Safety and pharmacokinetics study in healthy Japanese volunteers

JRCT ID: jRCT2051210087

Registered date:22/09/2021

Basic Information

• Recruitment status: Complete
• Health condition(s) or Problem(s) studied: Ulcerative colitis
• Date of first enrollment: 17/09/2021
• Target sample size: 48
• Study type: Interventional

Intervention(s)

Part A
Part A includes the following two dose regimen groups:
- 25 mg dose regimen group: ABX464 25 mg or placebo
- 50 mg dose regimen group: ABX464 50 mg or placebo
In each dose regimen group, 12 subjects will be randomly assigned, according to a 3:1 ratio, to receive either ABX464 (9 subjects) or its matching placebo (3 subjects). Enrolment will start with the 25 mg dose regimen group.
Following a blinded review of available safety data by the DSMB after the subjects of the first dose regimen have received the study treatment (ABX464, 9 subjects and placebo, 3 subjects), the 50 mg dose regimen group will open for enrolment and receive the study treatment.
For each dose regimen group, subjects will be admitted to the study center on D?1, administered the study treatment on D1, orally in the morning in the standardized fed conditions, and discharged from the study center on D4 after completion of study assessments. Subjects will visit the study center on D8 and D15 (End of Study [EoS] visit) for PK and safety assessments.
Body weight, vital signs, laboratory parameters including renal and hepatic markers, will be evaluated at screening and at each visit to the study center.

Part B
Following a blinded review of available safety and PK data by the DSMB after the subjects of part A have received the study treatment (ABX464 or placebo), the part B will start for enrolment.
Part B includes the following two dose regimen groups:
- 25 mg dose regimen group: ABX464 25 mg or placebo for 28 days
- 50 mg dose regimen group: ABX464 50 mg or placebo for 28 days

In each dose regimen group, 12 subjects will be randomly assigned, according to a 3:1 ratio, to receive either ABX464 (9 subjects) or its matching placebo (3 subjects).
Enrolment will start with the 25 mg dose regimen. The 50 mg dose regimen group will be open for enrolment and receive the study treatment after discussion and decision by the Sponsor and the Investigator based on available safety data for at least 7 days of treatment in the lower dose regimen group.
For each dose regimen group, subjects will be admitted to the study center on D?1, administered study treatment once daily from D1 to D28, and discharged from the study center on D31 (72 hours after the last intake of the study drug). Subjects will visit the study center on D35 and D42 (EoS visit) for PK and safety assessments.
Body weight, vital signs, laboratory parameters including renal and hepatic markers, and physical examination will be evaluated at screening and at each visit to the study center.

Outcome(s)

Primary Outcome

Part A
Primary safety endpoints:
- The number of incidences of treatment-emergent serious adverse events (SAEs).
- The number of incidences of treatment-emergent adverse events of special interest (AESIs).
- The number of incidences of clinically significant laboratory abnormalities.
- The number of incidences of all adverse events (AEs) (causally related and non-related) and SAEs, further categorized by severity.
Pharmacokinetic endpoints:
- Pre-dose plasma concentrations of ABX464 and ABX464-N-Glu at D1.
- Post-dose plasma concentrations of ABX464 and ABX464-N-Glu at 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 168 and 336 hours after treatment intake at D1.

Part B
Primary safety endpoints:
- The number of incidences of treatment-emergent SAEs.
- The number of incidences of treatment-emergent AESIs.
- The number of incidences of adverse events leading to investigational product discontinuation.
- The number of incidences of clinically significant laboratory abnormalities.
- The number of incidences of all AE (causally related and non-related) and SAE, further categorized by severity.
Pharmacokinetic endpoints:
- Pre-dose plasma concentrations of ABX464 and ABX464-N-Glu at D1, D7, D14, D21, and D28.
- Post-dose plasma concentrations of ABX464 and ABX464-N-Glu at 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours (D2 pre-dose) after treatment intake at D1.
- Post-dose plasma concentrations of ABX464 and ABX464-N-Glu at 1, 2, 3, 4 hours after treatment intake at D7, D14, and D21.
- Post-dose plasma concentrations of ABX464 and ABX464-N-Glu at 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 168 and 336 hours after treatment intake at D28.
Pharmacodynamic endpoints:
- Levels of miR-124 expression in total blood (determined by quantitative polymerase chain reaction) pre-dose at D1, D7 and at D28.

Key inclusion & exclusion criteria

• Age minimum: >= 20age old
• Age maximum: <= 45age old
• Gender: Male

Include criteria

1.Male Japanese volunteers.
2.20 to 45 years old.
3.Considered by the Investigator, as healthy based on history, physical examination, and complete laboratory evaluation (laboratory parameters should be within normal ranges of the study center's laboratory or considered not clinically significant by the Investigator).
4.Vital signs (supine blood pressure, resting pulse rate, body temperature) should be within normal ranges and no deviation from standard 12-lead electrocardiogram (ECG) should be observed at screening.
Body mass index (BMI) should be between 18 (inclusive) and 27 kg/m2 (inclusive).
5.Non-smokers at enrolment.
6.Subjects must understand, sign and date the written voluntary Informed Consent Form at the visit prior to any protocol-specific procedures.
7.Able and willing to comply with study visits and procedures as per protocol.
8.Males receiving the study treatment and their partners must agree to use a highly effective contraceptive method during the study and for 6 months after the last dose of study drug. Highly effective methods of contraception include true abstinence, intrauterine device (IUD) or hormonal contraception aiming at inhibition of ovulation, intrauterine hormone releasing system, bilateral tubal ligation, and vasectomized partner. True abstinence is defined when this is in line with the preferred and usual lifestyle of the subject. In each case of delayed menstrual period (over 1 month between menstruations) in a female partner of a male subject, confirmation of absence of pregnancy of the partner is required. Male subjects must not be planning pregnancy, should use a condom and must not donate sperm during the study and for 6 months after the last dose of study drug.

Exclude criteria

1.Acute disease state (e.g., nausea, vomiting, diarrhea, or fever within a week) or chronic infectious disease (positive results for hepatitis B surface antigen [HBsAg], hepatitis C virus antibody, human immunodeficiency virus antigen/antibody, tuberculosis determined by QuantiFERON-TB Gold Plus test). Subjects who have positive hepatitis B core antibody [HBcAb] can be enrolled but must have an undetectable hepatitis B virus [HBV] viral load (HBV DNA test).
2.Positive results for SARS-CoV-2 antigen determined by polymerase chain reaction method.
3.History of recent grade 3 or 4 opportunistic infection or underlying conditions that may predispose them to grade 3 or grade 4 infection.
4.History of cardiovascular, pulmonary, gastrointestinal, hepatic, pancreatic, renal, metabolic, hematological, neurological, psychiatric, or systemic disease that could jeopardize the safety of the subject or the validity of the study results.
5.Illicit drug or alcohol abuse, or dependence within a year.
6.Blood donation within 3 months prior to screening.
7.Use of any investigational or non-registered product within 3 months or within 5 half-lives preceding baseline, whichever is longer.
8.Use of any immunosuppressive drugs (except topical steroids) within 3 months prior to first dose.
9.Any history of hypersensitivity to drugs.
10.Any condition, which in the opinion of the Investigator, could compromise the subject's safety or adherence to the study protocol.

Related Information

• Primary Sponsor: Owada Yasuko