A 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

• Sponsor: Jazz Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02221869
• Collaborator: (none)
• Enrollment: 106
• Locations: 20
• Arms: 2
• Actual Duration (Months): 51.8
• Patients Per Site: 5.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this trial is to assess the efficacy and safety of Xyrem in pediatrics subjects with narcolepsy that includes cataplexy.

Condition or Disease	Intervention/Treatment	Phase
Narcolepsy With Cataplexy	Drug: Xyrem	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 106 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Actual Study Start Date: Oct 1, 2014
• Actual Primary Completion Date: Feb 1, 2017
• Actual Study Completion Date: Jan 25, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Xyrem Active Xyrem at a dose ≤9 g/night	Drug: Xyrem
Placebo Comparator: Xyrem Placebo Xyrem placebo at a volume and regimen equivalent to the stable dose of Xyrem.	Drug: Xyrem

Outcome Measures

Primary Outcome Measures

1. Change in Weekly Number of Cataplexy Attacks [From the end of the Stable Dose Period to the end of the Double-blind Treatment Period (2 weeks)]

   Double-blind comparison of the change in weekly number of cataplexy attacks from the last 2 weeks of the Stable Dose Period to the 2 weeks of the Double-blind Treatment Period.

Secondary Outcome Measures

1. Clinical Global Impression of Change (CGIc) for Cataplexy Severity [From the end of the Stable Dose Period to the end of the Double-blind Treatment Period (2 weeks)]

   CGIc for cataplexy severity from the end of the Stable Dose Period to the end of the Double-blind Treatment Period. The CGIc is a 7-point scale ranging from "very much improved" to "very much worse." A score of 0 = no change, a score of 3 = very much improved, and a score of -3 = very much worse.

2. Change in the Epworth Sleepiness Scale (ESS) (CHAD) Score [From the end of the Stable Dose Period to the end of the Double-blind Treatment Period (2 weeks)]

   Change in the ESS (CHAD) score from the end of the Stable Dose Period to the end of the Double-blind Treatment Period. The ESS is a self-administered questionnaire with 8 questions. It provides a measure of a person's general level of daytime sleepiness, or their average sleep propensity in daily life. In the ESS for children and adolescents (CHAD), certain activities were modified. Each activity is scored on a scale ranging from 0-3, with 0 = would never fall asleep, and 3 = high chance of falling asleep. The total score ranges from 0-24, with a higher number representing an increased propensity for sleepiness.

3. CGIc for Narcolepsy Overall [From the end of the Stable Dose Period to the end of the Double-blind Treatment Period (2 weeks)]

   CGIc for narcolepsy overall from the end of the Stable Dose Period to the end of the Double-blind Treatment Period. The CGIc is a 7-point scale ranging from "very much improved" to "very much worse." A score of 0 = no change, a score of 3 = very much improved, and a score of -3 = very much worse.

4. Change in Quality of Life (QoL; SF-10 Physical and Psychosocial Summary Score) From the End of the Stable Dose Period to the End of the Double-blind Treatment Period [From the end of the Stable Dose Period to the end of the Double-blind Treatment Period (2 weeks)]

   The SF-10 Health Survey for Children is a parent-completed survey that contains 10 questions adapted from the Child Health Questionnaire. The SF-10 is intended to produce physical and psychosocial health summary measures. Each of the 10 questions responses is scored with a point value from 1 to 6 (1 is the worst possible condition and 6 is the best possible condition). The SF-10 physical and psychosocial measures are scored such that higher scores indicate more favorable functioning. The questions and associated point values are separated into the Physical Health (PHS-10 domain) and Psychosocial Health (PSS-10 domain). The sums of the scores in each domain are standardized using the mean and standard deviation from a normal population (2006 sample). The standardized scores are transformed to norm based scoring (NBS) metric. Through NBS, scale scores are standardized to a mean of 50 and SD of 10 in the combined U.S. general population and clinical samples. NBS scores are reported

Eligibility Criteria

Criteria

• Ages Eligible for Study: 7 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 (i.e., the subject meets all other ICSD-3 criteria for Type 1 narcolepsy)

3. 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

4. Have parent(s)/guardian(s) who have given informed consent for his/her/their child's participation in the study

5. Be willing to spend the required number of nights (2 to 3) in a sleep laboratory for PSG evaluations

6. 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

In addition to the above inclusion criteria, subjects participating in the PK evaluation must meet the following inclusion criteria:

1. Be willing to spend 2 additional nights in the clinic for PK evaluation

Exclusion Criteria:

1. Inability to understand assent or follow study instructions for any reason, in the opinion of the Investigator

2. Parent(s) or guardian(s) unable to comply with the requirements of the study for any reason, in the opinion of the Investigator

3. Other documented clinically significant condition (including an unstable medical condition, chronic disease other than narcolepsy with cataplexy, 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 opinion of the Investigator

4. 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)

5. 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

6. Unsafe for the subject to receive placebo treatment for 2 weeks, in the opinion of the Investigator

In addition to the above exclusion criteria, subjects participating in the PK evaluation must not demonstrate the following:

-

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Miller Children's Hospital - Long Beach	Long Beach	California	United States	90806
2	SDS Clinical Trials, Inc.	Orange	California	United States	92868
3	Stanford Sleep Medicine Center	Redwood City	California	United States	94063
4	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois	United States	60611
5	The U-M Sleep Disorders Center	Ann Arbor	Michigan	United States	48109
6	Montefiore Medical Center	Bronx	New York	United States	10467
7	Duke Children's Hospital	Durham	North Carolina	United States	27710
8	ARSM Research, LLC	Huntersville	North Carolina	United States	28078
9	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
10	University Hospitals Cleveland Medical Center	Cleveland	Ohio	United States	44106
11	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
12	SleepMed of SC	Columbia	South Carolina	United States	29201
13	Greenville Health System	Greenville	South Carolina	United States	29615
14	UT/LeBonheur Neuroscience Institute	Memphis	Tennessee	United States	38105
15	Todd Swick, MD, PA	Houston	Texas	United States	77063
16	Children's Hospital of The King's Daughters	Norfolk	Virginia	United States	23507
17	Seattle Children's Hospital	Seattle	Washington	United States	98105
18	Hospital Robert Debre	Paris		France	75019
19	Dipartimento di Scienze Biomediche e Biomotorie	Bologna		Italy	40139
20	Sleep Wake Center SEIN Heemstede	Heemstede	Noord Holland	Netherlands	2103 SW

Sponsors and Collaborators

• Jazz Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Feb 23, 2017
• Statistical Analysis Plan - Jan 19, 2018

More Information

Publications

None provided.

• Responsible Party: Jazz Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02221869
• Other Study ID Numbers: 13-005
• First Posted: Aug 21, 2014
• Last Update Posted: Apr 30, 2019
• Last Verified: Apr 1, 2019

• Additional relevant MeSH terms: Narcolepsy; Cataplexy

Study Results

Participant Flow

Recruitment Details	106 subjects were enrolled. Xyrem-naïve subjects (n=74) entered the Dose Titration Period (3 to 10 weeks). Xyrem-naïve and on Xyrem subjects (n= 99) entered the Stable Dose Period (2 to 3 weeks). 96 subjects then entered the Double-Blind Randomized Withdrawal Period (2 weeks). 95 subjects then entered the Open-label Safety Period (38 to 47 weeks).
Pre-assignment Detail	Subjects aged 7-17 who were being treated with Xyrem or Xyrem naïve were eligible for the study. 63 subjects were randomized and 33 received open-label Xyrem during the Double-blind Treatment Period. 106 and 63 subjects comprised the Enrolled population and the Efficacy population respectively.

Arm/Group Title	Randomized to Xyrem	Randomized to Xyrem Placebo	Open-label Xyrem
Arm/Group Description	Active Xyrem continued as a double-blind treatment at the stable dose taken and regimen taken in the prior 2 weeks.	Xyrem placebo was initiated as a double-blind treatment at a volume and regimen equivalent to the Xyrem dose taken in the prior 2 weeks.	Subjects who were not randomized or continued to receive open-label Xyrem during the Double-blind Treatment Period.
Period Title: Overall Study
STARTED	31	32	43
COMPLETED	30	32	33
NOT COMPLETED	1	0	10

Baseline Characteristics

Arm/Group Title	Enrolled Population	Placebo (Efficacy Population)	Xyrem (Efficacy Population)	Total
Arm/Group Description	The Enrolled Population consists of all subjects who were dispensed study drug.	Xyrem placebo was initiated as a double-blind treatment at a volume and regimen equivalent to the Xyrem dose taken in the prior 2 weeks in the 2-week double-blind treatment period.	Active Xyrem continued as a double-blind treatment at the stable dose taken and regimen taken in the prior 2 weeks in the 2-week double-blind treatment period.	Total of all reporting groups
Overall Participants	106	32	31	169
Age (Count of Participants)
<=18 years	106 100%	106 331.3%
Between 18 and 65 years	0 0%	0 0%
>=65 years	0 0%	0 0%
<=18 years	32 30.2%	31 96.9%	63 203.2%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	43 40.6%	0 0%	43 138.7%
Male	63 59.4%	0 0%	63 203.2%
Female	15 14.2%	13 40.6%	28 90.3%
Male	17 16%	18 56.3%	35 112.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	6 5.7%	6 18.8%
Not Hispanic or Latino	100 94.3%	100 312.5%
Unknown or Not Reported	0 0%	0 0%
Hispanic or Latino	2 1.9%	0 0%	2 6.5%
Not Hispanic or Latino	30 28.3%	31 96.9%	61 196.8%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
Netherlands	8 7.5%	0 0%	0 0%	8 4.7%
United States	62 58.5%	62 193.8%
Italy	25 23.6%	25 78.1%
France	10 9.4%	10 31.3%
Finland	1 0.9%	1 3.1%
Region of Enrollment (participants) [Number]
Netherlands	3 2.8%	2 6.3%	5 16.1%
United States	17 16%	16 50%	33 106.5%
Italy	9 8.5%	9 28.1%	18 58.1%
France	3 2.8%	4 12.5%	7 22.6%

Outcome Measures

1. Primary Outcome

Title	Change in Weekly Number of Cataplexy Attacks
Description	Double-blind comparison of the change in weekly number of cataplexy attacks from the last 2 weeks of the Stable Dose Period to the 2 weeks of the Double-blind Treatment Period.
Time Frame	From the end of the Stable Dose Period to the end of the Double-blind Treatment Period (2 weeks)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Xyrem	Xyrem Placebo
Arm/Group Description	Active Xyrem continued as a double-blind treatment at the stable dose taken and regimen used in the prior 2 weeks.	Xyrem placebo was initiated as a double-blind treatment at a volume and regimen equivalent to the Xyrem dose taken in the prior 2 weeks.
Measure Participants	31	32
Median (Inter-Quartile Range) [number of attacks]	0.27	12.71

2. Secondary Outcome

Title	Clinical Global Impression of Change (CGIc) for Cataplexy Severity
Description	CGIc for cataplexy severity from the end of the Stable Dose Period to the end of the Double-blind Treatment Period. The CGIc is a 7-point scale ranging from "very much improved" to "very much worse." A score of 0 = no change, a score of 3 = very much improved, and a score of -3 = very much worse.
Time Frame	From the end of the Stable Dose Period to the end of the Double-blind Treatment Period (2 weeks)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Xyrem	Xyrem Placebo
Arm/Group Description	Active Xyrem continued as a double-blind treatment at the stable dose taken and regimen used in the prior 2 weeks.	Xyrem placebo was initiated as a double-blind treatment at a volume and regimen equivalent to the Xyrem dose taken in the prior 2 weeks.
Measure Participants	29	32
Mean (Standard Deviation) [score on a scale]	-0.4 (1.12)	-1.5 (1.19)

3. Secondary Outcome

Title	Change in the Epworth Sleepiness Scale (ESS) (CHAD) Score
Description	Change in the ESS (CHAD) score from the end of the Stable Dose Period to the end of the Double-blind Treatment Period. The ESS is a self-administered questionnaire with 8 questions. It provides a measure of a person's general level of daytime sleepiness, or their average sleep propensity in daily life. In the ESS for children and adolescents (CHAD), certain activities were modified. Each activity is scored on a scale ranging from 0-3, with 0 = would never fall asleep, and 3 = high chance of falling asleep. The total score ranges from 0-24, with a higher number representing an increased propensity for sleepiness.
Time Frame	From the end of the Stable Dose Period to the end of the Double-blind Treatment Period (2 weeks)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Xyrem	Xyrem Placebo
Arm/Group Description	Active Xyrem continued as a double-blind treatment at the stable dose taken and regimen used in the prior 2 weeks.	Xyrem placebo was initiated as a double-blind treatment at a volume and regimen equivalent to the Xyrem dose taken in the prior 2 weeks.
Measure Participants	30	31
Median (Inter-Quartile Range) [score on a scale]	0.0	3.0

4. Secondary Outcome

Title	CGIc for Narcolepsy Overall
Description	CGIc for narcolepsy overall from the end of the Stable Dose Period to the end of the Double-blind Treatment Period. The CGIc is a 7-point scale ranging from "very much improved" to "very much worse." A score of 0 = no change, a score of 3 = very much improved, and a score of -3 = very much worse.
Time Frame	From the end of the Stable Dose Period to the end of the Double-blind Treatment Period (2 weeks)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Xyrem	Xyrem Placebo
Arm/Group Description	Active Xyrem continued as a double-blind treatment at the stable dose taken and regimen used in the prior 2 weeks.	Xyrem placebo was initiated as a double-blind treatment at a volume and regimen equivalent to the Xyrem dose taken in the prior 2 weeks.
Measure Participants	29	32
Mean (Standard Deviation) [score on a scale]	-0.4 (0.95)	-1.4 (1.13)

5. Secondary Outcome

Title	Change in Quality of Life (QoL; SF-10 Physical and Psychosocial Summary Score) From the End of the Stable Dose Period to the End of the Double-blind Treatment Period
Description	The SF-10 Health Survey for Children is a parent-completed survey that contains 10 questions adapted from the Child Health Questionnaire. The SF-10 is intended to produce physical and psychosocial health summary measures. Each of the 10 questions responses is scored with a point value from 1 to 6 (1 is the worst possible condition and 6 is the best possible condition). The SF-10 physical and psychosocial measures are scored such that higher scores indicate more favorable functioning. The questions and associated point values are separated into the Physical Health (PHS-10 domain) and Psychosocial Health (PSS-10 domain). The sums of the scores in each domain are standardized using the mean and standard deviation from a normal population (2006 sample). The standardized scores are transformed to norm based scoring (NBS) metric. Through NBS, scale scores are standardized to a mean of 50 and SD of 10 in the combined U.S. general population and clinical samples. NBS scores are reported
Time Frame	From the end of the Stable Dose Period to the end of the Double-blind Treatment Period (2 weeks)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Xyrem	Xyrem Placebo
Arm/Group Description	Active Xyrem continued as a double-blind treatment at the stable dose taken and regimen used in the prior 2 weeks.	Xyrem placebo was initiated as a double-blind treatment at a volume and regimen equivalent to the Xyrem dose taken in the prior 2 weeks.
Measure Participants	30	30
SF-10 Physical Summary Score	0	0
SF-10 Psychosocial Summary Score	0	-2.670

Adverse Events

Time Frame	Safety data are provided through the 120 day update.
Adverse Event Reporting Description	The Safety Population included all subjects who took study drug, and consisted of 104 subjects. There are 2 subjects included in the Enrolled Population who were dispensed study drug, but did not take the medication and were subsequently discontinued. As a result, safety analyses focused on the 104 subjects in the Safety Population. Adverse events are reported by the Safety Population in order to capture adverse events occurring across all treatment periods.
Arm/Group Title	Safety Population		Randomized Placebo
Arm/Group Description	Safety population who took study drug		Subjects assigned to the Randomized Placebo group during the Double-blind Treatment Period. Adverse events with onset on or after the first dose in the Double-blind Treatment Period and prior to the date of first dose in the Open-label Safety Period are presented.
All Cause Mortality
	Safety Population		Randomized Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/104 (0%)		0/32 (0%)
Serious Adverse Events
	Safety Population		Randomized Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/104 (1.9%)		0/32 (0%)
Psychiatric disorders
Acute Psychosis	1/104 (1%)		0/32 (0%)
Suicidal Ideation	1/104 (1%)		0/32 (0%)
Other (Not Including Serious) Adverse Events
	Safety Population		Randomized Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	80/104 (76.9%)		10/32 (31.3%)
Gastrointestinal disorders
Nausea	20/104 (19.2%)		0/32 (0%)
Vomiting	19/104 (18.3%)		0/32 (0%)
Infections and infestations
Nasopharyngitis	9/104 (8.7%)		0/32 (0%)
Upper respiratory tract infection	9/104 (8.7%)		0/32 (0%)
Investigations
Weight decreased	12/104 (11.5%)		1/32 (3.1%)
Metabolism and nutrition disorders
Decreased appetite	9/104 (8.7%)		0/32 (0%)
Nervous system disorders
Headache	18/104 (17.3%)		0/32 (0%)
Dizziness	8/104 (7.7%)		0/32 (0%)
Somnolence	2/104 (1.9%)		7/32 (21.9%)
Cataplexy	2/104 (1.9%)		6/32 (18.8%)
Psychiatric disorders
Sleep disorder	1/104 (1%)		2/32 (6.3%)
Renal and urinary disorders
Enuresis	20/104 (19.2%)		1/32 (3.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The sponsor can review trial results communications prior to public release and can embargo such communications for a period of at least 60 days from the time submitted to sponsor for review. If requested by sponsor, the PI will withhold publication for up to an additional 30 days. Furthermore, the first publication of study results must be a joint publication of all study sites unless a joint manuscript has not been submitted for publication within 12 months of completion of the study.