A Double-Blind, Placebo-Controlled, Randomized-Withdrawal, Multicenter Study of the Efficacy and Safety of Xyrem with an Open- Label Pharmacokinetic Evaluation and Safety Extension in Pediatric Subjects with Narcolepsy with Cataplexy.

Study ID
STU 052015-072

Cancer Related
No

Healthy Volunteers
No

Study Sites

  • Children’s Medical Center (Dallas, Plano, Southlake)

Contact
Amber Crabb
214/456-7651
amber.skachcrabb@childrens.com

Principal Investigator
Syed Naqvi, M.D.

Summary

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 has been
amended (amendment 4) to replace placebo treatment in the Double-
Blind Treatment Period with open-label Xyrem treatment. When
amendment 4 becomes effective, all subjects entering the Double-
Blind Treatment Period will receive open-label Xyrem treatment. For
administrative reasons, the term [Quote]Double-Blind Treatment Period[Quote]
will continue to be used throughout amendment 4. 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 addition, the PK of Xyrem will be
evaluated in a subset of subjects.

Children and adolescents, diagnosed with narcolepsy with cataplexy
who are currently treated with Xyrem or are Xyrem naive, with or
without concomitant stable stimulant use, are eligible to enter the
study. For this study, a Xyrem naive 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 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 Screening
Period (up to 30 days [if needed, additional time may be granted with
permission of the Medical Monitor]).

Following screening, subjects who are Xyrem naive 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 becomes 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.

Participant Eligibility

Each subject must meet the following criteria to be enrolled in the study.

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-naive 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 (i.e., 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[Single Quote]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[Single Quote]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

In addition to the above inclusion criteria, prior to participating in the PK evaluation,
subjects must meet the following inclusion criteria:
13. Be willing to spend 2 additional nights in the clinic for PK evaluation
14. This criterion was removed during Amendment 2
15. Have given additional documented assent and consent by the parent(s) or guardian(s)
indicating awareness of the investigational nature of the PK evaluation and the
required procedures and restrictions before participation in any PK-related activities
16. Have sufficient blood volume for PK sampling based on body weight in accordance
with Seattle Children[Single Quote]s Hospital guideline (Appendix 4) or, for any particular
investigational site, Institutional Review Board (IRB) eligibility guidelines for
pediatric blood collection relevant to that site
17. Demonstrate normal values on clinical laboratory coagulation tests (prothrombin time
[PT]/international normalized ratio [INR], and activated partial thromboplastin time
[PTT]) within 30 days prior to PK Night 1