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Efficacy, Safety, and Pharmacokinetics of ES-481 in Adult Patients With Essential Tremors

Primary Purpose

Tremor, Essential

Status
Recruiting
Phase
Phase 2
Locations
Canada
Study Type
Interventional
Intervention
ES-481
Placebo
Sponsored by
ES Therapeutics Australia Pty Ltd
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Tremor, Essential

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Written and Signed Informed Consent
  • Age 18 to 75 years old
  • The Subject must have Essential Tremor (ET). ET is defined as at least 1 upper extremity with a tremor score ≥ 1.5 in forward posture, wing beating posture, or finger-to-nose movement using the Performance subscale of The Essential Tremor Rating Assessment Scale (as per by the Tremor Investigation Group criteria).
  • Subject has a diagnosis of essential tremor, as defined by all the following criteria: (a) isolated tremor syndrome consisting of bilateral upper limb action; (b) at least three years duration; (c) with or without tremor in other location (e.g., head, voice, or lower limb).
  • The Subject must be on stable dose of anti-tremor medication in the four (4) weeks prior to screening and must willing to maintain their current dose for the duration of the study.
  • The Subject had no prior surgery for tremor.
  • The Subject had no botulinum injection for at least six (6) months prior to -screening.
  • The Subject does not have a significant imbalance or risk fall.
  • The Subject has not previously taken perampanel.

Exclusion Criteria:

Subjects will be excluded from 7-day screening period or study enrollment into the Treatment Period 1, if they meet any of the following criteria:

  • Unwilling or inability to follow the procedures specified by the protocol
  • Pregnancy or breast feeding
  • Women of child-bearing potential and men who are unable or unwilling to take adequate contraceptive precautions, including one of the following:

    • Hormonal contraception (birth control pills, injected hormones, or vaginal ring)
    • Intrauterine device
    • Barrier methods (condom or diaphragm) combined with spermicide
    • Surgical sterilization (hysterectomy, tubal ligation, or vasectomy)
  • History (within the last year) of illicit drug use or alcohol dependence or a positive screen for alcohol on the Day 1 visit, or a positive screen for drugs of abuse at Screening or at the Day 1 visit
  • Subject is unwilling or unable to refrain from alcohol 24 hours before and during clinical trial visits, or regular use of alcohol that would preclude abstinence from alcohol for time periods around visits.
  • Subject has a history of substance use disorder consistent with Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 criteria, in the opinion of the Principal Investigator,
  • Concomitant treatment with more than three drugs to treat essential tremors
  • Subject has had recent exposure (14 days prior to Day 1) to tremorgenic drugs.
  • Subject has had direct or indirect injury or trauma to the nervous system within 3 months before the onset of tremor.
  • Subject has a history or clinical evidence of other medical, neurological, or psychiatric conditions that may explain or cause tremors, including but not limited to Parkinson's disease, Huntington's disease, cerebellar disease (including spinocerebellar ataxias, primary dystonia, Fragile X Tremor/Ataxia syndrome or Family history of Fragile X syndrome, traumatic brain injury, psychogenic tremor, alcohol or benzodiazepines abuse or withdrawal, multiple sclerosis, polyneuropathy, and endocrine states such as hyperthyroidism or unstable treatment of hypothyroidism or medication, food, or supplement induced movement disorder (e.g., tremor related to beta agonists or caffeine), or other medical, neurological or psychiatric condition that may explain or cause tremors.
  • Subject has had a previous procedure for the treatment of ET, deep brain stimulation, brain lesioning, or magnetic resonance (MR)-guided procedure, e.g., MR-guided focused ultrasound.
  • Subject has historical or clinical evidence of tremor with psychogenic origin (including but not limited to eating disorders, major depression, etc.).
  • Subject has history of suicidal behavior within 2 years or is currently at risk for suicide in the opinion of the investigator.
  • Subject has any neurological abnormality other than ET upon neurological exam, including dystonia, ataxia, or any other neurodegenerative disease, including multiple sclerosis.
  • Subject has alkaline phosphatase, aspartate aminotransferase (AST), and/or alanine aminotransferase (ALT) level >3.0 x upper limit of normal (ULN) at Screening and/or at Pre-dose.
  • Subject has serum creatinine >120 μmol/L and/or creatinine clearance <60 mL/min (according to Cockcroft-Gault formula) at Screening.
  • Subject has a history of Long QT syndrome and/or QTcF (Fridericia's correction) interval >450 msec (males) or >470 msec (females) per 12-lead ECG done at Screening.
  • Subject has a diagnosis of epilepsy or any history of seizure as an adult; head trauma, stroke, transient ischemic attack within 1 year prior to Screening; unexplained loss of consciousness within 1 year prior to Screening; or any lifetime history of asymptomatic or symptomatic orthostatic hypotension (e.g., postural syncope)
  • Subject has a history of unstable angina, myocardial infarction, chronic heart failure (New York Heart Association Class 3 or 4), or clinically significant conduction abnormalities (e.g., unstable atrial fibrillation) within 1 year prior to screening.
  • Subject has any major psychiatric disorder that is uncontrolled (for the past 90 days) that, per the Investigator's judgment, can interfere with any of the study procedures.
  • Subject should not have received treatment with another investigational drug within 30 days or 5 half-lives (whichever is longer), prior to the screening visit.
  • Subject should not have received a vaccine within 60 days prior to study drug administration, except for vaccines related to Covid-19.
  • Subject should not have donated or lost more than 450mL of blood or received a transfusion of any blood or blood products within 90 days prior to screening, or donated plasma within 7 days prior to admission.
  • Subject has a known allergy to ES-481 or its excipients.

Sites / Locations

  • Clinique Neuro-LevisRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

ES-481

Placebo

Arm Description

Week 1 - 25 mg qd (2 x 25 mg capsule in the mornings Days 1 to 7 in Treatment Period 1 and Days 44 to 50 in Treatment Period 2) Week 2 - 50 mg bid (2 x 25 mg capsule in the mornings and 2 x 25 mg capsules in the evening on Days 8 to 14 in Treatment Period 1 and Days 51 to 57 in Treatment Period 2) Week 3 - 75 mg bid (2 x 25 mg capsule in the mornings and 2 x 25 mg capsules in the evening on Days 15 to 21 in Treatment Period 1 and Days 58 to 64 in Treatment Period 2) Week 4 - 75 mg bid (2 x 25 mg capsule in the mornings and 2 x 25 mg capsules in the evening on Days 22 to 28 in Treatment Period 1 and Days 65 to 71 in Treatment Period 2)

Placebo will be dosed at the same quantity and frequency as ES-481 just as Placebo HPMC capsules

Outcomes

Primary Outcome Measures

Performance Subscale of The Essential Tremor Rating Assessment Scale (TETRAS-P)
To evaluate postural and kinetic tremor of body parts affected by ET, with emphasis on upper extremity tremor. Items are scored from 0 to 4, with 4 representing the highest severity.
Number of participants with abnormal laboratory test results
Collection of: Total protein
Number of participants with abnormal laboratory test results
Collection of: Sodium
Number of participants with abnormal laboratory test results
Collection of: Potassium
Number of participants with abnormal laboratory test results
Collection of: Calcium
Number of participants with abnormal laboratory test results
Collection of: Chloride
Number of participants with abnormal laboratory test results
Collection of: Albumin
Number of participants with abnormal laboratory test results
Collection of: Glucose
Number of participants with abnormal laboratory test results
Collection of: Blood urea nitrogen (BUN)
Number of participants with abnormal laboratory test results
Collection of: Creatinine
Number of participants with abnormal laboratory test results
Collection of: Carbon dioxide (CO2)
Number of participants with abnormal laboratory test results
Collection of: Uric acid
Number of participants with abnormal laboratory test results
Collection of: Total bilirubin
Number of participants with abnormal laboratory test results
Collection of: Alkaline phosphatase (AP)
Number of participants with abnormal laboratory test results
Collection of: AST
Number of participants with abnormal laboratory test results
Collection of: ALT
Number of participants with abnormal laboratory test results
Collection of: Gamma-glutamyl transpeptidase (GGT)
Number of participants with abnormal laboratory test results
Collection of: Lactate dehydrogenase (LDH)
Number of participants with abnormal laboratory test results
Collection of: Creatine phosphokinase (CPK)
Number of participants with abnormal laboratory test results
Collection of: Hemoglobin
Number of participants with abnormal laboratory test results
Collection of: Hematocrit
Number of participants with abnormal laboratory test results
Collection of: Red blood cell (RBC) count
Number of participants with abnormal laboratory test results
Collection of: White blood cell (WBC) count with differential
Number of participants with abnormal laboratory test results
Collection of: Mean corpuscular volume (MCV)
Number of participants with abnormal laboratory test results
Collection of: Mean corpuscular hemoglobin (MCH)
Number of participants with abnormal laboratory test results
Collection of: Mean corpuscular hemoglobin (MCHC)
Number of participants with abnormal laboratory test results
Collection of: Absolute platelet count
Safety assessments through collection of serious adverse events
Collection of Serious Adverse Events
Safety assessments through collection of adverse events
Collection of Adverse Events
Safety assessments through collection of treatment emergent adverse events
Collection of Treatment Emergent Adverse Events
Plama samples for PK
Will be collected to assess the plasma concentration of ES-481 during the 28-day treatment periods from both ES-481 and Placebo subjects to estimate the PK of ES-481 After the study blind is broken, only the samples from subjects who took ES-481 will be analyzed.

Secondary Outcome Measures

Activity of Daily Living
Subjects will complete a 12-item (0-4 ratings) Activity of Daily Living questionnaire.
Subject Global Impression of Change Scale (SGIC)
Subjects will rate overall change with the Subject Global Impression of Change Scale in which change was rated between minus 3 and plus 3, with 1 connoting mild change, 2 moderate change, and 3 marked changes, with minus indicating improvement and plus worsening

Full Information

First Posted
November 27, 2021
Last Updated
March 1, 2023
Sponsor
ES Therapeutics Australia Pty Ltd
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1. Study Identification

Unique Protocol Identification Number
NCT05234762
Brief Title
Efficacy, Safety, and Pharmacokinetics of ES-481 in Adult Patients With Essential Tremors
Official Title
A Phase 2A, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of ES-481 in Adult Patients With Essential Tremors
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Recruiting
Study Start Date
November 21, 2021 (Actual)
Primary Completion Date
December 31, 2023 (Anticipated)
Study Completion Date
December 31, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
ES Therapeutics Australia Pty Ltd

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

Brief Summary
This Pilot Phase 2A study will investigate the safety, tolerability, and pharmacokinetics (PK) of ES-481 in adult patients with essential tremor.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Tremor, Essential

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
24 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
ES-481
Arm Type
Experimental
Arm Description
Week 1 - 25 mg qd (2 x 25 mg capsule in the mornings Days 1 to 7 in Treatment Period 1 and Days 44 to 50 in Treatment Period 2) Week 2 - 50 mg bid (2 x 25 mg capsule in the mornings and 2 x 25 mg capsules in the evening on Days 8 to 14 in Treatment Period 1 and Days 51 to 57 in Treatment Period 2) Week 3 - 75 mg bid (2 x 25 mg capsule in the mornings and 2 x 25 mg capsules in the evening on Days 15 to 21 in Treatment Period 1 and Days 58 to 64 in Treatment Period 2) Week 4 - 75 mg bid (2 x 25 mg capsule in the mornings and 2 x 25 mg capsules in the evening on Days 22 to 28 in Treatment Period 1 and Days 65 to 71 in Treatment Period 2)
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo will be dosed at the same quantity and frequency as ES-481 just as Placebo HPMC capsules
Intervention Type
Drug
Intervention Name(s)
ES-481
Intervention Description
Dose escalation during two Treatment Periods
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Placebo dosed at same dosing as ES-481
Primary Outcome Measure Information:
Title
Performance Subscale of The Essential Tremor Rating Assessment Scale (TETRAS-P)
Description
To evaluate postural and kinetic tremor of body parts affected by ET, with emphasis on upper extremity tremor. Items are scored from 0 to 4, with 4 representing the highest severity.
Time Frame
Collected during 6 days throughout the study, scores to be combined.
Title
Number of participants with abnormal laboratory test results
Description
Collection of: Total protein
Time Frame
Through study completion, an average of 78 days.
Title
Number of participants with abnormal laboratory test results
Description
Collection of: Sodium
Time Frame
Through study completion, an average of 78 days.
Title
Number of participants with abnormal laboratory test results
Description
Collection of: Potassium
Time Frame
Through study completion, an average of 78 days.
Title
Number of participants with abnormal laboratory test results
Description
Collection of: Calcium
Time Frame
Through study completion, an average of 78 days.
Title
Number of participants with abnormal laboratory test results
Description
Collection of: Chloride
Time Frame
Through study completion, an average of 78 days.
Title
Number of participants with abnormal laboratory test results
Description
Collection of: Albumin
Time Frame
Through study completion, an average of 78 days.
Title
Number of participants with abnormal laboratory test results
Description
Collection of: Glucose
Time Frame
Through study completion, an average of 78 days.
Title
Number of participants with abnormal laboratory test results
Description
Collection of: Blood urea nitrogen (BUN)
Time Frame
Through study completion, an average of 78 days.
Title
Number of participants with abnormal laboratory test results
Description
Collection of: Creatinine
Time Frame
Through study completion, an average of 78 days.
Title
Number of participants with abnormal laboratory test results
Description
Collection of: Carbon dioxide (CO2)
Time Frame
Through study completion, an average of 78 days.
Title
Number of participants with abnormal laboratory test results
Description
Collection of: Uric acid
Time Frame
Through study completion, an average of 78 days.
Title
Number of participants with abnormal laboratory test results
Description
Collection of: Total bilirubin
Time Frame
Through study completion, an average of 78 days.
Title
Number of participants with abnormal laboratory test results
Description
Collection of: Alkaline phosphatase (AP)
Time Frame
Through study completion, an average of 78 days.
Title
Number of participants with abnormal laboratory test results
Description
Collection of: AST
Time Frame
Through study completion, an average of 78 days.
Title
Number of participants with abnormal laboratory test results
Description
Collection of: ALT
Time Frame
Through study completion, an average of 78 days.
Title
Number of participants with abnormal laboratory test results
Description
Collection of: Gamma-glutamyl transpeptidase (GGT)
Time Frame
Through study completion, an average of 78 days.
Title
Number of participants with abnormal laboratory test results
Description
Collection of: Lactate dehydrogenase (LDH)
Time Frame
Through study completion, an average of 78 days.
Title
Number of participants with abnormal laboratory test results
Description
Collection of: Creatine phosphokinase (CPK)
Time Frame
Through study completion, an average of 78 days.
Title
Number of participants with abnormal laboratory test results
Description
Collection of: Hemoglobin
Time Frame
Through study completion, an average of 78 days.
Title
Number of participants with abnormal laboratory test results
Description
Collection of: Hematocrit
Time Frame
Through study completion, an average of 78 days.
Title
Number of participants with abnormal laboratory test results
Description
Collection of: Red blood cell (RBC) count
Time Frame
Through study completion, an average of 78 days.
Title
Number of participants with abnormal laboratory test results
Description
Collection of: White blood cell (WBC) count with differential
Time Frame
Through study completion, an average of 78 days.
Title
Number of participants with abnormal laboratory test results
Description
Collection of: Mean corpuscular volume (MCV)
Time Frame
Through study completion, an average of 78 days.
Title
Number of participants with abnormal laboratory test results
Description
Collection of: Mean corpuscular hemoglobin (MCH)
Time Frame
Through study completion, an average of 78 days.
Title
Number of participants with abnormal laboratory test results
Description
Collection of: Mean corpuscular hemoglobin (MCHC)
Time Frame
Through study completion, an average of 78 days.
Title
Number of participants with abnormal laboratory test results
Description
Collection of: Absolute platelet count
Time Frame
Through study completion, an average of 78 days.
Title
Safety assessments through collection of serious adverse events
Description
Collection of Serious Adverse Events
Time Frame
Through study completion, an average of 78 days.
Title
Safety assessments through collection of adverse events
Description
Collection of Adverse Events
Time Frame
Through study completion, an average of 78 days.
Title
Safety assessments through collection of treatment emergent adverse events
Description
Collection of Treatment Emergent Adverse Events
Time Frame
Through study completion, an average of 78 days.
Title
Plama samples for PK
Description
Will be collected to assess the plasma concentration of ES-481 during the 28-day treatment periods from both ES-481 and Placebo subjects to estimate the PK of ES-481 After the study blind is broken, only the samples from subjects who took ES-481 will be analyzed.
Time Frame
Will be collected on Days 1, 22, 29, 44, 65, and 72
Secondary Outcome Measure Information:
Title
Activity of Daily Living
Description
Subjects will complete a 12-item (0-4 ratings) Activity of Daily Living questionnaire.
Time Frame
Will be completed on Days 1 (baseline and prior to administration of study medication on Day 1 in Treatment Period 1), and Days 22, 29, 44 (baseline and prior to administration of study medication on Day 44 in Treatment Period 2), 65, and 72
Title
Subject Global Impression of Change Scale (SGIC)
Description
Subjects will rate overall change with the Subject Global Impression of Change Scale in which change was rated between minus 3 and plus 3, with 1 connoting mild change, 2 moderate change, and 3 marked changes, with minus indicating improvement and plus worsening
Time Frame
Will be completed on Days 1 (baseline and prior to administration of study medication on Day 1 in Treatment Period 1), and Days 22, 29, 44 (baseline and prior to administration of study medication on Day 44 in Treatment Period 2), 65, and 72

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Written and Signed Informed Consent Age 18 to 75 years old The Subject must have Essential Tremor (ET). ET is defined as at least 1 upper extremity with a tremor score ≥ 1.5 in forward posture, wing beating posture, or finger-to-nose movement using the Performance subscale of The Essential Tremor Rating Assessment Scale (as per by the Tremor Investigation Group criteria). Subject has a diagnosis of essential tremor, as defined by all the following criteria: (a) isolated tremor syndrome consisting of bilateral upper limb action; (b) at least three years duration; (c) with or without tremor in other location (e.g., head, voice, or lower limb). The Subject must be on stable dose of anti-tremor medication in the four (4) weeks prior to screening and must willing to maintain their current dose for the duration of the study. The Subject had no prior surgery for tremor. The Subject had no botulinum injection for at least six (6) months prior to -screening. The Subject does not have a significant imbalance or risk fall. The Subject has not previously taken perampanel. Exclusion Criteria: Subjects will be excluded from 7-day screening period or study enrollment into the Treatment Period 1, if they meet any of the following criteria: Unwilling or inability to follow the procedures specified by the protocol Pregnancy or breast feeding Women of child-bearing potential and men who are unable or unwilling to take adequate contraceptive precautions, including one of the following: Hormonal contraception (birth control pills, injected hormones, or vaginal ring) Intrauterine device Barrier methods (condom or diaphragm) combined with spermicide Surgical sterilization (hysterectomy, tubal ligation, or vasectomy) History (within the last year) of illicit drug use or alcohol dependence or a positive screen for alcohol on the Day 1 visit, or a positive screen for drugs of abuse at Screening or at the Day 1 visit Subject is unwilling or unable to refrain from alcohol 24 hours before and during clinical trial visits, or regular use of alcohol that would preclude abstinence from alcohol for time periods around visits. Subject has a history of substance use disorder consistent with Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 criteria, in the opinion of the Principal Investigator, Concomitant treatment with more than three drugs to treat essential tremors Subject has had recent exposure (14 days prior to Day 1) to tremorgenic drugs. Subject has had direct or indirect injury or trauma to the nervous system within 3 months before the onset of tremor. Subject has a history or clinical evidence of other medical, neurological, or psychiatric conditions that may explain or cause tremors, including but not limited to Parkinson's disease, Huntington's disease, cerebellar disease (including spinocerebellar ataxias, primary dystonia, Fragile X Tremor/Ataxia syndrome or Family history of Fragile X syndrome, traumatic brain injury, psychogenic tremor, alcohol or benzodiazepines abuse or withdrawal, multiple sclerosis, polyneuropathy, and endocrine states such as hyperthyroidism or unstable treatment of hypothyroidism or medication, food, or supplement induced movement disorder (e.g., tremor related to beta agonists or caffeine), or other medical, neurological or psychiatric condition that may explain or cause tremors. Subject has had a previous procedure for the treatment of ET, deep brain stimulation, brain lesioning, or magnetic resonance (MR)-guided procedure, e.g., MR-guided focused ultrasound. Subject has historical or clinical evidence of tremor with psychogenic origin (including but not limited to eating disorders, major depression, etc.). Subject has history of suicidal behavior within 2 years or is currently at risk for suicide in the opinion of the investigator. Subject has any neurological abnormality other than ET upon neurological exam, including dystonia, ataxia, or any other neurodegenerative disease, including multiple sclerosis. Subject has alkaline phosphatase, aspartate aminotransferase (AST), and/or alanine aminotransferase (ALT) level >3.0 x upper limit of normal (ULN) at Screening and/or at Pre-dose. Subject has serum creatinine >120 μmol/L and/or creatinine clearance <60 mL/min (according to Cockcroft-Gault formula) at Screening. Subject has a history of Long QT syndrome and/or QTcF (Fridericia's correction) interval >450 msec (males) or >470 msec (females) per 12-lead ECG done at Screening. Subject has a diagnosis of epilepsy or any history of seizure as an adult; head trauma, stroke, transient ischemic attack within 1 year prior to Screening; unexplained loss of consciousness within 1 year prior to Screening; or any lifetime history of asymptomatic or symptomatic orthostatic hypotension (e.g., postural syncope) Subject has a history of unstable angina, myocardial infarction, chronic heart failure (New York Heart Association Class 3 or 4), or clinically significant conduction abnormalities (e.g., unstable atrial fibrillation) within 1 year prior to screening. Subject has any major psychiatric disorder that is uncontrolled (for the past 90 days) that, per the Investigator's judgment, can interfere with any of the study procedures. Subject should not have received treatment with another investigational drug within 30 days or 5 half-lives (whichever is longer), prior to the screening visit. Subject should not have received a vaccine within 60 days prior to study drug administration, except for vaccines related to Covid-19. Subject should not have donated or lost more than 450mL of blood or received a transfusion of any blood or blood products within 90 days prior to screening, or donated plasma within 7 days prior to admission. Subject has a known allergy to ES-481 or its excipients.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Robert Niecestro, PhD
Phone
+1-917-733-5311
Email
rniecestro@estherapeutics.com
Facility Information:
Facility Name
Clinique Neuro-Levis
City
Levis
State/Province
Quebec
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Manon Bouchard

12. IPD Sharing Statement

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Efficacy, Safety, and Pharmacokinetics of ES-481 in Adult Patients With Essential Tremors

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