A Phase 2 Study of CX-8998 in Adults With Tremor Associated With Parkinson's Disease

Jazz Pharmaceuticals

Overview

This is a Phase 2, multicenter, double-blind, placebo-controlled, parallel-group study consisting of a screening period of up to 4 weeks, a 4 week randomized double-blind, dose-titration treatment period, followed by a 1 week safety follow-up period after the last dose of study medication, and a scheduled follow-up safety telephone call one week later. Subjects will be randomized 1:1 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. Subjects will participate for a total of up to 12 weeks, including screening, the 4-week treatment period and follow-up.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Conditions

Parkinson's Disease Tremor

Interventions

CX-8998DRUG

T-type calcium channel blocker

PlaceboDRUG

Placebo comparator

Eligibility

Sex: ALLMin age: 40 YearsMax age: 80 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Men or non-pregnant, non-breastfeeding women 40 to 80 years-of-age who are able to read and understand English. * Mini Mental State Exam (MMSE) score ≥ 24. * Clinical diagnosis of idiopathic Parkinson's disease and presence of at least 2 out of 3 cardinal characteristics (tremor, rigidity, and/or bradykinesia). * Hoehn \& Yahr Stage I III (inclusive) if not experiencing motor fluctuations. If experiencing motor fluctuations, must be Hoehn \& Yahr Stage I IV (inclusive) when OFF or I-III (inclusive) when ON. * An MDS-UPDRS tremor score (sum of items 2.10, 3.15, 3.16, 3.17, 3.18) of a least 10 (during ON for subjects experiencing fluctuations) (centrally rated) (Forjaz et al., 2015). A limited number of subjects with an MDS-UPDRS of 8 or 9 may be included with Sponsor approval. * Treated with a stable regimen of anti-parkinsonian and/or anti-tremor medication (with the exception of primidone) for at least 2 weeks prior to screening. Changes to anti-parkinsonian or anti-tremor medications after screening is not permitted. Exclusion Criteria: * Current diagnosis of: a. essential tremor / b. cerebellar disease * Presence or known history of: a. significant visual hallucinations (in the opinion of the Investigator and/or Study Safety Representative) / b. significant impulse control disorder (ICD) (in the opinion of the Investigator and/or Study Safety Representative). * History or clinical features consistent with an atypical parkinsonian syndrome. * Dyskinesia or dystonia that would, in the opinion of the investigator, central rater, or Sponsor, interfere with the assessment of tremor. * Exposure to tremorigenic drugs or drug withdrawal states within the 30 days prior to the first planned dose of study drug. * Direct or indirect trauma to the nervous system within 3 months preceding the onset of tremor. * History or clinical evidence of psychogenic tremor origin. Known history of other medical or neurological conditions that may cause or explain subject's tremor. * Prior MR-guided Focused Ultrasound or surgical intervention (e.g., deep brain stimulation, ablative thalamotomy or gamma knife thalamotomy) for treatment of tremor or Parkinson's disease. * Use of medication(s) in the past month that might produce tremor or interfere with the evaluation of tremor. * Inability to refrain from use of medication/substance(s) that might produce tremor or interfere with the evaluation of tremor on study visit days. * Positive urine drug screen for drugs of abuse, except if this is explained by use of an allowed prescription medicine. * Regular use of more than two units of alcohol per day. * 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. * Concurrent illnesses that would be a contraindication to trial participation. * Psychological, social, familial, or geographical reasons that would hinder or prevent compliance with the requirements of the protocol or compromise the informed consent process. * Any other condition and/or situation that causes the Investigator or Study Safety Representative to deem a subject unsuitable for the study (e.g., due to expected study medication non-compliance, inability to medically tolerate the study procedures, or a subject's unwillingness to comply with study-related procedures). * 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.

Outcomes

Primary Outcomes

Change from Baseline to Day 28 on the MDS-UPDRS Tremor Score as scored by the central rater

The MDS-UPDRS is a multi-dimensional scale that assesses the motor and non-motor impact of PD across four parts. Part I: Non-Motor Experiences of Daily Living; Part II: Motor Experiences of Daily Living; Part III: Motor Examination; and Part IV: Motor Complications.

Time frame: Baseline through completion of study treatment period, an average of 28 days

Secondary Outcomes

Change from Baseline to Day 28 on the TETRAS Activity of Daily Living subscale

The ADL section of TETRAS has 12 items, each rated 0, 1, 2, 3 or 4. The maximum total score is 48. Item 1 addresses speech; item 10 addresses occupational impairment; and item 12 assesses social impact. The other 9 items assess activities that are affected primarily by upper limb tremor

Time frame: Baseline through completion of study treatment period, an average of 28 days

Change from Baseline to Day 28 in accelerometry score

Accelerometry will be used to obtain quantitative measurements of tremor. The Kinesia ONE device will be placed on the index finger and worn in the clinic immediately after execution of the MDS-UPDRS and/or TETRAS performance subscale. A total of 4 tasks will be performed on the left side and then again on the right side to assess resting, postural, kinetic, and lateral wing beating tremor. Each task will be performed for 15 seconds.

Time frame: Baseline through completion of study treatment period, an average of 28 days

Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] as assessed by CTCAE v4.0

Treatment-emergent adverse events are all adverse events occurring during the treatment period or a pretreatment event that worsens in intensity during the treatment period.

Time frame: Through study completion, an average of 12 weeks

Changes from baseline in QTcF

Data from ClinicalTrials.gov

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