A Clinical Trial of PRAX-944 in Participants With Essential Tremor

Study Overview
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Brief Summary
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This is a 2-part clinical trial to evaluate the efficacy, safety, and tolerability of 40 and 120 mg oral PRAX-944 compared to placebo in the treatment of adults with essential tremor. Part A is designed to study the dose titration from 20 to 40 mg every morning (QAM) (ie, 2 weeks with 7 days at each dose level). Part B is designed to study the dose titration from 20 to up to 120 mg QAM with at least 14 days of dosing at the highest tolerated dose for each participant. Blood levels of PRAX-944 will also be measured throughout the trial and pharmacokinetics will be evaluated.

Official Title
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A Phase 2 Clinical Trial Evaluating the Efficacy, Safety, Tolerability, and Pharmacokinetics of PRAX-944 in Adults With Essential Tremor

Conditions
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Essential Tremor

Intervention / Treatment
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* Drug: Part A: 20 and 40 mg PRAX-944
* Drug: Part B: 120 mg PRAX-944
* Drug: Part B: 120 mg PRAX-944 and Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis of ET consistent with Movement Disorders Society Criteria, a duration of ET of at least 3 years and with onset before the age of 65 TETRAS upper limb score (ie, sum of bilateral upper limb items 4a, 4b, and 4c) of ≥10 as rated by the Investigator at Screening and Baseline OR A score of ≥2 on 2 or more of the following TETRAS activities of daily living (ADL) subscale items: (2) Feeding with a spoon, (3) Drinking from a glass, (5) Dressing, (6) Pouring, (9) Writing OR A score of ≥2 on 1 of the following TETRAS ADL subscale items: (2) Feeding with a spoon, (3) Drinking from a glass, (5) Dressing, (6) Pouring, or (9) Writing AND a score of ≥2 on both of the following TETRAS ADL subscale items: (10) Working and (12) Social Impact If currently receiving any medication for ET, is on a stable dose of any of these medications for ET for 28 days prior to Screening and is willing to maintain stable doses throughout the trial. If receiving primidone for ET, is willing and able to discontinue 14 days prior to Day 1. Body mass index (BMI) between 18 and 40 kg/m2 (inclusive). Exclusion Criteria: Sporadically using a benzodiazepine, sleep medication, or anxiolytic that would confound the assessment of tremor. Trauma to the nervous system within 3 months preceding the onset of tremor. History of other medical, neurological or psychiatric condition that may explain or cause tremor, including but not limited to Parkinson's disease, dystonia, cerebellar disease, family history of Fragile X syndrome, traumatic brain injury, alcohol abuse or withdrawal, benzodiazepine abuse or withdrawal, multiple sclerosis, polyneuropathy, and endocrine states such as hyperthyroidism. Prior magnetic resonance-guided focused ultrasound or surgical intervention for ET such as deep brain stimulation or thalamotomy. Botulinum toxin injection for ET in the 6 months prior to Screening. Unwilling or unable to refrain from alcohol 24 hours before and during clinical trial visits. History of substance use disorder

Ages Eligible for Study
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Minimum Age: 18 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
Interventional Model Description: Part A: Single group Part B: Parallel group, randomized withdrawal
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: Open-label 20 and 40 mg PRAX-944<br>Once daily, oral dosing with 7 days of 20 mg and 7 days of 40 mg | Drug: Part A: 20 and 40 mg PRAX-944<br>* Once daily oral treatment<br>|
| Experimental: Part B: Open-label titration PRAX-944 (120 mg) followed by blinded PRAX-944<br>Once daily, oral dosing with titration to 120 mg: 3 days of 20 mg, 4 days of 40 mg, 7 days of 60 mg, 7 days of 80 mg, 7 days of 100 mg, 28 days of 120 mg | Drug: Part B: 120 mg PRAX-944<br>* Once daily oral treatment with titration<br>|
| Active Comparator: Part B: Open-label titration PRAX-944 (120 mg) followed by blinded placebo<br>Once daily, oral dosing with titration to 120 mg: 3 days of 20 mg, 4 days of 40 mg, 7 days of 60 mg, 7 days of 80 mg, 7 days of 100 mg, 14 days of 120 mg, 14 days placebo | Drug: Part B: 120 mg PRAX-944 and Placebo<br>* Once daily oral treatment with titration followed by placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Change from baseline to Day 7 and Day 14 in the Essential Tremor Rating Assessment Scale (TETRAS) upper limb score | The TETRAS is a performance and activities of daily living (ADL) rating scale. The full scale has 2 sections, the Performance subscale (PS) and the ADL subscale. The PS consists of 9 items covering different body regions. The TETRAS upper limb score is item 4 of the TETRAS PS. This item is rated on a 5-point scale (ranging from 0 to 4). This item consists of ratings for 3 tasks rated separately for upper limbs on both sides of the body for a total of 6 ratings. The total score of the item ranges from 0 to 24 with higher scores indicating greater tremor severity. | 7 days, 14 days | 
| Part B: Incidence and severity of Adverse Events (AE) | An AE is any untoward medical occurrence in a clinical trial participant, temporally associated with the use of study drug, whether or not considered related to the study drug. | 56 days | 
| Part B: Incidence of AEs by preferred term | The incidence of AEs will be reported by preferred term, including any terms related to clinically significant changes in body temperature, pulse rate, respiratory rate, blood pressure (systolic and diastolic), clinical laboratory measures (chemistry, hematology, urinalysis, and coagulation), electrocardiogram parameters (heart rate, PR, QRS, QT, and corrected QT intervals), and Columbia-Suicide Severity Rating Scale (C-SSRS) responses. | 56 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Change from baseline to Day 7 and Day 14 on the Essential Tremor Rating Assessment Scale (TETRAS) Performance subscale | The TETRAS is an essential tremor and activities of daily living rating scale. The full scale has 2 sections, the Performance subscale (PS) and the ADL subscale. The PS consists of 9 items covering different body regions. These 9 items are rated on a 5-point scale (ranging from 0 to 4). One item, Item 4, consists of ratings for 3 tasks rated separately for upper limbs on both sides of the body for a total of 6 ratings. The total score of the 9 items (14 ratings) ranges from 0 to 70 with higher scores indicating greater tremor severity. The total score and individual item ratings will be evaluated as outcomes in this trial. | 7 days, 14 days | 
| Part A: Change from baseline to Day 7 and Day 14 in the Essential Tremor Rating Assessment Scale (TETRAS) upper limb score measured by accelerometry | The TETRAS is an essential tremor and activities of daily living (ADL) rating scale. The full scale has 2 sections, the Performance subscale (PS) and the ADL subscale. The PS consists of 9 items covering different body regions. The TETRAS upper limb score is item 4 of the upper limb body region. This item is rated on a 5-point scale (ranging from 0 to 4). This item consists of ratings for 3 tasks rated separately for upper limbs on both sides of the body for a total of 6 ratings. The total score of the item ranges from 0 to 24 with higher scores indicating greater tremor severity. This outcome will be measured by accelerometry with measurements of rotations and accelerations in 3D space over time converted into ratings according to the scale outlined above. | 7 days, 14 days | 
| Part A: Incidence of AEs by preferred term | The incidence of AEs will be reported by preferred term, including any terms related to clinically significant changes in body temperature, pulse rate, respiratory rate, blood pressure (systolic and diastolic), clinical laboratory measures (chemistry, hematology, urinalysis, and coagulation), electrocardiogram parameters (heart rate, PR, QRS, QT, and corrected QT intervals), and Columbia-Suicide Severity Rating Scale (C-SSRS) responses. | 14 days | 
| Part A: Incidence and severity of Adverse Events (AE) | An AE is any untoward medical occurrence in a clinical trial participant, temporally associated with the use of study drug, whether or not considered related to the study drug. | 14 days | 
| Part B: Change from baseline to Day 42 in the Essential Tremor Rating Assessment Scale (TETRAS) upper limb score | The TETRAS is an essential tremor and activities of daily living (ADL) rating scale. The full scale has 2 sections, the Performance subscale (PS) and the ADL subscale. The PS consists of 9 items covering different body regions. The TETRAS upper limb score is item 4 of the upper limb body region. This item is rated on a 5-point scale (ranging from 0 to 4). This item consists of ratings for 3 tasks rated separately for upper limbs on both sides of the body for a total of 6 ratings. The total score of the item ranges from 0 to 24 with higher scores indicating greater tremor severity. | 42 days | 
| Part B: Change from baseline to Day 7 and Day 21 in the Essential Tremor Rating Assessment Scale (TETRAS) upper limb score | The TETRAS is an essential tremor and activities of daily living (ADL) rating scale. The full scale has 2 sections, the Performance subscale (PS) and the ADL subscale. The PS consists of 9 items covering different body regions. The TETRAS upper limb score is item 4 of the upper limb body region. This item is rated on a 5-point scale (ranging from 0 to 4). This item consists of ratings for 3 tasks rated separately for upper limbs on both sides of the body for a total of 6 ratings. The total score of the item ranges from 0 to 24 with higher scores indicating greater tremor severity. | 7 days, 21 days | 
| Part B: Change from baseline to Day 7, Day 21, and Day 42 on the Essential Tremor Rating Assessment Scale (TETRAS) Performance subscale | The TETRAS is an essential tremor and activities of daily living rating scale. The full scale has 2 sections, the Performance subscale (PS) and the ADL subscale. The PS consists of 9 items covering different body regions. These 9 items are rated on a 5-point scale (ranging from 0 to 4). One item, Item 4, consists of ratings for 3 tasks rated separately for upper limbs on both sides of the body for a total of 6 ratings. The total score of the 9 items (14 ratings) ranges from 0 to 70 with higher scores indicating greater tremor severity. The total score and individual item ratings will be evaluated as outcomes in this trial. | 7 days, 21 days, 42 days | 
| Part B: Change from baseline to Day 7, Day 21, and Day 42 in the Essential Tremor Rating Assessment Scale (TETRAS) upper limb score measured by accelerometry | The TETRAS is an essential tremor and activities of daily living (ADL) rating scale. The full scale has 2 sections, the Performance subscale (PS) and the ADL subscale. The PS consists of 9 items covering different body regions. The TETRAS upper limb score is item 4 of the upper limb body region. This item is rated on a 5-point scale (ranging from 0 to 4). This item consists of ratings for 3 tasks rated separately for upper limbs on both sides of the body for a total of 6 ratings. The total score of the item ranges from 0 to 24 with higher scores indicating greater tremor severity. This outcome will be measured by accelerometry with measurements of rotations and accelerations in 3D space over time converted into ratings according to the scale outlined above. | 7 days, 21 days, 42 days | 
| Part B: Change from baseline to Day 7, Day 21, and Day 42 on the TETRAS Activities of Daily Living (ADL) score | The TETRAS is an essential tremor and ADL rating scale. The full scale has 2 sections, the Performance subscale and the ADL subscale. The ADL subscale consists of 12 items measuring the impact of essential tremor on typical daily activities. These 12 items are rated on a 5-point scale (ranging from 0 to 4). The total score of the 12 items ranges from 0 to 60 with higher scores indicating greater tremor severity. | 7 days, 21 days, 42 days | 
| Part B: Change from baseline to Day 7, Day 21, and Day 42 on the Quality of Life in Essential Tremor Questionnaire (QUEST) total and subscale scores. | The QUEST is a brief, 30-item, patient-reported ET-specific quality of life scale. The scale contains 5 subscales that cover physical, psychosocial, communication, hobbies/leisure, and work/finance dimensions. The individual items are rated either on a 5-level Likert scale from 0 to 4 (never, rarely, sometimes, frequently, always) or a 2-level scale from 0 (no) to 4 (yes) relative to the respondent's current situation. Five items could also be rated as not applicable. Respondents are also asked to indicate which tremor was perceived to impact a function or be associated with the feeling or attitude in question. The QUEST total and subscale scores are calculated as the sum of all applicable items divided by the number of applicable items times 100. Higher scores indicate greater impact of tremor on quality of life. | 7 days, 21 days, 42 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Movement Disorder, Benign Essential Tremor, Familial Tremor, Hereditary Essential Tremor, Movement Disorder Agents, Calcium Channels, T-type