Narcolepsy
Conditions
Brief summary
The rationale for the interventional, open-label, single-arm design of JZP258-401 is to evaluate the clinical experience in participants with narcolepsy transitioning treatment from Xyrem to XYWAV.
Interventions
DRUGJZP-258
Maximum nightly dosage of 9 grams, administered once, twice or thrice nightly, with no single dose \> 6 g
Sponsors
Jazz Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Age 1. Participant must be 18 to 80 years of age (inclusive), at the time of signing the informed consent. Type of Participant and Disease Characteristics 2. Participants who have a primary diagnosis of Type 1 or Type 2 narcolepsy that meets ICSD-3 criteria or DSM-5 criteria (Ruoff and Rye 2016), and are being currently treated with Xyrem, with or without additional anticataplectics or stimulants. 3. Participants who have been taking Xyrem (with or without additional anticataplectics or stimulants eg, TCA, SNRI, SSRI, atomoxetine) in a stable dose and regimen for at least two months prior to screening, with evidence of clinical improvement on their current regimen, per the investigator's judgement. Only Xyrem will be substituted with XYWAV, with dose and regimen of any concomitant anticataplectics or stimulants remaining unchanged throughout the study. Sex and Contraceptive/Barrier Requirements 4. 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 non-childbearing potential (WONCBP) as defined in Appendix 3 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 3, 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) during screening. * The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. Informed Consent 5. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
Exclusion criteria
Medical Conditions 1. Have a diagnosis of narcolepsy, secondary to another medical condition (eg, central nervous system injury or lesion) 2. Are currently prescribed a Xyrem regimen exceeding a dose of 9 grams nightly, or any single dose in excess of 6 grams. 3. Have been diagnosed with restless leg syndrome (RLS) requiring treatment other than iron supplements 4. Exhibit succinic semi-aldehyde dehydrogenase deficiency (SSADH) 5. Have uncontrolled hypothyroidism 6. Have a history of seizures, excluding early childhood non-pathological febrile seizures 7. Have a history of head trauma associated with loss of consciousness in the past 5 years, or if the event occurred more than 5 years prior to screening and the participant experiences sequelae due to the event 8. Show evidence of untreated or inadequately treated sleep-disordered breathing including: 1. Presence of clinically significant and untreated obstructive or central sleep apnea (as determined by the investigator or documented previously); or one of the following: 2. Apnea index (AI) \>10 if on Obstructive Sleep Apnea (OSA) treatment or untreated, or 3. Clinically significant hypoventilation, or 4. Noncompliance with primary OSA therapy Note: Non-compliance is defined as positive airway pressure use of \<4 hours per night on \<70% of nights (\<5 of 7 nights/week) per historical report (with investigator concurrence) of use of an oral appliance on \<70% of nights (≥5 of 7 nights/week), or receipt of an effective surgical intervention for OSA symptoms. 9. Experience parasomnias (eg, sleep walking, REM Sleep Behavior Disorder, etc.) considered by the investigator to negatively impact the conduct of the study. Parasomnia events associated with physical injury to the participant (or others) shall be discussed with the sponsor Medical Monitor. 10. Meet criteria for current major depression based on clinical interview 11. Have any clinically relevant medical, behavioral, or psychiatric disorder (other than narcolepsy) that is associated with excessive sleepiness 12. Have a history or presence of bipolar disorder, bipolar related disorders, schizophrenia, schizophrenia spectrum disorders, or other psychotic disorders according to DSM-5 criteria 13. Have a 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 participant's safety and/or interfere with the conduct of the study, in the opinion of the investigator 14. Display relevant suicidality as indicated by Columbia Suicide Severity Rating Scale (C-SSRS) evaluation at screening 15. Display moderate to severe depression as indicated by the Participant Health Questionnaire - 9 (PHQ-9) at screening 16. Are a female participant who is pregnant or breastfeeding Prior/Concomitant Therapy 17. Have undergone treatment with any prohibited central nervous system (CNS) agents, including but not limited to benzodiazepines, non-benzodiazepine anxiolytics/ hypnotics/sedatives, neuroleptics, opioids, barbiturates, phenytoin, ethosuximide, or MCT inhibitors, eg, 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 Monitors. Prior/Concurrent Clinical Study Experience 18. Received any other investigational drug within 30 days or five half-lives (whichever is longer) prior to screening, or plan to use an investigational drug (other than the study intervention) during the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Weekly Rate of Cataplexy Attacks | Baseline to Week 8 | Mean weekly rate of cataplexy attack = (total number of cataplexy attacks reported during the period/number of days during the period where a diary was completed) x 7. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Patient Global Impression of Change (PGIc) Values | Week 8 | The PGIc is a 7-point Likert-type rating based on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). PGIc values were measured at the ET or E/D, as applicable. |
| Change in Epworth Sleepiness Scale (ESS) | Baseline to Week 8 | The ESS questionnaire included a set of 8 questions regarding how likely the participant would be to doze off or fall asleep in different situations. The ESS measures EDS or average sleep propensity in daily life. Responses range from 0 = would never doze (better outcome) to 3 = high chance of dozing (worse outcome). Changes in ESS scores were assessed between the Baseline period and ET or E/D, as applicable |
| Time to Achieve Optimized Dose and Regimen | Baseline to Week 8 | Defined as the time from the first dose and regimen to the optimized dose and regimen of XYWAV, where the optimized dose and regimen indicates the final dose and regimen that remains unchanged throughout the remainder of the Intervention period. |
| Change in the Nausea Visual Analog Scale (NVAS) | Baseline to Week 8 | Tolerability associated with Xyrem and XYWAV was measured based on an NVAS assessment administered electronically. NVAS was captured daily during the last 7 days of the Baseline (Xyrem-stable dose and regimen) period and the last 7 days of the Intervention period (on XYWAV) prior to the ET visit or prior to the E/D visit, if possible. For participants with at least one day of NVAS data, the NVAS for that week was the average daily score from days with non-missing data within the week, then multiplied by 7. The NVAS ranges 0-100 mm, with higher scores representing more severe/intense nausea. |
| Number of Participants Dosing Fasted Versus Dosing Without Consideration of Food | Baseline to Week 8 | Once the participant reached an optimized dose and regimen, the investigator could decide to instruct the participant to dose without regard to food. |
| Duration of Time Between the Last Meal Relative to Dosing | Baseline to Week 8 | The difference between the time of day that participants ate their last meal and the time of day participants take their first dose. |
| Characterization of Meals Relative to Dosing | Baseline to Week 8 | Types of meals consumed before dosing. |
| Number of Changes From the First Dose and Regimen to Optimized Dose and Regimen | Baseline to Week 8 | The amount of times the dose and regimen were changed before an optimized dose and regimen were achieved. |
Countries
United States
Participant flow
Recruitment details
A total of 62 participants were enrolled in trial sites across the United States.
Participants by arm
| Arm | Count |
|---|---|
| Overall Participants received JZP258 (XYWAV) at a maximum nightly dosage of 9 g administered orally 1 to 3 times nightly, with no single dose exceeding 6 g. | 62 |
| Total | 62 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Alcohol or Urine Drug Screen Result Is Positive | 4 |
| Overall Study | Noncompliance With Study Intervention | 1 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Overall |
|---|---|
| Age, Continuous | 44.3 years STANDARD_DEVIATION 15.22 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 58 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 54 Participants |
| Sex: Female, Male Female | 37 Participants |
| Sex: Female, Male Male | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 60 |
| other Total, other adverse events | 18 / 60 |
| serious Total, serious adverse events | 2 / 60 |
Outcome results
Primary
Change in Weekly Rate of Cataplexy Attacks
Mean weekly rate of cataplexy attack = (total number of cataplexy attacks reported during the period/number of days during the period where a diary was completed) x 7.
Time frame: Baseline to Week 8
Population: The weekly rate of cataplexy attacks was assessed using the XYWAV Efficacy Analysis Set, which included all participants in the XYWAV Safety Analysis Set who finished the course of study. Includes Narcolepsy type 1 participants with a mean weekly rate of cataplexy attack at both the first 7 days of the baseline period and the week 8 visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Overall | Change in Weekly Rate of Cataplexy Attacks | 0.98 cataplexy attacks per week | Standard Deviation 4.1222 |
Other Pre-specified
Change in Epworth Sleepiness Scale (ESS)
The ESS questionnaire included a set of 8 questions regarding how likely the participant would be to doze off or fall asleep in different situations. The ESS measures EDS or average sleep propensity in daily life. Responses range from 0 = would never doze (better outcome) to 3 = high chance of dozing (worse outcome). Changes in ESS scores were assessed between the Baseline period and ET or E/D, as applicable
Time frame: Baseline to Week 8
Population: ESS was assessed using the XYWAV Efficacy Analysis Set, which included all participants in the XYWAV Safety Analysis Set who finished the course of study. Includes participants with Epworth Sleeping Scale assessments at both Baseline and ET or E/D visits.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Overall | Change in Epworth Sleepiness Scale (ESS) | -0.6 units on a scale | Standard Deviation 2.33 |
Other Pre-specified
Change in the Nausea Visual Analog Scale (NVAS)
Tolerability associated with Xyrem and XYWAV was measured based on an NVAS assessment administered electronically. NVAS was captured daily during the last 7 days of the Baseline (Xyrem-stable dose and regimen) period and the last 7 days of the Intervention period (on XYWAV) prior to the ET visit or prior to the E/D visit, if possible. For participants with at least one day of NVAS data, the NVAS for that week was the average daily score from days with non-missing data within the week, then multiplied by 7. The NVAS ranges 0-100 mm, with higher scores representing more severe/intense nausea.
Time frame: Baseline to Week 8
Population: NVAS was assessed using the XYWAV Efficacy Analysis Set, which included all participants in the XYWAV Safety Analysis Set who finished the course of study. Includes participants with a baseline value and a post-baseline value at the end of treatment (ET) or early discontinuation ( E/D).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Overall | Change in the Nausea Visual Analog Scale (NVAS) | 3.13 score on a scale | Standard Deviation 29.089 |
Other Pre-specified
Characterization of Meals Relative to Dosing
Types of meals consumed before dosing.
Time frame: Baseline to Week 8
Population: Characterization of meals was assessed using the XYWAV Efficacy Analysis Set, which included all participants in the XYWAV Safety Analysis Set who finished the course of study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Overall | Characterization of Meals Relative to Dosing | Regular Meal | 54 Participants |
| Overall | Characterization of Meals Relative to Dosing | Snack | 45 Participants |
| Overall | Characterization of Meals Relative to Dosing | Beverage Other than Water | 19 Participants |
Other Pre-specified
Duration of Time Between the Last Meal Relative to Dosing
The difference between the time of day that participants ate their last meal and the time of day participants take their first dose.
Time frame: Baseline to Week 8
Population: The duration of time between the last meal and dosing was assessed using the XYWAV Efficacy Analysis Set, which included all participants in the XYWAV Safety Analysis Set who finished the course of study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Overall | Duration of Time Between the Last Meal Relative to Dosing | 113.7 minute | Standard Deviation 313.31 |
Other Pre-specified
Number of Changes From the First Dose and Regimen to Optimized Dose and Regimen
The amount of times the dose and regimen were changed before an optimized dose and regimen were achieved.
Time frame: Baseline to Week 8
Population: The number of changes from the first dose and regimen to the optimized was assessed using the XYWAV Efficacy Analysis Set, which included all participants in the XYWAV Safety Analysis Set who finished the course of study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Overall | Number of Changes From the First Dose and Regimen to Optimized Dose and Regimen | Never Changed | 48 Participants |
| Overall | Number of Changes From the First Dose and Regimen to Optimized Dose and Regimen | Changed Once | 6 Participants |
| Overall | Number of Changes From the First Dose and Regimen to Optimized Dose and Regimen | Changed Twice | 0 Participants |
| Overall | Number of Changes From the First Dose and Regimen to Optimized Dose and Regimen | Changed More than Twice | 0 Participants |
Other Pre-specified
Number of Participants Dosing Fasted Versus Dosing Without Consideration of Food
Once the participant reached an optimized dose and regimen, the investigator could decide to instruct the participant to dose without regard to food.
Time frame: Baseline to Week 8
Population: The number of participants who dosed fasted versus without food consideration was assessed using the XYWAV Efficacy Analysis Set, which included all participants in the XYWAV Safety Analysis Set who finished the course of study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Overall | Number of Participants Dosing Fasted Versus Dosing Without Consideration of Food | Dosing Fasted | 53 Participants |
| Overall | Number of Participants Dosing Fasted Versus Dosing Without Consideration of Food | Dosing without Food Consideration | 1 Participants |
Other Pre-specified
Number of Participants With Patient Global Impression of Change (PGIc) Values
The PGIc is a 7-point Likert-type rating based on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). PGIc values were measured at the ET or E/D, as applicable.
Time frame: Week 8
Population: PGIC was assessed using the XYWAV Efficacy Analysis Set, which included all participants in the XYWAV Safety Analysis Set who finished the course of study. Includes participants who have at least one PGIc assessment performed at the end of the intervention period or early discontinuation (E/D) visit.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Overall | Number of Participants With Patient Global Impression of Change (PGIc) Values | Very Much Improved | 1 Participants |
| Overall | Number of Participants With Patient Global Impression of Change (PGIc) Values | Much Improved | 9 Participants |
| Overall | Number of Participants With Patient Global Impression of Change (PGIc) Values | Minimally Improved | 12 Participants |
| Overall | Number of Participants With Patient Global Impression of Change (PGIc) Values | No Change | 26 Participants |
| Overall | Number of Participants With Patient Global Impression of Change (PGIc) Values | Minimally Worse | 3 Participants |
| Overall | Number of Participants With Patient Global Impression of Change (PGIc) Values | Much Worse | 0 Participants |
| Overall | Number of Participants With Patient Global Impression of Change (PGIc) Values | Very Much Worse | 0 Participants |
Other Pre-specified
Time to Achieve Optimized Dose and Regimen
Defined as the time from the first dose and regimen to the optimized dose and regimen of XYWAV, where the optimized dose and regimen indicates the final dose and regimen that remains unchanged throughout the remainder of the Intervention period.
Time frame: Baseline to Week 8
Population: The time to achieve an optimized dose and regimen was assessed using the XYWAV Efficacy Analysis Set, which included all participants in the XYWAV Safety Analysis Set who finished the course of study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Overall | Time to Achieve Optimized Dose and Regimen | 2.6 day | Standard Deviation 4.9 |