E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Blind males or females with no conscious light perception and the complaint of a sleep-wake disorder associated with Non-24 Hour Sleep-Wake Disorder. |
|
E.1.1.1 | Medical condition in easily understood language |
Blind males or females with no conscious light perception and the complaint of a sleep-wake disorder associated with Non-24 Hour Sleep-Wake Disorder. |
|
E.1.1.2 | Therapeutic area | Body processes [G] - Biological Phenomena [G16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10009191 |
E.1.2 | Term | Circadian rhythm sleep disorder |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine the efficacy of tasimelteon in subjects with N24HSWD as measured by the proportion of entrainment.
(A step-down objective): To determine the efficacy of tasimelteon in subjects with N24HSWD as measured by the proportion of patients with a clinical response;
Clinical response is defined as the coincident demonstration of :
1.) Entrainment of the aMT6s rhythm, and
2.) A score of ≥3 on the Non-24 Clinical Response Scale (N24CRS)
The success of the trial will be based on the rejection of the null hypothesis associated with the proportion of entrainment as measured by aMT6s. |
|
E.2.2 | Secondary objectives of the trial |
Key Secondary Objectives
• To determine the efficacy of tasimelteon in subjects with N24HSWD as measured by the proportion of responders with a combined sleep/wake response for nighttime sleep duration and daytime sleep duration defined as:
1. Increase of 90 minutes or greater in LQ-nTST and
2. Decrease of 90 minutes or greater in UQ-dTSD
• To determine the efficacy of tasimelteon in subjects with N24HSWD as measured by the proportion of entrainment as assessed by urinary cortisol
Additional Secondary Objectives: See protocol |
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacogenomic sub-study |
|
E.3 | Principal inclusion criteria |
1. Ability and acceptance to provide informed consent;
2. Men or women between 18 – 75 years, inclusive;
3. Body Mass Index (BMI) of ≥ 18 and ≤ 33 kg/m2 (BMI = weight (kg)/ [height (m)]2);
4. Males, non-fecund females (i.e., surgically sterilized, if procedure was done 6 months before screening or subject is postmenopausal, without menses for 1 year before screening), or females of child-bearing potential using 2 independent barrier methods of birth control (i.e., condoms, diaphragm, spermicidal agents, cervical cap) for a period of 35 days before the first dosing, during the study and for one month after the last dose and must have a negative at the screening and baseline visits;
Note: Hormonal contraception is not considered a reliable method of birth control in this study.
Note: For patients over 55 years of age at the screening visit absence of menses for 1 year before screening is sufficient to establish the postmenopausal status. The postmenopausal status of a patient under 55 years of age at the screening visit will be confirmed by measuring the following hormones:
Follicle-stimulating hormone (FSH) ≥40 mIU/mL
Estradiol ≤ 30 pg/mL (110.1 pmol/L)
5. Willing to comply with study requirements and restrictions including commitment to a fixed 9-hour sleep opportunity during the study;
6. Fluent in English or German respectively;
7. No perception of light by the subject’s own report;
8. Tau length of ≥ 24.25 and the lower bound of 95% CI > 24.0 and the upper bound of 95% CI < 24.9 based on urinary aMT6s rhythms;
9. Diagnosis of N24HSWD as determined by:
a. 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
b. Urinary aMT6s demonstrates a progressive delay of the aMT6 acrophase time.
|
|
E.4 | Principal exclusion criteria |
1. 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;
2. 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;
3. Subjects who take NSAIDs daily and would not interrupt their use for the 48-hour urine collections and the 24 hours preceding them;
4. History of intolerance and/or hypersensitivity to melatonin or melatonin agonists;
5. 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
o 12-ounces of beer
o 8-ounces of malt liquor
o 5-ounces of wine
o 1.5-ounces or a “shot” of 80-proof distilled spirits or liquor (e.g., gin, rum, vodka, or whiskey);
6. Subjects having any suicidal ideation of type 4 or 5 on the C-SSRS at Screening or Baseline;
7. 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;
8. Current clinically significant cardiovascular, respiratory, neurologic, hepatic, hematopoietic, renal, gastrointestinal or metabolic dysfunction unless currently controlled and stable;
9. Subjects who have estimated creatinine clearance (CLcr; based on the Cockcroft-Gault equation) ≤ to 55 mL/min;
10. Clinically significant deviation from normal in clinical laboratory results, vital signs measurements, or physical examination findings at screening or baseline as determined by the clinical investigator;
11. Indication of impaired liver function (values for AST, ALT or bilirubin > 2 times Upper Limit of Normal);
12. Pregnant or lactating females;
13. 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.
14. Smoke more than 10 cigarettes/day;
15. 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;
16. Participation in a previous tasimelteon (aka VEC-162 or BMS-214778) trial;
17. Exposure to any investigational drug, including placebo, within 30 days or 5 half-lives (whichever was longer) of screening;
18. 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
19. Use of melatonin or melatonin agonist within 1 week of the tau identification segment;
20. Unable to perform calls to the study IVR system to report questionnaire results;
21. Any other sound medical reason as determined by the clinical investigator.
22. Legal incompetence or limited legal competence, detainment in an institution for official or legal reasons.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
• The entrainment of the circadian melatonin rhythm as measured by urinary 6-sulfatoxymelatonin (aMT6s)
• The Clinical Response rate corresponding to individuals who have both:
1. Entrainment of the aMT6s rhythm, and
2. A score of ≥ 3 on the Non-24 Clinical Response Scale (N24CRS)
Entrainment is defined as having a τ value ≤ 24.1 and a 95% CI that includes 24.0. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
Key Secondary Endpoints
• The proportion of responders with a combined sleep/wake response for nighttime sleep duration and daytime sleep duration defined as:
1. Increase of 90 minutes or greater in LQ-nTST, and
2. Decrease of 90 minutes or greater in UQ-dTSD
• The entrainment of the circadian rhythm as measured by cortisol
Additional Secondary Endpoints
• The subtype I response rate (sleep time subtype)
• The subtype II response rate (daytime sleep subtype)
• The subtype III response rate (MoST subtype)
• The subtype IV response rate (CGI-C subtype)
• Treatment response association with aMT6s excretion rate
• The average of LQ-nTST
• The average of UQ-dTSD
• The average of MoST
• The Clinical Global Impression-Change (CGI-C
• The entrainment of circadian analytes
Nighttime sleep is defined as the amount of time slept between the daily dosing time and the scheduled wake time (a 10 hour interval). This will be evaluated through the PSQ.
Daytime sleep is defined as any sleep episode, lasting more than 5 minutes, occurring during the 14-hours between the subject’s scheduled wake time and their daily dosing time. This will be evaluated through the Pre-SQ. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
with a single-blind phase and open label extension |
|
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |