| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| The treatment of cataplexy and excessive daytime sleepiness on narcolepsy. |
|
| E.1.1.1 | Medical condition in easily understood language |
Cataplexy which is an abrupt temporary loss of voluntary muscular function and tone.
Narcolepsy which is a neurological disorder that affects the control of sleep and wakefulness |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10007738 |
| E.1.2 | Term | Cataplexy and narcolepsy |
| E.1.2 | System Organ Class | 100000004852 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary Objectives
• To compare the efficacy of 6.0, 7.5, and 9.0 g of FT218 to placebo in treating excessive daytime sleepiness (EDS) in both type 1 narcolepsy (NT1) and type 2 narcolepsy (NT2) subjects as measured by mean sleep latency on the Maintenance of Wakefulness Test (MWT) and by the Clinical Global Impression (CGI) rating of sleepiness, and to compare the efficacy of 6.0, 7.5, and 9.0 g of FT218 to placebo in treating cataplexy in NT1 subjects as measured by the number of cataplexy attacks (NCA) determined from the cataplexy frequency item in the Sleep and Symptom Daily Diary. |
|
| E.2.2 | Secondary objectives of the trial |
| To compare the efficacy of 6.0, 7.5, and 9.0 g of FT218 to placebo in treating disturbed nocturnal sleep (DNS) in both NT1 and NT2 subjects as determined by polysomnography (PSG) measures of sleep fragmentation defined as shifts to Wake or N1 from any sleep change. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female subjects 18 years of age or older
2. Willing and able to give written informed consent for study participation.
3. Documented evidence of a diagnosis of NT1 or NT2 as, in part, determined by an overnight PSG and next-day MSLT with 2 or more SOREMPs with mean sleep latency in the pathological range ie, < 8 minutes or meeting the NT1 or the NT2 as defined by the International Classification of Sleep Disorders -3 Criteria
4. Current continuing presence of EDS as defined by subject report for the last 3 months and an ESS > 10
5. For NT1 only, current continuing presence of cataplexy as defined by subject report for the last 3 months
6. Subjects may use concomitant stimulants, but must comply with the following:
a. They must be on a stable dose of stimulants for at least 3 weeks prior to starting the screening process for this study; AND
b. They must use the same stimulant regimen throughout the entire study period, including during screening and post treatment periods
c. They must discontinue all anti cataplexy drugs
7. Female subjects who:
a. Are postmenopausal for at least 1 year before the screening visit
b. Are surgically sterile, OR
c. If of childbearing potential agree to practice at least one highly effective method of contraception, from the time of the signing of informed consent through the last dose of study drug and for 30 days after dosing stops (1 ovulatory cycle), or complete abstain from heterosexual intercourse if in line with the preferred and usual lifestyle of the subject.
8. Willing and able to comply with all study mandated requirements and procedures for the duration of the clinical study
9. Willing to adhere to all study restrictions including:
a. Willingness to comply with the requirement to remain in bed for a minimum of 6 hours after taking the study drug
b. Adherence to concomitant drug washout requirements, as applicable, for the duration of the clinical study.
c. Willing to refrain from operating a car or heavy machinery if determined necessary by the investigator or willingness to refrain from operating a car or heavy machinery for at least 6 hours after taking the nightly dose of FT218
d. Willing to abstain from alcohol for the duration of the clinical study
e. If a smoker, willing to abstain from smoking at night from approximately 9 pm to 7 am for the duration of the clinical study
10. Evidence of adequate support for the duration of the study, including transportation to and from the study site if needed
To be eligible for inclusion, subjects must satisfy all of the following criteria at the Visit 3 dosing visit:
1. Written informed consent obtained during the screening assessment visit
2. Still eligible as per requirements in Protocol Section 8.3.2
3. Compliance with drug washout requirements
4. Compliance in completing the study screening/baseline Sleep and Symptom Daily Diary. Compliance is defined as completing the diary at least 4 times in each of the screening weeks.
5. Confirmation of EDS as defined by all of the following
a. Baseline ESS score > 10 points; AND
b. Baseline MWT mean sleep latency < 11 minutes following baseline PSG and as confirmed by the central scoring laboratory.
6. For NT1 only, current continuing presence of cataplexy as defined by an average of 8 reported cataplexy attacks per week in the screening/baseline Sleep and Symptom Daily Diary
7. Women of childbearing potential must have a negative serum pregnancy test at screening and a negative urine test within 7 days prior to treatment.
|
|
| E.4 | Principal exclusion criteria |
Subjects will be excluded from the study if one or more of the following criteria are applicable:
1. Prior use of sodium oxybate is allowed in the study but within the following exclusions:
a. Previous dosing must have been limited to no more than 4.5g per night.
b. Patient should not have taken sodium oxybate for more than 2 weeks.
c. All previous dosing must not have occurred within the last year prior to entry to the study.
2. Current use of sodium valproate
3. Any use of the following prohibited medications for the duration of the clinical study: (Section 8.4.8.1)
a. Anticonvulsants
b. Clonidine
c. SSRIs and serotonin and norepinephrine re-uptake inhibitors (SNRIs)
d. MAOIs
e. TCAs
f. Sedative Antihistamines
g. Antipsychotics
h. Tramadol
i. Benzodiazepines
j. Barbiturates
k. Alcohol and CNS depressants
l. Gamma hydroxybutyrate (GHB) dehydrogenase inhibitors
m. Topiramate
n. Opioids
o. Other experimental medications designed to treat narcolepsy, cataplexy or any other condition
4. Treatment with any investigational products within 3 months before study enrollment
5. Any drug known to affect sleep-wake function. Concomitant stimulant use is permitted.
6. A diagnosis of sleep apnea or any other sleep disorder known to cause EDS as determined by PSG and sleep
history, including any PSG results indicating an apnea-hypopnea index (AHI) ≥ 15
7. The presence of any unstable or clinically significant medical and psychiatric disorders (as determined by medical or psychiatric history, physical examination, and/or clinical laboratory test) which in the opinion of the investigator may either put the subject at risk by participation in the study, or may influence the results of the study
8. Subjects with a previous history or current ideation of suicide attempt
9. Subjects who have a history of drug or alcohol use that, in the opinion of the investigator would interfere with study subject safety and adherence to study requirements
10. Required commercial or equivalent driving during the study period
11. An occupation that requires variable shift work or routine night shifts
12. Any travel across more than 3 time zones during the course of the study
13. Consuming more than 14 standard alcoholic drinks per week, on average, before participating in the clinical research study
14. Smoking during the night (approximately between 9 pm and 7 am) during the course of the study
15. Female subjects who are lactating or have a positive pregnancy test. Females of reproductive potential not willing or able to employ at least one highly effective method of contraception to prevent pregnancy for the duration of the study and for up to 30 days after completing study treatment
16. Any current malignancy and/or any history of malignancy within last 3 years
17. A history of seizure disorder, head trauma, or past invasive intracranial surgery
18. Subjects with severe chronic obstructive pulmonary disease. Subjects with mild to moderate chronic obstructive pulmonary disease and assessed as stable by the principal investigator (PI) are eligible
19. Principal investigator judgement on other underlying respiratory and/or other underlying condition or disorder that would potentiate risk of respiratory or CNS depression with concomitant use of sodium oxybate
20. Known hepatitis B surface antigen-positive status or known or suspected active hepatitis C infection
21. Known human immunodeficiency virus infection or acquired immunodeficiency syndrome related illness
22. Scheduled for procedures requiring general anesthesia during the study
23. Known contraindication/allergy/sensitivity/intolerance to the study drug, sodium oxybate, or the inactive
ingredients of FT218 or placebo
24. Atrial fibrillation or an abnormal electrocardiogram (ECG) demonstrating clinically significant dysrhythmia(s)
25. Recent myocardial infarction or coronary revascularization (less than 3 months)
26. Uncontrolled hypertension
27. Known succinic semi-aldehyde dehydrogenase deficiency
28. Moderately or severely altered blood chemistry as defined by any one of the following:
a. A Cockcroft-Gault calculated creatinine clearance < 60 mL/min; OR
b. Liver function tests more than twice the upper limit of normal; OR
c. Serum bilirubin more than 1.5 times the upper limit of normal
29. Subjects with a medical diagnosis of major depression as defined by the DSM-V Criteria for Major Depressive Disorder (MDD). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The co-primary endpoints for evaluating EDS in both NT1 and NT2 subjects are the mean sleep latency on the MWT and the CGI. The MWT is the mean latency across 5 naps, averaged over the test day and the CGI is the clinician’s global impression of improvement in daytime sleepiness from screening.
The primary endpoint for evaluating cataplexy is the NCA, which will be evaluated only in the NT1 subpopulation. The NCA is the mean number of cataplexy events recorded on the Sleep and Symptom Daily Diary during the period. Because of concern about the variability of this measure, a minimum number of diary entries of 3 per week will be required for the average to be considered an observation. If the number of days with entries is less than 3 per week, the mean NCA will be considered missing.
All ITT or PP subjects will be included in the evaluation of narcolepsy and all ITT or PP subjects with both conditions will be used in the evaluation of cataplexy.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Weeks 4 to 5, Weeks 6 to 8, Weeks 9 to 10, Weeks 11 to 13 and Week 14 |
|
| E.5.2 | Secondary end point(s) |
| The secondary criterion that efficacy determination will be based on is fewer PSG transitions from N1, N2, N3, and REM sleep to wake and N1 sleep and from N2, N3, and REM sleep to N1. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Weeks 4 to 5, Week9 to 10 and Week 14 |
|
| 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 | No |
| 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 | No |
| 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 | No |
| 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 | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| 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 |
| Australia |
| Canada |
| Czech Republic |
| Denmark |
| Finland |
| France |
| Germany |
| Netherlands |
| Switzerland |
| United Kingdom |
| United States |
|
| 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
|
| Defined as the date of the last visit of the last subject |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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