Clinical trial NCT03101241: A Phase 2 RCT Study of CX-8998 for Essential Tremor
Official title: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of CX-8998 for Essential Tremor
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Essential Tremor
Keywords: Essential Tremor
Movement Disorders
thalamocortical dysrhythmias
Lead sponsor: Jazz Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2017-04-05
Enrollment: 95
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a double-blind, placebo-controlled, parallel-group study.
Primary purpose: TREATMENT

Brief 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.

Detailed description: 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.

Participants will be randomized to one of two treatment groups. Group A will receive titrating doses of CX-8998 up to 10 mg BID and Group B will receive placebo. Participant randomization will be stratified by presence or absence of a single concomitant anti-tremor medication and by site-type (sub-study vs non sub-study).

Tremor will be assessed via The Essential Tremor Rating Assessment Scale (TETRAS) and accelerometry. To reduce the potential for bias in the assessments of efficacy, all participants will be videotaped during the TETRAS performance scale testing according to a consistent script. The videotapes will be rated in a blinded manner by qualified, independent raters. A subset of participants will participate in a digital biomarker sub-study.

Participants will be screened up to 4 weeks prior to initiation of dosing. Participants taking primidone at screening who are otherwise deemed eligible for participation and are willing to discontinue primidone will be allowed an additional 2 weeks of screening (a total of 6 weeks) to ensure safe primidone discontinuation. At Baseline, participants will undergo safety and tremor assessments prior to dosing, will receive their first dose of study drug and will be monitored for safety for one hour following dosing. For one week participants will receive 4 mg (or matching placebo) twice daily. Participants will return to the clinic on Day 8 for safety monitoring and dose up-titration to 8 mg (or matching placebo) twice daily. At Day 15 (Week 3) participants will return to clinic for safety and efficacy assessments and final dose up-titration to 10 mg (or matching placebo) twice daily. The final efficacy visit will occur at Day 28 (Week 4). A final safety visit will occur at Day 35 (Week 5). Should participants experience intolerable adverse events (AEs) at 4 mg BID, 8 mg BID or 10 mg BID, the dose may be decreased at Day 8 or Day 15 to the next lowest dose one time (or 2 mg BID in the case of the 4 mg BID dose.

Randomized participants will have the opportunity to participate in an optional exploratory sub-study designed to assess the utility of digital assessment tools for tremor (sub-study addendum #1). Participants with Parkinson's disease tremor will be enrolled in a second exploratory sub-study (addendum #2).

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.

Primary outcomes:
measure: Baseline and Day 28 on The Essential Tremor Rating Assessment Scale Performance Subscale (TETRAS-PS) Total Score
timeFrame: Baseline and Day 28 post-dose.
measure: Change From Baseline to Day 28 on The Essential Tremor Rating Assessment Scale Performance Subscale (TETRAS-PS)
timeFrame: Baseline up to Day 28 post-dose.
Secondary outcomes:
measure: Baseline and Day 28 on The Essential Tremor Rating Assessment Scale Activities of Daily Living (TETRAS-ADL) Subscale Score
timeFrame: Baseline and Day 28 post-dose.
measure: Change From Baseline to Day 28 on The Essential Tremor Rating Assessment Scale Activities of Daily Living (TETRAS-ADL) Subscale Score
timeFrame: Baseline up to Day 28 post-dose.
measure: Baseline and Day 28 in the Kinesia ONE Score
timeFrame: Baseline and Day 28 post-dose.
measure: Change From Baseline to Day 28 in the Kinesia ONE Score
timeFrame: Baseline up to Day 28 post-dose.
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Tucson Neuroscience Research
state: Arizona
city: Little Rock
country: United States
facility: Woodland International Research Group
state: Arkansas
city: Rogers
country: United States
facility: Woodland Research Northwest
state: Arkansas
city: La Jolla
country: United States
facility: University of California San Diego
state: California
city: San Diego
country: United States
facility: Pacific Research Network
state: California
city: Boca Raton
country: United States
facility: Parkinson's Disease and Movement Disorders Center of Boca Raton
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: Savannah
country: United States
facility: Meridian Neurology Clinical Research
state: Georgia
city: Chicago
country: United States
facility: Northwestern Medical Group
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Boston
country: United States
facility: Boston University Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Farmington Hills
country: United States
facility: Quest Research Institute
state: Michigan
city: West Bloomfield
country: United States
facility: Henry Ford Hospital West Bloomfield
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Saint Louis
country: United States
facility: St. Louis Clinical Trials
state: Missouri
city: New York
country: United States
facility: Columbia University
state: New York
city: Raleigh
country: United States
facility: Wake Research Associates, LLC
state: North Carolina
city: Dayton
country: United States
facility: Midwest Clinical Research Center
state: Ohio
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Houston
country: United States
facility: Houston Methodist Neurological Institute
state: Texas
Study officials:
References:
citation: Papapetropoulos S, Lee MS, Boyer S, Newbold EJ. A Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial of CX-8998, a Selective Modulator of the T-Type Calcium Channel in Inadequately Treated Moderate to Severe Essential Tremor: T-CALM Study Design and Methodology for Efficacy Endpoint and Digital Biomarker Selection. Front Neurol. 2019 Jun 11;10:597. doi: 10.3389/fneur.2019.00597. eCollection 2019.