A Phase 1, Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ISM8969

Official title

A Phase 1, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Ascending Oral Doses of ISM8969 in Healthy Adult and Elderly Participants and Obese Adult Participants at Risk of Cardiovascular Disease

Overview

This is a single center, phase 1, randomized, double-blind, placebo-controlled sequential study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple ascending oral doses of ISM8969 in healthy adults and elderly participants and obese adult participants at risk of cardiovascular disease.

Interventions

• Drug ISM8969 tablets or placebo
  Administration: Oral
• Drug ISM8969 tablets or placebo
  Administration: Oral
• Drug ISM8969 tablets or placebo
  Administration: Oral

Primary outcome measures

• The incidence of Adverse Events (AEs) after single or multiple doses of ISM8969 tablets. [Time frame: Up to 14 days after last dose.]
• Number of Participants with Clinical Laboratory Abnormalities, and Abnormalities in Vital Signs, Physical Examinations,12-lead ECG [Time frame: Up to 14 days after last dose.]
• C-SSRS Score(Type 1 to Type 5) [Time frame: Up to 14 days after last dose.]

Secondary outcome measures (12)

• Maximal observed plasma concentration (Cmax）. [Time frame: Day 1 and Day 14 after dose.]
• Time when the maximal concentration is observed (Tmax). [Time frame: Day 1 and day 14 after dose.]
• Area under the concentration-time curve from time zero to the last observed concentration (AUC0-t). [Time frame: Day 3 and Day 17 after dose.]
• Area under the concentration-time curve from time zero to infinity (extrapolated)(AUC0-inf). [Time frame: Day 3 and Day 17 after dose.]
• Terminal elimination half-life(T½). [Time frame: Day 3 and Day 17 after dose.]
• Apparent clearance (CL/F). [Time frame: Day 1 and Day 14 after dose.]
• Apparent volume of distribution (V/F). [Time frame: Day 1 and day 14 after dose.]
• Maximal observed cerebrospinal fluid(CSF) concentration (Cmax,csf). [Time frame: Day 14 after dose.]
• Minimal observed concentration at steady-state (Cmin,ss). [Time frame: Day 14 before the last dose.]
• Minimal observed cerebrospinal fluid(CSF) concentration at steady-state (Cmin,ss). [Time frame: Day 14 before the last dose.]
• Accumulation ratio (Day 14 : Day 1) (Racc). [Time frame: Day 14 after dose.]
• Change from baseline in the concentration of blood high sensitivity C-reactive protein(hsCRP). [Time frame: Day 14 after dose.]

Eligibility criteria

Inclusion criteria

Participants must meet all the following criteria to be included in the study:

Inclusion criteria 1\~4 are only for the healthy participants in the SAD and MAD study:

• Male or female participants, including adult participants (≥18 and <65 years of age) for the SAD cohorts 1-6 and MAD cohorts 1-3, and elderly participants (≥65 and ≤80 years of age) for MAD cohort 4.
• Body mass index (BMI) >18.5 and <30.0 kg/m2 and body weight ≥50.0 kg for males and ≥45.0 kg for females.
• Non-smokers (no use of tobacco or nicotine products within 1 month prior to screening).
• Healthy as defined the current protocol.

Inclusion criteria 5\~9 are only for the obese participants at risk of cardiovascular disease in MAD study):

• Male or female, ≥18 and ≤65 years of age.
• 30.0 kg/m2 ≤ BMI < 42.0 kg/m2.
• No change in body weight or self-reported change of less than 5.0% within 3 months before screening.
• Presence of 1 or more risk factors for cardiovascular disease such as hypertension, hyperlipidemia. If present, must be controlled with stable medication dose/therapy (defined as a stable medication dose/therapy for 3 months or longer).
• hsCRP ≥3 mg/L.

Exclusion criteria

Participants for whom any of the following applies will be excluded from the study:

• Columbia suicide severity rating scale (C-SSRS) score above Type 1 ideation.
• Positive serology test results for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, human immunodeficiency virus (HIV) antigen and antibody, treponema pallidum antibody or QuantiFERON®-TB test at screening.
• Positive pregnancy test or lactating female participant.
• History of any central nervous system (CNS) disorder or history of seizure of any cause.
• Clinically significant 12-lead ECG, physical examination, vital signs or laboratory abnormalities at screening, including but not limited to defined in the protocol.
• History of significant cardiovascular or cerebrovascular disease within 6 months before screening, including but not limited to defined in the protocol.
• History of an active or untreated malignancy or are in remission from a clinically significant malignancy (other than basal- or squamous-cell skin cancer, or in situ carcinomas of the cervix) for less than 5 years; or there is a potential malignancy during screening.
• Participation in a clinical research study involving the administration of an investigational or marketed drug or device within 30 days (or 5 half-lives, whichever is longer) prior to the first dosing, administration of a biological product in the context of a clinical research study within 90 days (or 5 half-lives, whichever is longer) prior to the first dosing, or concomitant participation in an investigational study involving no drug or device administration.
• Presence of contraindication to lumbar puncture or lumbar catheter as judged by Investigator.

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

Double blind

Primary purpose

Treatment

Study locations

Australia · 1 center

• Nucleus Network Pty Ltd. — Melbourne

Identifiers

NCT: NCT07581431 · ISM8969-101

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗