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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Praxis Precision Medicines Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

23 Aug 2023 → ongoing

Decision date (initial)

2023-05-17

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Praxis Precision Medicines

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Pharmacodynamic, Pharmacokinetic

Part A (Cohorts 1 and 2, randomized, double-blind): To evaluate the safety and tolerability of PRAX-562 in paediatric participants with SCN2A- and SCN8A- DEEs
Part A (Cohorts 3 and 4, randomized, double-blind): To assess the effect of PRAX-562 on the frequency of countable motor seizures in paediatric participants with SCN2A- and SCN8A- DEEs
Part B (Cohorts 1-4, open-label extension): To evaluate the long-term safety and tolerability of PRAX-562 in paediatric participants with SCN2A- and SCN8A- DEEs

Secondary objectives 6

1. Part A (Cohorts 1 and 2): To assess the effect of PRAX 562 on the frequency of countable motor seizures in pediatric participants with SCN2A- and SCN8A- DEEs
2. Part A (Cohorts 3 and 4): To evaluate the safety and tolerability of PRAX 562 in pediatric participants with SCN2A- and SCN8A- DEEs
3. Part A (Cohorts 3 and 4): To assess secondary efficacy outcomes of PRAX‑562 in pediatric participants with SCN2A- and SCN8A- DEEs
4. Part A and Part B: To characterize the PK of PRAX 562 oral suspension in pediatric participants with SCN2A- and SCN8A- DEEs
5. Part B (Cohorts 1 and 2): To assess the effect of PRAX 562 on the frequency of countable motor seizures in pediatric participants with SCN2A- and SCN8A- DEEs
6. Part B (Cohorts 3 and 4): To assess the long-term effect of PRAX 562 on the frequency of countable motor seizures in pediatric participants with SCN2A- and SCN8A- DEEs.

Conditions and MedDRA coding

SCN2A and SCN8A developmental and epileptic encephalopathy (SCN2A DEE and SCN8A DEE)

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. 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.
2. 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.
3. Is male or female aged ≥1 and ≤18 years at Screening.
4. Has a weight ≥7 kg at Screening.
5. 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).
6. Has been assessed as an appropriate and suitable candidate by the investigator and Eligibility Review Committee (ERC).
7. 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.
8. 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.
9. 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.
10. 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.
11. If sexually active and/or of childbearing potential, is willing to use a method of contraception (as defined in the protocol).

Exclusion criteria 16

1. 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.
2. 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.
3. 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
4. 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.
5. 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.
6. Has previously enrolled in or is currently participating in any PRAX-562 clinical trial.
7. 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.
8. Has a known hypersensitivity to any component of the formulation of PRAX-562.
9. 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).
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. Has 2 or more episodes of convulsive status epilepticus requiring hospitalization and intubation in the 6 months prior to Screening.
16. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Part A (Cohorts 1 and 2) & B: Incidence and severity of treatment-emergent adverse events (TEAEs)
2. Part A (Cohorts 3 and 4): Change from baseline in monthly (28-day) motor seizure frequency

Secondary endpoints 4

1. Part A (Cohorts 1 and 2) & B: Change from baseline in monthly (28-day) motor seizure frequency
2. Part A & B: Plasma concentrations of PRAX-562
3. Part A (Cohorts 3 and 4): Incidence and severity of treatment-emergent adverse events (TEAEs)
4. Part A (Cohorts 3 and 4): Number of motor seizure-free days -CGI-I at end of treatment -CgGI-I at end of treatment

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Praxis Precision Medicines Inc.

Sponsor organisation

Praxis Precision Medicines Inc.

Address

99 High Street Floor 30th

City

Boston

Postcode

02110-2320

Country

United States

Scientific contact point

Organisation

Praxis Precision Medicines Inc.

Contact name

Study sponsor contact

Public contact point

Organisation

Praxis Precision Medicines Inc.

Contact name

Study sponsor contact

Third parties 1

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Corrective measures 2 · Art. 77 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 84 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

10 submissions — initial application plus substantial / non-substantial modifications