Essential3 study 1

31 evidence topics · 11 sources

Objective

Efficacy, safety, and tolerability versus placebo

“Evaluating the efficacy, safety, and tolerability of ulixacaltamide vs. placebo in adults with essential tremor (ET)” (opens the source at this quote in a new tab)

Location and study date

Study country

“conducted within the United States” (opens the source at this quote in a new tab)

Reported program initiation

“In November 2023, Praxis initiated Essential3, the Phase 3 program for ulixacaltamide.” (opens the source at this quote in a new tab)

Primary results announcement

“October 16, 2025” (opens the source at this quote in a new tab)

Exact first-participant and last-participant visit dates

No evidence found.

Study design

Randomized parallel-group design

“Randomized, double-blind, placebo-controlled” (opens the source at this quote in a new tab)

Original planned treatment duration

“Essential3, the Phase 3 program for ulixacaltamide, comprises two simultaneous Phase 3 studies including a 12-week, parallel design study and 12-week randomized withdrawal study for stable responders.” (opens the source at this quote in a new tab)

Randomization and treatment schedule

Design feature	Reported value
Ulixacaltamide-to-placebo randomization	“1:1”
Titration period	“2-week”
Randomized treatment period	“12 weeks”

Eligibility criteria

Original age and primidone criteria

“age of 18 and 85 years (inclusive)” (opens the source at this quote in a new tab)
“Unwillingness or inability to discontinue primidone” (opens the source at this quote in a new tab)

Disease duration and stable background treatment

Criterion	Reported requirement
Essential tremor symptom duration	“≥3 years”
Stable background medication before screening	“≥28 days”

Prescreening survey population, distinct from enrolled participants

“Data are presented for 75,000 survey responders as of 08/2024.” (opens the source at this quote in a new tab)

Treatment

Investigational regimen

Treatment attribute	Reported value
Ulixacaltamide maintenance dose	“60 mg QD”
Initial titration	“2-week”
Comparator	“placebo”
Treatment duration	“12 weeks”

Study outcomes

Rationale for using mADL11 as the primary endpoint

Instrument composition and meaningful within-participant change

“comprising TETRAS-ADL items, excluding social impact, individually scored from 0-3” (opens the source at this quote in a new tab)
“An MSD was consistently defined as ≥2 points” (opens the source at this quote in a new tab)

Original primary endpoint timing

“mADL11 change from baseline to Day 84” (opens the source at this quote in a new tab)

Primary endpoint in the final results presentation

Endpoint component	Reported value
Instrument	“mADL11”
Primary assessment	“Day 56”
Additional treatment-period assessment	“Day 84”

Variability of performance-based tremor measurements

“Tremor is not constant: a single brief sample of a fluctuating signal cannot capture disability” (opens the source at this quote in a new tab)

Statistical analysis description

Number of participants (Planned and analyzed)

Original planned enrollment

Study component	Planned participants
Study 1 parallel design	“400”

Actual enrollment and analysis populations

Population	Ulixacaltamide	Placebo
Enrolled and ITT	“236 (100%)”	“237 (100%)”
Safety	“233 (98.7%)”	“234 (98.7%)”
mITT	“199 (84.3%)”	“233 (98.3%)”

Description of analysis sets

mITT eligibility after randomization

“received ≥1 dose of study drug and had ≥1 post-baseline efficacy assessment.” (opens the source at this quote in a new tab)

Interim futility recommendation and continuation

“the IDMC has recommended that the study be stopped for futility” (opens the source at this quote in a new tab)
“Praxis has decided to continue both studies to completion” (opens the source at this quote in a new tab)

Missing-data sensitivity analysis

Analysis parameter	Reported value
Tipping-point penalty	“2.5 points”
Estimated treatment difference and 95% CI	“-1.63 (-2.70, -0.57)”
Probability value	“p=0.0026”

Complete statistical analysis plan and multiplicity procedures

No evidence found.

Results

Participant disposition

Study discontinuation in the safety population

Disposition	Ulixacaltamide, 233 participants	Placebo, 234 participants
Discontinued from the study	“83 (35.6%)”	“13 (5.6%)”

Baseline characteristics

Demographic and clinical characteristics of the mITT population

Characteristic	Ulixacaltamide, 199 participants	Placebo, 233 participants
Age, mean years and SD	“67.9 (9.1)”	“68.9 (8.1)”
Male and female percentages	“57.3% / 42.7%”	“56.7% / 43.3%”
White and other race percentages	“98.5% / 1.5%”	“95.7% / 4.3%”
Years since essential tremor onset, mean and median	“29.8 (26.0)”	“31.1 (27.0)”
Currently receiving essential tremor medication	“44.2%”	“48.1%”
Currently receiving propranolol	“35.7%”	“36.5%”
mADL11, mean and SD	“18.5 (2.4)”	“18.4 (2.4)”

Efficacy results

Primary endpoint: mADL11 change from baseline to Day 56

“ULIXACALTAMIDE (N = 199)”	“PLACEBO (N= 233)”
“-4.3”	“-1.7”

“PRIMARY ENDPOINT” (opens the source at this quote in a new tab)
“Ulixacaltamide demonstrated a statistically significant clinical improvement of -2.57 points in the primary endpoint, mADL11 change at Day 56 vs. placebo (95% CI, -3.62 to -1.53; p=0.0000014).” (opens the source at this quote in a new tab)

Primary endpoint probability value in the results presentation

“Ulixacaltamide demonstrated a statistically significant clinical improvement of -2.57 points in the primary endpoint, mADL11 change at Day 56 vs. placebo (95% CI, -3.62 to -1.53; p=0.0000014).” (opens the source at this quote in a new tab)

Change over time

Outcome	Least-squares mean difference versus placebo and 95% CI	Probability value
Rate of disease improvement	“-2.27 (-3.11, -1.42)”	“<0.0001”

Day 84 sensitivity analysis

Outcome	Ulixacaltamide	Placebo	Probability value
mADL11 change from baseline to Day 84	“-3.4”	“-1.9”	“0.0049”

Health-related quality of life and patient-reported outcomes

Patient and clinician global impressions

Outcome	Least-squares mean difference versus placebo and 95% CI	Probability value
PGI-C at Day 56	“-0.60 (-0.81, -0.39)”	“<0.0001”
CGI-S change at Day 56	“-0.29 (-0.46, -0.12)”	“0.0007”

Generic health utility and preference-based quality-of-life outcomes

No evidence found.

Safety results

Drug-related TEAEs leading to discontinuation

“STUDY 1”· “ULIXACALTAMIDE”· “(N=233)”	“STUDY 1”· “PLACEBO”· “(N=234)”
“63 (27.0%)”	“4 (1.7%)”

Overall and serious adverse events

Safety outcome	Ulixacaltamide, 233 participants	Placebo, 234 participants
Any TEAE	“221 (94.9%)”	“177 (75.6%)”
Severe TEAE	“14 (6.0%)”	“10 (4.3%)”
Any serious adverse event	“2 (0.9%)”	“8 (3.4%)”

Common adverse events and serious treatment-related events across the Essential3 program

“The most common (≥10% patients) treatment emergent adverse events (TEAs) were constipation, dizziness, euphoric mood, brain fog, headache, paraesthesia and insomnia.” (opens the source at this quote in a new tab)
“There were no deaths and no drug-related serious adverse events.” (opens the source at this quote in a new tab)

Study limitations

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.