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

Tremor, Essential Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05234762
• Other study ID #: ES-481-C203
• Status: Recruiting
• Phase: Phase 2
• Start date: November 21, 2021
• Est. completion date: December 31, 2023

Study information

• Verified date: March 2023
• Source: ES Therapeutics Australia Pty Ltd
• Contact: Robert Niecestro, PhD
• Phone: +1-917-733-5311
• Email: rniecestro[@]estherapeutics.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 24
• Est. completion date: December 31, 2023
• Est. primary completion date: December 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Essential Tremor
• Tremor
• Tremor, Essential

Intervention

Drug:
• ES-481
Dose escalation during two Treatment Periods

Other:
• Placebo
Placebo dosed at same dosing as ES-481

Locations

Country	Name	City	State
Canada	Clinique Neuro-Levis	Levis	Quebec

Sponsors (1)

Lead Sponsor	Collaborator
ES Therapeutics Australia Pty Ltd

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Collected during 6 days throughout the study, scores to be combined.
Primary	Number of participants with abnormal laboratory test results	Collection of: Total protein	Through study completion, an average of 78 days.
Primary	Number of participants with abnormal laboratory test results	Collection of: Sodium	Through study completion, an average of 78 days.
Primary	Number of participants with abnormal laboratory test results	Collection of: Potassium	Through study completion, an average of 78 days.
Primary	Number of participants with abnormal laboratory test results	Collection of: Calcium	Through study completion, an average of 78 days.
Primary	Number of participants with abnormal laboratory test results	Collection of: Chloride	Through study completion, an average of 78 days.
Primary	Number of participants with abnormal laboratory test results	Collection of: Albumin	Through study completion, an average of 78 days.
Primary	Number of participants with abnormal laboratory test results	Collection of: Glucose	Through study completion, an average of 78 days.
Primary	Number of participants with abnormal laboratory test results	Collection of: Blood urea nitrogen (BUN)	Through study completion, an average of 78 days.
Primary	Number of participants with abnormal laboratory test results	Collection of: Creatinine	Through study completion, an average of 78 days.
Primary	Number of participants with abnormal laboratory test results	Collection of: Carbon dioxide (CO2)	Through study completion, an average of 78 days.
Primary	Number of participants with abnormal laboratory test results	Collection of: Uric acid	Through study completion, an average of 78 days.
Primary	Number of participants with abnormal laboratory test results	Collection of: Total bilirubin	Through study completion, an average of 78 days.
Primary	Number of participants with abnormal laboratory test results	Collection of: Alkaline phosphatase (AP)	Through study completion, an average of 78 days.
Primary	Number of participants with abnormal laboratory test results	Collection of: AST	Through study completion, an average of 78 days.
Primary	Number of participants with abnormal laboratory test results	Collection of: ALT	Through study completion, an average of 78 days.
Primary	Number of participants with abnormal laboratory test results	Collection of: Gamma-glutamyl transpeptidase (GGT)	Through study completion, an average of 78 days.
Primary	Number of participants with abnormal laboratory test results	Collection of: Lactate dehydrogenase (LDH)	Through study completion, an average of 78 days.
Primary	Number of participants with abnormal laboratory test results	Collection of: Creatine phosphokinase (CPK)	Through study completion, an average of 78 days.
Primary	Number of participants with abnormal laboratory test results	Collection of: Hemoglobin	Through study completion, an average of 78 days.
Primary	Number of participants with abnormal laboratory test results	Collection of: Hematocrit	Through study completion, an average of 78 days.
Primary	Number of participants with abnormal laboratory test results	Collection of: Red blood cell (RBC) count	Through study completion, an average of 78 days.
Primary	Number of participants with abnormal laboratory test results	Collection of: White blood cell (WBC) count with differential	Through study completion, an average of 78 days.
Primary	Number of participants with abnormal laboratory test results	Collection of: Mean corpuscular volume (MCV)	Through study completion, an average of 78 days.
Primary	Number of participants with abnormal laboratory test results	Collection of: Mean corpuscular hemoglobin (MCH)	Through study completion, an average of 78 days.
Primary	Number of participants with abnormal laboratory test results	Collection of: Mean corpuscular hemoglobin (MCHC)	Through study completion, an average of 78 days.
Primary	Number of participants with abnormal laboratory test results	Collection of: Absolute platelet count	Through study completion, an average of 78 days.
Primary	Safety assessments through collection of serious adverse events	Collection of Serious Adverse Events	Through study completion, an average of 78 days.
Primary	Safety assessments through collection of adverse events	Collection of Adverse Events	Through study completion, an average of 78 days.
Primary	Safety assessments through collection of treatment emergent adverse events	Collection of Treatment Emergent Adverse Events	Through study completion, an average of 78 days.
Primary	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.	Will be collected on Days 1, 22, 29, 44, 65, and 72
Secondary	Activity of Daily Living	Subjects will complete a 12-item (0-4 ratings) Activity of Daily Living questionnaire.	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
Secondary	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	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