EMBOLD

31 evidence topics · 10 sources

Objective

Initial protocol: safety, tolerability, efficacy, and pharmacokinetics

“safety, tolerability, efficacy, and pharmacokinetics (PK)” (opens the source at this quote in a new tab)

Location and study date

Study design

Multicenter randomized study

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

EMBOLD: confirmatory cohort study design

“DOUBLE-BLIND TREATMENT PERIOD” (opens the source at this quote in a new tab)
“1:1” (opens the source at this quote in a new tab)

Placebo-period masking

“timing blinded to families and investigators” (opens the source at this quote in a new tab)

EMBOLD: confirmatory cohort interim analysis

“Successful interim analysis triggered early stop for efficacy” (opens the source at this quote in a new tab)

Eligibility criteria

EMBOLD: cohort 1 age and weight criteria

“2-18 years inclusive; weight ≥10 kg” (opens the source at this quote in a new tab)

Cohort 1: genetic disease eligibility

“Documented severe DEE with mutations in SCN2A or SCN8A genes” (opens the source at this quote in a new tab)

Initial protocol: exclusion of loss-of-function variants

“loss-of-function missense variant or a presumed LoF variant” (opens the source at this quote in a new tab)

Initial protocol: SCN2A seizure-onset eligibility

“seizure onset in first 3 months of life” (opens the source at this quote in a new tab)

Treatment

Cohort 1 starting dose and permitted adjustment

“0.5 mg/kg/day PRAX-562 QD” (opens the source at this quote in a new tab)
“Dose adjustment is permitted to a maximum of 1.0 mg/kg/day and a minimum of 0.25 mg/kg/day.” (opens the source at this quote in a new tab)

EMBOLD: confirmatory cohort treatment regimens

Regimen	Direct quotations
Relutrigine throughout treatment	“Relutrigine for 4 x 4 weeks”
Relutrigine and placebo periods	“Placebo for 1 x 4 weeks”· “Relutrigine for 3 x 4 weeks”
Dose	“1 mg/kg/day”

Study outcomes

Rationale for using monthly motor seizure frequency as the primary endpoint

Confirmatory cohort: primary outcome definition

“Change from baseline in monthly (28 day) motor seizure frequency” (opens the source at this quote in a new tab)

Rationale for endpoint selection

No evidence found.

Statistical analysis description

Number of participants (Planned and analyzed)

Initial protocol: planned enrollment

“will enroll ≈20 eligible male and female participants aged 2-18 years, inclusive, with a diagnosis of early onset SCN2A-DEE or SCN8A-DEE” (opens the source at this quote in a new tab)

EMBOLD: cohort 1 enrollment and efficacy population

“Sixteen patients were randomized (1:1)” (opens the source at this quote in a new tab)
“Fifteen patients were determined to be eligible for efficacy assessments.” (opens the source at this quote in a new tab)

EMBOLD: cohort 2 enrollment

“Randomized (N = 53)” (opens the source at this quote in a new tab)

Cohort 2: treatment-exposure analysis counts, not independent parallel groups

Treatment exposure	Participants
Relutrigine	“51”
Placebo	“25”

Description of analysis sets

Efficacy analysis population

“All efficacy analyses were conducted in the ITT population” (opens the source at this quote in a new tab)

Efficacy model: adjustment factors

“baseline seizure frequency and exposure time” (opens the source at this quote in a new tab)

Cohort 1: derivation of placebo-adjusted percentage reduction

“log-transformed placebo-adjusted relutrigine effect” (opens the source at this quote in a new tab)

Results

Participant disposition

Cohort 2: discontinuations during placebo exposure

Reason	Participants
Withdrawal of consent	“1”
Death	“1”

Baseline characteristics

Cohort 2: relutrigine-exposed population

Characteristic	Value
Age, mean (minimum, maximum), years	“6.0 (1, 18)”
SCN2A, participants (%)	“13 (25%)”
SCN8A, participants (%)	“38 (75%)”

Efficacy results

EMBOLD: primary efficacy results, first and confirmatory cohorts

“Relutrigine demonstrated placebo-adjusted seizure reduction in 16 weeks of 46% (p=0.0354) in the first cohort and 53% (p<0.0002) in the confirmatory, registration cohort” (opens the source at this quote in a new tab)

EMBOLD: cohort 1 seizure-freedom report at 16 weeks

“33% of patients were seizure-free” (opens the source at this quote in a new tab)

EMBOLD: open-label extension

“OLE data through 11 months support sustained seizure reduction (90%, n=13)” (opens the source at this quote in a new tab)
“mean longest period without seizures, 67 days vs. 3 at baseline” (opens the source at this quote in a new tab)

EMBOLD cohort 2: motor seizure-free days

“Key Secondary”	Estimate	p-value
Motor seizure-free days	“+66.2%”	“0.0340”

Health-related quality of life and patient-reported outcomes

EMBOLD cohort 2: clinician and caregiver global improvement

“Key Secondary”	Estimate	p-value
CGI-I (Clinician)	“-2.62”	“<0.0001”
CgGI-I (Caregiver)	“-3.7”	“0.002”

Relutrigine-specific health-related quality-of-life instrument results

No evidence found.

Safety results

EMBOLD: cohort 1 most common adverse events

“infections, vomiting, pyrexia, somnolence and constipation” (opens the source at this quote in a new tab)

EMBOLD: cohort 1 serious adverse events

“All SAEs determined to be not drug-related and were consistent with disease background.” (opens the source at this quote in a new tab)

Cohort 2: adverse-event severity

“TEAEs were mostly mild to moderate.” (opens the source at this quote in a new tab)

Cohort 2: adverse event leading to discontinuation during relutrigine exposure

“1 patient randomized to placebo arm discontinued while in relutrigine period due to an AE” (opens the source at this quote in a new tab)

Study limitations

Summary

Cohort 1 randomized 16 participants, with 15 eligible for efficacy assessment. Cohort 2 randomized 53 participants and stopped early after an efficacy interim analysis. Its relutrigine and placebo exposure populations overlap because some participants received both treatments during masked periods; the exposure counts should not be interpreted as independent parallel groups. The extension result at 11 months concerns 13 participants without a concurrent placebo comparison. Clinician and caregiver global-improvement scales are reported, but they should not be treated as equivalent to a direct health-related quality-of-life measure.