To evaluate the efficacy of JZP-110 administered once daily for up to 12 weeks in doses of 75, 150, and 300 mg compared to placebo in the treatment of excessive sleepiness in adult subjects with narcolepsy.
ID
Source
Brief title
Condition
- Sleep disturbances (incl subtypes)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- MWT: Change in the mean sleep latency time (in minutes) as determined from
the first four trials of a 40-minute MWT from Baseline to Week 12
- ESS: Change in ESS score from Baseline to Week 12
Secondary outcome
- PGIc: Percentage of subjects reported as improved (minimally, much, or very
much) on the PGIc at Week 12
- Concentration data for JZP-110 will be tabulated by sampling time point and
will be included in a population PK analysis. The population PK model will be
used to characterize JZP-110 PK profile in narcolepsy patients and to explore
exposure-efficacy correlations
- Safety and tolerability evaluations will consist of treatmentemergent adverse
events (TEAEs) and changes in clinical laboratory tests (chemistry, hematology,
and urinalysis), vital signs, 24-hour ambulatory blood pressure monitoring,
12-lead ECGs, physical exams, and C-SSRS assessments.
Background summary
Narcolepsy is a life-long neurologic disease for which no cure has been
identified. It affects an estimated 0.02% to 0.067% of the population
worldwide, approximately 1 in 2000 individuals in the United States and 4.7 of
10,000 (0.047%) individuals in the general population of five European
countries (United Kingdom [UK], Germany, Italy, Portugal, and Spain). The
symptomatology of this condition is well described in the literature, with
consensus on the five core symptoms of narcolepsy: excessive daytime
sleepiness, cataplexy, sleep paralysis, sleep-related (hypnagogic and
hypnopompic) hallucinations, and disrupted nighttime sleep (DNS) with excessive
daytime sleepiness and cataplexy being the most common symptoms. Currently
approved medications to improve wakefulness and to treat excessive daytime
sleepiness in narcolepsy include dextroamphetamine (Dexedrine® ),
methylphenidate (Ritalin® ), sodium oxybate (Xyrem® ), modafinil (Provigil® ),
and armodafinil (Nuvigil® ). Each of these medications has limitations,
including those related to efficacy and safety. Dextroamphetamine and
methylphenidate are C-II stimulant medications with high potential for abuse.
Sodium oxybate is a C-III CNS depressant that requires twice nightly dosing.
Modafinil and armodafinil do not appear to adequately promote wakefulness
throughout the day with once daily dosing. As a result of the findings of
significant decreases in excessive sleepiness (lower ESS scores) and
significant increases in the ability to stay awake throughout the day (higher
MWT sleep latencies) when adult patients with narcolepsy were treated with
JZP-110, as well as the urgent clinical need reported by patients for therapies
that better treat the excessive sleepiness that significantly impacts their
daily lives, Jazz Pharmaceuticals is conducting this study with JZP-110 to
generate efficacy, safety, and pharmacokinetic (PK) information in this
population.
Study objective
To evaluate the efficacy of JZP-110 administered once daily for up to 12 weeks
in doses of 75, 150, and 300 mg compared to placebo in the treatment of
excessive sleepiness in adult subjects with narcolepsy.
Study design
This trial is a 12-week, randomized, double-blind, placebocontrolled,
multicenter, 4-treatment parallel group study of the safety and efficacy of
JZP-110 in the treatment of excessive sleepiness in adult subjects with
narcolepsy as defined by The International Classification of Sleep Disorders,
Third Edition (ICSD-3) or Diagnostic and Statistical Manual of Mental
Disorders, Fifth Edition (DSM-5). Following the successful completion of
Screening and Baseline visits, stratified randomization on the basis of the
presence or absence of cataplexy will occur. Subjects will be assigned to
receive JZP110 75, 150, or 300 mg or placebo in a 1:1:1:1 ratio once daily over
a 12-week Treatment Phase. Subjects randomized to the 150 mg dose will
initially receive 75 mg from Day 1 through Day 3 of the first week of the
Treatment Phase and will receive 150 mg starting on Day 4. Subjects randomized
to the 300 mg dose will initially receive 150 mg from Day 1 through Day 3 of
the first week of the Treatment Phase and will receive 300 mg starting on Day
4. Subjects randomized to the 75 mg group will not require titration. During
the Treatment Phase, subjects will return to the investigative site to complete
efficacy and safety assessments at the end of Weeks 1, 4, 8, and 12; the Week
1, 4, and 12 visits will include an overnight stay at the investigational site
for nocturnal polysomnography (PSG) followed by a Maintenance of Wakefulness
Test (MWT), and the Week 8 Visit will include 24-hour ambulatory blood pressure
monitoring. Subjects will take their final dose of study drug at the Week 12
visit prior to the Week 12 visit assessments. Subjects will return at the end
of Week 14 for follow-up assessments. Unless there are any outstanding safety
issues that require follow-up, subjects will be discharged from the study at
the Week 14 visit.
Intervention
JZP-110 [(R)-2-amino-3-phenylpropylcarbamate hydrochloride] will be supplied as
75 mg, 150 mg, and 300 mg tablets that will be overencapsulated in identical
opaque gelatin capsules. The doses of JZP-110 will be based on the free base of
the molecule. Subjects will be instructed to take a single oral daily dose of
study drug in the morning, on an empty stomach, within one hour of awakening.
Subjects will also be instructed to abstain from eating or drinking (except for
water) for 30 minutes after taking the study drug. Placebo tablets will also be
overencapsulated in opaque gelatin capsules that will be identical to those
used for the active JZP-110 treatments. Mode of administration will be the same
as for the test product above.
Study burden and risks
Patients are asked to undergo procedures described in the flowchart on pages 75
- 77 of the study protocol. These procedures include physical examination,
vital signs, urine pregnancy tests (female;chidbearing patients, ECG, overnight
sleep tests (PSG/MWT), completing questionnaire, diaries and adminsitration of
study drug (oral). Additionally, fertile patients who are sexually active must
agree to use an effective form of contraception with their sexual partners
throughout participation in the study. Patients are also asked to inform their
study doctor on their medication use and change in health status.
JZP-110 has been studied in healthy adults, patients with major depressive
disorder and in patients with narcolepsy. In these studies of JZP-110, most
side effects have been mild to moderate in severity; however, one patient with
major depressive disorder experienced a heart attack which was severe. The most
frequently reported side effects associated with the use of JZP-110 in
narcolepsy trials at the same doses (need to qualify the mg of 150 and 300)
that will be studied in this trial have included: Anxiety, Chest discomfort,
Diarrhea, Difficulty sleeping (insomnia), Excessive grinding of the teeth
and/or clenching of the jaw, Irritability, Headache, Loss of appetite for food
(anorexia), Nausea, Rapid, strong, or irregular heartbeat (palpitations).
Patients may have pain, swelling, or bruising or possible infection during
blood draws. Additionally, the adhesive used for the electrodes from the ECG
and the PSG may irritate patient's skin
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US
Listed location countries
Age
Inclusion criteria
1. Males and females between 18 and 75 years of age, inclusive.
2. Diagnosis of narcolepsy according to ICSD-3 or DSM-5 criteria.
3. Baseline mean sleep latency *25 minutes as documented by the mean of the first four trials of the
Baseline 5-trial MWT.
4. Baseline Epworth Sleepiness Scale (ESS) score *10.
5. Usual nightly total sleep time of at least 6 hours.
6. Body mass index from 18 to <45 kg/m2 .
7. Consent to use a medically acceptable method of contraception for at least 2 months prior to the first dose of study drug, throughout the entire study period, and for 30 days after the study is completed.
8. Willing and able to comply with the study design schedule and other requirements.
9. Willing and able to provide written informed consent.
Exclusion criteria
1. Female subjects who are pregnant, nursing, or lactating.
2. Usual bedtime later than 1 AM (0100 hours).
3. Occupation requiring nighttime or variable shift work.
4. Moderate or severe obstructive sleep apnea (OSA) on the baseline PSG.
5. Any other clinically relevant medical, behavioral, or psychiatric disorder other than narcolepsy that is associated with excessive sleepiness.
6. History or presence of bipolar disorder, bipolar related disorders, schizophrenia, schizophrenia spectrum disorders, or other psychotic disorders according to DSM-5 criteria.
7. History or presence of any acutely unstable medical condition, behavioral or psychiatric disorder (including active suicidal ideation), or surgical history that could affect the safety of the subject or interfere with study efficacy, safety, PK assessments, or the ability of the subject to complete the trial per the judgment of the Investigator.
8. History of bariatric surgery within the past year or a history of any gastric bypass procedure..
9. Presence of renal impairment or calculated creatinine clearance <60 mL/min.
10. Clinically significant ECG abnormality, in the opinion of the Investigator.
11. This criteria has been removed.
12. Presence of significant cardiovascular disease including but not limited to: myocardial infarction within the past year, unstable angina pectoris, symptomatic congestive heart failure (ACC/AHA stage C or D), revascularization procedures within the past year, ventricular cardiac arrhythmias requiring automatic implantable cardioverter defibrillatory (AICD) or medication therapy, uncontrolled hypertension, systolic blood pressure *155 mmHg or diastolic blood pressure *95 mmHg (at screening, or consistently across Baseline measures according to protocol specifications), or any history of cardiovascular disease or any significant cardiovascular condition that in the investigator's opinion may jeopardize subject safety in the study.
13. Laboratory value(s) outside the laboratory reference range that are considered to be clinically significant by the Investigator (clinical chemistry, hematology, and urinalysis); NOTE: Screening labs may be repeated once.
14. Excessive caffeine use one week prior to Baseline assessments or anticipated excessive use during the study defined as >600 mg/day of caffeine.
15. Use of any over-the-counter (OTC) or prescription medications that could affect the evaluation of
excessive sleepiness within a time period prior to the Baseline visit corresponding to at least five half-lives of the drug(s) or planned use of such drug(s) at some point throughout the duration of the study. Examples of excluded medications include OTC sleep aids or
stimulants (e.g., pseudoephedrine), methylphenidate, amphetamines, modafinil, armodafinil, sodium
oxybate, pemoline, trazodone, hypnotics, benzodiazepines, barbiturates, and opioids. Medications should be discontinued such that the subject has returned to his/her baseline level of daytime sleepiness at least 7 days prior to the Baseline visit, in the opinion of the Investigator.
16. Use of any medications that could affect the evaluation of cataplexy within a time period prior to the Baseline visit corresponding to at least five half-lives of the drug(s) or planned use of such drug(s) at some point throughout the duration of the study. Examples of excluded anti-cataplectic medications include selective serotonin reuptake inhibitors (SSRIs), serotoninnorepinephrine
reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), anti-convulsant agents, and sodium oxybate. These drugs will be discontinued if they are taken for the treatment of narcolepsy and discontinuation is deemed safe by the Investigator. Medications should be sufficiently washed out such that the subject has returned to his/her baseline level of cataplexy at least 7 days prior to the Baseline visit, in the opinion of the
Investigator.
17. Received an investigational drug in the past 30 days or five half-lives (whichever is longer) prior to the Baseline visit, or plans to use an investigational drug (other than the study drug) during the study.
18. Previous exposure to or participation in a previous clinical trial of JZP-110 (ADX-N05, R228060,
YKP10A).
19. Current or past (within the past 2 years) diagnosis of a moderate or severe substance use disorder according to DSM-5 criteria.
20. Nicotine dependence that has an effect on sleep (e.g., a subject who routinely awakens at night to smoke).
21. Current, past (within the past 2 years), or seeking treatment for a substance related disorder.
22. Urine drug screen positive for an illicit drug of abuse (including cannabinoids) at screening or at any point throughout the duration of the study, except for a prescribed drug (e.g., amphetamine) at screening.
23. History of phenylketonuria (PKU) or history of hypersensitivity to phenylalanine-derived products.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-005487-15-NL |
| CCMO | NL53351.058.15 |