnant or lactating females;
A positive test for drugs of abuse at the screening visit; Note: A positive drug screen at Visit 1 needs to be discussed with the medical monitor and will be evaluated on a case-by-case basis.
Smoke more than 10 cigarettes/day;
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;
Unwilling or unable to follow the medication restrictions described in Section 8.2., or unwilling or unable to sufficiently wash-out from use of a restricted medication
Unable to perform calls to the study IVR system to report questionnaire results;
Any other sound medical reason as determined by the clinical investigator;
Legal incompetence or limited legal competence, detainment in an institution for official or legal reasons.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Vanda Pharmaceuticals
Organizational Affiliation
Vanda Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Pulmonary Associates, PA
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85006
Country
United States
Facility Name
SDS Clinical Trials Inc.
City
Orange
State/Province
California
ZIP/Postal Code
92868
Country
United States
Facility Name
VA Palo Alto Health Care System/PAIRE (San Fransisco Bay Area)
City
Palo Alto
State/Province
California
ZIP/Postal Code
94304
Country
United States
Facility Name
St. Johns Sleep Disorder Center - St. Johns Medical Plaza
City
Santa Monica
State/Province
California
ZIP/Postal Code
90404
Country
United States
Facility Name
Radiant Research - Denver
City
Denver
State/Province
Colorado
ZIP/Postal Code
80239
Country
United States
Facility Name
PAB Clinical Research Inc.
City
Brandon
State/Province
Florida
ZIP/Postal Code
33511
Country
United States
Facility Name
Kendall South Medical Center, Inc.
City
Miami
State/Province
Florida
ZIP/Postal Code
33175
Country
United States
Facility Name
Ocean Sleep Disorders Center - Ormond Beach
City
Ormond Beach
State/Province
Florida
ZIP/Postal Code
32174
Country
United States
Facility Name
Sleep Disorders Center Of Georgia
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30342
Country
United States
Facility Name
Suburban Lung Associates SC
City
Elk Grove Village
State/Province
Illinois
ZIP/Postal Code
60007
Country
United States
Facility Name
The Center for Sleep and Wake Disorders (Washington, D.C. Metropolitan Area)
City
Chevy Chase
State/Province
Maryland
ZIP/Postal Code
20815
Country
United States
Facility Name
Brigham and Women's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Michigan Head-Pain Neurological Institute
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48104
Country
United States
Facility Name
St. Luke's Sleep Medicine and Research Center (St. Louis Metropolitan Area)
City
Chesterfield
State/Province
Missouri
ZIP/Postal Code
63017
Country
United States
Facility Name
New York Eye and Ear Infirmary
City
New York
State/Province
New York
ZIP/Postal Code
10003
Country
United States
Facility Name
Ohio Sleep Medicine Institute (Columbus Metropolitan Area)
City
Dublin
State/Province
Ohio
ZIP/Postal Code
43017
Country
United States
Facility Name
Lynn Health Science Institute
City
Oklahoma city
State/Province
Oklahoma
ZIP/Postal Code
73112
Country
United States
Facility Name
Columbia Research Group Inc.
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
Mercy Fitzgerald Hospital - Sleep Disorders Center (Philadelphia Metropolitan Area)
City
Lafayette Hill
State/Province
Pennsylvania
ZIP/Postal Code
19444
Country
United States
Facility Name
Consolidated Clinical trials
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15221
Country
United States
Facility Name
SleepMed, Inc. - Columbia
City
Columbia
State/Province
South Carolina
ZIP/Postal Code
29201
Country
United States
Facility Name
Todd J. Swick, M.D., P.A.
City
Houston
State/Province
Texas
ZIP/Postal Code
77063
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
26466871
Citation
Lockley SW, Dressman MA, Licamele L, Xiao C, Fisher DM, Flynn-Evans EE, Hull JT, Torres R, Lavedan C, Polymeropoulos MH. Tasimelteon for non-24-hour sleep-wake disorder in totally blind people (SET and RESET): two multicentre, randomised, double-masked, placebo-controlled phase 3 trials. Lancet. 2015 Oct 31;386(10005):1754-64. doi: 10.1016/S0140-6736(15)60031-9. Epub 2015 Aug 4.
Results Reference
derived
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Withdrawal Study to Demonstrate the Maintenance Effect in the Treatment of Non-24-Hour Sleep-Wake Disorder
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