Essential1

26 evidence topics · 8 sources

Objective

Efficacy, safety, and tolerability in essential tremor

“evaluating the efficacy, safety and tolerability of ulixacaltamide (PRAX-944)” (opens the source at this quote in a new tab)

Location and study date

Reported study initiation

“Praxis initiated the PRAX-944 Phase 2b Essential1 Study for treatment of ET in the third quarter of 2021” (opens the source at this quote in a new tab)

Study locations and exact completion date

No evidence found.

Study design

Randomized placebo-controlled study

“Multi-center, randomized, double-blinded, placebo-controlled” (opens the source at this quote in a new tab)

Allocation and follow-up

Design feature	Reported value
Allocation among two active regimens and placebo	“1:1:1”
Intervention period	“56 days”
Safety follow-up	“14 days”

Extension and randomized-withdrawal substudy design

Design component	Reported value
Extension efficacy assessment	“14 weeks”
Randomized-withdrawal substudy participants	“21”
Initial ulixacaltamide assignment in the substudy	“11”
Initial placebo assignment in the substudy	“10”
Initial randomized-withdrawal period before crossover	“the initial 3-week period, crossing over to either placebo or ulixacaltamide for an additional 3-week period”

Eligibility criteria

Disease duration and functional severity

Criterion	Reported requirement
Duration of clinical essential tremor diagnosis	“≥3 YEARS”
Functional impairment	“MODERATE TO SEVERE”
Instruments used to determine functional impairment	“TETRAS AND CGI-S”

Treatment

Randomized dose regimens and duration

“60 mg or 100 mg” (opens the source at this quote in a new tab)
“56 days” (opens the source at this quote in a new tab)

Background propranolol

“a stable dose of propranolol for the duration of the study.” (opens the source at this quote in a new tab)

Study outcomes

Rationale for using modified TETRAS activities of daily living as the primary endpoint

Primary scale and subsequent mADL11 analysis

Outcome component	Reported measure or value
Primary assessment	“Day 56”
Primary scale	“mADL”
Maximum primary scale score	“42”
Performance components included in the primary scale	“Spirals (left, right)”
Additional performance component	“Handwriting”
Post-hoc functional analysis	“mADL excluding TETRAS-PS items”

Meaningful change in the functional-only mADL11 scale

“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)

Reliability of the TETRAS performance scale

“The inter- and intra-rater intraclass correlations for head and upper limb tremor ranged from 0.86 to 0.96” (opens the source at this quote in a new tab)

Separate validation of the TETRAS-PRO instrument

“The 30-day estimate of minimum detectable change (MDC) was 6.6 (95%CI 5.2–8.0).” (opens the source at this quote in a new tab)

Statistical analysis description

Number of participants (Planned and analyzed)

Randomized and analyzed participants

“132 adults were randomized and treated; 116 were included in mITT analysis” (opens the source at this quote in a new tab)

Treatment-specific analysis populations

Population	Pooled ulixacaltamide regimens	Placebo
Safety	“n=91”	“n=41”
mITT	“n=78”	“n=38”

Extension completer populations

Population	Reported participants
Continued into the blinded lead-in extension	“75”
Included in the extension completer analysis	“65”
Continued ulixacaltamide	“n=39”
Delayed initiation of ulixacaltamide after placebo	“n=26”

Description 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

“Mixed Model Repeated Measures (MMRM), Adjusted by baseline value, propranolol use, and familial history of ET. All p values are nominal.” (opens the source at this quote in a new tab)

Results

Participant disposition

Discontinuation within the mITT population

Disposition	Ulixacaltamide, 78 participants	Placebo, 38 participants
Discontinued	“13 (17%)”	“4 (11%)”
Discontinued because of adverse events	“9 (12%)”	“1 (3%)”

Baseline characteristics

Demographic and clinical characteristics of the mITT population

Characteristic	Ulixacaltamide, 78 participants	Placebo, 38 participants
Age, mean and range	“70.4 (32, 86)”	“67.7 (29, 88)”
Family history of essential tremor	“59 (76%)”	“23 (61%)”
Propranolol use	“27 (35%)”	“9 (24%)”
Duration of essential tremor, mean years	“20.3”	“20.2”
mADL score, mean and range	“20.6 (12, 32)”	“20.8 (12, 34)”
TETRAS-ADL score, mean and range	“29.0 (20, 38)”	“28.6 (19, 39)”
mADL11 score, mean and range	“16.4 (9, 25)”	“16.4 (8, 25)”

Efficacy results

Primary and secondary endpoint interpretation in the initial results announcement

“primary efficacy endpoint relative to placebo that did not reach statistical significance (p=0.126)” (opens the source at this quote in a new tab)
“nominal statistical significance in TETRAS-ADL secondary endpoint (p=0.026)” (opens the source at this quote in a new tab)

Day 56 least-squares mean changes

Outcome	Ulixacaltamide	Placebo	Reported probability value
mADL primary endpoint	“-3.01”	“-1.44”	“p = 0.126”
mADL excluding performance items, post-hoc analysis	“-2.69”	“-0.88”	“p = 0.042”
TETRAS-ADL secondary endpoint	“-3.6”	“-1.07”	“p = 0.026”

Extension and randomized-withdrawal findings

“up to 14 weeks showed maintained or improved efficacy results” (opens the source at this quote in a new tab)
“Patients withdrawing from ulixacaltamide to placebo experienced worsening in mADL11” (opens the source at this quote in a new tab)

Extension completer analysis: mean mADL11 improvement

Treatment sequence	Week 8 improvement	Week 14 improvement
Continued ulixacaltamide	“3.09”	“4.81”
Placebo followed by ulixacaltamide	“1.21”	“4.36”

Health-related quality of life and patient-reported outcomes

Global impression outcomes

“Nominal statistically significant improvements observed in Clinical Global Impression-Severity (CGI-S) and in Patient Global Impression-Change (PGI-C)” (opens the source at this quote in a new tab)

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

No evidence found.

Safety results

Treatment-emergent adverse events

Safety outcome	Ulixacaltamide, 91 participants	Placebo, 41 participants
Any TEAE	“70 (76.9%)”	“21 (51.2%)”
Dizziness	“13 (14.3%)”	“2 (4.9%)”
Constipation	“9 (9.9%)”	“0”
Headache	“8 (8.8%)”	“1 (2.4%)”
Fatigue	“8 (8.8%)”	“1 (2.4%)”
Anxiety	“6 (6.6%)”	“0”
Feeling abnormal	“6 (6.6%)”	“0”
Paraesthesia	“6 (6.6%)”	“0”

Study limitations

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.