A Phase 2, Double-Blind, Randomized Clinical Trial to Explore the Safety, Tolerability, Efficacy, and Pharmacokinetics of PRAX-562 in Pediatric Participants with Developmental and Epileptic Encephalopathies Followed by an Open-Label Extension
- Trial ID
- 2022-502298-41-00
- Protocol
- PRAX-562-221
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 2, double-blind, randomized clinical trial is to evaluate the **safety** and **tolerability** of PRAX-562 in pediatric participants with **Developmental and Epileptic Encephalopathies** (DEEs). This is crucial for determining the potential of PRAX-562 as a therapeutic option for this population, ensuring that the treatment does not pose undue risk and is well-tolerated over the course of the study. Additionally, the trial aims to assess the effect of PRAX-562 on the frequency of countable motor seizures in these participants, which is clinically relevant for understanding its efficacy in reducing seizure burden.
The secondary objectives include:
- Assessing the effect of PRAX-562 on the frequency of countable motor seizures in pediatric participants with DEEs in Part A (Cohorts 1 and 2) and Part B.
- Evaluating the safety and tolerability of PRAX-562 in Part A (Cohorts 3 and 4).
- Assessing secondary efficacy outcomes of PRAX-562 in participants with early-onset SCN2A-DEE in Part A (Cohorts 3 and 4).
- Characterizing the pharmacokinetics of PRAX-562 oral suspension in pediatric participants with DEEs in both Part A and Part B.
Participants
The clinical trial involves a total of **10 participants** diagnosed with **SCN2A and SCN8A developmental and epileptic encephalopathy (SCN2A DEE and SCN8A DEE)**. The study population comprises both male and female pediatric subjects aged between 2 and 18 years. Participants were selected based on specific criteria, including a documented genetic variant in SCN2A or a diagnosis of SCN8A-DEE, with seizure onset occurring in the first three months of life. All participants are required to maintain stable antiseizure therapies, including any ketogenic or other dietary interventions, throughout the trial. The trial population includes individuals who are considered vulnerable due to their age and health condition. Participants must have a minimum weight of 10 kg and experience at least eight countable motor seizures in the four weeks prior to screening and during the 28-day baseline observation period. The selection process ensures that participants are suitable candidates as assessed by the investigator and the Eligibility Review Committee.
Plans and Procedures
The clinical trial is a **Phase 2, double-blind, randomized** study designed to evaluate the safety, tolerability, efficacy, and pharmacokinetics of PRAX-562 in pediatric participants with **developmental and epileptic encephalopathies** (DEE), specifically SCN2A and SCN8A DEE. The trial is structured into two parts: Part A, which is double-blind and randomized, and Part B, an open-label extension. The primary objective of Part A is to assess the safety and tolerability of PRAX-562, as well as its effect on the frequency of countable motor seizures. Part B aims to evaluate the long-term safety and tolerability of the treatment. The trial is expected to conclude by December 2025, with recruitment having commenced in June 2023.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, weight, seizure frequency, and genetic diagnosis. Following successful screening, participants will be randomized into cohorts for Part A, where they will receive either PRAX-562 or a placebo. Regular follow-up visits will be conducted to monitor treatment-emergent adverse events (TEAEs) and changes in seizure frequency. The end-of-study visit will mark the conclusion of the participant's involvement, with the option to continue into the open-label extension if applicable.
The expected duration of participant involvement is up to 64 weeks, depending on the cohort and progression into the open-label extension. Conditions that may lead to early termination from the study include non-compliance with study procedures, withdrawal of consent, or the occurrence of significant adverse events. The study employs a rigorous methodology to ensure the reliability and validity of the findings, with primary endpoints focusing on the incidence and severity of TEAEs and changes in seizure frequency. Secondary endpoints include plasma concentrations of PRAX-562 and changes in motor seizure-free days from baseline.
Treatment
The clinical trial involves the administration of **PRAX-562**, a powder for oral suspension, as the experimental medication. The active substance in PRAX-562 is **3-(ethoxydifluoromethyl)-6-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine**, a chemical compound. The pharmaceutical form of PRAX-562 is a powder intended for oral suspension, and it is administered via oral, nasogastric tube, or percutaneous endoscopic gastrostomy tube use. The dosing regimen involves a maximum daily dose of 1.0 mg/kg, with a total maximum dose of 448 mg/kg over a treatment period of up to 64 days. The medication is provided by Praxis Precision Medicines Inc. and is designated as an orphan drug under the numbers EU/3/21/2539 & 2540.
In addition to the experimental treatment, a **placebo** is used as a comparator in the study. The placebo is also formulated as a powder for oral suspension, mirroring the administration routes of the experimental drug, which include oral, nasogastric tube, or percutaneous endoscopic gastrostomy tube use. The placebo is designed to match the appearance and administration method of PRAX-562 to maintain the double-blind nature of the trial. The placebo does not contain the active substance and serves to evaluate the efficacy and safety of PRAX-562 by comparison.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. The trial is structured to assess the safety, tolerability, and efficacy of PRAX-562 in pediatric participants with developmental and epileptic encephalopathies, with a focus on the frequency of countable motor seizures. The study includes both a double-blind phase and an open-label extension to evaluate long-term outcomes.
Efficacy
Efficacy in this clinical trial will be assessed through several primary and secondary endpoints. The primary endpoints include the incidence and severity of treatment-emergent adverse events (TEAEs) for Part A (Cohorts 1 and 2) and Part B, as well as changes from baseline in monthly (28-day) motor seizure frequency for Part A (Cohorts 3 and 4). Secondary endpoints will evaluate changes from baseline in monthly motor seizure frequency for Part A (Cohorts 1 and 2) and Part B, plasma concentrations of PRAX-562, the incidence and severity of TEAEs for Part A (Cohorts 3 and 4), and changes in motor seizure-free days from baseline.
The efficacy parameters will be measured and collected at specified intervals throughout the trial. The frequency of motor seizures will be recorded in a daily seizure diary maintained by the participants' caregivers. This data will be analyzed to determine changes from baseline in seizure frequency and seizure-free days. Plasma concentrations of PRAX-562 will be measured to assess pharmacokinetics. The collection and analysis of these parameters will be conducted using validated methods to ensure accuracy and reliability of the results.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participant, or parent/legal guardian, is willing to sign a written or electronic informed consent form (ICF) (and assent form, if applicable) indicating that he/she understands the purpose of the clinical trial; understands, and can perform, complete, and comply with all the procedures and assessments that are required during the clinical trial (including the seizure diary); and is willing to participate in the clinical trial.
- Has a documented variant in SCN2A with onset of seizures occurring in the first 3 months of life or has a diagnosis of SCN8A-DEE supported by both clinical and genetic findings. Genetic testing must be obtained via a laboratory accredited per Clinical Laboratory Improvement Amendments (CLIA) or College of American Pathologists (CAP) or equivalent.
- Is male or female aged ≥1 and ≤18 years at Screening.
- Has a weight ≥7 kg at Screening.
- Has a seizure frequency as follows: (a) At least 8 countable motor seizures in the 4 weeks immediately prior to Screening (the start of which is deemed to be the date of signing the ICF/assent form) as reported by the parent/legal guardian or in the opinion of the investigator as documented in medical notes. AND (b) b. At least 8 countable motor seizures (as defined in the note below) within 28 consecutive days in the Baseline Observation Period (during which seizure frequency is recorded in a daily seizure diary).
- Has been assessed as an appropriate and suitable candidate by the investigator and Eligibility Review Committee (ERC).
- Is on stable doses of ASMs for at least 1 month prior to Screening. For Cohorts 1 and 2, no more than 1 can be a sodium channel-blocking ASM, while for Cohorts 3 and 4 no more than 2 can be a sodium channel-blocking ASM.
- If using vagus nerve stimulation (VNS), must have been placed at least 3 months prior to Screening with stable setting for at least 1 month prior to Screening; VNS is not counted as an ASM.
- If on a ketogenic or other diets for management of seizures, must have started the diet at least 3 months prior to Screening with stable parameters for at least 1 month prior to Screening; diets are not counted as an ASM.
- Is willing and able to keep all antiseizure therapies (ASMs, VNS settings, ketogenic or other diet parameters, etc) stable throughout the clinical trial, unless instructed by the investigator or per protocol.
- If sexually active and/or of childbearing potential, is willing to use a method of contraception (as defined in the protocol).
Exclusion Criteria
- Has any significant ongoing disease, disorder, laboratory abnormalities, alcohol or drug abuse or dependence, environmental factor, or ongoing or history of any psychiatric, medical, or surgical condition that, in the judgment of the investigator in consultation with the medical monitor and/or sponsor designee, might jeopardize the participant’s safety or interfere with the absorption, distribution, metabolism, or excretion of PRAX-562, impact the clinical trial scientific objectives, or interfere with participation in the clinical trial.
- Has a clinically significant laboratory test result at Screening that would jeopardize safe participation in the clinical trial in the judgment of the investigator in consultation with the medical monitor and/or sponsor designee.
- Has any of the following abnormal laboratory test results at Screening: a. Serum total bilirubin value >1.5×the upper limit of normal (ULN) b. Serum ALT or AST value >3×ULN
- Has a positive test result or a known history of a positive test result for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or anti-hepatitis C virus (HCV) antibody at Screening.
- Has an abnormal ECG reading, including a QT interval corrected for heart rate using Bazett’s formula (QTcB) <350 and >450 msec (males) or <360 and >460 msec (females) at Screening and/or at Day 1 (visit 3), based on the average of triplicate measurements.
- Has previously enrolled in or is currently participating in any PRAX-562 clinical trial.
- Has received any other experimental or investigational drug, device, or other therapy within 30 days or 5 half-lives (whichever is longer) prior to Screening, including any prior use of gene therapy.
- Has a known hypersensitivity to any component of the formulation of PRAX-562.
- Does not comply with completing the seizure diary for at least 75% of the 28-day Baseline Observation Period (ie, cannot miss more than 7 consecutive days).
- Has any clinically significant or known pathogenic or likely pathogenic genetic variant other than in SCN2A and SCN8A or a genetic variant that may explain the participant’s epilepsy and/or developmental disorder.
- Has any other/additional etiology for epilepsy and/or DEE (eg, cortical dysplasia, encephalomalacia, etc) in the opinion of the investigator or confirmed by the ERC.
- If female, is currently pregnant or breastfeeding or is planning to become pregnant during the clinical trial or within 5 half-lives of the last study drug dose.
- Is required to take any excluded medication, dietary supplement, or food listed in the protocol or is anticipated to require treatment with at least 1 excluded medication during the clinical trial.
- Has a documented, functionally characterized loss-of-function (LoF) variant based on genetic testing and/or has documented clinical evidence that prior exposure to an SCB medication worsened seizures.
- Has 2 or more episodes of convulsive status epilepticus requiring hospitalization and intubation in the 6 months prior to Screening.
- Has a history of left bundle branch block, arrhythmias, Brugada syndrome, congenital heart disease, familial short QT syndrome, or family history of sudden death or ventricular arrhythmias, including idiopathic ventricular fibrillation.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Not Recruiting | 01 Jun 2023 | 70 |
Sites & Investigators
Research sites
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
PRAX-562 placebo powder for oral suspension | Placebo | N/A | — | — | — | N/A |
Relutrigine | Test | POWDER FOR ORAL SUSPENSION | ORAL, NASOGASTRIC TUBE OR PERCUTANEOUS ENDOSCOPIC GASTROSTOMY TUBE USE | 1.0 | 64 | PRD10068879 |