Evaluation of Blood Pressure Changes in Narcolepsy Patients Transitioning from High-Sodium Oxybate to JZP258 (Sodium, Calcium, Magnesium, Potassium Oxybate)

Trial ID: 2023-504892-25-00
Sponsor: Jazz Pharmaceuticals PLC

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Diseases & Conditions

Narcolepsy

Objectives

The primary objective of this study is to evaluate the impact of switching from twice-nightly high-sodium **oxybate** to XYWAV on 24-hour ambulatory systolic blood pressure (SBP) in participants with **narcolepsy**. This is clinically relevant as it aims to assess the cardiovascular effects of a medication change in a population with narcolepsy, potentially influencing treatment decisions and improving patient outcomes.

Secondary objectives include:

Evaluating the impact of the switch on daytime ambulatory SBP.
Assessing changes in seated resting SBP.
Investigating the effects on night-time SBP.

These secondary objectives provide a comprehensive understanding of the blood pressure changes associated with the medication switch, offering insights into the safety and efficacy of XYWAV in managing narcolepsy-related symptoms while considering cardiovascular health.

Participants

The clinical trial involves a total of **84 participants** diagnosed with **narcolepsy**, specifically Type 1 or Type 2, as per ICSD-3 or DSM-5 criteria. The study population comprises both male and female subjects, aged between 18 to 70 years. Participants were selected based on their current treatment regimen, which includes a stable dose of high-sodium oxybate (e.g., XYREM) taken twice nightly for at least six consecutive weeks prior to screening. Additionally, participants may be on stable doses of stimulants, alerting agents, or antihypertensive therapies, provided these regimens have been consistent for at least two months before screening and remain unchanged throughout the study. The trial includes individuals with an average screening systolic blood pressure (SBP) between 130 and 155 mm Hg and a diastolic blood pressure (DBP) not exceeding 95 mm Hg. The study population is not limited by gender, and women of childbearing potential are required to use highly effective contraception and have a negative pregnancy test prior to participation. The trial does not include individuals with resistant hypertension. Participants' general health status is monitored to ensure compliance with the study's inclusion criteria, and lifestyle factors such as diet and physical activity are considered to maintain consistency in blood pressure measurements.

Plans and Procedures

The clinical trial is designed to evaluate the impact of switching from high-sodium oxybate to **XYWAV** on 24-hour ambulatory systolic blood pressure (SBP) in participants diagnosed with **narcolepsy**. This is an open-label, multicenter study with a focus on changes in blood pressure. The trial is structured as a Phase 3 study and is not classified as low intervention. The study will involve adult participants aged 18 to 70 years who have a documented diagnosis of Type 1 or Type 2 narcolepsy, meeting the criteria outlined in the ICSD-3 or DSM-5. Participants must have been on a stable dose of high-sodium oxybate, specifically between 6 to 9 grams per night, for at least six consecutive weeks prior to the screening phase.

The trial will commence with a screening visit to confirm eligibility based on inclusion criteria, such as age, diagnosis, and current treatment regimen. Participants will be required to maintain stable doses of any concomitant medications, including stimulants, alerting agents, and antihypertensive therapies, throughout the study. The primary endpoint is the change in 24-hour average SBP from baseline to the end-of-treatment (EOT) visit. Secondary endpoints include changes in daytime, nighttime, and seated resting average SBP.

Participants will be involved in the study for a maximum treatment period of six months. The study will include several follow-up visits to monitor blood pressure and ensure compliance with the study protocol. The end-of-study visit will assess the primary and secondary endpoints, with the final data collection expected by June 2025. Conditions that may lead to early termination from the study include non-compliance with the dosing regimen, significant adverse events, or any medical condition that, in the investigator's opinion, would compromise the participant's safety or the integrity of the study data.

Treatment

The clinical trial involves the administration of the experimental medication **JZP258**, an **oral solution** developed by Jazz Pharmaceuticals. This formulation is a mixed-salt oxybate solution, comprising **sodium oxybate**, **calcium oxybate**, **magnesium oxybate**, and **potassium oxybate**. The medication is administered orally, with a maximum daily dose of 9 grams and a total maximum dose of 378 grams over the course of the study. The treatment period is limited to a maximum of 6 months. The formulation is not a pediatric formulation and is not classified as an orphan drug. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.

In this study, there are no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments being utilized. The primary objective is to evaluate the impact of switching from a high-sodium oxybate regimen to JZP258 on 24-hour ambulatory systolic blood pressure in participants diagnosed with narcolepsy. The trial is designed as an open-label, multicenter switch study, focusing on the changes in blood pressure associated with the transition to the experimental medication.

Efficacy

The efficacy of the clinical trial will be assessed by evaluating changes in blood pressure among participants with narcolepsy who switch from high-sodium oxybate to XYWAV. The primary endpoint for efficacy assessment is the change from baseline to the end-of-treatment (EOT) visit in the 24-hour average **Systolic Blood Pressure (SBP)**, measured in mm Hg. Secondary endpoints include changes from baseline to the EOT visit in the daytime average SBP, seated resting average SBP, and nighttime average SBP, all measured in mm Hg. Blood pressure measurements will be collected using a device provided by the sponsor, ensuring consistency and accuracy in data collection. The trial is designed to monitor these parameters throughout the study duration, with specific timepoints for assessment aligned with the trial protocol.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Participants must be 18 to 70 years of age inclusive, at the time of signing the informed consent.
Participants have a documented diagnosis of Type 1 or Type 2 narcolepsy that meets ICSD-3 or DSM-5 criteria.
Participants must have been receiving a total dose of high-sodium oxybate (eg, XYREM) of 6 to 9 g/night (inclusive) with twice-nightly dosing for a minimum of 6 consecutive weeks prior to screening.
If currently treated with stimulants and/or alerting agents or other medications known to affect Blood Pressure, participant must have been taking the same dosing regimen for at least 2 months prior to screening and agree to take the same dose throughout the study.
If currently taking stable doses of antihypertensive therapies, participant must maintain these treatments at the same dose throughout the study unless otherwise advised by their medical care provider. Also refer to exclusion criterion 12.
Participant’s average screening SBP must be between 130 and 155 mm Hg (inclusive). Note: BP measurements will be collected using a device provided by the sponsor as described in Section 8.3.2.1. Participants with resistant hypertension are excluded (refer to exclusion criterion 12).
Participant’s average screening Diastolic blood pressure (DBP) must not be greater than 95 mm Hg. Note: BP measurements will be collected using a device provided by the sponsor as described in Section 8.3.2.1. Participants with resistant hypertension are excluded (refer to exclusion criterion 12).
Participant is male or female. • A female participant is eligible to participate if she is not pregnant or breastfeeding and one of the following conditions applies: − Is a woman of nonchildbearing potential OR − Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of < 1% per year), preferably with low user dependency, as described in Appendix 4 of the Protocol, during the study intervention period and for at least 7 days after the last dose of study intervention. The investigator should evaluate the potential for contraceptive method failure (eg, noncompliance, recently initiated) in relationship to the first dose of study intervention. • A WOCBP must have a negative highly sensitive pregnancy test (serum) as required by local regulations during screening (Section 8.3.5 of the Protocol). • Additional requirements for pregnancy testing during and after study intervention are provided in Section 8.3.5 of the Protocol. • The investigator is responsible for review of medical history, contraception history, menstrual history, and recent sexual activity to decrease the risk of inclusion of a woman with an early undetected pregnancy.

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Exclusion Criteria

History or presence of any acutely unstable medical condition, behavioral or psychiatric disorder (including active suicidal ideation), or surgical history that could affect the safety of the participant or interfere with study assessments or the ability of the participant to complete the study based on the judgment of the investigator.
Occupation requiring nighttime or variable shift work.
Participant was previously eligible for this study but either was terminated early or was discontinued.
Presence of significant cardiovascular disease including but not limited to: myocardial infarction within the past year, unstable angina pectoris, symptomatic or hospitalized congestive heart failure (ACC/AHA stage C or D), revascularization procedures within the past year, chronic/persistent atrial fibrillation, ventricular cardiac arrhythmias requiring automatic implantable cardioverter defibrillator or anti-arrhythmic therapy, or any significant cardiovascular condition that in the investigator’s opinion may jeopardize participant safety in the study, including screening ECG results.
Presence of atrial fibrillation detected on screening ECG.
Current or recent (within the past 2 years) diagnosis of a moderate or severe substance use disorder (excluding caffeine) according to DSM-5 criteria. Nicotine use disorder is excluded only if it impacts sleep (ie, a participant who routinely awakens at night to smoke).
History of phenylketonuria or history of hypersensitivity to phenylalanine-derived products.
Succinic semi-aldehyde dehydrogenase deficiency by medical history.
Received an investigational drug in the past 30 days or 5 half-lives (whichever is longer) prior to the Screening Period, or plans to use an investigational drug (other than the study drug) during the study.
Presence of renal impairment with a calculated creatinine clearance < 45 mL/min.
Laboratory value(s) outside the laboratory reference range that are considered to be clinically significant by the investigator (clinical chemistry). NOTE: clinical labs may be repeated once during the Screening Period
Participant has resistant hypertension, defined as one of the following: a. Controlled BP (ie, SBP < 140 mm Hg and DBP < 90 mm Hg) and treated with 4 or more antihypertensive medications. b. Uncontrolled BP (ie, SBP ≥ 140 mm Hg and/or DBP ≥ 90 mm Hg) despite concurrent use of 3 or more antihypertensive medications of different classes that include a diuretic.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Not Recruiting	01 Oct 2023	5
Czechia	Not Recruiting	01 Oct 2023	6
France	Not Recruiting	01 Oct 2023	6
Italy	Not Recruiting	01 Oct 2023	10
Spain	Not Recruiting	01 Oct 2023	10