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

• Sponsor: Ono Pharmaceutical Co. Ltd (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03919890
• Collaborator: (none)
• Enrollment: 72
• Location: 1
• Arms: 6
• Actual Duration (Months): 7.2
• Patients Per Site Per Month: 10.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Venous Thromboembolism	Drug: ONO-7684; Drug: ONO-7684 Placebo	Phase 1

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 Design

• Study Type: Interventional
• Actual Enrollment: 72 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Masking: Double (Participant, Investigator)
• Masking Description: Double-blinded
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Jan 17, 2019
• Actual Primary Completion Date: Aug 23, 2019
• Actual Study Completion Date: Aug 23, 2019

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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)

2. 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)

3. 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.

4. 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.

5. 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.

6. 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

1. 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

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. Pharmacokinetic (fe/F) [Day 1 through Day 4]

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

12. Pharmacokinetic (CLr) [Day 1 through Day 4]

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

13. Pharmacokinetic (Ctrough) [Day 1 through Day 14]

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

14. 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

15. Pharmacokinetic (CLSS/F) [Day 14]

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

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hammersmith Medicines Research (HMR)	London		United Kingdom	NW10 7EW

Sponsors and Collaborators

• Ono Pharmaceutical Co. Ltd

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Ono Pharmaceutical Co. Ltd
• ClinicalTrials.gov Identifier: NCT03919890
• Other Study ID Numbers: ONO-7684-01
• First Posted: Apr 18, 2019
• Last Update Posted: Dec 9, 2019
• Last Verified: Dec 1, 2019

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Thromboembolism; Venous Thromboembolism

Study Results

No Results Posted as of Dec 9, 2019