A Study of Suvecaltamide in Adults With Moderate to Severe Residual Tremor in Parkinson's Disease

Study Overview
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Brief Summary
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This is a 17-week double-blind, placebo-controlled, randomized, flexible-dosing, parallel-group, multicenter study designed to evaluate the efficacy and safety of suvecaltamide for the treatment of moderate to severe residual tremor in adult participants with Parkinson's disease (PD). The target population represents participants who have tremor that is not adequately controlled by PD medications and that interferes with their activities of daily living (ADL) and/or with their performance of tasks.

Detailed Description
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Participants will be randomized 1:1 to receive suvecaltamide or placebo and stratified by the Essential Tremor Rating Scale (TETRAS) composite outcome score (≤ 17 or > 17) as assessed at baseline. The maximum total duration of the study for each participant will be 23 weeks, with a maximum treatment duration of 17 weeks. For each participant, the study consists of a Screening Period (up to 4 weeks), a 5-week Dose Titration and Optimization Period, a 12-week Maintenance Period, and a 2-week Safety Follow-up Period.

Official Title
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A 17-week, Phase 2, Randomized, Double-blind, Placebo-controlled, Flexible-dosing, Parallel-group, Multicenter Study of the Efficacy and Safety of Suvecaltamide in the Treatment of Moderate to Severe Residual Tremor in Participants With Parkinson's Disease

Conditions
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Parkinson Disease, Tremor

Intervention / Treatment
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* Drug: Placebo
* Drug: Suvecaltamide


Participation Criteria
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Eligibility Criteria
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KEY Inclusion Criteria: Diagnosis of clinically probable or clinically established Parkinson's disease (PD) meeting the Movement Disorder Society (MDS) 2015 criteria. Participants must be individually optimized on PD medications for the treatment of other cardinal signs of PD (bradykinesia, rigidity) per the judgment of the investigator. Participants must be on a stable dosing regimen of their permitted PD and/or other tremor (eg, propranolol) medications for the treatment of motor symptoms for at least 6 weeks prior to screening and do not anticipate the need to make any changes for the duration of the study. A lack of use of medications used to treat motor symptoms also must be stable for 6 weeks prior to screening and remain stable for the duration of the study. Participants have moderate to severe impairment associated with tremor at both the screening and baseline visits, as determined by all the following: A score of > 21 on The Essential Tremor Assessment Rating Scale, Activities of Daily Living (TETRAS-ADL) subscale; and Clinician Global Impression of Severity (CGI-S) rating of tremor severity of > 2 (at least moderate for participant's ability to function). KEY Exclusion Criteria: Medical Conditions Female participants who are pregnant, nursing, or lactating or plan to become pregnant during the study or within 90 days of study completion. Known history or current evidence of other medical or neurological conditions that may cause or explain the participant's tremor in the opinion of the investigator. Note: Participants with a history of essential tremor are eligible. Hoehn & Yahr stage 5 (confinement to bed or wheelchair unless aided). Participants who only experience tremor during their OFF periods. Severity of motor fluctuations or medication-induced dyskinesia that would interfere with the assessment of tremor and/or ON/OFF periods that are unpredictable per the opinion of the investigator. Clinically significant symptomatic orthostatic hypotension in the opinion of the investigator. Has evidence at screening of cognitive impairment as defined by a Montreal Cognitive Assessment (MoCA) score < 22 or has a cognitive impairment that, in the investigator's opinion, would prevent completion of study procedures or the ability to provide informed consent. History or presence of gastrointestinal disease (including prior bariatric bypass surgery), hepatic (including ALT or AST ≥ 2 × ULN or total bilirubin ≥ 1.5 ULN), or severe renal impairment or end-stage renal disease, or any other condition that, in the opinion of the investigator, may interfere with the absorption, distribution, metabolism, or excretion of suvecaltamide. Presence of significant cardiovascular disease at Screening History or presence of bipolar and related mood disorders, schizophrenia, schizophrenia spectrum disorders, or other psychotic disorders according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria. Prior/Concomitant Therapy Treatment-naïve patients (ie, those who have never tried PD medication) are excluded from participating in the study. Use of PRN medication/substance(s) that might produce or interfere with the evaluation of tremor on study visit days prior to discharge Prior or planned surgical intervention to treat PD, including but not limited to magnetic resonance-guided focused ultrasound thalamotomy, deep brain stimulation, ablative thalamotomy, and gamma knife thalamotomy. Use of PRN medications to treat tremor or continuous infusion of PD medications. Note: Use of dopaminergic rescue medications (eg, PRN use of carbidopa/levodopa, including levodopa inhalation powder) for non-tremor PD symptoms (eg, rigidity or bradykinesia) is permitted. Botulinum toxin injection in the 6 months before screening or planned use at any time during the study. Note: Use of botulinum toxin for other reasons (eg, cosmetic, excessive salivation, dystonia) is permitted as long as the location of use is anatomically distinct from the region with tremor. Use of prescription or nonprescription drugs or other products (eg, St. John's Wort) known to be inducers of cytochrome 3A4 (CYP3A4) (cause > 30% reduction of sensitive substrates area under the plasma concentration-time curve [AUC]), which cannot be discontinued at least 4 weeks before baseline, or planned use at any time during the study. Use of prescription or nonprescription drugs or other products (eg, grapefruit) known to be strong or moderate inhibitors of CYP3A4, which cannot be discontinued 2 weeks or 5 half-lives, whichever is longer, before baseline, or planned use at any time during the study. Use of proton pump inhibitors, which cannot be discontinued at least 2 weeks before baseline, or planned use at any time during the study. (Occasional use of antacids or histamine receptor type 2 [H2] receptor antagonists will be permitted, but antacids should be taken at least 4 hours apart from study intervention; H2 receptor antagonists should be taken at least 4 hours after and/or 12 hours before study intervention). Diagnostic Assessments Known use of recreational drugs, inclusive of the following: phencyclidine, cocaine, opioids, barbiturates, amphetamines, or 3,4-methylenedioxymethamphetamine [ecstasy]. Opioid use at stable doses, either regularly or PRN, for pain management, as prescribed, is permitted. Use of cannabinoids (including cannabidiol) is permitted if there is no impact on tremor symptoms per the judgment of the investigator. Other protocol-defined inclusion and exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants who will receive a matching placebo during the Dose Titration, Optimization Period, and Maintenance Period. | Drug: Placebo<br>* Matching placebo capsule(s) administered every day (QD) orally. Titration may proceed at a rate of 1 matching placebo capsule per day every 7 days as required for optimal efficacy and tolerability up to a maximum number of 3 matching placebo capsules per day.<br>|
| Experimental: Sulvecaltamide<br>Participants who will receive an optimal dose of suvecaltamide during the Dose Titration, Optimization Period, and Maintenance Period. | Drug: Suvecaltamide<br>* Suvecaltamide capsule administered every day (QD) orally. Titration may proceed at a rate of 10 mg suvecaltamide per day every 7 days as required for optimal efficacy and tolerability up to a maximum dose of 30 mg suvecaltamide per day.<br>* Other names: MK-8998;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline to Week 17 on the Essential Tremor Rating Scale (TETRAS) Composite Outcome Score | The TETRAS composite outcome score is the sum of modified items 1 - 11 of the TETRAS-ADL subscale and modified items 6 - 7 of the TETRAS-PS. The TETRAS-ADL subscale is a patient-rated scale administered by a trained interviewer that assesses the impact of tremor on day-to-day functioning, such as eating, drinking, dressing, and other fine motor skills. The TETRAS-PS is a clinical rating scale that quantifies tremor in the head, face voice, limbs and trunk. Items 6 (drawing an Archimedes spiral using left and right hands) and 7 (handwriting) of the TETRAS-PS evaluate the impact of upper limb tremor on performance. Each item from the modified subscales ranges from 0 - 3, with 0 representing normal or slightly abnormal and 3 representing severely abnormal. The sum of the 14 items provides the TETRAS composite outcome score, which ranges from 0 - 42, with higher scores representing more severe tremor. | Baseline to Week 17 post-dose. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants Who Improved (≥ 1-point improvement) from Baseline to Week 17 on the Clinical Global Impression of Severity (CGI-S) | The CGI-S is a 5-point Likert-type rating scale assessed by qualified personnel to assess the severity of the impact of tremor in PD on the participants' ability to function. The responses to this investigator-completed scale range from 1 (no limitations) to 5 (severe), with higher scores indicating a worse outcome. | Baseline to Week 17 post-dose. | 
| Change from Baseline to Week 17 on The Essential Tremor Rating Scale, Activities of Daily Living Subscale (TETRAS-ADL) | The TETRAS-ADL subscale is a patient-rated scale of the impact of tremor on day-to-day functioning administered by a trained interviewer. The TETRAS-ADL subscale directly measures how a patient functions by assessing activities impacted by tremor, such as eating and drinking, dressing and personal hygiene, carrying items, and fine motor skills. The TETRAS-ADL has 12 items and each item is rated on a 0 (normal) to 4 (severe) scale, with higher scores representing more severe tremor. | Baseline to Week 17 post-dose. | 
| Proportion of participants who improved (≥ 1 point) from Baseline to Week 17 on the Patient's Global Impression of Severity (PGI-S) | The PGI-S is a 5-point Likert-type rating scale, with response options ranging from 1 (no limitations) to 5 (severe), with higher scores indicating a worse outcome. The participant will rate his/her impression of the severity of the impact of their tremor in PD on their current ability to function. | Baseline to Week 17 post-dose. | 
| Proportion of participants who were much improved on the Patient's Global Impression of Change (PGI-C) at Week 17 | The PGI-C is a 5-point Likert-type rating scale that participants use to rate the change in severity of their ability to function due to tremor since baseline. The responses to this scale range from 1 (Much improved) to 5 (Much worse), with higher scores indicating a worse outcome. | Week 17 post-dose. | 
| Proportion of Participants who were Much Improved on the Clinician's Global Impression of Change (CGI-C) at Week 17 | The CGI-C is a 5-point Likert-type rating scale that a qualified medical personnel will use to rate the change in severity of the participants' ability to function due to their tremor since baseline. The responses to this scale range from 1 (Much improved) to 5 (Much worse), with higher scores indicating a worse outcome. | Week 17 post-dose. | 
| Change from Baseline to Week 17 on The Essential Tremor Rating Scale, Performance Subscale (TETRAS-PS) | The TETRAS-PS is a clinical rating scale performed by a blinded rater that quantifies tremor in the head, face, voice, limbs, and trunk. Each item will be rated on a scale of 0 (normal) to 4 (severe). The sum of the individual scores provides the overall score, ranging from 0 to 64, with higher scores representing more severe tremor. | Baseline to Week 17 post-dose. | 
| Change from Baseline to Week 17 on TETRAS total score (TETRAS-ADL + TETRAS-PS) | The TETRAS total score is the sum of the scores of the full TETRAS-ADL and TETRAS-PS subscales. Each item is rated on a 0 (normal) to 4 (severe) scale, and total scores range from 0 to 112, with higher scores representing more severe tremor. The TETRAS-PS is performed by a blinded rater. | Baseline to Week 17 post-dose. | 
| Change from Baseline to Week 17 on the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Tremor Score | The tremor items from the MDS-UPDRS consist of 1 item from Part II (Item 2.10) and 10 items from Part III (Items 3.15a,b, 3.16a,b, 3.17a-e, and 3.18). These items are graded on a severity score of 0 to 4 (normal, slight, mild, moderate, severe). Item 2.10 assesses the patient report of the presence of tremor and impact on daily activities. Items 3.15, 3.16, and 3.17 are clinician assessments of the amplitude of distinct types of tremor (resting, postural, and kinetic respectively)in the right and left upper extremities separately. Item 3.17 also includes separate clinician assessments for both lower extremities and for the lip/jaw. Item 3.18 provides a clinician assessment of the constancy of rest tremor without regard to anatomical location. For the 11 individual assessments the maximum possible total score of these tremor items is 44, with higher scores indicating more | Baseline to Week 17 post-dose. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Suvecaltamide, Moderate tremor, Severe tremor, Parkinson's disease, JZP385, Residual tremor, T-type calcium channels, Movement disorders, Tremor, Parkinson's disease tremor