To evaluate the safety and tolerability of JZP-110 administered once daily for up to 52 weeks in doses of 75, 150, and 300 mg
ID
Source
Brief title
Condition
- Sleep disturbances (incl subtypes)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- Safety and tolerability evaluations will consist of treatmentemergent adverse
events (TEAEs) and changes in clinical laboratory tests (chemistry, hematology,
and urinalysis), vital signs, 12-lead electrocardiograms (ECGs), physical
exams, and the C-SSRS assessments.
- Efficacy endpoints (ESS, PGIc, CGIc) will be summarized by treatment using
descriptive statistics. ESS data will be compared to baseline data from this
study for subjects in Group B and to baseline data from the previous trial that
the subject had participated in for Group A. The outcome
measures in the FOSQ-10, SF-36v2, and EQ-5D-5L will be summarized and displayed
graphically. No adjustment of significance level for multiple testing will be
employed.
Secondary outcome
The outcome measures associated with the WPAI:SHP and the Resource Utilization
Questionnaire will be summarized by final dose and time point and displayed
graphically. For subjects who participated in Study 14-002 or 14-003, the
WPAI:SHP measures may also be summarized by the
previous treatment group. Where applicable, the changes in the WPAI:SHP
measures from prior study baseline and from the endpoint of the prior study
will be examined. Standard unit costs will be applied to the resources
identified with the Resource Utilization Questionnaire (as well as to any
hospitalizations reported as SAEs) in order to calculate the mean/median
healthcare costs over the one-year period.
Background summary
Narcolepsy is a life-long neurologic disease for which no cure has been
identified. It affects an estimated 0.02% to0.067% 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.
OSA is diagnosed on the basis of the number of predominantly obstructive
respiratory events that occur per hour of sleep during a nocturnal
polysomnogram (PSG) or per hour of monitoring during an out of center sleep
test (OCST. Essential features of OSA include repetitive episodes of complete
(apnea) or partial (hypopnea) upper airway obstruction during sleep and
excessive sleepiness that occurs during the day and is a complaint in many but
not all cases. Most patients with OSA awaken in the morning feeling tired
regardless of the duration of their time in bed. During the day, their
sleepiness is most evident during relaxing or inactive situations; however,
with extreme sleepiness, sleep may occur while actively conversing, eating,
walking, or driving.
Positive airway pressure (PAP) applied through a nasal, oral, or oronasal
interface during sleep is considered to be the reference- or gold-standard
treatment for OSA. However, the effectiveness of PAP is limited by patient
non-compliance or nonadherence to therapy. Non-compliance with PAP is a widely
recognized problem that limits its effectiveness. In addition to PAP, there are
alternative therapies that are used for the primary treatment of OSA when PAP
therapy is refused or is unsuccessful.
Although PAP therapy is considered to be the international reference- or
gold-standard treatment for OSA, the effectiveness of PAP therapy to adequately
treat objective and subjective sleepiness associated with OSA is less
definitive. It has been concluded that although PAP has been shown to be
effective in eliminating respiratory disturbances and reducing the
apnea/hypopnea index (AHI), Level I and Level II evidence for CPAP improving
objective measures of wakefulness in patients with OSA is equivocal. In
addition, data from a multicenter study on the relationships between hours of
PAP use and measures of sleepiness showed that subjective sleepiness did not
resolve with PAP therapy in 34% of OSA subjects who had ESS scores >10 at
baseline and that objective sleepiness did not resolve with PAP therapy in 65%
of OSA subjects who had an MSLT sleep latency <7.5 minutes at baseline.
Similarly, data from a multicenter study in France and from the French National
Sleep Registry have estimated the prevalence of residual excessive sleepiness
in OSA patients without major comorbidities who use CPAP to be 6 and 13%,
respectively. These findings highlight the unmet medical need for therapies
that reduce excessive sleepiness and increase the ability to stay awake during
the day in OSA.
JZP-110 studies found no unexpected drug-related toxicities and demonstrated
that JZP-110 was safe and well tolerated in narcolepsy patients under the
parameters tested. 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 information in this population.
Study objective
To evaluate the safety and tolerability of JZP-110 administered once daily for
up to 52 weeks in doses of 75, 150, and 300 mg
Study design
This is a Phase 3 study to assess the long-term safety and maintenance of
efficacy of JZP-110 under open-label and double-blind, placebo-controlled
conditions, in subjects who have completed Study 14-002, 14-003, 14-004,
15-004, 15- 005, ADX-N05 201, or ADX-N05 202. The study will consist of a
2-week Titration Phase for all subjects, a 38-week Maintenance Phase for
subjects who completed Study 14-002 or 14-003 or a 50-week Maintenance Phase
for subjects who completed Study 14-004, 15-004, 15-005, ADX-N05 201, or
ADX-N05 202, and a 2-week Safety Follow-up period
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.
Study burden and risks
Patients are asked to undergo procedures described in the flowchart on pages 72
- 73 of the study protocol. These procedures include physical examination,
vital signs, urine pregnancy tests (female;chidbearing patients, ECG,
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 theelectrodes from the ECG may
irritate patient's skin
Porter Drive 3180
California CA 94304
US
Porter Drive 3180
California CA 94304
US
Listed location countries
Age
Inclusion criteria
1. Subject meets one of the following:
a. Completed Study 14-002 or 14-003 (Group A)
b. Completed Study 14-004, 15-004, 15-005, ADX-N05 201 or ADX-N05 202 (Group B)
2. Subject is able, in the opinion of the investigator, to take JZP-110 for 40 weeks if continuing from 14-002 or 14-003 or for 52 weeks if the subject completed 14-004, 15-004, 15-005, ADX-N05 201, or ADXN05 202, and is able to complete all tests and visits described in this protocol.
3. Usual nightly total sleep time of at least 6 hours.
4. Body mass index from 18 to <45 kg/m2
5. 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.
6. Willing and able to comply with the study design schedule and other requirements.
7. 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. Experienced any serious adverse event (SAE) in a previous study that was deemed related to JZP-110 or experienced an AE in a previous study that might prevent him/her from safely participating in and completing the current study.
5. Any other clinically relevant medical, behavioral, or psychiatric disorder other than narcolepsy or OSA 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. 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 or safety 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 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 criterion 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 AICD or medication therapy, uncontrolled hypertension, or systolic blood *155 mmHg or diastolic blood pressure *95 mmHg at screening or Baseline for Group B subjects according to protocol specifications; or any history of cardiovascular disease or 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 the Baseline Visit or anticipated excessive use during the study defined as >600 mg/day of caffeine.
15. Use of a monoamine oxidase inhibitor (MAOI) in the past 14 days or five half-lives of the drug (whichever is longer) prior to the Baseline Visit, or plans to use an MAOI during the study.
16. Received an investigational drug other than JZP-110 in the past 30 days or five half-lives (whichever is longer) before the Baseline Visit, or plans to use an investigational drug (other than the study drug) during the study.
17. Current or past (within the past 2 years) diagnosis of a moderate or severe substance use disorder according to DSM-5 criteria.
18. Nicotine dependence that has an effect on sleep (e.g., a subject who routinely awakens at night to smoke).
19. Current, past (within the past 2 years), or seeking treatment for a substance related disorder.
20. 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.
21. History of phenylketonuria (PKU) or history of hypersensitivity to phenylalanine-derived products.
22. Group A: Planned use of any over-the-counter (OTC) or prescription medications that could affect the evaluation of excessive sleepiness at any time during the study.
Group B: 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. 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. 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
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 | EUCTR2014-005489-31-NL |
| CCMO | NL53470.058.15 |