A Clinical Study to Evaluate CAD-1883 in Essential Tremor
A Clinical Study to Evaluate CAD-1883 in Essential Tremor
This is an open-label study designed to evaluate the safety, tolerability and efficacy of
 CAD-1883, a positive allosteric modulator of the SK channel, administered twice daily orally
 to adult patients with ET. Patients with the diagnosis of ET based on the Movement Disorder
 Society (MDS) criteria with a documented severity of tremor based on the
 clinician-administered TETRAS Performance Subscale are eligible to be enrolled in the study.
This is an open-label study designed to evaluate the safety, tolerability and efficacy of
 CAD-1883, a positive allosteric modulator (PAM) of the SK channel, administered twice daily
 orally to adult subjects with ET. Positive modulation of the small-conductance
 calcium-activated potassium channels (SK) present in different regions of the brain aims to
 increase the channel sensitivity to calcium resulting in reduction in neuronal firing rate.
 In patients with ET, improving the regularity of firing of action potentials in the
 olivo-cerebellar network can lead to improvement in motor function.

 During the Screening period, each subject will undergo full assessment including medical and
 treatment history for ET, physical examination and other screening assessments. Patients with
 the diagnosis of ET based on the Movement Disorder Society (MDS) criteria with a documented
 severity of tremor based on the clinician-administered TETRAS Performance Subscale are
 eligible to be enrolled in the study. The study consists of treatment groups receiving twice
 daily oral dosing of CAD-1883 for a treatment period of 14 days.

 This study is designed to enable the assessment of safety and tolerability of CAD-1883 in
 patients with ET as well as the determination of early treatment effect on reducing the
 magnitude and severity of tremor while limiting the potential risk associated with a novel
 investigational drug.

 Safety and tolerability will be monitored throughout the study duration including in-clinic
 assessments of adverse events (AEs), serious adverse events (SAEs), vital signs, 12-lead ECG,
 urinalysis, hematology, clinical chemistry, and CAD-1883 plasma concentration level on Days
 1, 7, 14 and 21.

 Efficacy will be evaluated using the clinician-administered TETRAS Performance Subscale as
 well as the use of a wearable sensor in the clinic and at home.
Inclusion Criteria:

 1. Adult subjects aged between 18 and 75 years old, inclusive, with history of tremor
 that fulfills the diagnostic criteria of ET according to Movement Disorder Society
 (MDS) Consensus Statement on the classification of tremors from the task force on
 tremor of the International Parkinson and Movement Disorder Society (Bhatia, 2018).

 2. Duration of ET illness since the first symptoms were noticeable of at least 3 years or
 more prior to screening, based on the subject's self-report, with onset prior to age
 65 years old, per the Principal Investigator's assessment during screening.

 3. Except for ET, subjects must be otherwise healthy as determined by the Investigator,
 based upon a medical evaluation including medical history, physical examination,
 laboratory tests, and 12-lead ECG.

 4. Subjects are able to understand study activities required, can give written informed
 consent, and are willing to comply with the requirements and restrictions of the
 study.

 5. Women of childbearing potential must undertake a pregnancy test with documented
 negative serum pregnancy test at Screening and negative urine pregnancy test result at
 Pre-dose, Days 7 and 14 before administration of the study drug, and then at the
 Follow-up visit (Day 21).

 6. Postmenopausal women must have had ≥365 days of spontaneous amenorrhea, with
 documented follicle-stimulating hormone (FSH) ≥38 IU/mL, prior to screening. If
 needed, per Investigator's judgment, FSH level can be performed at Screening.

 7. Surgically sterile women must have documentation of a hysterectomy, bilateral
 ovariectomy, or bilateral tubal ligation.

 8. Female subjects with reproductive potential and male subjects with reproductive
 potential or who have female partners of reproductive potential, must agree to use two
 effective methods of contraception from signing informed consent until 90 days after
 the last dose of study drug. Acceptable forms of contraception include double barrier
 (ie, condom with spermicide); surgically sterilized partner (180-day minimum); or
 abstinence.

 Exclusion Criteria:

 1. Prior or ongoing medical condition or any abnormal finding on the Screening visit
 physical exam, ECG, laboratory testing that, in the Investigator's opinion, could
 adversely affect the safety of the subject or the conduct of the study assessments.

 2. Any neurological abnormality other than ET upon neurological exam, including dystonia,
 ataxia, or any other neurodegenerative disease, including multiple sclerosis or
 Parkinson's disease.

 3. Significant cognitive impairment or dementia that, in the opinion of the Investigator,
 would interfere with participation in the study.

 4. An unstable thyroid condition that, per the Investigator's judgment, has not
 stabilized over the past 90 days prior to screening. This includes current clinical
 history of hypo- or hyperthyroidism, thyrotoxicosis or significant abnormality of
 thyroid function testing at Screening.

 5. History of, or evidence of psychogenic tremor at Screening.

 6. History of anaphylaxis, hypersensitivity reactions (including to any of CAD-1883
 excipients), or clinically significant drug allergies.

 7. Alkaline phosphatase, aspartate aminotransferase (AST), and/or alanine
 aminotransferase (ALT) level >2.0 x upper limit of normal (ULN) at Screening and/or at
 Pre-dose.

 8. Serum creatinine >120 μmol/L and/or creatinine clearance <60 mL/min (according to
 Cockcroft-Gault formula) at Screening and/or at Pre-dose.

 9. Total bilirubin >2.0 x ULN at Screening and/or at Pre-dose. Note: isolated bilirubin
 >2.0 x ULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%.

 10. 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.

 11. History of Alcohol Use Disorder per Diagnostic Statistical Manual of Mental Disorders,
 Fifth Edition (DSM-V) criteria.

 12. History of human immunodeficiency virus (HIV) infection or positive screening result
 for: HIV 1 or 2 antibodies, hepatitis B surface antigen (HBsAg) or hepatitis B core
 antibody (HBcAb), or hepatitis C virus antibody (HCVAb).

 13. 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 (eg, postural syncope).

 14. History of unstable angina, myocardial infarction, chronic heart failure (New York
 Heart Association Class 3 or 4), or clinically significant conduction abnormalities
 (eg, unstable atrial fibrillation) within 1 year prior to screening.

 15. 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.

 16. Subject has cancer, except for the following: basal cell carcinoma or successfully
 treated squamous cell carcinoma of the skin; cervical carcinoma in situ; prostatic
 carcinoma in situ; or other malignancies curatively treated and with no evidence of
 disease recurrence for at least 3 years.

 17. Subjects with scheduled surgeries during the study period.