A Study To Assess the Safety and Efficacy of JZP385 in the Treatment of Adults With Moderate to Severe Essential Tremor (ET)

Study Overview
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Brief Summary
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This is a 12-week, double-blind, placebo-controlled, randomized, parallel-group, multicenter study of the safety and efficacy of JZP385 in the treatment of adult participants with moderate to severe ET.

Official Title
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A Phase 2b, 12-week, Double-blind, Placebo-controlled, Randomized, Parallel Group, Multicenter Study of the Safety and Efficacy of JZP385 in the Treatment of Adults With Moderate to Severe Essential Tremor

Conditions
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Essential Tremor

Intervention / Treatment
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* Drug: JZP385
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must be 18 to 80 years of age inclusive, at the time of signing the informed consent. Participants who are diagnosed with ET (including ET plus) according to the MDS Consensus Statement on the Classification of Tremors from the Task Force on Tremor of the International Parkinson's and Movement Disorder Society. Participants have moderate to severe disability associated with tremor as determined by a score of ≥ 22 on the TETRAS-ADL subscale and a CGI-S rating of at least moderate for participants' ability to function. Sex and Contraceptive/Barrier Requirements During the study intervention and for at least 30 days after the last dose of study intervention male participants must refrain from donating sperm. Non-abstinent males must agree to use a male condom in combination with female partner use of a highly effective contraceptive method with a failure rate of < 1% per year. All male participants must agree to use a male condom when engaging in any activity that allows for passage of ejaculate to another person. Female participants must not be pregnant or breastfeeding, are either women of non-childbearing potential (WONCBP), or are women of childbearing potential (WOCBP) using a highly effective contraceptive method with a failure rate of < 1% during the study intervention period and for at least 30 days after the last dose of study intervention. Male partners of WOCBP are required to use barrier protection, eg, condoms, from the first dose of study intervention until 30 days after the last dose of study intervention. A WOCBP must have a negative highly sensitive serum pregnancy test at Screening Visit 1 and negative urine pregnancy tests (unless serum is required by local regulations) at the Screening Visit 2 (if applicable) and at the Baseline Visit - If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. Prior/Concomitant Antitremor Medications If currently treated with antitremor medications, potential participants must be on a stable dosage for at least 6 weeks prior to Screening and must not anticipate making any changes to their antitremor medication for the duration of the study. Note: Treatment with some antitremor medications (eg, primidone) is not allowed in accordance with other exclusion criteria. Exclusion Criteria: Known history or current evidence of other medical or neurological conditions that may cause or explain the participant's tremor. Has evidence at Screening of severe cognitive impairment as defined by a Montreal Cognitive Assessment (MoCA; score < 20) or has cognitive impairment that in the opinion of the investigator would prevent completion of study procedures (including the ability to accurately self-report on study questionnaires) or the ability to provide informed consent. Current suicidal risk as determined from history, by presence of active suicidal ideation as indicated by positive response to item 4 or 5 on the C-SSRS (within the past 24 months), or any history of suicide attempt; current or past (within 1 year) major depressive episode according to DSM-5 criteria. History (within past 2 years at screening) or presence of a diagnosed substance use disorder (including alcohol, tobacco, and cannabis) according to DSM-5 criteria, known drug dependence, or seeking treatment for alcohol or substance abuse related disorder. Prior magnetic resonance (MR)-guided focused ultrasound thalamotomy, surgical intervention (eg, deep brain stimulation, ablative thalamotomy, gamma knife thalamotomy), or inability to refrain from using a device for treatment of tremor for the duration of the treatment period. Botulinum toxin injection for the treatment of upper limb tremor in the 6 months before screening or planned use at any time during the study. Treatment with any medication that could produce tremor taken within 2 weeks or 5 half-lives (whichever is longer) before screening or anticipated use at any time during participation in the study. Use of prescription of nonprescription drugs or other products known to be inducers of CYP3A4 that are known to decrease AUC by > 30% (eg, primidone) and which cannot be discontinued at least 4 weeks before Baseline or planned use at any time during the study. Use of prescription or nonprescription drugs, or other products (eg, grapefruit, grapefruit juice, or Seville oranges) known to be strong or moderate inhibitors of CYP3A4, that cannot be discontinued 2 weeks or 5 half-lives, whichever is longer, before Baseline or planned use at any time during the study. Use of proton pump inhibitors that cannot be discontinued at least 2 weeks before Baseline, or planned use at any time during the study. Occasional use of antacids or histamine-2 receptor antagonists will be permitted, but antacids should be taken at least 4 hours before or after study intervention; and histamine-2 receptor antagonists should be taken at least 4 hours after and at least 12 hours before study intervention. Inability to refrain from use of medication/substance(s) that might produce tremor or interfere with the evaluation of tremor on study visit days prior to discharge such as, but not limited to, stimulant decongestants, beta-agonist bronchodilators, and alcohol. Regular use of more than 3 units of alcohol per day. Regular consumption of caffeine > 400 mg/day or > 4 cups of coffee per day

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 10 milligram (mg) JZP385<br>Participants will initially receive 5 mg/day from Day 1 through Day 7, and 10 mg/day starting on Day 8. | Drug: JZP385<br>* JZP385 capsules will be administered orally (PO) once daily in the morning on an empty stomach for 12 weeks.<br>|
| Experimental: 20 mg JZP385<br>Participants will initially receive 5 mg/day from Day 1 through Day 7, 10 mg/day from Day 8 through Day 14, and 20 mg/day starting on Day 15. | Drug: JZP385<br>* JZP385 capsules will be administered orally (PO) once daily in the morning on an empty stomach for 12 weeks.<br>|
| Experimental: 30 mg JZP385<br>Participants will initially receive 5 mg/day from Day 1 through Day 7, 10 mg/day from Day 8 through Day 14, 20 mg/day from Day 15 through Day 21, and 30 mg/day starting on Day 22. | Drug: JZP385<br>* JZP385 capsules will be administered orally (PO) once daily in the morning on an empty stomach for 12 weeks.<br>|
| Placebo Comparator: Placebo<br>Participants will receive placebo from Day 1. | Other: Placebo<br>* Placebo capsules will be administered orally (PO) once daily in the morning on an empty stomach for 12 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline to Week 12 on the TETRAS composite outcome score as summarized by each dose of JZP385 and placebo | The TETRAS composite outcome score is the sum of modified items 1 - 11 of the TETRAS-ADL subscale and modified items 6 - 7 of the TETRAS-PS. The TETRAS-ADL subscale is a patient-rated scale administered by a trained interviewer that assesses the impact of tremor on day-to-day functioning, such as eating, drinking, dressing, and other fine motor skills. The TETRAS-PS is a clinical rating scale that quantifies tremor in the head, face voice, limbs and trunk. Items 6 (drawing an Archimedes spiral using left and right hands) and 7 (handwriting) of the TETRAS-PS evaluate the impact of upper limb tremor on performance. Each item from the modified subscales ranges from 0 - 3, with 0 representing normal or slightly abnormal and 3 representing severely abnormal. The sum of the 14 items provides the TETRAS composite outcome score, which ranges from 0 - 42, with higher scores representing more severe ET. | Change from baseline to week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants who Improved (≥ 1-Point Improvement) from Baseline to Week 12 on the Clinical Global Impression- Severity scale (CGI-S) | The CGI-S is a 5-point Likert-type rating scale that a qualified medical personnel (ie, a clinician)will use to rate the severity of the participants' ability to function due to their ET. The responses to this scale range from 1 (no limitations) to 5 (severe). | Change from Baseline to Week 12 | 
| Proportion of Participants Reported as Much Improved on the Clinical Global Impression of Change (CGI-C) | The CGI-C is a 5-point Likert-type rating scale that a qualified medical personnel (ie, a clinician) will use to rate the change in severity of the participants' ability to function due to their ET since baseline. The responses to this scale range from 1 (Much improved) to 5 (Much worse). | Week 12 | 
| Proportion of Participants Reported as Much Improved on the Patient Global Impression of Change (PGI-C) at Week 12 | The PGI-C is a 5-point Likert-type rating scale that participants use to rate the change in severity of their ability to function due to ET since baseline. The responses to this scale range from 1 (Much improved) to 5 (Much worse). | Week 12 | 
| Change from Baseline to Week 12 on the TETRAS-ADL subscale as Summarized by Each Dose of JZP385 and Placebo | The TETRAS-ADL subscale is a patient-rated scale of the impact of tremor on day-to-day functioning administered by a trained interviewer. The TETRAS-ADL subscale directly measures how a patient functions by assessing activities impacted by tremor, such as eating and drinking, dressing and personal hygiene, carrying items, and fine motor skills. The TETRAS-ADL has 12 items and each item is rated on a 0 (normal) to 4 (severe) scale, with higher scores representing more severe ET. | Change from baseline to week 12 | 
| Change from Baseline to Week 12 on the TETRAS-PS Subscale as Summarized by Each Dose of JZP385 and Placebo | The TETRAS-PS is a clinical rating scale performed by a blinded rater that quantifies tremor in the head, face, voice, limbs, and trunk. Each item will be rated on a scale of 0 (normal) to 4 (severe). The sum of the individual scores provides the overall score, ranging from 0 to 64, with higher scores representing more severe ET. | Change from baseline to week 12 | 
| Change from Baseline to Week 12 on the Upper Limb Score (item 4) of the TETRAS-PS as Summarized by Each Dose of JZP385 and Placebo | Item 4 of the TETRAS-PS measures upper limb tremor, and includes 3 maneuvers for each arm that assess postural and kinetic tremor. Each item is rated on a scale of 0 (normal) to 4 (severe) in 0.5-point increments. The total score is the sum of each of the 6 items and ranges from 0 to 24, with higher scores representing more severe ET. The TETRAS-PS is performed by a blinded rater. | Change from baseline to week 12 | 
| Change from Baseline to Week 12 on the TETRAS Total Score, as Summarized by Each Dose of JZP385 and Placebo. | The TETRAS total score is the sum of the scores of the full TETRAS-ADL and TETRAS-PS subscales. Each item is rated on a 0 (normal) to 4 (severe) scale, and total scores range from 0 to 112, with higher scores representing more severe ET. The TETRAS-PS is performed by a blinded rater. | Change from baseline to week 12 | 
| Change from Baseline to Week 12 on the Quality of Life in Essential Tremor Questionnaire (QUEST) as Summarized by Each Dose of JZP385 and Placebo | The Quality of Life in Essential Tremor Questionnaire (QUEST) was developed to specifically assess the impact of ET on health-related quality of life. The QUEST is a 30-item questionnaire comprising 5 subscales (physical, psychosocial, communication, hobbies/leisure, and work/finance) and a total score, plus 3 additional items relating to sexual function and satisfaction with tremor control and medication side effects. Each item is rated by frequency on a scale from 0 (never) to 4 (always), with higher scores indicating greater dissatisfaction or disability due to ET. | Change from baseline to week 12 | 
| Change from Baseline to Week 12 on the Essential Tremor Embarrassment Assessment (ETEA) as Summarized by Each Dose of JZP385 and Placebo | The Essential Tremor Embarrassment Assessment (ETEA) is a participant-rated questionnaire administered by a health care provider or researcher that contains 14-items assessing embarrassment related to tremor. Participants provide a simple response (disagree or agree) to each of the 14-items, the sum of which yields an initial score (Score A, range = 0 to 14). Participants then provide a more nuanced response to each question on a 0 to 5 point Likert scale ranging from disagree (0) to agree strongly (5). The sum of the nuanced responses yields a second score (Score B, range = 0 to 70). Higher scores on both the simple and nuanced responses indicate greater embarrassment. | Change from Baseline to Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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JZP385, T-type calcium channels, Movement disorder, Tremor, Moderate to severe essential tremor