CompletedNCT03030599Updated Nov 12, 2020Results posted

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

A Phase 3 interventional study of JZP-258 and Placebo in Narcolepsy With Cataplexy, sponsored by Jazz Pharmaceuticals. Completed at 25 sites in 6 countries. Open to participants aged 18 Years to 70 Years. Per ClinicalTrials.gov, last updated 2020-11-12.

Sponsored by Jazz Pharmaceuticals · Phase 3, Interventional, and Treatment

Phase: Phase 3
Study type: Interventional
Enrollment: 201
Allocation: Randomized
Ages: 18 Years to 70 Years
Sex: All

Study summary

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

Read the 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.

Conditions studied

Narcolepsy With Cataplexy

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Who can participate

Ages eligible: 18 Years to 70 Years
Sexes eligible: All
Accepts healthy volunteers: No

Inclusion criteria

Male or female subjects between 18 and 70 years of age, inclusive.
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.
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.
Willing and able to comply with the study design schedule and other requirements.
Willing and able to provide written informed consent.

Exclusion criteria

Exclusion Criteria:

Narcolepsy secondary to another medical condition (e.g., CNS injury or lesion)
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.
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).
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.
Unsafe for the subject to receive placebo treatment for 2 weeks, in the opinion of the Investigator.

Study design

Phase: Phase 3
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel assignment
Masking: Double (Participant, Investigator)
Enrollment: 201 participants (actual)

Study arms

Placebo comparator
Placebo
Placebo
Other: Placebo
Experimental
JZP-258
JZP-258
Drug: JZP-258

Interventions

DrugJZP-258
JZP-258 oral solution 0.5 g/mL, which is equivalent to 0.413 g/mL of oxybate
Also known as: Xyrem®
OtherPlacebo
Matching placebo solution (aqueous solution containing sodium citrate, malic acid, and sucralose; all ingredients were compendial \[United States Pharmacopeia/ National Formulary\])

What researchers measure

Primary outcomes

Change in Weekly Number of Cataplexy Attacks
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)

Secondary outcomes

Change in the Epworth Sleepiness Scale (ESS) Score
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
Number of Participants With Worsening Patient Global Impression of Change (PGIc) for Narcolepsy Overall
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
Number of Participants With Worsening Clinical Global Impression of Change (CGIc) for Narcolepsy Overall
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
Change in 36-Item Short Form Health Survey Version 2 (SF-36v2) Scores
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
Change in 5-level EQ-5D (EQ-5D-5L) Crosswalk Index Score and Visual Analog Scale
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

Results

Posted Nov 12, 2020

Participant flow

Open Label Treatment and Titration

Participant flow — Open Label Treatment and Titration
Milestone	Open-label JZP-258	JZP-258	Placebo
Started	201	0	0
Completed	155	0	0
Not completed	46	0	0
Withdrew: Protocol deviation	8	0	0
Withdrew: Other	1	0	0
Withdrew: Physician decision	3	0	0
Withdrew: Lack of efficacy	1	0	0
Withdrew: Non-compliance with study drug	4	0	0
Withdrew: Adverse event	18	0	0
Withdrew: Withdrawal by subject	6	0	0
Withdrew: Sponsor decision	2	0	0
Withdrew: Lost to follow-up	3	0	0

Stable Dose

Participant flow — Stable Dose
Milestone	Open-label JZP-258	JZP-258	Placebo
Started	149	0	0
Completed	144	0	0
Not completed	5	0	0
Withdrew: Protocol deviation	3	0	0
Withdrew: Adverse event	1	0	0
Withdrew: Lost to follow-up	1	0	0

Double Blind Randomized Withdrawal

Participant flow — Double Blind Randomized Withdrawal
Milestone	JZP-258	Placebo
Started	69	67
Completed	69	59
Not completed	0	8
Withdrew: Lack of efficacy	0	2
Withdrew: Adverse event	0	3
Withdrew: Randomized in error	0	2
Withdrew: Withdrawal by subject	0	1

Open-label Extension

Participant flow — Open-label Extension
Milestone	Open-label JZP-258	JZP-258	Placebo
Started	74	0	0
Completed	67	0	0
Not completed	7	0	0
Withdrew: Adverse event	3	0	0
Withdrew: Lost to follow-up	2	0	0
Withdrew: Lack of efficacy	1	0	0
Withdrew: Other reason	1	0	0

Outcome measures

PrimaryChange in Weekly Number of Cataplexy Attacks

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)
Reported as:: Median · attacks

Change in Weekly Number of Cataplexy Attacks
attacks	JZP-258	Placebo
Change in Weekly Number of Cataplexy Attacks	0.00 (-0.49 to 1.75)	2.35 (0.00 to 11.61)

SecondaryChange in the Epworth Sleepiness Scale (ESS) Score

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
Reported as:: Median · score on a scale

Change in the Epworth Sleepiness Scale (ESS) Score
score on a scale	JZP-258	Placebo
Change in the Epworth Sleepiness Scale (ESS) Score	0.00 (-1.0 to 1.0)	2.0 (0.00 to 5.0)

SecondaryNumber of Participants With Worsening Patient Global Impression of Change (PGIc) for Narcolepsy Overall

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
Reported as:: Count of participants · Participants

Number of Participants With Worsening Patient Global Impression of Change (PGIc) for Narcolepsy Overall
Participants	JZP-258	Placebo
Number of Participants With Worsening Patient Global Impression of Change (PGIc) for Narcolepsy Overall	3	29

SecondaryNumber of Participants With Worsening Clinical Global Impression of Change (CGIc) for Narcolepsy Overall

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
Reported as:: Count of participants · Participants

Number of Participants With Worsening Clinical Global Impression of Change (CGIc) for Narcolepsy Overall
Participants	JZP-258	Placebo
Number of Participants With Worsening Clinical Global Impression of Change (CGIc) for Narcolepsy Overall	4	39

SecondaryChange in 36-Item Short Form Health Survey Version 2 (SF-36v2) Scores

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
Reported as:: Median · score on a scale

Change in 36-Item Short Form Health Survey Version 2 (SF-36v2) Scores
score on a scale	JZP-258	Placebo
Physical Component Summary	-0.03 (-2.07 to 2.41)	-1.92 (-3.46 to 1.73)
Mental Component Summary	1.55 (-1.88 to 3.78)	-1.92 (-6.28 to 1.34)

SecondaryChange in 5-level EQ-5D (EQ-5D-5L) Crosswalk Index Score and Visual Analog Scale

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
Reported as:: Median · score on a scale

Change in 5-level EQ-5D (EQ-5D-5L) Crosswalk Index Score and Visual Analog Scale
score on a scale	JZP-258	Placebo
Crosswalk index	0.00 (-0.01 to 0.03)	0.00 (-0.05 to 0.03)
VAS Score	0.00 (0.00 to 5.00)	-5.00 (-10.00 to 5.00)

Adverse events

Collected over Through week 18 or early termination.. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
JZP-258	0/201 (0%)	5/201 (2.5%)	108/201 (53.7%)
Placebo	0/65 (0%)	2/65 (3.1%)	12/65 (18.5%)

Most frequent serious events

Most frequent serious events
Event	JZP-258	Placebo
Muscle enzyme increasedInvestigations	0/201	1/65
InfluenzaInfections and infestations	0/201	1/65
Accidental overdoseInjury, poisoning and procedural complications	1/201	0/65
Invasive ductal breast carcinomaNeoplasms benign, malignant and unspecified (incl cysts and polyps)	1/201	0/65
Peripheral nerve paresisNervous system disorders	1/201	0/65
Confusional statePsychiatric disorders	1/201	0/65
Bile duct stoneHepatobiliary disorders	1/201	0/65
Viral cardiomyopathyInfections and infestations	1/201	0/65
HallucinationPsychiatric disorders	1/201	0/65

Most frequent other events

Most frequent other events
Event	JZP-258	Placebo
HeadacheNervous system disorders	45/201	1/65
NauseaGastrointestinal disorders	27/201	0/65
DizzinessNervous system disorders	23/201	0/65
CataplexyNervous system disorders	21/201	5/65
NasopharyngitisInfections and infestations	19/201	2/65
SomnolenceNervous system disorders	5/201	6/65
InfluenzaInfections and infestations	17/201	1/65
Decreased appetiteMetabolism and nutrition disorders	15/201	1/65
DiarrhoeaGastrointestinal disorders	13/201	0/65
Upper respiratory tract infectionInfections and infestations	11/201	0/65

Baseline characteristics

Age, Categorical
Age, Categorical(Participants)	Open Label Treatment and Titration
<=18 years	0
Between 18 and 65 years	195
>=65 years	6

Sex: Female, Male
Sex: Female, Male(Participants)	Open Label Treatment and Titration
Female	122
Male	79

Race (NIH/OMB)
Race (NIH/OMB)(Participants)	Open Label Treatment and Titration
American Indian or Alaska Native	0
Asian	3
Native Hawaiian or Other Pacific Islander	0
Black or African American	11
White	177
More than one race	2
Unknown or Not Reported	8

Study locations

25 sites

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

References and documents

Publications

Dauvilliers Y, Sonka K, Bogan RK, Partinen M, Del Rio Villegas R, Foldvary-Schaefer N, Skowronski R, Chen A, Black J, Skobieranda F, Thorpy MJ. Changes in Cataplexy Frequency in a Clinical Trial of Lower-Sodium Oxybate with Taper and Discontinuation of Other Anticataplectic Medications. CNS Drugs. 2022 Jun;36(6):633-647. doi: 10.1007/s40263-022-00926-0. Epub 2022 May 30. Erratum In: CNS Drugs. 2022 Jul;36(7):785-786. doi: 10.1007/s40263-022-00933-1. PubMed 35635687 ↗
Bogan RK, Thorpy MJ, Dauvilliers Y, Partinen M, Del Rio Villegas R, Foldvary-Schaefer N, Skowronski R, Tang L, Skobieranda F, Sonka K. Efficacy and safety of calcium, magnesium, potassium, and sodium oxybates (lower-sodium oxybate [LXB]; JZP-258) in a placebo-controlled, double-blind, randomized withdrawal study in adults with narcolepsy with cataplexy. Sleep. 2021 Mar 12;44(3):zsaa206. doi: 10.1093/sleep/zsaa206. Erratum In: Sleep. 2021 Jul 9;44(7):zsab033. doi: 10.1093/sleep/zsab033. Sleep. 2021 Nov 12;44(11):zsab188. doi: 10.1093/sleep/zsab188. PubMed 33184650 ↗

Study documents

Study protocol · May 15, 2018
Statistical analysis plan · Feb 25, 2019

Documents are hosted by the registry — open the source record to download them.

Registry details

Key details

Study ID: NCT03030599
Lead sponsor: Jazz Pharmaceuticals
Responsible party: Sponsor
First posted: Jan 25, 2017
Start date: Mar 14, 2017
Primary completion: Jan 24, 2019
Completion: Jul 10, 2019
Results posted: Nov 12, 2020
Last update: Nov 12, 2020

Study contacts

Director Clinical Trial Disclosure & Transparency

study director · Jazz Pharmaceuticals

Oversight

Data monitoring committee: No
FDA-regulated drug: Yes
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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