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

Essential Tremor Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05021978
• Other study ID #: PRAX-944-221
• Status: Completed
• Phase: Phase 2
• Start date: March 3, 2020
• Est. completion date: March 24, 2022

Study information

• Verified date: January 2024
• Source: Praxis Precision Medicines
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 24
• Est. completion date: March 24, 2022
• Est. primary completion date: March 24, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. 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

2. 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

3. 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.

4. Body mass index (BMI) between 18 and 40 kg/m2 (inclusive).

Exclusion Criteria:

1. Sporadically using a benzodiazepine, sleep medication, or anxiolytic that would confound the assessment of tremor.

2. Trauma to the nervous system within 3 months preceding the onset of tremor.

3. 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.

4. Prior magnetic resonance-guided focused ultrasound or surgical intervention for ET such as deep brain stimulation or thalamotomy.

5. Botulinum toxin injection for ET in the 6 months prior to Screening.

6. Unwilling or unable to refrain from alcohol 24 hours before and during clinical trial visits.

7. History of substance use disorder

Related Conditions & MeSH terms

• Essential Tremor
• Tremor

Intervention

Drug:
• Part A: 20 and 40 mg PRAX-944
Once daily oral treatment
• Part B: 120 mg PRAX-944
Once daily oral treatment with titration
• Part B: 120 mg PRAX-944 and Placebo
Once daily oral treatment with titration followed by placebo

Locations

Country	Name	City	State
Australia	Praxis Research Site	Fitzroy	Victoria
Australia	Praxis Research Site	Melbourne	Victoria
Australia	Praxis Research Site	New Lambton Heights	New South Whales
Australia	Praxis Research Site	Parkville	Victoria
Australia	Praxis Research Site	Southport	Queensland
New Zealand	Praxis Research Site	Christchurch
New Zealand	Praxis Research Site	Grafton	Auckland
United States	Praxis Research Site	Port Charlotte	Florida
United States	Praxis Research Site	Spokane	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Praxis Precision Medicines

Countries where clinical trial is conducted

United States,  Australia,  New Zealand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part A: Change From Baseline in Essential Tremor Rating Assessment Scale (TETRAS) Upper Limb Score	The TETRAS upper limb score is calculated as the sum of the 6 separate upper-limb maneuvers assessed by the clinician: forward-outstretched postural tremor [right], forward outstretched postural tremor [left], lateral wing-beating postural tremor [right], lateral wing-beating postural tremor [left], kinetic tremor [right], kinetic tremor [left], each on a 0 (no tremor) to 4 (maximum tremor) severity scale in 0.5-point increments. TETRAS Part 4 score for both upper limbs ranged from 0 to 24, higher scores indicated more severe tremor. A negative change from baseline indicated less tremor. Baseline is defined as the last non-missing value collected prior to receiving first dose of study drug. Change from baseline will be defined as assessment value minus baseline value.	Baseline (Day 0), Days 7 and 14
Primary	Part B: Number of Participants With Adverse Events (AE), Related AE, and AE Leading to Treatment Discontinuation	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. Incidence and Severity of Adverse Events have been reported.	Up to Day 70
Primary	Part B: Number of Participants With Clinically Significant Abnormalities in Vital Signs, Laboratory Values and Electrocardiogram Parameters	Vital signs parameters included 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). Any change in vital sign abnormalities that was clinically significant in the medical and scientific judgment of the investigator and not related to an underlying disease was reported as an unsolicited adverse event (AE). Any clinically significant abnormality associated with underlying disease does not require reporting as an (S)AE unless judged by the investigator to be more severe than expected for the participant's condition.	Up to Day 70
Primary	Part B: Number of Participants With Suicidal Ideation or Behavior Assessed Using Columbia Suicide Severity Rating Scale (C-SSRS)	The C-SSRS is described as a scale developed at Columbia University that has 2-6 questions each in categories of Suicidal Ideation, Intensity of Ideation, Suicidal Behavior, and Actual Attempts. Four constructs were measured. Severity of Suicidal ideation is rated on a 5-point ordinal scale. Intensity of ideation is comprised of 5 items (frequency, duration, controllability, deterrents, and reason for ideation), each rated on a 5-point ordinal scale. Suicidal behavior is rated on a nominal scale that includes actual, aborted, and interrupted attempts; preparatory behavior; and non-suicidal self-injurious behavior. Lethality, assesses actual attempts; actual lethality is rated on a 6-point ordinal scale, and if actual lethality is 0, potential lethality of attempts is rated on a 3-point ordinal scale.The higher the C-SSRS score, the higher the suicide risk (ie. worse outcome).	Up to Day 70
Secondary	Part A: Change From Baseline in 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. Baseline is defined as the last non-missing value collected prior to receiving first dose of study drug.	Baseline (Day 0), Days 7 and 14
Secondary	Part A: Change From Baseline in Essential Tremor Rating Assessment Scale (TETRAS) Upper Limb Score Measured by Accelerometry	Accelerometer was used to evaluate record coordinates and accelerations in the 3D space over time. The 3 maneuvers in the upper limb item will be completed for both arms, first for the right arm and then for the left. Each upper limb sub-item is scored on a scale from 0 to 4 including to 0.1 increments. The accelerometer upper limb total score, ranges from 0 to 24. A decrease in score is indicative of improvement. Baseline is defined as the last non-missing value collected prior to receiving first dose of study drug. Change from baseline will be defined as assessment value minus baseline value.	Baseline (Day 0), Days 7 and 14
Secondary	Part A: Change From Baseline in Essential Tremor Rating Assessment Scale (TETRAS) Performance Subscale Individual Items # 6 (Spiral Drawing) and Items #7 (Handwriting)	The TETRAS ADL subscale is a 12-item assessment of typical daily activities that are impacted by tremor. Activities are assessed in the following functional domains: speaking, feeding, drinking, personal hygiene, dressing, writing, and social activity. The impact to each function is rated on a 5-point Likert scale from 0 to 4. The ADL subscale score is calculated as the sum of all 12 items and ranges from 0 to 48 with higher scores reflecting higher impact. Baseline is defined as the last non-missing value collected prior to receiving first dose of study drug. Change from baseline will be defined as assessment value minus baseline value.	Baseline (Day 0), Days 7 and 14
Secondary	Part A: Number of Participants With Adverse Events (AE), Related AE, and AE Leading to Treatment Discontinuation	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. Incidence and Severity of Adverse Events have been reported.	Up to Day 21
Secondary	Part A: Number of Participants With Clinically Significant Abnormalities in Vital Signs, Laboratory Values and Electrocardiogram Parameters	Vital signs parameters included 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). Any change in vital sign abnormalities that was clinically significant in the medical and scientific judgment of the investigator and not related to an underlying disease was reported as an unsolicited adverse event (AE). Any clinically significant abnormality associated with underlying disease does not require reporting as an (S)AE unless judged by the investigator to be more severe than expected for the participant's condition.	Up to Day 21
Secondary	Part A: Number of Participants With Suicidal Ideation or Behavior Assessed Using Columbia Suicide Severity Rating Scale (C-SSRS)	The C-SSRS is described as a scale developed at Columbia University that has 2-6 questions each in categories of Suicidal Ideation, Intensity of Ideation, Suicidal Behavior, and Actual Attempts. Four constructs were measured. Severity of Suicidal ideation is rated on a 5-point ordinal scale. Intensity of ideation is comprised of 5 items (frequency, duration, controllability, deterrents, and reason for ideation), each rated on a 5-point ordinal scale. Suicidal behavior is rated on a nominal scale that includes actual, aborted, and interrupted attempts; preparatory behavior; and non-suicidal self-injurious behavior. Lethality, assesses actual attempts; actual lethality is rated on a 6-point ordinal scale, and if actual lethality is 0, potential lethality of attempts is rated on a 3-point ordinal scale.The higher the C-SSRS score, the higher the suicide risk (ie. worse outcome).	Up to Day 21
Secondary	Part B: Change From Baseline in Essential Tremor Rating Assessment Scale (TETRAS) Upper Limb Score During OLT Phase	The TETRAS upper limb score is calculated as the sum of the 6 separate upper-limb maneuvers assessed by the clinician: forward-outstretched postural tremor [right], forward outstretched postural tremor [left], lateral wing-beating postural tremor [right], lateral wing-beating postural tremor [left], kinetic tremor [right], kinetic tremor [left], each on a 0 (no tremor) to 4 (maximum tremor) severity scale in 0.5-point increments. TETRAS Part 4 score for both upper limbs ranged from 0 to 24, higher scores indicated more severe tremor. A negative change from baseline indicated less tremor. Baseline is defined as the last non-missing value collected prior to receiving first dose of study drug. Change from baseline will be defined as assessment value minus baseline value.	Baseline (Day 0) and Day 42
Secondary	Part B: Change From Baseline in Essential Tremor Rating Assessment Scale (TETRAS) Upper Limb Score During OLT Phase	The TETRAS upper limb score is calculated as the sum of the 6 separate upper-limb maneuvers assessed by the clinician: forward-outstretched postural tremor [right], forward outstretched postural tremor [left], lateral wing-beating postural tremor [right], lateral wing-beating postural tremor [left], kinetic tremor [right], kinetic tremor [left], each on a 0 (no tremor) to 4 (maximum tremor) severity scale in 0.5-point increments. TETRAS Part 4 score for both upper limbs ranged from 0 to 24, higher scores indicated more severe tremor. A negative change from baseline indicated less tremor. Baseline is defined as the last non-missing value collected prior to receiving first dose of study drug. Change from baseline will be defined as assessment value minus baseline value.	Baseline (Day 0), Days 7 and 21
Secondary	Part B: Change From Baseline in Essential Tremor Rating Assessment Scale (TETRAS) Performance Subscale During OLT Phase	TETRAS Performance Subscale was used to assess essential tremor as scored by the independent video raters. The performance subscale consists of 9 items, i.e. item 1 (head), item 2 (face), item 3 (voice), each of the 6 sub-items for item 4 (upper limb), the maximum of the 4 sub-items for item 5 (lower limb), 2 sub-items (right and left side) for item 6 (Archimedes spirals), item 7 (handwriting), 2 sub-items (right and left side) for item 8 (dot approximation), and item 9 (standing) for a total score ranging from 0 to 64 from 16 sub-items. Each item is rated on a scale of 0 to 4, including 0.5 increments. A lower score is indicative of improvement. The total score has been presented. Baseline is defined as the last non-missing value collected prior to receiving first dose of study drug. Change from baseline will be defined as assessment value minus baseline value.	Baseline (Day 0) and Days 7, 21 and 42
Secondary	Part B: Change From Baseline in Essential Tremor Rating Assessment Scale (TETRAS) Upper Limb Score Measured by Accelerometry During OLT Phase	Accelerometer was used to evaluate record coordinates and accelerations in the 3D space over time. The 3 maneuvers in the upper limb item will be completed for both arms, first for the right arm and then for the left. Each upper limb sub-item is scored on a scale from 0 to 4 including to 0.1 increments. The accelerometer upper limb total score, ranges from 0 to 24. A decrease in score is indicative of improvement. Baseline is defined as the last non-missing value collected prior to receiving first dose of study drug. Change from baseline will be defined as assessment value minus baseline value.	Baseline (Day 0), and Days 7, 21 and 42
Secondary	Part B: Change From Baseline in TETRAS Performance Subscale Individual Items # 6 (Spiral Drawing) and Items #7 (Handwriting)	TETRAS Performance Subscale was used to assess essential tremor as scored by the independent video raters. The performance subscale consists of 9 items, i.e. item 1 (head), item 2 (face), item 3 (voice), each of the 6 sub-items for item 4 (upper limb), the maximum of the 4 sub-items for item 5 (lower limb), 2 sub-items (right and left side) for item 6 (Archimedes spirals), item 7 (handwriting), 2 sub-items (right and left side) for item 8 (dot approximation), and item 9 (standing) for a total score ranging from 0 to 64 from 16 sub-items. Each item is rated on a scale of 0 to 4, including 0.5 increments. A lower score is indicative of improvement. Baseline is defined as the last non-missing value collected prior to receiving first dose of study drug. Change from baseline will be defined as assessment value minus baseline value.	Baseline (Day 0), Days 7, 21 and 42
Secondary	Part B: Change From Baseline in TETRAS Activities of Daily Living (ADL) Score	The TETRAS ADL subscale is a 12-item assessment of typical daily activities that are impacted by tremor. Activities are assessed in the following functional domains: speaking, feeding, drinking, personal hygiene, dressing, writing, and social activity. The impact to each function is rated on a 5-point Likert scale from 0 to 4. The ADL subscale score is calculated as the sum of all 12 items and ranges from 0 to 48 with higher scores reflecting higher impact. Baseline is defined as the last non-missing value collected prior to receiving first dose of study drug. Change from baseline will be defined as assessment value minus baseline value.	Baseline (Day 0), Days 7, 21 and 42
Secondary	Part B: Change From Baseline in Quality of Life in Essential Tremor Questionnaire (QUEST) Total Scores.	Quality of Life in Essential Tremor Questionnaire (QUEST) is a patient-reported ET-specific 30-item, specific quality of life scale. Items contribute to five dimensions. Physical/ADL (9 items ), Psychosocial (9 items), Communication (3 items), Hobbies/Leisure (3 items), and Work/Finances (6 items). 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 score indicates greater dissatisfaction with that domain of QOL. Maximal score 100: worse quality of life. Minimal Score 0: best quality of life. Baseline is defined as the last non-missing value collected prior to receiving first dose of study drug. Change from baseline will be defined as assessment value minus baseline value.	Baseline (Day 0), Days 7, 21 and 42