Essential 3 - Decentralized, Phase 3 Study Evaluating the Safety and Efficacy of Ulixacaltamide in Essential Tremor (ET)

Study Overview
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Brief Summary
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The goal of this clinical study is to compare ulixacaltamide and placebo treatment in essential tremor. The main question it aims to answer is: • Is ulixacaltamide a safe and efficacious treatment for patients with essential tremor? Participants will be asked to participate in one of two clinical studies where they will be treated with either ulixacaltamide or placebo for a period of up to 12 weeks. After the controlled study completion, they will be eligible to participate in a long-term, open-label safety study and be treated with ulixacaltamide.

Detailed Description
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PRAX-944-321 is a decentralized, Phase 3, multi-study, clinical trial evaluating the safety and efficacy of ulixacaltamide in essential tremor (ET). The study includes 2 separate and simultaneous phase 3 pivotal studies, of which one is a parallel design (PD) and the other a randomized withdrawal (RW), with all participants undergoing one screening process and a long-term safety study (LTSS). This study also includes a separate LTSS study for eligible pivotal study and PRAX-944-222 open label extension (OLE) participants.

Official Title
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Phase 3, Decentralized, Randomized, Double-Blind, Placebo Controlled, Parallel Design, Randomized Withdrawal, and Long-term Safety Study to Evaluate the Efficacy and Safety of Ulixacaltamide (PRAX-944) in Adults With Essential Tremor

Conditions
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Essential Tremor

Intervention / Treatment
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* Drug: 60 mg ulixacaltamide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has a body mass index (BMI) at Screening between 18 and 40 kg/m2, inclusive. Has a clinical diagnosis of ET prior to screening as characterized by postural and action tremor If currently receiving medication prescribed for ET, must be on ≤1 medications, on stable dose(s) for at least 1 month prior to Screening, and willing to maintain stable dose(s) throughout the study. As needed (PRN) use of prescribed ET medicines is not allowed. Primidone use is not allowed within 2 weeks prior to screening and throughout duration of study. Women of childbearing potential must undertake pregnancy tests, with a documented negative serum pregnancy test at Screening on Day -28, negative urine pregnancy tests Baseline (Day 1) prior to administration of study drug, throughout the intervention periods (as outlined in the SoA) and at the SFU or ED Visit, as appropriate. Is willing and able to use contraception as defined in the protocol and ICF. Has been assessed as an appropriate and suitable candidate by investigator and has a neurological exam and medical record(s) consistent with ET diagnosis, as confirmed by the ERC central reviewer. Confirm key inclusion criteria at Baseline Exclusion Criteria: Neuropathy, muscle weakness, arthropathy or other musculoskeletal diagnosis of the upper extremity that impairs dexterity or function. Has a known hypersensitivity to any component of the formulation of ulixacaltamide. Is unwilling or unable to refrain from episodic use of medication(s)/substance(s) that might interfere with the evaluation of tremor during the study. Is sporadically using a benzodiazepine, sleep medication or anxiolytic (as further defined in the protocol), that in the judgement of the investigator or sponsor would confound the assessment of tremor. Has trauma to the nervous system within 3 months preceding the onset of tremor. Has a history of unilateral tremor or clinical evidence of another medical, neurological, or psychiatric condition that may explain or cause tremor, including but not limited to Parkinson's disease, Huntington's disease, Alzheimer's disease, stroke with neurologic sequelae, intention tremor (IT) caused by etiology other than ET, cerebellar disease (including spinocerebellar ataxias), primary dystonia, Fragile X Tremor/Ataxia syndrome or family history of Fragile X syndrome, traumatic brain injury, psychogenic tremor, alcohol or benzodiazepine abuse or withdrawal, multiple sclerosis, polyneuropathy (diabetic neuropathy allowed if disease does not affect gait or balance and does not involve upper extremity), and endocrine states such as uncontrolled or inadequately treated hypothyroidism, food, or supplement induced movement disorders (e.g., tremor related to beta agonists or caffeine), or other medical, neurological, or psychiatric conditions that may explain or cause tremor. Has had prior magnetic resonance-guided focused ultrasound or surgical intervention for ET such as a deep brain stimulator (DBS) or lesion therapy such as thalamotomy. Has had botulinum toxin injection for ET in the 6 months prior to Screening or throughout the study. Is using the Cala kIQ™ health device for ET in 14 days prior to Screening or throughout the study. Is unwilling or unable to refrain from drinking alcohol 24 hours before and during clinical study assessments, or regular use of alcohol that would preclude abstinence from alcohol for this time period around visits. Has a history of substance use disorder consistent with Diagnostic and Statistical Manual of Mental Disorders Fifth Edition Text Revision (DSM-5-TR) criteria. Participants with a previous diagnosis of substance use disorder who have been in remission for at least 2 years can participate in the study. Is currently taking a prescription or non-prescription product(s) and food known to be moderate or strong inhibitors or strong inducers (moderate inducers are not prohibited) of cytochrome P450 (CYP3A4), which cannot be discontinued at least 5 half-lives or 14 days prior (whichever is the longer period of time) to Baseline and withheld throughout the clinical study. Prior participation in an ulixacaltamide clinical study, with the exception of participants that are currently enrolled in and complete the EOT visit in PRAX-944-222 extension period.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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
Interventional Model Description: Parallel Design: A 12-week parallel design (PD) randomized, double-blind, placebo-controlled study to evaluate the proportion of participants that respond to and the efficacy and safety of ulixacaltamide compared with placebo. Randomized Withdrawal: A 12-week randomized withdrawal (RW), double-blind, placebo-controlled study to evaluate the efficacy, maintenance of response, and durability of effect in participants who respond to ulixacaltamide and safety. Long-term Safety Study: A LTSS study to evaluate the long-term safety of ulixacaltamide for up to 1 approximately 1 year. The first 2 weeks of the LTSS will be double-blind.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Randomized Withdrawal<br>Double-blind Part: Oral dosing, once daily in the morning with titration over 14 days to 60 mg ulixacaltamide: 7 days of 20 mg, 7 days of 40 mg, 42 days of 60 mg Randomized Withdrawal Part: Following double-blind part: 1:1 randomization to placebo or 60 mg ulixacaltamide for 28 days | Drug: 60 mg ulixacaltamide<br>* Once daily oral treatment with titration<br>Drug: Placebo<br>* Once daily oral treatment<br>|
| Experimental: Long-term Safety Study: Essential1 rollovers<br>Open-label Part: Oral dosing, once daily in the morning up to one year (365 days) of 60 mg ulixacaltamide | Drug: 60 mg ulixacaltamide<br>* Once daily oral treatment with titration<br>|
| Experimental: Long-term Safety Study: Parallel Design and Randomized Withdrawal rollovers<br>Open-label Part for patients previously on placebo: Oral dosing, once daily in the morning with titration over 14 days to 60 mg ulixacaltamide: 7 days of 20 mg, 7 days of 40 mg, up to 351 days of 60 mg Open-label Part for patients previously on 60 mg ulixacaltamide: Oral dosing, once daily in the morning up to 365 days 60 mg ulixacaltamide | Drug: 60 mg ulixacaltamide<br>* Once daily oral treatment with titration<br>|
| Experimental: Parallel Design: ulixacaltamide arm<br>Double-blind Part: Oral dosing, once daily in the morning with titration over 14 days to 60 mg ulixacaltamide: 7 days of 20 mg, 7 days of 40 mg, 70 days of 60 mg | Drug: 60 mg ulixacaltamide<br>* Once daily oral treatment with titration<br>|
| Placebo Comparator: Parallel Design: placebo arm<br>Double-blind Part: Oral dosing, once daily in the morning: 84 days of placebo | Drug: Placebo<br>* Once daily oral treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parallel Design: Change from Baseline (CFB) to Week 12 on mADL11 | Modified Activities of Daily Living 11 (mADL11) is a composite sum of items 1 to 11 of the TETRAS-ADL subscale. The impact to each function is rated on a 5-point Likert scale from 0 to 4. Before calculating the total score, a scoring adjustment is applied to each item score. The modified score is calculated as the sum of all 11 items (with scoring adjustments) and ranges from 0 to 33 where larger values represent increased direct tremor impact to activities of daily living. | 12 weeks (84 days) | 
| Randomized Withdrawal: The proportion of participants that maintain response, as defined by change in mADL11 score, following randomized withdrawal | Modified Activities of Daily Living 11 (mADL11) is a composite sum of items 1 to 11 of the TETRAS-ADL subscale. The impact to each function is rated on a 5-point Likert scale from 0 to 4. Before calculating the total score, a scoring adjustment is applied to each item score. The modified score is calculated as the sum of all 11 items (with scoring adjustments) and ranges from 0 to 33 where larger values represent increased direct tremor impact to activities of daily living. Change in patient response will compare the proportion of patients in the ulixacaltamide and placebo arm who maintain response based on RW baseline established at Week 8 (Day 56) following randomized withdrawal. | 12 weeks (84 days) | 
| Long-term Safety Study: Number of participants with Adverse Events (AE) | The number of participants with Adverse Events (AE) will be reported by preferred term | Up to 52 weeks (365 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Randomized Withdrawal: TETRAS-ADL Change from RW Baseline (Day 56) to Day 63, Day 70, Day 77, and Day 84 | The TETRAS-ADL subscale is a 12-item assessment of typical daily activities that are impacted by tremor. Activities are assessed in the following functional domains: speaking, feeding, drinking, personal hygiene, dressing, writing, and social activity. The impact to each function is rated on a 5-point Likert scale from 0 to 4. The ADL subscale score is calculated as the sum of all 12 items and ranges from 0 to 48 where larger values represent increased direct tremor impact to activities of daily living. | 4 weeks (28 days) | 
| Randomized Withdrawal: PGI-C Change from RW Baseline (Day 56) to Day 63, Day 70, Day 77, and Day 84 | PGI-C assesses the participant's change in condition. The participant is required to assess their condition relative to Baseline on a 7-point scale from 1 (very much improved) to 7 (very much worse). In all cases, the assessment should be made independent of whether the participant believes the change is drug-related or not. | 4 weeks (28 days) | 
| Randomized Withdrawal: CGI-S Change from RW Baseline (Day 56) to Day 63, Day 70, Day 77, and Day 84 | CGI-S assesses the clinician's impression of the participant's current illness state. The clinician should use is/her total clinical experience with this patient population and rate the current severity of the participant's ET on a 7-point scale from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). | 4 weeks (28 days) | 
| Randomized Withdrawal: PGI-S Change from RW Baseline (Day 56) to Day 63, Day 70, Day 77, and Day 84 | PGI-S assesses the participants' impression of their current illness state. The participant is required to assess their condition on a 7-point scale from 1 (Not present) to 7 (extremely severe). | 4 weeks (28 days) | 
| Parallel Design and Randomized Withdrawal: Number of participants with Adverse Events (AE) | The number of participants with Adverse Events (AE) will be reported by preferred term. | 12 weeks (84 days) | 
| Parallel Design: The proportion of participants responding to ulixacaltamide, as defined by change in mADL11 score after 12 weeks (84 days) of treatment | Compare the proportion of patients in the ulixacaltamide and placebo arms who meet a pre-specified response criteria threshold. | 12 weeks (84 days) | 
| Parallel Design: TETRAS-ADL Change from Baseline to Week 12 (Day 84) | The TETRAS-ADL subscale is a 12-item assessment of typical daily activities that are impacted by tremor. Activities are assessed in the following functional domains: speaking, feeding, drinking, personal hygiene, dressing, writing, and social activity. The impact to each function is rated on a 5-point Likert scale from 0 to 4. The ADL subscale score is calculated as the sum of all 12 items and ranges from 0 to 48 where larger values represent increased direct tremor impact to activities of daily living. | 12 weeks (84 Days) | 
| Parallel Design: PGI-C Change from Baseline to Week 12 (Day 84) | PGI-C assesses the participant's change in condition. The participant is required to assess their condition relative to Baseline (Pre-dose on Day 1) on a 7-point scale from 1 (very much improved) to 7 (very much worse). In all cases, the assessment should be made independent of whether the participant believes the change is drug-related or not. | 12 weeks (84 Days) | 
| Parallel Design: CGI-S Change from Baseline to Week 12 (Day 84) | CGI-S assesses the clinician's impression of the participant's current illness state. The clinician should use his/her total clinical experience with this patient population and rate the current severity of the participant's ET on a 7-point scale from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). | 12 weeks (84 Days) | 
| Parallel Design: PGI-S Change from Baseline to Week 12 (Day 84) | PGI-S assesses the participants' impression of their current illness state. The participant is required to assess their condition on a 7-point scale from 1 (Not present) to 7 (extremely severe). | 12 weeks (84 Days) | 
| Parallel Design: Proportion of participants responding to ulixacaltamide, as defined by change in mADL11 score after 14, 28, 56, and 70 days of treatment | Compare the proportion of patients in the ulixacaltamide and placebo arms who meet a pre-specified response criteria threshold. | 10 weeks (70 days) | 
| Parallel Design: mADL11 Change from Baseline to Day 14, Day 28, Day 56, and Day 70 | Modified Activities of Daily Living 11 (mADL11) is a composite sum of items 1 to 11 of the TETRAS-ADL subscale. The impact to each function is rated on a 5-point Likert scale from 0 to 4. Before calculating the total score, a scoring adjustment is applied to each item score. The modified score is calculated as the sum of all 11 items (with scoring adjustments) and ranges from 0 to 33 where larger values represent increased direct tremor impact to activities of daily living. | 10 weeks (70 days) | 
| Parallel Design: TETRAS-ADL Change from Baseline to Day 14, Day 28, Day 56, and Day 70 | The TETRAS-ADL subscale is a 12-item assessment of typical daily activities that are impacted by tremor. Activities are assessed in the following functional domains: speaking, feeding, drinking, personal hygiene, dressing, writing, and social activity. The impact to each function is rated on a 5-point Likert scale from 0 to 4. The ADL subscale score is calculated as the sum of all 12 items and ranges from 0 to 48 where larger values represent increased direct tremor impact to activities of daily living. | 10 weeks (70 days) | 
| Parallel Design: PGI-C Change from Baseline, Day 28, Day 56, and Day 70 | PGI-C assesses the participant's change in condition. The participant is required to assess their condition relative to Baseline (Pre-dose on Day 1) on a 7-point scale from 1 (very much improved) to 7 (very much worse). In all cases, the assessment should be made independent of whether the participant believes the change is drug-related or not. | 10 weeks (70 days) | 
| Parallel Design: CGI-S Change from Baseline to Day 14, Day 28, Day 56, and Day 70 | CGI-S assesses the clinician's impression of the participant's current illness state. The clinician should use is/her total clinical experience with this patient population and rate the current severity of the participant's ET on a 7-point scale from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). | 10 weeks (70 days) | 
| Parallel Design: PGI-S Change from Baseline to Day 14, Day 28, Day 56, and Day 70 | PGI-S assesses the participants' impression of their current illness state. The participant is required to assess their condition on a 7-point scale from 1 (Not present) to 7 (extremely severe). | 10 weeks (70 days) | 
| Parallel Design and Randomized Withdrawal: Dominant Hand Archimedes Spiral (Day 1, Day 56, Day 84) | Participants will draw Archimedes Spirals with their dominant hand. Descriptive analyses will be used to summarize the findings | 12 weeks (84 days) | 
| Randomized Withdrawal: mADL11 Change from RW Baseline (Day 56) to Day 63, Day 70, Day 77, and Day 84 | Modified Activities of Daily Living 11 (mADL11) is a composite sum of items 1 to 11 of the TETRAS-ADL subscale. The impact to each function is rated on a 5-point Likert scale from 0 to 4. Before calculating the total score, a scoring adjustment is applied to each item score. The modified score is calculated as the sum of all 11 items (with scoring adjustments) and ranges from 0 to 33 where larger values represent increased direct tremor impact to activities of daily living. | 4 weeks (28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Movement Disorder, Benign Essential Tremor, Familial Tremor, Hereditary Essential Tremor, Movement Disorder Agents, Calcium Channels, T-type