A Two-Part Study to Assess the Safety, Tolerability, PK and PD of ONO-7684 in Healthy Adult Volunteers

Phase 1CompletedNCT03919890

Ono Pharmaceutical Co., Ltd.72 enrolled

Overview

This is a first in human study to determine the safety, tolerability, pharmacokinetics and pharmacodynamics of ONO-7684 in healthy adult volunteers. This study will be conducted in 2 parts: Part A is a single-ascending dose and Part B is a multiple-ascending dose.

This study aims to obtain safety, tolerability, pharmacokinetic and pharmacodynamic data when ONO-7684 is administered orally as single doses and as multiple doses to healthy subjects. The study will consist of 2 parts: A single ascending dose (SAD) phase (Part A); a multiple ascending dose (MAD) phase (Part B). One cohort of Part A will receive ONO-7684 under both fasted and fed conditions to investigate the effect of food.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Conditions

Venous Thromboembolism

Interventions

ONO-7684DRUG

Single ascending doses for cohorts A1-A8 and multiple ascending doses cohorts B1-3

ONO-7684 PlaceboDRUG

Placebo comparator

Eligibility

Sex: ALLMin age: 18 YearsMax age: 55 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: 1. 18-55 years 2. normotensive male volunteers, or female volunteers of non-childbearing potential (Part B only) 3. body mass index 18.0-30.0 kg/m2 4. deemed healthy on the basis of a clinical history, physical examination, ECG, vital signs, and laboratory tests of blood and urine 5. registered with a General Practitioner (GP) in the UK 6. agree to use an effective method of contraception 7. able to give fully informed written consent Exclusion Criteria: 1. Positive tests for hepatitis B \& C, HIV 2. severe adverse reaction to any drug 3. sensitivity to trial medication 4. drug or alcohol abuse 5. current smoker or use of nicotine containing products in the previous 6 months 6. vegetarians or vegans, or unwilling to eat a high-fat breakfast (Part A food effect cohorts only) 7. use of strong CYP3A4/5 or P-glycoprotein inhibitors or inducers, anticoagulants, antiplatelet agents, non-steroidal anti-inflammatory drugs and/or acetylsalicylic acid within the previous 30 days 8. prescription or over-the-counter medication, vitamins, herbal treatments or dietary supplements within the previous 7 days (with the exception of paracetamol \[acetaminophen\]) 9. participation in other clinical trials of unlicensed medicines, or loss of more than 400 mL blood, within the previous 3 months or plan to donate blood or blood products in the 3 months after the trial 10. vital signs outside the acceptable range 11. clinically relevant abnormal findings at the screening assessment (including creatinine clearance, haemoglobin levels and QTcF) 12. acute or chronic illness 13. clinically relevant abnormal medical history or concurrent medical condition 14. objection by GP 15. possibility that volunteer will not cooperate 16. pre-menopausal females who are pregnant or lactating, or who are of childbearing potential

Locations (1)

Hammersmith Medicines Research (HMR)

London, United Kingdom

Outcomes

Primary Outcomes

Number of participants with clinically significant changes in vital signs (Part A & B)

Pulse rate (bpm), systolic and diastolic blood pressure (mmHg), Respiratory rate (bpm)

Time frame: Part A: Day 1-4 & Follow-up and Part B: Day 1-15, 17 & Follow up

Number of participants with clinically significant changes observed on 12-lead electrocardiogram (ECG) (Part A & B)

Ventricular rate (beats/min), PR interval (msec), QRS interval (msec), QT (msec), QTcF interval (msec)

Time frame: Part A: Day 1-4 & Follow up & Part B: Day 1,3,5,7,9,11,14,17 & Follow up

Number of participants with clinically significant changes in cardiac telemetry (Part A only)

Number of participants with cardiac telemetry abnormalities will be reported.

Time frame: Part A: From 0.5-1 hours pre-dose until 12 hours after dosing at Day 1

Number of participants with clinically significant changes in physical examination (Part A & B)

Number of participants with physical examination abnormalities will be reported.

Time frame: Part A: Day -1, 1-4 & Follow-up and Part B: Day-1, 1-17 & Follow up

Number of participants with clinically significant changes in laboratory safety tests (haematology, biochemistry and urinalysis) (Part A & B)

Number of participants with abnormalities in laboratory safety tests will be reported.

Time frame: Part A: Day-1, 1-4 & Follow up and Part B: Day-1, 1-17 & Follow up

Number of participants with adverse events (AE) (Part A & B)

AE is any untoward medical occurrence in a subject or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

Time frame: Part A: Day-1, 1-4 & Follow up and Part B: Day-1, 1-17 & Follow up

Data from ClinicalTrials.gov

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Secondary Outcomes

Pharmacokinetics (Cmax)

Assessment of the maximum observed plasma concentration of ONO-7684 and 3-hydroxybenzoic acid in Parts A and B

Time frame: Part A: Day 1 through Day 4. Part B: Day 1 and Day 14

Pharmacokinetics (tmax)

Assessment of the maximum observed plasma concentration of ONO-7684 and 3-hydroxybenzoic acid in Parts A and B

Time frame: Part A: Day 1 through Day 4. Part B: Day 1 and Day 14

Pharmacokinetics (AUClast)

Assessment of the area under the curve of ONO-7684 and 3-hydroxybenzoic acid in Parts A and B

Time frame: Part A: Day 1 through Day 4. Part B: Day 14

Pharmacokinetics (AUCinf)

Assessment of the area under the curve of ONO-7684 and 3-hydroxybenzoic acid in Parts A and B

Time frame: Part A: Day 1 through Day 4. Part B: Day 14

Pharmacokinetics (AUCt)

Assessment of the area under the curve of concentration of ONO-7684 and 3-hydroxybenzoic acid - time from zero up to a definitive time, t in Parts A and B

Time frame: Part A: Day 1 through Day 4. Part B: Day 1

Pharmacokinetics (%AUCextrap)

Assessment of the percentage of AUC∞ extrapolated from tlast to infinity of ONO-7684 and 3-hydroxybenzoic acid in Parts A and B

Time frame: Part A: Day 1 through Day 4. Part B: Day 14

Pharmacokinetics (t1/2)

Assessment of the elimination half-time of ONO-7684 and 3-hydroxybenzoic acid in Parts A and B

Time frame: Part A: Day 1 through Day 4. Part B: Day 14

Pharmacokinetics (CL/F)

Assessment of the apparent clearance rate of ONO-7684 and 3-hydroxybenzoic acid in Part A only

Time frame: Day 1 through Day 4

Pharmacokinetics (Terminal Rate Constant)

Assessment of the terminal rate constant (slowest rate constant of the disposition) of ONO-7684 and 3-hydroxybenzoic acid in plasma in Part A only

Time frame: Day 1 through Day 4

Pharmacokinetics (Aet)

Assessment of the amount of ONO-7684 excreted in urine over the period of sample collection in Part A only

Time frame: Day 1 through Day 4

Pharmacokinetic (fe/F)

Assessment of the fraction of orally administered ONO-7684 excreted into urine in Part A only

Time frame: Day 1 through Day 4

Pharmacokinetic (CLr)

Assessment of the renal clearance of ONO-7684 from plasma in Part A only

Time frame: Day 1 through Day 4

Pharmacokinetic (Ctrough)

Assessment of the trough plasma concentration of ONO-7684 and 3-hydroxybenzoic acid in Part B only

Time frame: Day 1 through Day 14

Pharmacokinetic (AUCtau)

Assessment of the area under the plasma concentration of ONO-7684 and 3-hydroxybenzoic acid -time during a dosing interval in Part B only

Time frame: Day 14

Pharmacokinetic (CLSS/F)

Assessment of total clearance of ONO-7684 from plasma after oral administration in Part B only

Time frame: Day 14

Pharmacokinetic (VZ/F)

Assessment of apparent volume of distribution of ONO-7684 after non-intravenous administration calculated at steady state in Part B only

Time frame: Day 14

Pharmacodynamic (change from baseline in aPTT activity) in serum

Assessment of the effect of ONO-7684 in activated partial thromboplastin time in Parts A and B