A Study of the Efficacy and Safety of JZP-258 in Subjects With Narcolepsy With Cataplexy

• Sponsor: Jazz Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03030599
• Collaborator: (none)
• Enrollment: 201
• Locations: 25
• Arms: 2
• Actual Duration (Months): 27.9
• Patients Per Site: 8
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This is a double-blind, placebo-controlled, randomized-withdrawal, multicenter study of the efficacy and safety of JZP-258.

Condition or Disease	Intervention/Treatment	Phase
Narcolepsy With Cataplexy	Drug: JZP-258; Other: Placebo	Phase 3

Detailed Description

Subjects will be transitioned to JZP-258 based on their treatment status at study entry. All subjects will begin JZP-258 treatment at the beginning of this period and continue through Week 12. They will be treated with JZP-258 alone for the final two weeks of this 12-week period. Once the JZP-258 dose has been optimized per the Investigator's judgment, these subjects may enter the 2-week Stable-Dose Period with that dose. Subjects are eligible to enter the Double-Blind Randomized-Withdrawal Period if the dose of JZP-258 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 JZP-258 treatment have occurred. Subjects will return for a Safety Follow-up visit 2 weeks after the Double-Blind Randomized-Withdrawal Period. Subjects who complete the double-blind treatment period during the Main Study are eligible to enter a 24-week Open-Label Extension. During this period subjects will receive open label JZP-258. Subjects will return for a Safety Follow-up visit 2 weeks after the Open-Label Extension Period.

Study Design

• Study Type: Interventional
• Actual Enrollment: 201 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Double-Blind, Placebo-Controlled, Randomized-Withdrawal, Multicenter Study of the Efficacy and Safety of JZP-258 in Subjects With Narcolepsy With Cataplexy
• Actual Study Start Date: Mar 14, 2017
• Actual Primary Completion Date: Jan 24, 2019
• Actual Study Completion Date: Jul 10, 2019

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo	Other: Placebo; Matching placebo solution (aqueous solution containing sodium citrate, malic acid, and sucralose; all ingredients were compendial [United States Pharmacopeia/ National Formulary])
Experimental: JZP-258 JZP-258	Drug: JZP-258; JZP-258 oral solution 0.5 g/mL, which is equivalent to 0.413 g/mL of oxybate; Other Names: Xyrem®

Outcome Measures

Primary Outcome Measures

1. Change in Weekly Number of Cataplexy Attacks [Change from baseline (2 weeks of the Stable Dose Period) to the 2 weeks of the Double Blind Randomized Withdrawal Period (DB RWP)]

   Participants completed a daily Cataplexy Frequency Diary each night prior to bedtime. Participants were to record the number of cataplexy attacks that they had each day.

Secondary Outcome Measures

1. 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]

   This is the key secondary endpoint. The Epworth Sleepiness Scale (ESS) was a self-administered questionnaire with 8 questions. Participants were asked to rate, on a 4-point scale (0-3), their usual chances of dozing off or falling asleep while engaged in eight different activities. Most participants engaged in those activities at least occasionally, although not necessarily every day. The ESS score (the sum of 8 item scores, 0-3) can range from 0 to 24. The higher the ESS score, the higher that participants average sleep propensity in daily life (ASP), or their 'daytime sleepiness'.

2. Number of Participants With Worsening Patient Global Impression of Change (PGIc) for Narcolepsy Overall [At the end of the Double Blind Randomized Withdrawal Period]

   At the end of the Double Blind Randomized Withdrawal Period (DB RWP), participants rated the change in their condition on a 7-point scale ranging from 1 = "very much improved" to 7 = "very much worse" since the last visit. This endpoint measures the percentage of participants with worsening PGIc scores for narcolepsy overall (defined as scores of Much Worse or Very Much Worse).

3. Number of Participants With Worsening Clinical Global Impression of Change (CGIc) for Narcolepsy Overall [At the end of the Double Blind Randomized Withdrawal Period]

   At the end of the Double Blind Randomized Withdrawal Period, Investigators rated their impression of any change in the severity of the participant's narcolepsy overall condition since the start of the Double Blind Randomized Withdrawal Period on a 7-point scale ranging from 1 = "very much improved" to 7 = "very much worse". This endpoint measures the percentage of participants with worsening CGIc scores for narcolepsy overall, defined as scores of Much Worse or Very Much Worse.

4. Change in 36-Item Short Form Health Survey Version 2 (SF-36v2) Scores [At the End of the Stable Dose Period to the End of the Double Blind Randomized Withdrawal Period]

   The SF-36v2 is a multi-purpose, short-form health survey with 36 questions/ items. It yields an 8-scale profile of functional health and well-being scores as well as a psychometrically-based physical and mental overall component summary measures. Two summary scores were derived using the SF-36v2. Physical Component Summary measures dimensions of functional health that are meaningful to respondents, including the impact of health and health-related changes on physical function, pain, and the ability to carry out daily roles. The Mental Component Summary component scale measures the impact of health and health-related changes on well-being, including vitality, social function, and emotional well-being. Participants self-report on items in a summary that have between 2-6 choices per item (e.g. none of the time, some of the time, etc.). Summations of item scores were transformed into a range from 0 to 100; zero= worst HRQL, 100=best HRQL. Higher scores indicate better health status.

5. Change in 5-level EQ-5D (EQ-5D-5L) Crosswalk Index Score and Visual Analog Scale [At the End of the Stable Dose Period to the End of the Double Blind Randomized Withdrawal Period]

   The EQ-5D-5L is a measure of health outcome that includes a descriptive system consisting of 5 dimensions (mobility, self-care, usual activities, pain/ discomfort, and anxiety/ depression). The EQ-5D-5L includes 5 levels of severity for each of the 5 dimensions of the descriptive system (1= no problems, 2= slight problems, 3= moderate problems, 4= severe problems, and 5= extreme problems) that reflect increasing levels of difficulty. The 5 digit health states for each dimension are converted into a single value per country (0= equivalent to death, 1= equivalent to best imaginable health and values below 0= health states rated worse than death capped at -1), using the EQ-5D-5L crosswalk index value calculator as recommended by EuroQol group. A visual analogue scale (VAS) used within this scale recorded the participants self-rated health on a VAS and the endpoints resulted in a numeric value set ranging from 0 (= worst imaginable health state) up to 100 (= best imaginable health state).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male or female subjects between 18 and 70 years of age, inclusive.

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. 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.

4. Willing and able to comply with the study design schedule and other requirements.

5. Willing and able to provide written informed consent.

Exclusion Criteria:

1. Narcolepsy secondary to another medical condition (e.g., CNS injury or lesion)

2. 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.

3. Treatment with any central nervous system sedating agents, including but not limited to benzodiazepines, nonbenzodiazepine anxiolytics/ hypnotics/sedatives, neuroleptics, opioids, barbiturates, phenytoin, ethosuximide, or MCT inhibitors, e.g. diclofenac, valproate, ibuprofen, 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).

4. 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.

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	SDS Clinical Trials, Inc.	Orange	California	United States	92858
2	Stanford Health Services	Stanford	California	United States	94305
3	Colorado Sleep Institute	Boulder	Colorado	United States	80301
4	Pulmonary Disease Specialists	Kissimmee	Florida	United States	34741
5	Fort Wayne Neurological Center	Fort Wayne	Indiana	United States	46804
6	Kentucky Research Group	Louisville	Kentucky	United States	40218
7	Center for Sleep & Wake Disorders	Chevy Chase	Maryland	United States	20815
8	Montefiore/ Sleep-Wake Disorders Center	Bronx	New York	United States	10467
9	Gastonia Medical Specialty Clinic	Gastonia	North Carolina	United States	94305
10	Research Carolina	Huntersville	North Carolina	United States	28078
11	Intrepid Research	Cincinnati	Ohio	United States	45245
12	Cleveland Clinic, Sleep Disorder Center	Cleveland	Ohio	United States	44195
13	UZ Antwerpen	Edegem		Belgium	2650
14	Universitair Ziekenhuis Gent	Gent		Belgium	9000
15	UZ Leuven	Leuven		Belgium	3000
16	Fakultni nemocnice Ostrava	Ostrava-Poruba		Czechia	70800
17	Vseobecna fakultni nemocnice v Praze	Praha 2		Czechia	128 21
18	Helsingin Uniklinikka, Vitalmed Oy	Helsinki		Finland	00380
19	Hôpital Gui de Chauliac	Montpellier	Herault	France	34295
20	Hopital Roger Salengro - CHU Lille	Lille		France	59037
21	Hospital Universitari Vall d'Hebron	Barcelona		Spain	08035
22	Hospital Clinic i Provincial de Barcelona	Barcelona		Spain	08036
23	Hospital General de Castellón	Castelló		Spain	12004
24	Instituto de Investigaciones del Sueño	Madrid		Spain	28036
25	Hospital Vithas Nuestra Señora de America	Madrid		Spain	28043

Sponsors and Collaborators

• Jazz Pharmaceuticals

Investigators

• Study Director: Director Clinical Trial Disclosure & Transparency, Jazz Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - May 15, 2018
• Statistical Analysis Plan - Feb 25, 2019

More Information

Publications

None provided.

• Responsible Party: Jazz Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03030599
• Other Study ID Numbers: 15-006; 2016-000426-20
• First Posted: Jan 25, 2017
• Last Update Posted: Nov 12, 2020
• Last Verified: Nov 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Narcolepsy; Cataplexy

Study Results

Participant Flow

Pre-assignment Detail	Subjects were evaluated for eligibility during the Screening Period (up to 30 days).

Arm/Group Title	Open-label JZP-258	JZP-258	Placebo
Arm/Group Description	All 201 subjects entered the Open Label Optimized Treatment and Titration Period (OL OTTP) and received at least 1 dose of study drug. During the OL OTTP (12 weeks), eligible subjects were transitioned to JZP-258 treatment based on their pre-treatment status. During the Stable Dose Period, subjects received open-label JZP-258 at the same unchanged dose that they received during the last 2 weeks of the Open Label Treatment and Titration Period.	JZP-258 at the dose taken during the last 2 weeks of the Stable Dose Period.	A matching oral solution to JZP-258.
Period Title: Open Label Treatment and Titration
STARTED	201	0	0
COMPLETED	155	0	0
NOT COMPLETED	46	0	0
Period Title: Open Label Treatment and Titration
STARTED	149	0	0
COMPLETED	144	0	0
NOT COMPLETED	5	0	0
Period Title: Open Label Treatment and Titration
STARTED	0	69	67
COMPLETED	0	69	59
NOT COMPLETED	0	0	8
Period Title: Open Label Treatment and Titration
STARTED	74	0	0
COMPLETED	67	0	0
NOT COMPLETED	7	0	0

Baseline Characteristics

Arm/Group Title	Open Label Treatment and Titration
Arm/Group Description	All 201 subjects entered the Open Label Optimized Treatment and Titration Period (OL OTTP) and received at least 1 dose of study drug. During the OL OTTP (12 weeks), eligible subjects were transitioned to JZP-258 treatment based on their pre-treatment status. During the Stable Dose Period, subjects received open-label JZP-258 at the same unchanged dose that they received during the last 2 weeks of the Open Label Treatment and Titration Period.
Overall Participants	201
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	195 97%
>=65 years	6 3%
Sex: Female, Male (Count of Participants)
Female	122 60.7%
Male	79 39.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	3 1.5%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	11 5.5%
White	177 88.1%
More than one race	2 1%
Unknown or Not Reported	8 4%

Outcome Measures

1. Primary Outcome

Title	Change in Weekly Number of Cataplexy Attacks
Description	Participants completed a daily Cataplexy Frequency Diary each night prior to bedtime. Participants were to record the number of cataplexy attacks that they had each day.
Time Frame	Change from baseline (2 weeks of the Stable Dose Period) to the 2 weeks of the Double Blind Randomized Withdrawal Period (DB RWP)

Outcome Measure Data

Analysis Population Description

The efficacy population contains all randomized subjects who received at least one dose of double-blind study drug and had at least one set of post-randomization efficacy data.

Arm/Group Title	JZP-258	Placebo
Arm/Group Description	JZP-258 at the dose taken during the last 2 weeks of the Stable Dose Period.	A matching oral solution to JZP-258.
Measure Participants	69	65
Median (Inter-Quartile Range) [attacks]	0.00	2.35

2. Secondary Outcome

Title	Change in the Epworth Sleepiness Scale (ESS) Score
Description	This is the key secondary endpoint. The Epworth Sleepiness Scale (ESS) was a self-administered questionnaire with 8 questions. Participants were asked to rate, on a 4-point scale (0-3), their usual chances of dozing off or falling asleep while engaged in eight different activities. Most participants engaged in those activities at least occasionally, although not necessarily every day. The ESS score (the sum of 8 item scores, 0-3) can range from 0 to 24. The higher the ESS score, the higher that participants average sleep propensity in daily life (ASP), or their 'daytime sleepiness'.
Time Frame	From the end of the Stable Dose Period to the end of the Double Blind Randomized Withdrawal Period

Outcome Measure Data

Analysis Population Description

The efficacy population contains all randomized subjects who received at least one dose of double-blind study drug and had at least one set of post-randomization efficacy data.

Arm/Group Title	JZP-258	Placebo
Arm/Group Description	JZP-258 at the dose taken during the last 2 weeks of the Stable Dose Period.	A matching oral solution to JZP-258.
Measure Participants	69	65
Median (Inter-Quartile Range) [score on a scale]	0.00	2.0

3. Secondary Outcome

Title	Number of Participants With Worsening Patient Global Impression of Change (PGIc) for Narcolepsy Overall
Description	At the end of the Double Blind Randomized Withdrawal Period (DB RWP), participants rated the change in their condition on a 7-point scale ranging from 1 = "very much improved" to 7 = "very much worse" since the last visit. This endpoint measures the percentage of participants with worsening PGIc scores for narcolepsy overall (defined as scores of Much Worse or Very Much Worse).
Time Frame	At the end of the Double Blind Randomized Withdrawal Period

Outcome Measure Data

Analysis Population Description

The efficacy population contains all randomized subjects who received at least one dose of double-blind study drug and had at least one set of post-randomization efficacy data.

Arm/Group Title	JZP-258	Placebo
Arm/Group Description	JZP-258 at the dose taken during the last 2 weeks of the Stable Dose Period.	A matching oral solution to JZP-258.
Measure Participants	69	65
Count of Participants [Participants]	3 1.5%	29 NaN

4. Secondary Outcome

Title	Number of Participants With Worsening Clinical Global Impression of Change (CGIc) for Narcolepsy Overall
Description	At the end of the Double Blind Randomized Withdrawal Period, Investigators rated their impression of any change in the severity of the participant's narcolepsy overall condition since the start of the Double Blind Randomized Withdrawal Period on a 7-point scale ranging from 1 = "very much improved" to 7 = "very much worse". This endpoint measures the percentage of participants with worsening CGIc scores for narcolepsy overall, defined as scores of Much Worse or Very Much Worse.
Time Frame	At the end of the Double Blind Randomized Withdrawal Period

Outcome Measure Data

Analysis Population Description

The efficacy population contains all randomized subjects who received at least one dose of double-blind study drug and had at least one set of post-randomization efficacy data.

Arm/Group Title	JZP-258	Placebo
Arm/Group Description	JZP-258 at the dose taken during the last 2 weeks of the Stable Dose Period.	A matching oral solution to JZP-258.
Measure Participants	68	65
Count of Participants [Participants]	4 2%	39 NaN

5. Secondary Outcome

Title	Change in 36-Item Short Form Health Survey Version 2 (SF-36v2) Scores
Description	The SF-36v2 is a multi-purpose, short-form health survey with 36 questions/ items. It yields an 8-scale profile of functional health and well-being scores as well as a psychometrically-based physical and mental overall component summary measures. Two summary scores were derived using the SF-36v2. Physical Component Summary measures dimensions of functional health that are meaningful to respondents, including the impact of health and health-related changes on physical function, pain, and the ability to carry out daily roles. The Mental Component Summary component scale measures the impact of health and health-related changes on well-being, including vitality, social function, and emotional well-being. Participants self-report on items in a summary that have between 2-6 choices per item (e.g. none of the time, some of the time, etc.). Summations of item scores were transformed into a range from 0 to 100; zero= worst HRQL, 100=best HRQL. Higher scores indicate better health status.
Time Frame	At the End of the Stable Dose Period to the End of the Double Blind Randomized Withdrawal Period

Outcome Measure Data

Analysis Population Description

The efficacy population contains all randomized subjects who received at least one dose of double-blind study drug and had at least one set of post-randomization efficacy data.

Arm/Group Title	JZP-258	Placebo
Arm/Group Description	JZP-258 at the dose taken during the last 2 weeks of the Stable Dose Period.	A matching oral solution to JZP-258.
Measure Participants	67	65
Physical Component Summary	-0.03	-1.92
Mental Component Summary	1.55	-1.92

6. Secondary Outcome

Title	Change in 5-level EQ-5D (EQ-5D-5L) Crosswalk Index Score and Visual Analog Scale
Description	The EQ-5D-5L is a measure of health outcome that includes a descriptive system consisting of 5 dimensions (mobility, self-care, usual activities, pain/ discomfort, and anxiety/ depression). The EQ-5D-5L includes 5 levels of severity for each of the 5 dimensions of the descriptive system (1= no problems, 2= slight problems, 3= moderate problems, 4= severe problems, and 5= extreme problems) that reflect increasing levels of difficulty. The 5 digit health states for each dimension are converted into a single value per country (0= equivalent to death, 1= equivalent to best imaginable health and values below 0= health states rated worse than death capped at -1), using the EQ-5D-5L crosswalk index value calculator as recommended by EuroQol group. A visual analogue scale (VAS) used within this scale recorded the participants self-rated health on a VAS and the endpoints resulted in a numeric value set ranging from 0 (= worst imaginable health state) up to 100 (= best imaginable health state).
Time Frame	At the End of the Stable Dose Period to the End of the Double Blind Randomized Withdrawal Period

Outcome Measure Data

Analysis Population Description

There were 68 JZP-258 participants included in the Crosswalk Index, and 69 JZP-258 participants in the VAS Score. The efficacy population contains all randomized subjects who received at least one dose of double-blind study drug and had at least one set of post-randomization efficacy data.

Arm/Group Title	JZP-258	Placebo
Arm/Group Description	JZP-258 at the dose taken during the last 2 weeks of the Stable Dose Period.	A matching oral solution to JZP-258.
Measure Participants	69	65
Crosswalk index	0.00	0.00
VAS Score	0.00	-5.00

Adverse Events

Time Frame	Through week 18 or early termination.
Adverse Event Reporting Description	Safety data are summarized for all subjects who received at least 1 dose of study medication across all periods.
Arm/Group Title	JZP-258		Placebo
Arm/Group Description	JZP-258 at the dose taken during the last 2 weeks of the Stable Dose Period.		A matching oral solution to JZP-258.
All Cause Mortality
	JZP-258		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/201 (0%)		0/65 (0%)
Serious Adverse Events
	JZP-258		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/201 (2.5%)		2/65 (3.1%)
Hepatobiliary disorders
Bile duct stone	1/201 (0.5%)		0/65 (0%)
Infections and infestations
Influenza	0/201 (0%)		1/65 (1.5%)
Viral cardiomyopathy	1/201 (0.5%)		0/65 (0%)
Injury, poisoning and procedural complications
Accidental overdose	1/201 (0.5%)		0/65 (0%)
Investigations
Muscle enzyme increased	0/201 (0%)		1/65 (1.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Invasive ductal breast carcinoma	1/201 (0.5%)		0/65 (0%)
Nervous system disorders
Peripheral nerve paresis	1/201 (0.5%)		0/65 (0%)
Psychiatric disorders
Confusional state	1/201 (0.5%)		0/65 (0%)
Hallucination	1/201 (0.5%)		0/65 (0%)
Other (Not Including Serious) Adverse Events
	JZP-258		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	108/201 (53.7%)		12/65 (18.5%)
Gastrointestinal disorders
Diarrhoea	13/201 (6.5%)		0/65 (0%)
Nausea	27/201 (13.4%)		0/65 (0%)
Infections and infestations
Influenza	17/201 (8.5%)		1/65 (1.5%)
Nasopharyngitis	19/201 (9.5%)		2/65 (3.1%)
Upper respiratory tract infection	11/201 (5.5%)		0/65 (0%)
Metabolism and nutrition disorders
Decreased appetite	15/201 (7.5%)		1/65 (1.5%)
Nervous system disorders
Cataplexy	21/201 (10.4%)		5/65 (7.7%)
Dizziness	23/201 (11.4%)		0/65 (0%)
Headache	45/201 (22.4%)		1/65 (1.5%)
Somnolence	5/201 (2.5%)		6/65 (9.2%)

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.