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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Venous Thromboembolism

Intervention / Treatment
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* Drug: ONO-7684
* Drug: ONO-7684 Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18-55 years normotensive male volunteers, or female volunteers of non-childbearing potential (Part B only) body mass index 18.0-30.0 kg/m2 deemed healthy on the basis of a clinical history, physical examination, ECG, vital signs, and laboratory tests of blood and urine registered with a General Practitioner (GP) in the UK agree to use an effective method of contraception able to give fully informed written consent Exclusion Criteria: Positive tests for hepatitis B & C, HIV severe adverse reaction to any drug sensitivity to trial medication drug or alcohol abuse current smoker or use of nicotine containing products in the previous 6 months vegetarians or vegans, or unwilling to eat a high-fat breakfast (Part A food effect cohorts only) 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 prescription or over-the-counter medication, vitamins, herbal treatments or dietary supplements within the previous 7 days (with the exception of paracetamol [acetaminophen]) 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 vital signs outside the acceptable range clinically relevant abnormal findings at the screening assessment (including creatinine clearance, haemoglobin levels and QTcF) acute or chronic illness clinically relevant abnormal medical history or concurrent medical condition objection by GP possibility that volunteer will not cooperate pre-menopausal females who are pregnant or lactating, or who are of childbearing potential

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

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

What is the study measuring?
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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 |