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

Phase 1

Completed

• Conditions: Venous Thromboembolism
• Interventions: Drug: ONO-7684; Drug: ONO-7684 Placebo

• Registration Number: NCT03919890
• Lead Sponsor: Ono Pharmaceutical Co. Ltd

Brief Summary

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.

Detailed Description

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 Timeline

• Study Start: 2019-01-17
• Study First Submitted: 2019-03-14
• Study First Submitted QC: 2019-04-15
• Study First Posted: 2019-04-18
• Primary Completion: 2019-08-23
• Study Completion: 2019-08-23
• Status Verified: 2019-12
• Last Update Submitted: 2019-12-06
• Last Update Posted: 2019-12-09

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 72

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
ONO-7684 Part A1	ONO-7684	Single ascending doses of ONO-7684 or placebo orally under fasted conditions
ONO-7684 Placebo Part B1	ONO-7684 Placebo	Eligible subjects will receive multiple doses of ONO-7684 or placebo orally
ONO-7684 Placebo Part A2	ONO-7684 Placebo	Single doses of ONO-7684 or placebo orally under fed conditions
ONO-7684 Part B1	ONO-7684	Eligible subjects will receive multiple doses of ONO-7684 or placebo orally
ONO-7684 Placebo Part A1	ONO-7684 Placebo	Single ascending doses of ONO-7684 or placebo orally under fasted conditions
ONO-7684 Part A2	ONO-7684	Single doses of ONO-7684 or placebo orally under fed conditions

Primary Outcome Measures

Name	Time	Method
Number of participants with clinically significant changes in vital signs (Part A & B)	Part A: Day 1-4 & Follow-up and Part B: Day 1-15, 17 & Follow up	Pulse rate (bpm), systolic and diastolic blood pressure (mmHg), Respiratory rate (bpm)
Number of participants with clinically significant changes in laboratory safety tests (haematology, biochemistry and urinalysis) (Part A & B)	Part A: Day-1, 1-4 & Follow up and Part B: Day-1, 1-17 & Follow up	Number of participants with abnormalities in laboratory safety tests will be reported.
Number of participants with clinically significant changes observed on 12-lead electrocardiogram (ECG) (Part A & B)	Part A: Day 1-4 & Follow up & Part B: Day 1,3,5,7,9,11,14,17 & Follow up	Ventricular rate (beats/min), PR interval (msec), QRS interval (msec), QT (msec), QTcF interval (msec)
Number of participants with clinically significant changes in physical examination (Part A & B)	Part A: Day -1, 1-4 & Follow-up and Part B: Day-1, 1-17 & Follow up	Number of participants with physical examination abnormalities will be reported.
Number of participants with clinically significant changes in cardiac telemetry (Part A only)	Part A: From 0.5-1 hours pre-dose until 12 hours after dosing at Day 1	Number of participants with cardiac telemetry abnormalities will be reported.
Number of participants with adverse events (AE) (Part A & B)	Part A: Day-1, 1-4 & Follow up and Part B: Day-1, 1-17 & Follow up	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.

Secondary Outcome Measures

Name	Time	Method
Pharmacokinetics (CL/F)	Day 1 through Day 4	Assessment of the apparent clearance rate of ONO-7684 and 3-hydroxybenzoic acid in Part A only
Pharmacodynamic (change from baseline in aPTT activity) in serum	Part A: Day 1 through Day 4. Part B: Day 1 through Day 17	Assessment of the effect of ONO-7684 in activated partial thromboplastin time in Parts A and B
Pharmacokinetics (t1/2)	Part A: Day 1 through Day 4. Part B: Day 14	Assessment of the elimination half-time of ONO-7684 and 3-hydroxybenzoic acid in Parts A and B
Pharmacokinetic (fe/F)	Day 1 through Day 4	Assessment of the fraction of orally administered ONO-7684 excreted into urine in Part A only
Pharmacokinetic (Ctrough)	Day 1 through Day 14	Assessment of the trough plasma concentration of ONO-7684 and 3-hydroxybenzoic acid in Part B only
Pharmacokinetic (AUCtau)	Day 14	Assessment of the area under the plasma concentration of ONO-7684 and 3-hydroxybenzoic acid -time during a dosing interval in Part B only
Pharmacokinetics (AUClast)	Part A: Day 1 through Day 4. Part B: Day 14	Assessment of the area under the curve of ONO-7684 and 3-hydroxybenzoic acid in Parts A and B
Pharmacokinetics (%AUCextrap)	Part A: Day 1 through Day 4. Part B: Day 14	Assessment of the percentage of AUC∞ extrapolated from tlast to infinity of ONO-7684 and 3-hydroxybenzoic acid in Parts A and B
Pharmacokinetics (Aet)	Day 1 through Day 4	Assessment of the amount of ONO-7684 excreted in urine over the period of sample collection in Part A only
Pharmacodynamic (change from baseline in PT activity) in serum	Part A: Day 1 through Day 4. Part B: Day 1 through Day 17	Assessment of the effect of ONO-7684 in prothrombin time in Parts A and B
Pharmacokinetics (Cmax)	Part A: Day 1 through Day 4. Part B: Day 1 and Day 14	Assessment of the maximum observed plasma concentration of ONO-7684 and 3-hydroxybenzoic acid in Parts A and B
Pharmacokinetics (AUCinf)	Part A: Day 1 through Day 4. Part B: Day 14	Assessment of the area under the curve of ONO-7684 and 3-hydroxybenzoic acid in Parts A and B
Pharmacokinetics (AUCt)	Part A: Day 1 through Day 4. Part B: Day 1	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
Pharmacokinetics (Terminal Rate Constant)	Day 1 through Day 4	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
Pharmacokinetic (CLr)	Day 1 through Day 4	Assessment of the renal clearance of ONO-7684 from plasma in Part A only
Pharmacokinetic (CLSS/F)	Day 14	Assessment of total clearance of ONO-7684 from plasma after oral administration in Part B only
Pharmacokinetics (tmax)	Part A: Day 1 through Day 4. Part B: Day 1 and Day 14	Assessment of the maximum observed plasma concentration of ONO-7684 and 3-hydroxybenzoic acid in Parts A and B
Pharmacodynamic (correlation of aPTT and FXIa activity) in serum	Part A: Day 1 through Day 4. Part B: Day 1 through Day 17	Assessment of the effect of ONO-7684 in the correlation of activated partial thromboplastin time to blood coagulation activated factor XI in Parts A and B
Pharmacokinetic (VZ/F)	Day 14	Assessment of apparent volume of distribution of ONO-7684 after non-intravenous administration calculated at steady state in Part B only
Pharmacodynamic (change from baseline in PT-INR activity) in serum	Part A: Day 1 through Day 4. Part B: Day 1 through Day 17	Assessment of the effect of ONO-7684 in prothrombin time-international normalised ratio in Parts A and B
Pharmacodynamic (change from baseline in FXIa activity) in serum	Part A: Day 1 through Day 4. Part B: Day 1 through Day 17	Assessment of the effect of ONO-7684 in blood coagulation activated factor XI in Parts A and B

Trial Locations

Locations (1)

Hammersmith Medicines Research (HMR); 🇬🇧 London, United Kingdom