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

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ClinicalTrials.gov Identifier: NCT03919890
Recruitment Status : Completed
First Posted : April 18, 2019
Last Update Posted : December 9, 2019
Sponsor:
Information provided by (Responsible Party):
Ono Pharmaceutical Co. Ltd

Study Description
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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
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Study Type : Interventional  (Clinical Trial)
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 : January 17, 2019
Actual Primary Completion Date : August 23, 2019
Actual Study Completion Date : August 23, 2019
Arms and Interventions
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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
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Primary Outcome Measures :
  1. Number of participants with clinically significant changes in vital signs (Part A & B) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: Day 1 through Day 4 ]
    Assessment of the fraction of orally administered ONO-7684 excreted into urine in Part A only

  12. Pharmacokinetic (CLr) [ Time Frame: Day 1 through Day 4 ]
    Assessment of the renal clearance of ONO-7684 from plasma in Part A only

  13. Pharmacokinetic (Ctrough) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: Day 14 ]
    Assessment of total clearance of ONO-7684 from plasma after oral administration in Part B only

  16. Pharmacokinetic (VZ/F) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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
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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03919890


Locations
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United Kingdom
Hammersmith Medicines Research (HMR)
London, United Kingdom, NW10 7EW
Sponsors and Collaborators
Ono Pharmaceutical Co. Ltd
More Information
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Responsible Party: Ono Pharmaceutical Co. Ltd
ClinicalTrials.gov Identifier: NCT03919890    
Other Study ID Numbers: ONO-7684-01
First Posted: April 18, 2019    Key Record Dates
Last Update Posted: December 9, 2019
Last Verified: December 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Thromboembolism
Venous Thromboembolism
Embolism and Thrombosis
Vascular Diseases
Cardiovascular Diseases