Part A (Single Ascending Dose):Primary: To assess the safety and tolerability of single oral doses of PRAX-628 Secondary: To evaluate the pharmacokinetics (PK) of single oral doses of PRAX-628 Part B (Multiple Ascending Dose):Primary: To assess the…
ID
Source
Brief title
Condition
- Seizures (incl subtypes)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Part A (SAD):
• Incidence and severity of adverse events (AEs)
• Changes in vital sign measurements
• Changes in clinical laboratory results
• Changes in electrocardiogram (ECG) parameters
Part B (MAD):
• Incidence and severity of AEs
• Changes in vital sign measurements
• Changes in clinical laboratory results
• Changes in ECG parameters
• Incidence of Columbia-Suicide Severity Rating Scale (C-SSRS) measured
suicidal ideation or behavior
Part C (Food Effect):
• Incidence and severity of AEs
• Changes in vital sign measurements
• Changes in clinical laboratory results
• Changes in ECG parameters
Secondary outcome
Part A:
• Plasma concentrations of PRAX-628
• Maximum observed concentration (Cmax)
• Time to maximum observed concentration (tmax)
• Area under the drug concentration-time curve from time zero to infinity
(AUCinf)
• Area under the concentration time curve from time zero to the last measurable
concentration (AUClast)
• Apparent terminal elimination half-life (t*)
• Clearance (CL/F)
• Volume of distribution (Vd/F)
• Dose normalized Cmax
• Dose normalized AUCinf
Part B (MAD):
• Plasma concentrations of PRAX-628
• Cmax
• tmax
• AUClast
• AUCtau
• t*
• Accumulation ratio based on AUC (Rac(AUC))
• Accumulation ratio based on Cmax (Rac(Cmax))
Part C (Food Effect):
• Plasma concentrations of PRAX-628
• Cmax
• tmax
• AUCinf
• AUClast
• AUC0-120
• CL/F
• Vz/F
• t*
• %AUCex
Background summary
There is a significant need for better tolerated NaV blockers for patients with
focal epilepsy. PRAX-628 has the potential to be a safe and effective treatment
for patients with this condition and has shown efficacy in rodent models of
epilepsy. Currently available standard-of-care NaV blockers used to treat
epilepsy are limited by a low therapeutic index and a requirement to titrate to
an efficacious concentration while managing tolerability. Significant
class-related adverse effects are CNS related, including ataxia, drowsiness,
and dizziness, which may be due to the excessive and long-lasting inhibition of
peak INa resulting in an inability of existing NaV blockers to selectivity
reduce hyperexcitability while sparing normal brain function.
Preclinical data demonstrate PRAX-628 differentiates from approved NaV blockers
in several ways leading to an increased preclinical protective index (range
between exposures that are efficacious in the maximal electroshock assay [MES]
seizure model and exposures that reduce spontaneous movement in the spontaneous
locomotor activity assay [sLMA] model). This increased protective index may
predict greater clinical tolerability for PRAX-628. Features of PRAX-628 that
may support this increased protective index are proposed to be an increase in
the potency for persistent and peak INa, rapid INa inhibition kinetics,
increase in activity-dependent inhibition of peak INa, and increased
selectivity against non-NaV mediated activity.
PRAX-628 has completed evaluation in 4-week Good Laboratory Practice (GLP)
toxicology studies in 2 species, rat and dog. Dose levels for this
first-in-human (FIH) study have been determined based on data from nonclinical
safety and toxicology studies, efficacy in an epilepsy mouse model, and the
human equivalent dose (HED) of the no observed adverse effect level (NOAEL) in
the most sensitive species, rat. Based on predicted human PK exposures and
latency of extension seizures in the MES mouse model of generalized seizures, a
single 4.6 mg dose of PRAX-628 was predicted to achieve exposures resulting in
a minimal anticipated biological effect level (MABEL) (maximum observed
concentration [Cmax] < mouse MES EC50). Based on a 60 kg person, the HED to the
NOAEL in rats (5 mg/kg/day dose), with the incorporation of a 10-fold safety
margin, is 4.8 mg. Also, based on predicted human PK exposures, a dose of 6.6
mg is predicted to produce an AUC of 300 ng/mL, 1/50th the rat NOAEL exposure.
Given the convergence of the recommended starting dose based on these 3
methods, a starting dose of 5 mg was selected, which is predicted to provide a
safety margin greater than 20-fold the exposure (based on free Cmax) at the
NOAEL in both the rat and dog. Further information is available in the
Investigator*s Brochure.
Study objective
Part A (Single Ascending Dose):
Primary: To assess the safety and tolerability of single oral doses of PRAX-628
Secondary: To evaluate the pharmacokinetics (PK) of single oral doses of
PRAX-628
Part B (Multiple Ascending Dose):
Primary: To assess the safety and tolerability of 10-day repeat oral doses of
PRAX-628
Secondary: To evaluate the PK of 10-day repeat oral doses of PRAX-628
Part C (Food Effect):
Primary: To assess the safety and tolerability of oral doses of PRAX-628 in the
fed and fasted state
Secondary: To evaluate the effect of food on the PK of PRAX-628
Study design
This is a trial to assess the safety, tolerability, PK, and PD of PRAX-628 in
healthy participants aged 18 to 55 years (inclusive). The trial is initially
comprised of 3*parts, as follows:
Part A is randomized, double-blinded, and placebo-controlled. Part A is
designed to investigate the safety, PK, and PD of single ascending doses of
PRAX-628.
Part B is randomized, double-blinded, and placebo-controlled. Part B is
designed to investigate the safety, PK, and PD of multiple ascending doses
(selected based on the results from Part A) of PRAX-628.
Part C is a randomized, open-label, crossover design food effect evaluation to
investigate the PK of a single 30 mg dose of PRAX-628 in the fasted and fed
state.
Parts A and B are double blinded. Parts A, B, and C consist of 3*periods:
Screening/Baseline, Intervention, and Safety Follow-up.
Intervention
Part A (Single Ascending Dose) active PRAX-628 or placebo:
A1:5 mg, oral, fasted
A2:Up to 15 mg, oral, fasted
A3:Up to 45 mg, oral, fasted
A4:Up to 130 mg, oral, fasted
A5 and beyond: Maximum of 3-fold over of the highest prior dose tested, oral,
fasted
Part B (Multiple Ascending Dose) active PRAX-628 or placebo:
A1:5 mg, oral, fasted
A2:Up to 15 mg, oral, fasted
A3:Up to 45 mg, oral, fasted
A4:Up to 130 mg, oral, fasted
A5 and beyond: Maximum of 3-fold over of the highest prior dose tested, oral,
fasted
Part C (Food Effect Evaluation):
30 mg, oral, in the fasted and fed state.
Study burden and risks
PRAX-628 has not previously been studied in humans and there are no known
benefits.
The most notable findings in the GLP toxicology studies in rats and dogs were
ataxia in high dose rats and hypoactivity and muscle fasciculation (one animal)
in high dose dogs. These findings were not considered adverse given the lack of
effect on body weights and/or food consumption and lack of an adverse impact on
the overall health and well-being of the animals. Tremors and/or more severe
CNS-related clinical signs were noted at higher doses in preliminary
range-finding toxicity studies. More detailed information can be found in the
IB.
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Listed location countries
Age
Inclusion criteria
1. Willing and able to provide informed consent indicating that they understand
the purpose of the clinical trial and the procedures that are required for the
clinical trial, and that they are willing to comply with scheduled visits, and
all studyrelated procedures.
2. Male or female between the ages of 18 and 55 years, inclusive.
3. Body mass index (BMI) of 18.0 to 32.0 kg/m2, inclusive, and a total body
weight of at least 50 kg.
4. Females of childbearing potential are not pregnant or breast-feeding, have a
negative serum pregnancy test at Screening and a negative urine pregnancy test
at Baseline and are not planning to get pregnant for the duration of the trial.
5. Female of nonchildbearing potential by reason of surgery or at least 1 year
postmenopausal (ie, 12 months since last menses) with confirmation by follicle
stimulating hormone (FSH) at Screening only,
or
Female of childbearing potential who is willing to use a highly effective
method or methods of contraception as defined in this protocol and for the
duration prescribed in this protocol,
or
Male who is willing and able to use a highly effective method or methods of
contraception as defined in this protocol and for the duration prescribed in
this protocol.
Exclusion criteria
1. Any clinically significant abnormalities, medical, or psychiatric conditions
identified by a detailed medical history, or physical examination, that in the
opinion of the investigator would pose an additional safety risk to the
participant or compromise the objectives of the study.
2. A history of cardiac disease(s)/cardiac conduction disorders/or cardiac
structural abnormality(ies) (e.g., atrial or ventricular septal defects,
valvular heart disease, coarctation of the aorta, or hypertrophic obstructive
cardiomyopathy).
3. Has a history of any lifetime suicide attempt or active suicidal ideation as
confirmed by C-SSRS Baseline Version (Part B only).
4. Any surgical or medical condition which might significantly alter the
absorption, distribution, metabolism, or excretion of drugs or which may
jeopardize the participant in case of participation in the study. Examples of
such conditions include (but are not limited to):
a. History of inflammatory bowel syndrome, gastritis, gastrointestinal or
rectal bleeding;
b. History of major gastrointestinal tract surgery (ie, gastrectomy, bowel
resection, etc.);
c. History or evidence of pancreatic injury or pancreatitis;
d. History or presence of impaired renal function as indicated by abnormal
renal function (estimated glomerular filtration rate [eGFR] <90 mL/min/1.73m2)
or abnormal urinary constituents (eg, albuminuria).
5. Abnormal vital signs after at least 5 minutes resting in the supine
position:
a. Systolic blood pressure <=90 or >=140 mmHg
b. Diastolic blood pressure <=40 or >=90 mmHg
c. Heart rate <=40 or >=100 bpm
d. Body temperature <=35.5°C or >=37.5°C
6. Abnormal standard 12-lead ECG after at least 5 minutes resting in the supine
position:
a. PR interval <120 with evidence of pre-excitation syndrome (e.g, delta wave)
or >220 ms
b. QRS >120 ms
c. QTcF <320 ms or >=450 ms if male or <320 ms or >=470 ms if female
7. Any finding that, in the judgement of the investigator, is a clinically
significant abnormality, including serum chemistry, hematology, coagulation,
and urinalysis test values (abnormal test results may be repeated for
confirmation).
8. An elevation of >=1.5× ULN for AST or ALT/ serum glutamic pyruvic
transaminase (SGPT) or >=2×ULN for total bilirubin.
9. Positive test for HIV, hepatitis B (HBsAg), or hepatitis C.
10. History of drug or alcohol abuse.
11. Positive drug or alcohol test at Screening or Baseline. (Abnormal test
results may be repeated for confirmation).
12. Smoker (use of tobacco or nicotine-containing products in the previous 3
months) or evidence of such use as indicated by cotinine testing at Screening
and Baseline.
13. Use of an investigational drug or device within 90 days or 5 half-lives
preceding the first dose of study drug, whichever is longer.
14. Use of prescription or nonprescription drugs or dietary or herbal
supplements of clinical concern within 7 days or within 5 times the elimination
half-life (whichever is longer) prior to the first dose of study drug. Refer to
the relevant section(s) of the protocol for potential exceptions which must be
approved by the sponsor/designee.
15. Inability to abstain from eating or drinking grapefruit or
grapefruit-related citrus fruits (eg, Seville oranges, pomelos) from 7 days
prior to the first dose of study drug until collection of the final PK blood
sample.
16. Any vaccination within 14 days of the first dose of study drug.
17. Blood donation (excluding plasma donations) or significant blood loss of
approximately 500 mL or more within 90 days (male) or 120 days (female) prior
to first dose of study drug.
18. Presence or history of any allergy or hypersensitivity to any component of
the study drug product , or history of severe allergy or anaphylaxis to a
drug, food, or other exposure.
19. Unwilling or unable to comply with the lifestyle considerations described
in this protocol.
20. An employee or family member of an employee of the sponsor, or an employee
or family member of the study site staff.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2022-003054-31-NL |
| CCMO | NL82665.056.22 |