Section 4 of 6
Clinical evidence
114 evidence topics · 25 sources
Efficacy, safety, and tolerability versus placebo
3.1.1.2Location and study date
Reported program initiation
Primary results announcement
Exact first-participant and last-participant visit dates
No evidence found.
Randomized parallel-group design
Original planned treatment duration
Randomization and treatment schedule
3.1.1.4Eligibility criteria
Original age and primidone criteria
Disease duration and stable background treatment
Prescreening survey population, distinct from enrolled participants
3.1.1.6.1Rationale for using mADL11 as the primary endpoint
Instrument composition and meaningful within-participant change
Original primary endpoint timing
Primary endpoint in the final results presentation
Variability of performance-based tremor measurements
3.1.1.7Statistical analysis description
3.1.1.7.1Number of participants (Planned and analyzed)
Original planned enrollment
Actual enrollment and analysis populations
3.1.1.7.2Description of analysis sets
mITT eligibility after randomization
Interim futility recommendation and continuation
Missing-data sensitivity analysis
Complete statistical analysis plan and multiplicity procedures
No evidence found.
3.1.1.8.1Participant disposition
Study discontinuation in the safety population
3.1.1.8.2Baseline characteristics
Demographic and clinical characteristics of the mITT population
3.1.1.8.3Efficacy results
Primary endpoint: mADL11 change from baseline to Day 56
Primary endpoint probability value in the results presentation
Day 84 sensitivity analysis
3.1.1.8.4Health-related quality of life and patient-reported outcomes
Patient and clinician global impressions
Generic health utility and preference-based quality-of-life outcomes
No evidence found.
Drug-related TEAEs leading to discontinuation
Overall and serious adverse events
Common adverse events and serious treatment-related events across the Essential3 program
Summary
The mITT analysis included 199 of 236 participants assigned ulixacaltamide and 233 of 237 assigned placebo. Study discontinuation was 35.6% versus 5.6% in the safety populations. These imbalances warrant consideration alongside the reported missing-data sensitivity analysis. The original design specified a Day 84 primary assessment, whereas the final report used Day 56; the Day 84 sensitivity result also favored ulixacaltamide. The IDMC had recommended stopping for futility before the sponsor continued the studies. Treatment lasted 12 weeks, the comparator was placebo, and more than 95% of each mITT group was White, limiting conclusions about longer-term comparative effectiveness and other populations.
Maintenance of response and durability
3.1.2.2Location and study date
Reported initiation of the shared Essential3 program
Exact first-participant and last-participant visit dates
No evidence found.
Blinded lead-in followed by randomized withdrawal
Randomization of qualifying responders
3.1.2.4Eligibility criteria
Adult essential tremor population
Response required for randomized withdrawal
Ulixacaltamide lead-in regimen
Randomized-withdrawal treatment groups
3.1.2.6.1Rationale for using mADL11 response maintenance as the primary endpoint
Primary response-maintenance outcome
Functional relevance of the underlying scale
3.1.2.7Statistical analysis description
3.1.2.7.1Number of participants (Planned and analyzed)
Original planned enrollment
Stable responders entering randomized withdrawal
3.1.2.7.2Description of analysis sets
Randomized-withdrawal mITT population
Additional model specifications and missing-data procedures
No evidence found.
3.1.2.8.1Participant disposition
Overall study discontinuation
Disposition separately within each randomized-withdrawal treatment group
No evidence found.
3.1.2.8.2Baseline characteristics
Baseline characteristics separately for the randomized-withdrawal treatment groups
No evidence found.
3.1.2.8.3Efficacy results
Maintenance of response during randomized withdrawal
Rate of change during randomized withdrawal
3.1.2.8.4Health-related quality of life and patient-reported outcomes
Patient and clinician global impressions during randomized withdrawal
Generic health utility and preference-based quality-of-life outcomes
No evidence found.
Drug-related TEAEs leading to discontinuation
Overall safety population
Safety separately within each randomized-withdrawal treatment group
No evidence found.
Summary
The randomized comparison included 80 selected responders from 238 enrolled participants and assessed withdrawal over four weeks. Its response-maintenance estimate therefore applies to participants who reached the response threshold after initial treatment, rather than all adults starting ulixacaltamide. The safety population included 231 participants; drug-related adverse events led to discontinuation in 28.1%. PGI-C and CGI-S comparisons during withdrawal did not reach statistical significance, with p-values of 0.087 and 0.055. The reported overall safety results should not be interpreted as adverse-event comparisons between the two randomized-withdrawal groups.
Efficacy, safety, and tolerability in essential tremor
3.1.3.2Location and study date
Reported study initiation
Study locations and exact completion date
No evidence found.
Randomized placebo-controlled study
Extension and randomized-withdrawal substudy design
3.1.3.4Eligibility criteria
Disease duration and functional severity
Randomized dose regimens and duration
3.1.3.6.1Rationale for using modified TETRAS activities of daily living as the primary endpoint
Primary scale and subsequent mADL11 analysis
Meaningful change in the functional-only mADL11 scale
Reliability of the TETRAS performance scale
Separate validation of the TETRAS-PRO instrument
3.1.3.7Statistical analysis description
3.1.3.7.1Number of participants (Planned and analyzed)
Randomized and analyzed participants
Treatment-specific analysis populations
Extension completer populations
3.1.3.7.2Description of analysis sets
Summary
The reported mITT population comprised 116 participants who met the protocol version 4 eligibility requirements and received study treatment. Sixteen treated participants from an earlier protocol version were excluded from this analysis. Active-dose groups were pooled in the reported efficacy comparisons. The repeated-measures model adjusted for baseline value, propranolol use, and family history of essential tremor. The poster identifies the reported p-values as nominal.
Repeated-measures analysis
3.1.3.8.1Participant disposition
Discontinuation within the mITT population
3.1.3.8.2Baseline characteristics
Demographic and clinical characteristics of the mITT population
3.1.3.8.3Efficacy results
Primary and secondary endpoint interpretation in the initial results announcement
Day 56 least-squares mean changes
Extension and randomized-withdrawal findings
Extension completer analysis: mean mADL11 improvement
3.1.3.8.4Health-related quality of life and patient-reported outcomes
Global impression outcomes
Generic health utility and preference-based quality-of-life outcomes
No evidence found.
Treatment-emergent adverse events
Summary
The primary mADL endpoint did not reach statistical significance. Secondary endpoint p-values were nominal, and the functional-only mADL analysis was post hoc. The mITT analysis excluded 16 of 132 treated participants based on protocol-version eligibility and pooled the active-dose regimens. The randomized treatment period lasted eight weeks. Extension results were based on 65 completers, and the randomized-withdrawal substudy included 21 participants. These analyses provide supporting information but do not replace the unsuccessful primary comparison or establish long-term comparative effectiveness.
Clinical and pharmacokinetic evaluation
3.1.4.2Location and study date
Study locations and exact conduct dates
No evidence found.
Part B lead-in and withdrawal periods
3.1.4.4Eligibility criteria
Adult population and background treatment
3.1.4.6.1Rationale for using TETRAS upper limb score as the primary endpoint
Primary outcomes by study part
Reliability of head and upper-limb tremor assessments
3.1.4.7Statistical analysis description
3.1.4.7.1Number of participants (Planned and analyzed)
Convenience-sample planning
Part A efficacy population
3.1.4.7.2Description of analysis sets
Summary
The protocol defined the safety population by receipt of at least one dose. The full analysis population additionally required valid baseline and post-baseline TETRAS assessments. The pharmacokinetic population required at least one evaluable plasma concentration. Analyses were primarily descriptive and separated the study parts; the randomized portion of Part B was summarized by assigned continuation treatment. The sample size was selected for feasibility rather than a formal confirmatory power calculation.
Safety analysis population
3.1.4.8.1Participant disposition
Part B evaluable and completion populations
3.1.4.8.2Baseline characteristics
Part A baseline severity and propranolol use
3.1.4.8.3Efficacy results
Part A upper-limb tremor change at Day 14
Part B instrument-measured tremor during randomized withdrawal
3.1.4.8.4Health-related quality of life and patient-reported outcomes
Part B functional change during randomized withdrawal
Disease-specific quality-of-life questionnaire results
No evidence found.
Part B dose completion and tolerability
Summary
Part A was open label, with seven treated participants and six completing all visits. Five of the six efficacy participants were receiving propranolol. Part B reported 14 evaluable participants and 11 completing the open-label and randomized-withdrawal phases. These small populations, the uncontrolled initial treatment periods, and the brief withdrawal comparison limit precision and generalizability. The protocol describes feasibility-based sampling and primarily descriptive analyses. The findings support dose and endpoint development but do not independently establish confirmatory efficacy or long-term safety.
Safety and clinical pharmacology
3.1.5.2Location and study date
Location and conduct dates
Open-label and randomized parts
3.1.5.4Eligibility criteria
3.1.5.6.1Rationale for using NREM Sigma-Power as a pharmacodynamic endpoint
Summary
NREM sigma-power was investigated as a pharmacodynamic measure of central T-type calcium-channel blockade. The study compared human changes in this signal with preclinical findings at exposures associated with tremor reduction. This is target-engagement evidence in healthy participants, not direct evidence that a specified sigma-power reduction produces a clinically meaningful benefit in essential tremor.
Frequency range used for sigma-power measurement
3.1.5.7Statistical analysis description
3.1.5.7.1Number of participants (Planned and analyzed)
Part B pharmacodynamic analysis population
3.1.5.7.2Description of analysis sets
Summary
The Part B pharmacodynamic analysis used natural-log-transformed NREM sigma-power values. The repeated-measures model included timepoint, treatment, their interaction, and baseline value, with an unstructured covariance pattern. Treatment-to-placebo ratios were obtained by exponentiating the estimated between-group differences. The published analysis table included ten PRAX-944 participants and four placebo participants.
3.1.5.8.1Participant disposition
Full participant flow and reasons for exclusions from pharmacodynamic analysis
No evidence found.
3.1.5.8.2Baseline characteristics
No evidence found.
3.1.5.8.3Efficacy results
Pharmacodynamic response in healthy participants
Part B NREM sigma-power ratios versus placebo
Clinical efficacy in essential tremor
Not applicable.
3.1.5.8.4Health-related quality of life and patient-reported outcomes
Not applicable.
Frequent adverse events in Part B
Summary
The study enrolled healthy adults rather than participants with essential tremor. Part A included eight participants; Part B allocated twelve to PRAX-944 and four to placebo, with ten active-treatment participants represented in the reported pharmacodynamic analysis. The treatment periods and small placebo population limit safety precision. NREM sigma-power is a target-engagement measure rather than a patient-centered clinical outcome, so these results do not establish essential tremor efficacy, a clinically meaningful response threshold, or long-term tolerability.