Narcolepsy With Cataplexy
Conditions
Brief summary
This is a double-blind, placebo-controlled, randomized-withdrawal, multicenter study of the efficacy and safety of JZP-258.
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.
Interventions
DRUGJZP-258
JZP-258 oral solution 0.5 g/mL, which is equivalent to 0.413 g/mL of oxybate
OTHERPlacebo
Matching placebo solution (aqueous solution containing sodium citrate, malic acid, and sucralose; all ingredients were compendial \[United States Pharmacopeia/ National Formulary\])
Sponsors
Jazz Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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'. |
| 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). |
| 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. |
| 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. |
| 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). |
Countries
Belgium, Czechia, Finland, France, Spain, United States
Participant flow
Pre-assignment details
Subjects were evaluated for eligibility during the Screening Period (up to 30 days).
Participants by arm
| Arm | Count |
|---|---|
| Open Label Treatment and Titration 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. | 201 |
| Total | 201 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Double Blind Randomized Withdrawal | Adverse Event | 0 | 0 | 3 |
| Double Blind Randomized Withdrawal | Lack of Efficacy | 0 | 0 | 2 |
| Double Blind Randomized Withdrawal | Randomized in error | 0 | 0 | 2 |
| Double Blind Randomized Withdrawal | Withdrawal by Subject | 0 | 0 | 1 |
| Open-label Extension | Adverse Event | 3 | 0 | 0 |
| Open-label Extension | Lack of Efficacy | 1 | 0 | 0 |
| Open-label Extension | Lost to Follow-up | 2 | 0 | 0 |
| Open-label Extension | Other Reason | 1 | 0 | 0 |
| Open Label Treatment and Titration | Adverse Event | 18 | 0 | 0 |
| Open Label Treatment and Titration | Lack of Efficacy | 1 | 0 | 0 |
| Open Label Treatment and Titration | Lost to Follow-up | 3 | 0 | 0 |
| Open Label Treatment and Titration | Non-Compliance with Study Drug | 4 | 0 | 0 |
| Open Label Treatment and Titration | Other | 1 | 0 | 0 |
| Open Label Treatment and Titration | Physician Decision | 3 | 0 | 0 |
| Open Label Treatment and Titration | Protocol deviation | 8 | 0 | 0 |
| Open Label Treatment and Titration | Sponsor decision | 2 | 0 | 0 |
| Open Label Treatment and Titration | Withdrawal by Subject | 6 | 0 | 0 |
| Stable Dose | Adverse Event | 1 | 0 | 0 |
| Stable Dose | Lost to Follow-up | 1 | 0 | 0 |
| Stable Dose | Protocol deviation | 3 | 0 | 0 |
Baseline characteristics
| Characteristic | Open Label Treatment and Titration |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 6 Participants |
| Age, Categorical Between 18 and 65 years | 195 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants |
| Race (NIH/OMB) More than one race | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 8 Participants |
| Race (NIH/OMB) White | 177 Participants |
| Sex: Female, Male Female | 122 Participants |
| Sex: Female, Male Male | 79 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 201 | 0 / 65 |
| other Total, other adverse events | 108 / 201 | 12 / 65 |
| serious Total, serious adverse events | 5 / 201 | 2 / 65 |
Outcome results
Primary
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)
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| JZP-258 | Change in Weekly Number of Cataplexy Attacks | 0.00 attacks |
| Placebo | Change in Weekly Number of Cataplexy Attacks | 2.35 attacks |
Secondary
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
Population: 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 | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| JZP-258 | Change in 36-Item Short Form Health Survey Version 2 (SF-36v2) Scores | Physical Component Summary | -0.03 score on a scale |
| JZP-258 | Change in 36-Item Short Form Health Survey Version 2 (SF-36v2) Scores | Mental Component Summary | 1.55 score on a scale |
| Placebo | Change in 36-Item Short Form Health Survey Version 2 (SF-36v2) Scores | Physical Component Summary | -1.92 score on a scale |
| Placebo | Change in 36-Item Short Form Health Survey Version 2 (SF-36v2) Scores | Mental Component Summary | -1.92 score on a scale |
Secondary
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
Population: 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 | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| JZP-258 | Change in 5-level EQ-5D (EQ-5D-5L) Crosswalk Index Score and Visual Analog Scale | Crosswalk index | 0.00 score on a scale |
| JZP-258 | Change in 5-level EQ-5D (EQ-5D-5L) Crosswalk Index Score and Visual Analog Scale | VAS Score | 0.00 score on a scale |
| Placebo | Change in 5-level EQ-5D (EQ-5D-5L) Crosswalk Index Score and Visual Analog Scale | Crosswalk index | 0.00 score on a scale |
| Placebo | Change in 5-level EQ-5D (EQ-5D-5L) Crosswalk Index Score and Visual Analog Scale | VAS Score | -5.00 score on a scale |
Secondary
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
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| JZP-258 | Change in the Epworth Sleepiness Scale (ESS) Score | 0.00 score on a scale |
| Placebo | Change in the Epworth Sleepiness Scale (ESS) Score | 2.0 score on a scale |
Secondary
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
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| JZP-258 | Number of Participants With Worsening Clinical Global Impression of Change (CGIc) for Narcolepsy Overall | 4 Participants |
| Placebo | Number of Participants With Worsening Clinical Global Impression of Change (CGIc) for Narcolepsy Overall | 39 Participants |
Secondary
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
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| JZP-258 | Number of Participants With Worsening Patient Global Impression of Change (PGIc) for Narcolepsy Overall | 3 Participants |
| Placebo | Number of Participants With Worsening Patient Global Impression of Change (PGIc) for Narcolepsy Overall | 29 Participants |