A Phase 2 RCT Study of CX-8998 for Essential Tremor
Condition: Essential Tremor
MeSH terms: Tremor; Essential Tremor
Intervention: CX-8998; Placebo
Intervention description: T-type calcium channel blocker; Placebo comparator
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: This is a double-blind, placebo-controlled, parallel-group study.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 95.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Essential Tremor; Movement Disorders; thalamocortical dysrhythmias

Summary:

      This is a multicenter, double-blind, placebo-controlled, parallel-group study consisting of a
      screening period of up to 4 weeks (with the exception of participants on primidone at
      baseline who will be allowed 6 weeks of screening to allow for safe discontinuation).
      Screening results from all patients meeting the eligibility requirements will be further
      assessed by the sponsor medical personnel for final approval of suitability for inclusion in
      the study. Randomized participants will enter a 4 week double-blind dose-titration treatment
      period, followed by a 1 week safety follow-up period following the last dose of study
      medication, and a scheduled follow-up safety telephone call one week later.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Signed informed consent form indicating that the subject has been informed of the
             procedures to be followed, the experimental nature of the therapy, alternatives,
             potential benefits, side effects, risks, and discomforts.

          2. Men or non-pregnant, non-breastfeeding women 18 to 75 years-of-age who are able to
             read and understand English.

          3. Diagnosis of definite or probable essential tremor (ET) as defined by the Tremor
             Investigational Group with involvement of the hands and arms without present causes of
             enhanced physiologic tremor (Deuschl et al.,1998).

          4. Diagnosis of ET before the age of 65.

          5. Tremor severity score of at least 2 in at least one upper extremity on at least one of
             the three maneuvers on the TETRAS scale.

          6. Total TETRAS performance score of at least 15.

          7. One concomitant anti-tremor medication (other than primidone) is allowed. Note:
             Primidone is NOT an allowed anti-tremor medication. If on primidone, subjects are
             allowed to extend their screening period by 2 weeks (for a total of 6 weeks) and
             discontinue primidone under the supervision of the investigator.

          8. Subjects with reproductive capability including all males and women of child-bearing
             potential (WOCBP) must agree to practice continuous abstinence or adequate
             contraception methods (appropriate double barrier method or oral, patch, implant, or
             injectable contraception) from as soon as feasible during screening period until at
             least 30 days after the last dose.

          9. Approval by the sponsor medical personnel as to final suitability for the study.

        Exclusion Criteria:

          1. Exposure to tremorigenic drugs or drug withdrawal states within the 30 days prior to
             the first planned dose of study drug.

          2. Direct or indirect trauma to the nervous system within 3 months preceding the onset of
             tremor

          3. History or clinical evidence of psychogenic tremor origin

          4. Known history of other medical or neurological conditions that may cause or explain
             subject's tremor, including, but not limited to: a. Parkinson's disease b. dystonia c.
             cerebellar disease, other than essential tremor d. Traumatic Brain Injury e. alcohol
             abuse or withdrawal f. mercury poisoning g. hyperthyroidism h. pheochromocytoma i.
             head trauma or cerebrovascular disease within 3 months prior to the onset of essential
             tremor j. multiple sclerosis k. polyneuropathy l. family history of Fragile X syndrome

          5. Prior MR-guided Focused Ultrasound or surgical intervention (e.g., deep brain
             stimulation, ablative thalamotomy or gamma knife thalamotomy).

          6. Botulinum toxin injection in the 6 months prior to screening.

          7. Currently using more than one anti-tremor medication.

          8. Experiencing clinical benefit from and/or is not willing to discontinue primidone

          9. Use of medication(s) in the past month that might produce tremor or interfere with the
             evaluation of tremor, such as, but not limited to: CNS-stimulants, lithium,
             amiodarone, metoclopramide, theophylline, and valproate

         10. Inability to refrain from use of medication/substance(s) that might produce tremor or
             interfere with the evaluation of tremor on study visit days, such as but not limited
             to stimulant decongestants, beta-agonist bronchodilators, caffeine, alcohol and
             tobacco, based on Investigator assessment at baseline.

         11. Positive urine drug screen.

         12. Regular use of more than two units of alcohol per day.

         13. Sporadic use of a benzodiazepine, sleep medication or anxiolytic to improve sleep
             performance. Stable use at a consistent dose is allowed as long as tremor persists
             against the background of regular medication use. Use on the evening prior to a study
             visit is prohibited.

         14. Use of prescription or non-prescription drugs or other products (i.e. grapefruit
             juice) known to be strong inhibitors or inducers of CYP3A4 which cannot be
             discontinued 2 weeks prior to Day 1 of dosing and withheld throughout the study,
             including primidone.

         15. Concurrent illnesses that would be a contraindication to trial participation,
             including, but not limited to: a. Severe arterial thromboembolic events (myocardial
             infarction, unstable angina pectoris, stroke) less than 6 months before screening b.
             NYHA Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled
             blood pressure c. Clinically significant ECG d. Known infection with HIV, hepatitis B,
             or hepatitis C, unless curative therapy completed for hepatitis C with negative PCR
             for HCV RNA e. Significant hepatic (AST/ALT > 2X upper limit of normal) or renal
             disease (creatinine clearance <39 mL/min) f. Significant psychiatric history including
             mood disorders and alcohol or substance abuse within the last year g. A current C-SSRS
             score of 4 or 5 at screening or history of suicide attempt at any time during the past
             year h. Clinically significant impaired balance or is considered at increased risk for
             falls i. Symptomatic orthostatic hypotension.

         16. Treatment with an investigational agent within 30 days prior to the first dose of
             CX-8998 or planning to receive an investigational agent during the study.