Primary objectives are:1) To evaluate the efficacy of Xyrem (sodium oxybate) oral solution in the treatment of cataplexy in pediatric subjects with narcolepsy2) To evaluate the safety of Xyrem in the treatment of cataplexy in pediatric subjects with…
ID
Source
Brief title
Condition
- Sleep disturbances (incl subtypes)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
For subjects who entered the Double-Blind Treatment Period prior to Amendment 4
becoming effective all efficacy assessments will be comparisons of the
measurement made during, or at the end of, the last 2 weeks of the Stable-Dose
Period compared with the
2 weeks of Double-Blind Treatment Period. These assessments will continue to be
collected after Amendment 4 becomes effective.
Primary endpoint:
- Change in weekly number of cataplexy attacks.
Secondary outcome
Key secondary efficacy endpoints:
- Clinical Global Impression of Change (CGIc) for cataplexy severity
- Change in the Epworth Sleepiness Scale for Children and Adolescents (ESS
[CHAD]) score
Other secondary endpoints:
- CGIc for narcolepsy overall
- Change in Quality of Life (QoL) (SF-10)
Exploratory endpoints:
- Change in weekly school attendance (if enrollment overlaps with school
attendance period)
- Patient Global Impression of Change (PGIc) for narcolepsy overall
Safety assessments will include the following:
- Adverse event (AE) monitoring
- Vital signs
- Physical examinations (including weight and height)
- 12-lead ECG
- Polysomnography (PSG) parameters (including respiratory measures)
- Clinical laboratory tests (chemistry, hematology, and urinalysis)
- Assessments of growth and precocious puberty
- C-SSRS for emergent suicidality
- CDI 2:SR[S] for emergent or worsening depression
- MASC-10 for emergent or worsening anxiety
- Serum pregnancy tests (if applicable)
Exploratory endpoint:
- CO2 monitoring (end tidal CO2 [EtCO2] or transcutaneous CO2 [TcCO2]) in sites
where monitoring is routinely performed and performance will not negatively
impact study participation or PSG data integrity
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.
The most common symptoms of narcolepsy are excessive daytime sleepiness (EDS),
cataplexy, sleep paralysis, sleep-related hallucinations, and disrupted
nighttime sleep (DNS).
Narcolepsy effects include daily functioning and daily activities, psychosocial
functioning, quality of life and work performance. The effects of narcolepsy on
the lives of pediatric patients are less commonly described but equally
burdensome: limitations on activities, poor performance in school, difficulty
with peers and a variety of psychiatric and medical comorbidities including
depression, obesity and precocious puberty.
Although the majority of adult patients with narcolepsy had symptoms develop
before 15 years of age there are no approved treatments for pediatric
narcolepsy/cataplexy. All treatments used for the treatment of adults are used
to treat children with narcolepsy.
A need exists for safe and effective treatments for pediatric patients with
narcolepsy/cataplexy.
Xyrem is currently marketed in the US, Canada, and 20 European countries.
Xyrem has been used to treat narcolepsy symptoms in children and adolescents.
Data from published studies in pediatric and adult patients indicate a similar
safety profile and therapeutic response to Xyrem in the two age groups (<18 and
*18 years).
The objective of this study is to generate efficacy, safety, and
pharmacokinetics (PK) information on Xyrem in the pediatric population.
Study objective
Primary objectives are:
1) To evaluate the efficacy of Xyrem (sodium oxybate) oral solution in the
treatment of cataplexy in pediatric subjects with narcolepsy
2) To evaluate the safety of Xyrem in the treatment of cataplexy in pediatric
subjects with narcolepsy for up to one year (and potentially more than one year
in some subjects participating in a continuation of the open-label safety
evaluation)
Secondary objectives are:
1) To evaluate the efficacy of Xyrem in the treatment of excessive daytime
sleepiness (EDS) in pediatric subjects with narcolepsy with cataplexy
2) To characterize the pharmacokinetics (PK) of Xyrem in pediatric subjects
(ages 7-17 years) with narcolepsy with cataplexy
3) To evaluate the safety of titrating Xyrem in pediatric subjects to an
effective and tolerable dose
Study design
Under Amendment 5, this study is divided into two parts: Part 1 includes one
year of treatment, and Part 2, the Open-Label Continuation Period, provides the
opportunity to continue treatment for up to an additional 2 years.
Part 1
Part 1 of this study was initially designed as a double-blind,
placebo-controlled, randomized-withdrawal, multicenter study of the efficacy
and safety of Xyrem (sodium oxybate) oral solution. As a result of a preplanned
interim analysis, which demonstrated positive efficacy results on the primary
efficacy endpoint, the protocol was amended (Amendment 4) to replace placebo
treatment in the Double-Blind Treatment Period with open-label Xyrem treatment.
After Amendment 4 becoming effective, all subjects entering the Double-Blind
Treatment Period will receive open-label Xyrem treatment. For administrative
reasons, the term *Double-Blind Treatment Period* will continue to be used
throughout the protocol. Following the double-blind treatment period (2 weeks),
this study also includes an open-label safety extension allowing subjects to
continue Xyrem treatment for up to one year in Part 1.
In addition, the PK of Xyrem will be evaluated in a subset of subjects (Not in
The Netherlands).
Children and adolescents, diagnosed with narcolepsy with cataplexy who are
currently treated with Xyrem or are Xyrem naïve, with or without concomitant
stable stimulant use, are eligible to enter the study. For this study, a Xyrem
naïve subject is defined as a subject who has never been treated with Xyrem or
who was previously treated with Xyrem and discontinued Xyrem for at least one
month prior to the Part 1 Screening visit for reasons other than lack of
efficacy and/or tolerability issues (e.g., lost insurance coverage, could not
afford Xyrem, changed prescribers).
All subjects will be evaluated for eligibility during the Part 1 Screening
Period (up to 30 days [if needed, additional time may be granted with
permission of the Medical Monitor]).
Following Part 1 screening, subjects who are Xyrem naïve will enter the
Open-Label Titration Period of up to 10 weeks. Once the Xyrem dose has been
optimized per the Investigator*s judgment, these subjects may enter the
open-label Stable-Dose Period with that dose.
Subjects who are on Xyrem at study entry will remain on their stable dose and
regimen (i.e., two equally divided doses or two unequally divided doses) of
Xyrem and enter the Stable-Dose Period following screening.
Subjects are eligible to enter the Double-Blind Treatment Period if the dose
and regimen of Xyrem remains unchanged during the Stable-Dose Period and, in
the judgment of the Investigator, no clinically significant worsening in
narcolepsy symptoms or clinically significant adverse events due to Xyrem
treatment have occurred. .
Subjects entering the Double-Blind Treatment Period prior to Amendment 4
becoming effective, had been randomized 1:1 to receive one of the following two
treatments during the 2-week Double-Blind Treatment Period
(randomized-withdrawal):
* Xyrem: Active Xyrem will be continued as a double-blind treatment at the
stable dose taken and regimen used in the prior 2 weeks
* Xyrem placebo: Xyrem placebo will be initiated as a double-blind treatment at
a volume and regimen equivalent to the Xyrem dose taken in the prior 2 weeks.
Subjects entering the Double-Blind Treatment Period after Amendment 4 becoming
effective will receive open-label Xyrem treatment in this period.
Subjects who complete the entire Double-Blind Treatment Period will be eligible
to continue in the Open-Label Safety Period. The Open-Label Safety Period will
allow subjects to continue Xyrem treatment for up to one year in Part 1.
Part 2
Upon approval of Amendment 5, subjects who complete one year in the study (Part
1) will have the opportunity to continue open-label Xyrem treatment in Part 2
until the first occurrence of any of the following:
* Up to an additional 2 years
* Until the subject reaches 18 years of age
* Until up to 3 months after the US FDA decision on the addition of pediatric
data to the Xyrem US prescribing information (PI)
Subjects who have already completed Part 1 may re-enroll in Part 2.
Intervention
Test product:
Xyrem (sodium oxybate) oral solution
Xyrem placebo (sodium citrate oral solution) - Placebo treatment only
applicable to subjects who had already entered the Double-Blind Treatment prior
to Amendment 4 becoming effective.
Flavorant that can be added to the water that is used as diluent will be
provided, if available, for study drug preparation if flavored diluent is
requested by the subject/parent/guardian for palatability.
Refer to 'Study design' for dosing information.
Study burden and risks
Narcolepsy is a life-long neurologic disease for which no cure has been
identified. The symptoms of narcolepsy effects daily functioning, daily
activities, psychosocial functioning and the quality of life: excessive daytime
sleepiness (EDS), cataplexy, sleep paralysis, sleep-related hallucinations, and
disrupted nighttime sleep (DNS).
There are no approved treatments for pediatric narcolepsy/cataplexy. All
treatments used for the treatment of adults are used to treat children with
narcolepsy. A need exists for safe and effective treatments for pediatric
patients with narcolepsy/cataplexy.
Xyrem is currently marketed and has been already used to treat narcolepsy
symptoms in children and adolescents. The objective of this study is to
generate efficacy, safety, and pharmacokinetics (PK) information on Xyrem in
the pediatric population.
This study design ensures that all subjects are able to receive Xyrem treatment
and minimizes the duration of placebo exposure. Placebo is the only control
group used. In this year-long study, the maximal time that any pediatric
subject will receive placebo is only 2 weeks.
As a result of a preplanned interim analysis, which demonstrated positive
efficacy results on the primary efficacy endpoint, the protocol has been
amended (Amendment 4) to replace the placebo treatment in the Double-Blind
Treatment Period with open-label Xyrem treatmentWhen Amendment 4 becomes
effective all subjects entering the Double-Blind Treatment Period will receive
open-label Xyrem treatment.
It is expected that the potential benefits of participating in the trial
outweigh the risks.
Market street 1818
Philadelphia PA 19103
US
Market street 1818
Philadelphia PA 19103
US
Listed location countries
Age
Inclusion criteria
1. Male or female subjects aged 7-16 years at Visit 2 for subjects on Xyrem at study entry and at Visit 1.1 for Xyrem-naïve subjects (to ensure subjects are <18 years of age at the end of the study).;2. Have a primary diagnosis of narcolepsy with cataplexy that meets International Classification of Sleep Disorders (ICSD)-2 or ICSD-3 criteria, whichever was in effect at the time of the diagnosis or, with the permission of the Medical Monitor, completes a Multiple Sleep Latency Test (MSLT) during Screening to confirm the diagnosis of Type 1 narcolepsy by ICSD-3 criteria (ie., the subject meets all other ICSD-3 criteria for Type 1 narcolepsy).;3. Be positive for the Human Leukocyte Antigen (HLA) DQB1:0602 haplotype, determined prior to the study or as part of the study screening procedures, or have cerebrospinal fluid (CSF) hypocretin level *110 pg/ml determined prior to the study. In the absence of both, be evaluated by a panel of narcolepsy experts to confirm the diagnosis of narcolepsy with cataplexy in accordance with ICSD-3.;4. Have given documented assent indicating that he/she was aware of the investigational nature of the study and the required procedures and restrictions before participation in any protocol-related activities.;5. Have parent(s)/guardian(s) who have given informed consent for his/her/their child*s participation in the study.;6. 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 .;7. Be willing to spend the required number of nights (2 to 3) in a sleep laboratory for PSG evaluations.;8. If currently treated with Xyrem, must have been taking unchanged doses (twice nightly dosing no higher than 9 g/night) of Xyrem, and stimulants, if applicable, for the treatment of narcolepsy symptoms for at least 2 months prior to screening. ;9. If currently treated with Xyrem, must have demonstrated clinical improvement of cataplexy per investigator*s clinical judgment.;10. Have agreed to abstain from caffeinated products during PSG and PK nights. ;11. Any female subject of child-bearing potential must be willing to use a method of contraception, deemed medically acceptable by the Investigator, or agree to abstain from sexual intercourse for the duration of the study and for 30 days after study termination.;12. Any male subject who is sexually active with a female partner must be willing to use a method of contraception, deemed medically acceptable by the Investigator, or agree to abstain from sexual intercourse for the duration of the study and for 30 days after study termination.;Subjects who have completed Part 1 of the study are eligible to re-enroll in Part 2 regardless of their current Xyrem treatment status if they meet Inclusion Criteria 4, 5, 11, and 12 and the following criteria at the Part 2 Screening visit (Visit 17) and the first drug-dispensing visit (Visit 18):
- Are less than 18 years of age
- If currently being treated with Xyrem, the subject is on a stable dose
- If currently being treated with Xyrem, the subject's total twice nightly Xyrem dose must be no higher than 9 g/night
Exclusion criteria
1. Not able to understand assent or follow study instructions, in the investigator's opinion.;2. Parent(s)/guardian(s) unable to comply with the study requirements, in the investigator's opinion.;3. Previously treated with Xyrem and discontinued because of lack of efficacy and/or tolerability issues.;4. Narcolepsy secondary to another medical condition, e.g., CNS injury or lesion.;5. Restless leg syndrome requiring treatment other than iron supplements.;6. Succinic semi-aldehyde dehydrogenase deficiency.;7. Uncontrolled hypothyroidism.;8. History of seizure disorders.;9. History of head trauma associated with loss of consciousness.;10. Evidence of sleep-disordered breathing including:
a. Presence of clinically significant obstructive or central sleep apnea as determined by the investigator or documented previously; or
b. Obstructive AHI >5 for subjects 7-11 years of age or obstructive AHI>10 for subjects 12-17 years of age; or
c. Oxygen saturation nadir *85% at night; or
d. Clinically significant hypoventilation.;11. Oxygen saturation level <95% for at least 5 minutes on room air as measured by pulse oximetry while fully awake during daytime monitoring, or subjects with known or suspected respiratory difficulty, or any condition that may compromise a subject*s breathing. If oxygen saturation values lower than 95% are observed at study sites at high geographic elevations and are acceptable to the investigator, enrollment of the subject requires permission from the Medical Monitor.;12. Past or current major thought disorder, e.g., schizophrenia, paranoia, mania, etc.;13. Recent history of clinically significant parasomnia (e.g., sleep walking, REM behavior disorder, etc.) that would negatively affect the conduct of the study.;14. Current suicidal risk as determined from history or Columbia Suicide Severity Rating
Scale or history of suicide attempt.;15. If the T-score is at or above 65 on the Children*s Depression Inventory 2nd Edition Self-Report Short Version (CDI 2:SR[S]), an evaluation of depression by the Investigator (if qualified as a mental health professional) or by the Investigator in consultation with a mental health professional must be performed to exclude a clinically significant depression.;16. Other documented clinically significant condition (including unstable medical and/or psychiatric conditions, chronic disease other than narcolepsy with cataplexy, porphyria, or history or presence of another neurological disorder) that might affect the subject*s safety and/or interfere with the conduct of the study in the investigator's opinion.;17. An ECG with clinically significant deviation(s) from normal, or clinically significant physical examination findings, as determined by the investigator.;18. Any clinically significant lab abnormality as determined by the investigator.;19. A positive pregnancy test result at screening (pregnancy tests will be performed for any female subject who has reached menarche).;20. 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).;21. Treatment with benzodiazepines, non-benzodiazepine anxiolytics/
hypnotics/sedatives, neuroleptics, opioids, barbiturates, diclofenac, valproate,
phenytoin, ethosuximide within 2 weeks prior to enrollment (discontinuation for the purpose of study enrollment is permitted only if considered safe by the investigator and approved by the Medical Monitor).;22. Treatment with any other medications that have anticataplectic effect (e.g., serotonin*norepinephrine reuptake inhibitors [SNRIs], selective serotonin reuptake inhibitors [SSRIs], or tricyclic antidepressants [TCAs]) within 1 month before Screening;23. Current treatment with oral isotretinoin;24. Inability to fast for 2 hours before the first dose through 4 hours after the last dose of Xyrem on PSG and PK nights;25. Lack of parental (or legal guardian) commitment to ensuring home situation is safe for Xyrem use, in the opinion of investigator.;26. Received any investigational drug within 30 days or 5 half-lives (whichever is longer) before screening.;27. Allergy to any components of topical, local anesthetics that might be used for blood collection (not applicable if numbing agents will not be used).;28. Allergy or sensitivity to malic acid, sucralose, or ingredients in the study drug formulation and/or the flavorant, if used;Subjects will be excluded from re-enrolling in Part 2 if they meet Exclusion criteria: 1-10, 12, 17, 19-22, 24, 26-29 or any of the following criteria at the Part 2 Screening visit (Visit 17) and the first drug-dispensing visit (Visit18):
- Have not completed Part 1
- If they are 18 years of age
- If they have suicidal risk or clinically significant depression independent of narcolepsy symptoms as determined by the investigator
Design
Recruitment
Medical products/devices used
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
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 | EUCTR2014-001389-93-NL |
| ClinicalTrials.gov | NCT02221869 |
| CCMO | NL50646.058.14 |