A Study Evaluating the Efficacy and Safety of Xywav Expanded Dosing vs Placebo in Participants With Narcolepsy or IH (XYRISE)

A Phase 3, Multicenter, Double-blind, Placebo-controlled, Randomized-withdrawal Study to Evaluate the Efficacy and Safety of Expanded Dosing Regimens for Xywav in Adult Participants With Narcolepsy or Idiopathic Hypersomnia

The purpose of this study is to evaluate the efficacy and safety of expanded Xywav dosing regimens in adult participants with narcolepsy or idiopathic hypersomnia (IH).

Study Overview

• Status: Not yet recruiting
• Conditions: Narcolepsy; Idiopathic Hypersomnia
• Intervention / Treatment: Drug: Xywav; Other: Placebo

Detailed Description

The trial has 2 treatment periods: titration and optimization period and the randomized withdrawal period. Once eligibility to participate in the trial is confirmed, eligible participants will begin the titration and optimization treatment period where they will be assigned to either cohort 1 or cohort 2. Participants assigned to Cohort 1 will receive once-nightly dosing of Xywav and participants assigned to Cohort 2 will receive twice-nightly dosing of Xywav. Assignment is dependent on participant's standard oxybate treatment and the treating investigator's decision. During the titration and optimization treatment period, participants' Xywav dosing will be adjusted until they achieve a stable dose in this period. This period will last up to 14 weeks. After a stable dose is achieved, the participants will begin the randomized withdrawal treatment period. During the withdrawal treatment period, participants assigned in both cohorts will be randomized to either continue on their stable dose of Xywav or receive placebo for 2 additional weeks of treatment in the trial.

• Study Type: Interventional
• Enrollment (Estimated): 108
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Clinical Trial Disclosure & Transparency; Phone Number: 215-832-3750; Email: ClinicalTrialDisclosure@JazzPharma.com

Study Locations

• United States
  • Ohio
    • Cincinnati, Ohio, United States, 45245
      • Intrepid Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Has a primary diagnosis of IH or narcolepsy Type 1 or Type 2 (NT1 or NT2)
2. If not currently treated with oxybate, has clinically significant symptoms of excessive daytime sleepiness (EDS) with an Epworth Sleepiness Scale (ESS) score > 11 at screening.
3. If currently treated with oxybate, must have documented improvement of EDS with oxybate treatment per the investigator's clinical judgement.
4. If currently treated with oxybate, has been taking the same stable dosing regimen at a total nightly dosage of 3 g to 9 g (inclusive) for at least 2 months at screening.
5. If previously treated with (and not currently taking) oxybate, must have been off oxybate treatment for at least 2 weeks prior to screening. Must not have previously discontinued oxybate due to reasons related to intolerability, safety, or lack of efficacy.
6. If currently treated with anticataplectics (NT1 only) and/or alerting agents, has been taking the same dosage for at least 1 month prior to screening and has no current plans to adjust the dosage during the study period.
7. If currently treated with nicotine replacement therapy, has been taking the same dosage for at least 1 month prior to screening and has no current plans to adjust the dosage during the study period.
8. Adequate contraceptive precautions

Exclusion criteria:

1. Shows evidence of a previous untreated or inadequately treated sleep disorder considered by the investigator to negatively impact the conduct of the study, including sleep-disordered breathing, parasomnias, circadian rhythm sleep disorders, or restless legs syndrome determined by a previous sleep-laboratory diagnosis or interview utilizing modules of the Diagnostic Interview for Sleep Patterns and Disorders.
2. Has succinic semi-aldehyde dehydrogenase deficiency by medical history.
3. Has uncontrolled hypothyroidism as determined by central clinical laboratory test results.
4. Has a current seizure disorder.
5. Has a history of head trauma associated with loss of consciousness in the past 5 years
6. Has a history or presence of bipolar disorder, bipolar-related disorders, schizophrenia, schizophrenia spectrum disorders, or other psychotic disorders
7. Has a history or presence of any unstable or clinically significant medical condition, behavioral or psychiatric disorder, or history or presence of another neurologic disorder or surgical history that might affect the participant's safety and/or interfere with the conduct of the study, in the opinion of the investigator.
8. Has any other significant disease or disorder that, in the opinion of the investigator, may either put the participant, other participants, or study staff at risk because of participation in the study, may influence the result of the study, or may affect the participant's safety or ability to take part in the study.
9. Any past or current medical conditions or experience that, in the investigator's clinical judgment, would preclude treatment with a once-nightly dose > 6 g up to 7.5 g dose or twice-nightly regimen with a total nightly dosage > 9 g up to 12 g (divided into 2 doses).
10. Has any severe drug allergy or a history of allergic or severe adverse reactions or intolerance to Xyrem, Xywav, Gamma-hydroxybutyrate (GHB), or any components of the dosage forms.

11. Has recently taken, is taking, or plans to take any of the following:

    1. A substance or medication contraindicated with Xywav use
    2. A medication with a known drug-drug interaction with Xywav
    3. Medications known to have clinically significant CNS sedating effects:
    4. Other medications, natural health products, or substances from which the participant experiences clinically significant sedation
12. Has recently taken, is taking, or plans to take an Orexin 2 receptor (OX2R) agonist during the study.
13. Has tobacco-use disorder or uses vaping products that impact sleep
14. Has excessive caffeine consumption that may impact sleep
15. Has clinically significant abnormal laboratory values
16. Has an occupation that requires nighttime or variable shift work
17. Has plans for travel across more than 3 time zones during the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Once-nightly stable dose Xywav group; Participants assigned to cohort 1 will receive once-nightly dosing of Xywav for up to 14 weeks until they reach a stable dose. Once stable dose is achieved, participants will continue taking their stable dose of Xywav for 2 additional weeks.	Drug: Xywav; 0.5 g/ml calcium, magnesium, potassium, and sodium oxybates solution taken by mouth; Other Names: JZP258
Placebo Comparator: Once-nightly placebo group; Participants assigned to cohort 1 will receive once-nightly dosing of Xywav for up to 14 weeks until they reach a stable dose. Once stable dose is achieved, participants will take placebo for 2 additional weeks.	Drug: Xywav; 0.5 g/ml calcium, magnesium, potassium, and sodium oxybates solution taken by mouth; Other Names: JZP258; Other: Placebo; Placebo solution taken by mouth
Active Comparator: Twice nightly stable dose Xywav group; Participants assigned to cohort 2 will receive twice-nightly dosing of Xywav for up to 14 weeks until they reach a stable dose. Once stable dose is achieved, participants will continue taking their stable dose of Xywav for 2 additional weeks.	Drug: Xywav; 0.5 g/ml calcium, magnesium, potassium, and sodium oxybates solution taken by mouth; Other Names: JZP258
Placebo Comparator: Twice nightly placebo group; Participants assigned to cohort 2 will receive twice-nightly dosing of Xywav for up to 14 weeks until they reach a stable dose. Once stable dose is achieved, participants will take placebo for 2 additional weeks.	Drug: Xywav; 0.5 g/ml calcium, magnesium, potassium, and sodium oxybates solution taken by mouth; Other Names: JZP258; Other: Placebo; Placebo solution taken by mouth

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Epworth Sleepiness Scale (ESS) scores	ESS is a self-administered questionnaire with 8 questions. Each question is scored on a scale ranging from 0 (would never fall asleep) to 3 (high chance of falling asleep). It has a total score ranging from 0 to 24, with a higher score representing increased daytime sleepiness.	End of stable dose visit (up to Week 14), up to end of Double-Blind Randomized-Withdrawal Period (up to Week 16)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Global Impression of Change (CGIc) scores	CGIc is a 7-point questionnaire completed by the treating physician that evaluates how the physician thinks the participant is responding to treatment since the end of stable dose visit (up to week 14). Responses are graded from 1 (very much improved) to 7 (very much worse)	At the end of Double-Blind Randomized-Withdrawal Period (up to Week 16)
Patient Global Impression of Change (PGIc) scores	PGIc is a 7-point questionnaire completed by the participant evaluating how they think they are responding to treatment since the end of stable dose visit (up to week 14). Responses are graded from 1 (very much improved) to 7 (very much worse)	At the end of Double-Blind Randomized-Withdrawal Period (up to Week 16)
Change in IHSS scores in participants with IH	Idiopathic Hypersomnia Severity Scare (IHSS) is a 14-item self-reported questionnaire that assesses the severity and functional consequences of IH symptoms. Questions capture symptoms of excessive sleepiness, sleep inertia, and long sleep duration. The total score for the IHSS ranges from 0 to 50, with higher scores reflecting greater symptom severity.	End of stable dose visit (up to Week 14), up to end of Double-Blind Randomized-Withdrawal Period (up to Week 16)
Change in NSS scores in participants with NT1	Narcolepsy Severity Scale (NSS) is a 15-item self-administered questionnaire that assesses the severity and consequences of the 5 major narcolepsy symptoms such as daytime sleepiness, cataplexy, hallucinations, sleep paralysis, and disrupted nighttime sleep. The total score for NSS ranges from 0 to 57, with the higher score indicating greater symptom severity	End of stable dose visit (up to Week 14), up to end of Double-Blind Randomized-Withdrawal Period (up to Week 16)
Change in NSS-2 scores in participants with NT2	NSS-2 is a modified NSS self-administered questionnaire with only 12 items (omits questions regarding cataplexy). The total score for NSS-2 ranges from 0 to 44, with the higher score indicating greater symptom severity	End of stable dose visit (up to Week 14), up to end of Double-Blind Randomized-Withdrawal Period (up to Week 16)
Change in weekly rate of cataplexy (WRC) in participants with NT1	WRC will be assessed for participants with NT1 using a cataplexy frequency electronic diary. Participants will be recording the number of daily cataplexy attacks experienced.	End of stable dose visit (up to Week 14), up to end of Double-Blind Randomized-Withdrawal Period (up to Week 16)
Number of Participants Reporting Treatment-emergent Adverse Events (TEAEs)		Up to the end of the Safety follow up visit (Up to Week 18)

Collaborators and Investigators

• Sponsor: Jazz Pharmaceuticals
• Collaborators: Jazz Pharmaceuticals Ireland Limited

Study record dates

Study Major Dates

• Study Start (Estimated): June 30, 2026
• Primary Completion (Estimated): December 23, 2027
• Study Completion (Estimated): January 6, 2028

Study Registration Dates

• First Submitted: May 27, 2026
• First Submitted That Met QC Criteria: May 27, 2026
• First Posted (Actual): June 4, 2026

Study Record Updates

• Last Update Posted (Actual): June 4, 2026
• Last Update Submitted That Met QC Criteria: May 27, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Narcolepsy Type 1; Narcolepsy Type 2; IH; NT2; NT1; Xywav
• Additional Relevant MeSH Terms: Nervous System Diseases; Mental Disorders; Sleep Wake Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Disorders of Excessive Somnolence; Narcolepsy; Idiopathic Hypersomnia
• Other Study ID Numbers: JZP258-304

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: In accordance with ICMJE requirements, Jazz Pharmaceuticals may provide qualified external researchers access to individual participant data (IPD) and clinical trial data that underlie the results of this trial upon request. Qualified researchers can submit a request on https://www.jazzpharma.com/science/clinical-trial-data-sharing/ as outlined. Jazz Pharmaceuticals reserves the right not to consider a request. For inquiries about Jazz's data sharing policy contact clinicaldatasharing@jazzpharma.com.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No