Dose Escalation Study to Assess the Safety, Tolerability, Pharmacokinetics And Pharmacodynamics of SIF001 in Healthy Subjects and in Epilepsy Patients

Official title

A Phase 1, Double-Blind, Placebo-Controlled, Randomized, Single and Multiple Ascending Dose Escalation Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of SIF001 in Healthy Subjects and in a Patient Cohort With Epilepsy

Overview

This is a dose escalation study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of SIF001, a monoclonal antibody with the potential to treat epilespy

Detailed description

Nonclinical studies including disease animal model studies and toxicological studies indicate that SIF001 has the potential to be a therapeutical agent for epilepsy treatment through addressing the underlying pathology. This a phase 1 dose escalation study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of SIF001 in healthy subjects and in a patient cohort with epilepsy.

Interventions

• Biological SIF001
  SIF001 intravenous infusion every two weeks
• Drug Placebo
  Placebo

Primary outcome measures

• Numbers of participants and rate of treatment-related adverse events assessed by dose group and by active treatment vs placebo [Time frame: Day 1 to Day 15 for SAD, and Day 1 to Day 43 for MAD]

Secondary outcome measures (8)

• Pharmacokinetic (PK) parameters/ profiles:Area under the plasma concentration versus time curve (AUC) [Time frame: Through Day 75]
• Pharmacokinetic (PK) profile/parameters: Maximum observed plasma concentration [Time frame: Through Day 75]
• Pharmacokinetic (PK) profile/parameters: Time at which maximum plasma concentration occurs [Time frame: Through Day 75]
• Pharmacokinetic (PK) profile/parameters: terminal elimination phase half life [Time frame: Through Day 75]
• Pharmacokinetic (PK) profile/parameters: total clearance [Time frame: Through Day 75]
• Pharmacokinetic (PK) profile/parameters: volume of distribution [Time frame: Through Day 75]
• Incidence of immunogenicity of SIF001 (production of anti-SIF001 antibodies) [Time frame: Through Day 75]
• To evaluate the change from baseline in seizure frequency (patient cohort only) [Time frame: from Day 1 to 29 (4 weeks), from Day 29 to 57 (4 weeks), and up to Day 57 in patients with epilepsy]

Eligibility criteria

Inclusion criteria

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Healthy Volunteers Only (Stage I and II (Phase 1a and 1b)):

• Male or female 18 to 55 years of age at the time of signing the informed consent.
• In good health as determined by the Investigator, based on medical history and screening evaluations.
• Body weight of ≥ 50 kg and BMI within the range 18-30 kg/m2 (inclusive)

Patients with Epilepsy Only (Stage II (Phase 1b)):

• Male or female 18 to 70 years of age at the time of signing the informed consent.
• A clinical diagnosis of focal or generalized epilepsy. Subjects must have motor seizures, with or without impaired awareness.
• Has a minimum of 4 seizures per 4-week period while taking 1 to 3 anti-seizure medications
• All medications and epilepsy interventions must be stable for 8 weeks before screening and are expected to remain stable during the study

All Subjects:

• Negative serum pregnancy test at screening and urine pregnancy test on Day -1 before starting study treatment in all pre-menopausal women and women < 12 months after the onset of menopause.
• Female participants of child-bearing potential and male participants must agree to use adequate contraception for the duration of the protocol.
• Able to sign informed consent and comply with the protocol.

Exclusion criteria

• Healthy Volunteers (Stage I and II (Phase 1a and 1b)):

• Subjects with any unresolved history of clinically significant disease, in the opinion of the investigator.
• Past or intended use of over-the-counter (OTC) or prescription medication (other than ≤ 2 g/day paracetamol \[acetaminophen\] or ≤ 800-mg/day ibuprofen), vitamins, and dietary or herbal supplements within 7 days or 5 half-lives of the respective drug, if known (whichever is longer), prior to dosing.

Patients with Epilepsy (Stage II (Phase 1b)):

• Acute precipitant of seizure within the past 3 months prior to screening such as major trauma, hypoglycemia, hyperglycemia, cardiac arrest, or post-anoxia

All Subjects:

• Any uncontrolled medical or psychiatric condition (e.g., hypertension, diabetes, chronic obstructive pulmonary disorder, asthma, depression) as judged by the investigator.
• Any clinically significant findings in medical examination, including physical examination, 12-lead ECG, vital signs, clinical laboratory tests. Specifically:

• alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3 × upper limit of normal (ULN), Total bilirubin ≥ 2 × ULN
• QT interval corrected by Fridericia's formula (QTcF) > 450 msec (male) or > 470 msec (female)
• Undergone major surgery ≤ 2 months prior to Day -1.
• Received any investigational drug within 30 days or 5 half-lives (whichever is longer, if known) before screening.
• Received any vaccine within 6 weeks before planned SIF001 administration.
• Loss of more than 100 mL blood (e.g., a blood donation) within 2 months before Day -1, or has received any blood, plasma, or platelet transfusions within 3 months before admission.
• Active liver disease or severe renal impairment, including serum creatinine ≥ 1.5 × ULN or estimated glomerular filtration rate of < 60 mL/min/1.73m2.
• Known history of substance use disorder.
• History of active human immunodeficiency virus (HIV), active hepatitis C virus (HCV), or active hepatitis B virus (HBV)
• Recent (2 weeks) history of a positive COVID-19 test result or disease symptoms of COVID-19 disease such as shortness of breath, cough, rhinorrhea, sore throat etc.
• Known history of hypersensitivity or anaphylactic reaction to intravenous medications, biologicals, or fluids.
• History of any clinically significant disease or disorder which, in the opinion of the investigators, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study.
• History of status epilepticus within 2 years of screening
• Known history of suicidality within 2 years of screening, or answering "yes" to questions 4 and 5 of the Columbia Suicide Severity Rating Scale (C-SSRS)
• Unable to complete this study for other reasons or the investigator believes that the subject should be excluded.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Sequential

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

United States · 10 centers

• Center for Neurosciences — Tucson
• Accel Research sites network — DeLand
• D&H Tamarac Research Center, LLC — Tamarac
• Encore Medical Research of Weston, LLC — Weston
• Hawaii Pacific Neuroscience, Comprehensive Epilepsy Center — Honolulu
• Mid-Atlantic Epilepsy and Sleep Center — Bathesda
• Quest Research Institute — Farmington Hills
• Dent Neurologic Institute — Amherst
• … and 2 more centers

Identifiers

NCT: NCT07051629 · SIF001-001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗