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

A First-in-human, Randomised, Placebo-controlled, Double-blind, Single and Multiple Dose Study to Explore the Safety, Tolerability, PK and PD of Oral Doses of ONO-7684 in Healthy Subjects Under Fed and Fasted Conditions

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.

Study Overview

• Status: Completed
• Conditions: Venous Thromboembolism
• Intervention / Treatment: Drug: ONO-7684; Drug: ONO-7684 Placebo

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 Type: Interventional
• Enrollment (Actual): 72
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, NW10 7EW
    • Hammersmith Medicines Research (HMR)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 53 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Double

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ONO-7684 Part A1; Single ascending doses of ONO-7684 or placebo orally under fasted conditions	Drug: ONO-7684; Single ascending doses for cohorts A1-A8 and multiple ascending doses cohorts B1-3
Placebo Comparator: ONO-7684 Placebo Part A1; Single ascending doses of ONO-7684 or placebo orally under fasted conditions	Drug: ONO-7684 Placebo; Placebo comparator
Experimental: ONO-7684 Part A2; Single doses of ONO-7684 or placebo orally under fed conditions	Drug: ONO-7684; Single ascending doses for cohorts A1-A8 and multiple ascending doses cohorts B1-3
Placebo Comparator: ONO-7684 Placebo Part A2; Single doses of ONO-7684 or placebo orally under fed conditions	Drug: ONO-7684 Placebo; Placebo comparator
Experimental: ONO-7684 Part B1; Eligible subjects will receive multiple doses of ONO-7684 or placebo orally	Drug: ONO-7684; Single ascending doses for cohorts A1-A8 and multiple ascending doses cohorts B1-3
Placebo Comparator: ONO-7684 Placebo Part B1; Eligible subjects will receive multiple doses of ONO-7684 or placebo orally	Drug: ONO-7684 Placebo; Placebo comparator

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	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)	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.	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.	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.	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.	Part A: Day-1, 1-4 & Follow up and Part B: Day-1, 1-17 & Follow up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics (Cmax)	Assessment of the maximum observed plasma concentration of ONO-7684 and 3-hydroxybenzoic acid in Parts A and B	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	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	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	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	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	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	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	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	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	Day 1 through Day 4
Pharmacokinetic (fe/F)	Assessment of the fraction of orally administered ONO-7684 excreted into urine in Part A only	Day 1 through Day 4
Pharmacokinetic (CLr)	Assessment of the renal clearance of ONO-7684 from plasma in Part A only	Day 1 through Day 4
Pharmacokinetic (Ctrough)	Assessment of the trough plasma concentration of ONO-7684 and 3-hydroxybenzoic acid in Part B only	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	Day 14
Pharmacokinetic (CLSS/F)	Assessment of total clearance of ONO-7684 from plasma after oral administration in Part B only	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	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	Part A: Day 1 through Day 4. Part B: Day 1 through Day 17
Pharmacodynamic (change from baseline in PT activity) in serum	Assessment of the effect of ONO-7684 in prothrombin time in Parts A and B	Part A: Day 1 through Day 4. Part B: Day 1 through Day 17
Pharmacodynamic (change from baseline in PT-INR activity) in serum	Assessment of the effect of ONO-7684 in prothrombin time-international normalised ratio in Parts A and B	Part A: Day 1 through Day 4. Part B: Day 1 through Day 17
Pharmacodynamic (change from baseline in FXIa activity) in serum	Assessment of the effect of ONO-7684 in blood coagulation activated factor XI in Parts A and B	Part A: Day 1 through Day 4. Part B: Day 1 through Day 17
Pharmacodynamic (correlation of aPTT and FXIa activity) in serum	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	Part A: Day 1 through Day 4. Part B: Day 1 through Day 17

Collaborators and Investigators

• Sponsor: Ono Pharmaceutical Co. Ltd

Study record dates

Study Major Dates

• Study Start (Actual): January 17, 2019
• Primary Completion (Actual): August 23, 2019
• Study Completion (Actual): August 23, 2019

Study Registration Dates

• First Submitted: March 14, 2019
• First Submitted That Met QC Criteria: April 15, 2019
• First Posted (Actual): April 18, 2019

Study Record Updates

• Last Update Posted (Actual): December 9, 2019
• Last Update Submitted That Met QC Criteria: December 6, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Thromboembolism; Venous Thromboembolism
• Other Study ID Numbers: ONO-7684-01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No