Primary objective:To evaluate the efficacy of JZP-258 in the treatment of cataplexy in subjects with narcolepsyKey Secondary objective:To evaluate the efficacy of JZP-258 in the treatment of excessive daytime sleepiness (EDS) in…
ID
Source
Brief title
Condition
- Sleep disturbances (incl subtypes)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint:
Change in weekly number of cataplexy attacks from the two weeks of the
Stable-Dose Period to the two weeks of the Double-Blind Randomized-Withdrawal
Period
Secondary outcome
Key secondary endpoint:
Change in the Epworth Sleepiness Scale (ESS) score from the end of the Stable-
Dose Period to the end of the Double-Blind Randomized-Withdrawal Period
Other secondary endpoints:
Patient Global Impression of Change (PGIc) for narcolepsy overall at the end of
the Double-Blind Randomized-Withdrawal Period
Clinical Global Impression of Change (CGIc) for narcolepsy overall at the end
of the Double-Blind Randomized-Withdrawal Period
Change in Quality of Life (QoL) (SF-36) at the end of the Double-Blind
Randomized-Withdrawal Period
EuroQol 5 Dimensions Self-Report Questionnaire at the end of the Double-Blind
Randomized-Withdrawal Period
Background summary
Narcolepsy is a life-long neurologic disease for which no cure has been
identified. The worldwide prevalence of narcolepsy is estimated to be 0.02% to
0.067%. Narcolepsy has been defined as a rapid eye movement (REM) sleep
disorder resulting from the dysregulation of the sleep-wake cycle. It is
characterized by pathological sleepiness, commonly termed excessive daytime
sleepiness, or EDS, and includes disrupted nighttime sleep (DNS) and abnormal
REM sleep manifestations, including cataplexy, sleep paralysis, and hypnagogic
or hypnopompic hallucinations. At the moment only one treatment is approved for
the treatment of cataplexy in narcolepsy: Xyrem (sodium oxybate). However, this
treatment does has a downside. Due to the sodium in the formulation it adds a
significant amount of sodium to the patient diet. This can pose a problem in a
patient population that is not uncommon with a high incidence of cardiovascular
morbidity. Jazz Pharmaceuticals has been developing an investigational
formulation called JZP-258 combining four oxybate salts: sodium oxybate,
potassium oxybate, calcium oxybate, and magnesium oxybate. JZP-258 could
provide the known benefits of Xyrem treatment with an improved safety profile,
particularly for patients with sodium-sensitive conditions but also for any
patient concerned about salt intake. It could also enable patients with
narcolepsy and cardiovascular, hypertensive, or renal conditions to continue on
their Xyrem treatment or initiate oxybate treatment.
Study objective
Primary objective:
To evaluate the efficacy of JZP-258 in the treatment of cataplexy in subjects
with narcolepsy
Key Secondary objective:
To evaluate the efficacy of JZP-258 in the treatment of excessive daytime
sleepiness (EDS) in subjects with narcolepsy
Secondary objective:
To evaluate the safety of JZP-258 in the treatment of subjects with narcolepsy
with cataplexy
Exploratory objective:
To characterize the conversion from non-Xyrem anticataplectic treatment
regimens to JZP-258 in subjects with narcolepsy with cataplexy
Study design
This is a 2-part study consisting of the MAIN Study (a double-blind,
placebo-controlled, randomized-withdrawal, multicenter study of the efficacy
and safety of JZP-258) followed by a 24-week Open-Label Extension study.
Part 1 MAIN STUDY
The Main Study consists of the following periods, which are described further
below:
* Screening Period for up to 30 days
* Optimized Treatment and Titration Period for 12 weeks
* Stable-Dose Period for 2 weeks
* Double-Blind Randomized-Withdrawal Period for 2 weeks
* Safety Follow-up Period
Subjects are eligible to enter the Main Study if they meet all eligibility
criteria and their treatment status is:
* Currently treated with a stable dose of Xyrem (sodium oxybate) at least 2
months prior to screening
* Currently treated with a stable dose of Xyrem and an additional
anticataplectic at least 2 months prior to screening
* Currently treated with an anticataplectic and not treated with Xyrem
* Not currently treated with any anticataplectic at Screening.
Part 2 OPEN-LABEL EXTENSION
Subjects who complete the double-blind treatment during the Main Study are
eligible to enter a 24-week Open Label Extension which consists of the
following:
* Open-Label Extension Period for 24 weeks
* Open-Label Safety Follow-up Period
During this period subjects will receive open-label JZP-258.
Subjects are eligible to enter the Open-Label Extension if they meet all
eligibility criteria and their treatment status is:
* Completed double-blind treatment in the Main Study and rolling over into the
Open-Label Extension
* Completed the Main Study and currently treated with Xyrem alone or Xyrem plus
an additional anticataplectic
* Completed the Main Study and currently treated with a non-Xyrem
anticataplectic or not receiving treatment
Open-Label Extension Period (24 weeks)
Subjects can enter the Open-Label Extension directly from the Main Study (enter
at Visit 16) or after completion of the Main Study (enter at Visit 18).
* Rollover Subjects: those who enter the Open-Label Extension at Visit 16
(i.e., *rollover* directly from the Main Study (after a few additional
procedures). Their Visit 16 has the dual purpose of being the last day
of the Main Study and Day 1 for the Open-Label
Extension.
* Re-entry Subjects: those who enter the Open-Label Extension following
completion of the Main Study (i.e., require *re-entry* into the study).
Their Open-Label Extension Day 1 is at Visit 19 and they undergo
Open-Label screening at Visit 18
Intervention
Main Study: The trial consists of an open label and a double blind randomized
phase.
In the open label phase:
subjects can be in four groups:
- on stable dose Xyrem --> straight conversion of dose Xyrem to dose JZP-258.
- on stable dose Xyrem and other anticataplectics --> straight conversion of
dose Xyrem to dose JZP-258 and cross titration of other anitcataplectics with
JZP-258.
- on other non Xyrem anticatapletics --> cross titration other catapletics with
JZP-258.
- not on any anticatapletics --> titrate JZP-258.
After the titration a 2 week open-label stable-dose period follows.
After being titrated or converted all subjects should be on a tolerable and
effective dose of JZP-258. if this dose remains stable in this period subjects
are allowed to enter the double blind randomized phase.
After this phase a double blind randomized phase follows, in which subjects
will be treated with either JZP-258 or placebo.
JZP-258 will be continued as a double-blind treatment at the stable dose taken
in the prior 2 weeks.
Placebo will be initiated as a double-blind treatment at a volume equivalent to
the JZP-258 dose taken in the prior 2 weeks.
Optional Open Label Extension:
Roll over subject (Visit 16- Day 1 of OLE) + assessments
Start w/dose not more than 1/2 that of dose from end of Stable Dose Period.
Titrated up to optimal dose per Investigator
(rate of 1 1.5 g/night/wk; not more than a total dose of 9 g/per night).
Re-Entry Subjects: (Visit 19- Day 1 of OLE)
Xyrem Alone +/- Additional Anticataplectic)
Switch from current Xyrem dose to JZP 258 on a g to g straight conversion
(If needed, titration at a rate of 1 1.5 g/ night/wk; not more than a total
dose of 9 g/night)
Additional, non Xyrem anticataplectics must be tapered by Visit 30, during
initial 12 weeks of OLE
Non-Xyrem Anticataplectic or Not Receiving Treatment
Initial JZP-258 dose of 4.5 g/night.
(Adjust at rate of 1-1.5 g/night/wk; not more than 9 g/night.
Study burden and risks
The experimental formulation JZP-258 is based upon the already approved drug
Xyrem, from which the active ingredient is sodium oxybate. Xyrem is already
proven to be safe and effective as treatment, however it does add a significant
amount of sodium to the patient diet. JZP-258 is formulated in such a way that
it limits the intake of sodium by patients. The formulation of JZP-258 consists
of four oxyybate salts (sodium oxybate, potassium oxybate, calcium oxybate, and
magnesium oxybate), for which the daily intake is all within the Recommended
Dietary Allowance (RDA). Therefore little risk for the patients participating
in this trial is expected.
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Age
Inclusion criteria
Each subject must meet the following criteria to be enrolled in the study.
1. Male or female subjects between 18 and 70 years of age, inclusive at screening.
2. Have a primary diagnosis of narcolepsy with cataplexy that
meets ICSD-3 criteria or DSM-5 criteria, and currently untreated or treated with or without anticataplectics.
3. Have a history of having at least 14 cataplexy attacks in a
typical 2-week period and clinically significant symptoms of EDS prior to any narcolepsy treatment.
4. Treatment status (Pre-randomization Group) at study entry:
a) Have been taking Xyrem at unchanged doses (twice or thrice nightly dosing no higher than a total of 9 g/night), for the treatment of cataplexy in narcolepsy for at least
2 months prior to screening; or
b) Have been taking Xyrem at unchanged doses (twice or thrice nightly dosing no higher than a total of 9 g/night), and another anticataplectic (TCA, SNRI, SSRI, atomoxetine, or
other) for the treatment of cataplexy in narcolepsy for at least 2 months prior to screening; or
c) Treated with a non-Xyrem anticataplectic (TCA, SNRI, SSRI, atomoxetine, or other) and not treated with Xyrem; or
d) Not treated with any agent with anticataplectic properties.
5. If currently treated with Xyrem, must have documented clinical improvement of cataplexy and EDS per Investigator*s clinical judgment.
6. If applicable, treated with a stimulant or alerting agent at unchanged doses for at least 2 months prior to dosing or not treated with a stimulant or alerting agent.
7. Have used a medically acceptable method of contraception for at least 2 months prior to the first dose of study drug and consent to use a medically acceptable method of contraception
throughout the entire study period and for 90 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.
Open Label
1. Completion of the JZP-258 double-blind treatment and completion of Visit 16.
2. Is able, in the opinion of the investigator, to take JZP-258 for an additional 24 weeks.
3. Agrees to continue to use a medically acceptable method of contraception throughout the entire study period and for 90 days after the Open-Label Extension is completed.
4. Willing and able to comply with the study design schedule and other requirements.
5. Willing and able to provide written informed consent for Open-Label Extension.
6. If currently being treated with Xyrem, the subject's total twice nightly Xyrem dose must be no higher than 9 g/night.
Exclusion criteria
Subjects who demonstrate any of the following will be excluded from
the study.
1. Narcolepsy secondary to another medical condition (e.g., CNS
injury or lesion).
2. Restless leg syndrome (RLS) requiring treatment other than
iron supplements.
3. Succinic semi-aldehyde dehydrogenase deficiency (SSADH).
4. Uncontrolled hypothyroidism.
5. History of seizures, excluding early childhood nonpathological
febrile seizures.
6. History of head trauma associated with loss of consciousness
in the past 5 years or if the event occurred more than 5 years
prior to screening and the subject has sequelae due to the
event.
7. Evidence of untreated or inadequately treated sleep-disordered
breathing including:
a. Presence of clinically significant and untreated obstructive
or central sleep apnea as determined by the Investigator or
documented previously;
or documentation of one of the following:
b. Apnea index (AI) >10 if on OSA treatment or untreated;
or
c. Clinically significant hypoventilation; or
d. Noncompliance with primary OSA therapy. (Compliance
defined as positive airway pressure use of *4 hours per
night on *70% of nights [*5 of 7 nights/week], historical
report [with Investigator concurrence] of use of an oral
appliance on *70% of nights [*5 of 7 nights/week], or
receipt of an effective surgical intervention for OSA
symptoms.)
8. Parasomnias (e.g., sleep walking, REM Sleep Behavior
Disorder, etc.) felt by the investigator to negatively affect the
conduct of the study. Parasomnia events associated with
physical injury to the subject (or others) shall be discussed
with the Medical Monitor.
9. Meets criteria for current major depression by clinical
interview.
10. Any other clinically relevant medical, behavioral, or
psychiatric disorder other than narcolepsy that is associated
with excessive sleepiness.
11. History or presence of bipolar disorder, bipolar related
disorders, schizophrenia, schizophrenia spectrum disorders, or
other psychotic disorders according to DSM-5 criteria.
12. History or presence of any unstable or clinically significant
medical condition, behavioral or psychiatric disorder
(including active suicidal ideation), or history or presence of
another neurological disorder or surgical history that might
affect the subject*s safety and/or interfere with the conduct of
the study in the opinion of the Investigator.
13. A current electrocardiogram (ECG) with clinically significant
deviation(s) from normal, or clinically significant physical
examination findings, as determined by the Investigator at
screening.
14. Any current clinically significant laboratory abnormality as
determined by the Investigator at screening.
15. Is a female subject who is pregnant, nursing, or lactating.
16. A positive urine drug screen for benzodiazepines or drugs of
abuse, a positive alcohol test, a history of substance abuse
including alcohol abuse, or unwillingness to refrain from
consuming alcohol during the study (if the subject takes
prescribed amphetamines, a positive result for amphetamines
will not exclude the subject).
17. Treatment with any central nervous system sedating agents,
including but not limited to benzodiazepines, nonbenzodiazepine
anxiolytics/ hypnotics/sedatives, neuroleptics,
opioids, barbiturates, phenytoin, ethosuximide, or the monocarboxylate transporter (MCT) inhibitor valproate, within 2 weeks prior to enrollment (Day 1) (discontinuation for the purpose of study enrollment is permitted only if considered safe by the Investigator and approved by the Medical Monitor).
18. Treatment with an antidepressant for cataplexy, if the
withdrawal of the antidepressant during cross-titration with
JZP-258 might be unsafe due to prior history of depression.
19. Current treatment with oral isotretinoin.
20. Received any investigational drug within 30 days or 5 halflives
(whichever is longer) before the Screening Visit.
21. Allergy or sensitivity to malic acid, sucralose or ingredients in
the study drug formulation or placebo.
22. Unsafe for the subject to receive placebo treatment for
2 weeks, in the opinion of the Investigator.
Open Label
1. Meet Exclusion Criteria 1 through 19 from the Main Study at Visits 18 and 19.
2. Received any investigational drug (with the exception of JZP 258) within 30 days or 5 half-lives (whichever is longer) before the screening visit.
3. Allergy or sensitivity to malic acid, sucralose or ingredients in the study drug formulation.
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 | EUCTR2016-00426-20-NL |
| ClinicalTrials.gov | NCT03030599 |
| CCMO | NL62769.028.17 |