A Study to Evaluate Safety, Tolerability, Pharmacokinetics, Immunogenicity, and Pharmacodynamics of JNJ-64179375 in Healthy Male Subjects

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety and tolerability of JNJ-64179375 in Part 1 (Intravenous dose) and Part 3 (Subcutaneous dose) and potential for reversibility of JNJ-64179375 induced Pharmacodynamic effects on coagulation parameters and platelet function (Part 2) in healthy male participants.

Official Title
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A 3-Part First-in-Human Study to Assess the Safety, Tolerability, Pharmacokinetics, Immunogenicity, and Pharmacodynamics of JNJ-64179375 in Healthy Male Subjects

Conditions
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Healthy

Intervention / Treatment
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* Drug: JNJ-64179375
* Drug: Placebo
* Drug: 4 Factor Prothrombin Complex Concentrate (PCC)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body mass index [weight kilogram per meter square (kg/m^2)] between 18 and 30 kg/m^2 (inclusive), and body weight greater than 50 kilogram (kg) but less than 100 kg Generally in good health on the basis of physical examination, medical history, vital signs, laboratory tests, and electrocardiogram (ECG) performed at screening and/or prior to administration of the initial dose of study drug Must sign an informed consent form (ICF) indicating that he understands the purpose of, and procedures required for, the study and is willing to participate in the study contraceptive use by men should be consistent with local regulations regarding the use of contraceptive methods for subject participating in clinical studies willing and able to adhere to the study visit schedule and other requirements, prohibitions, and restrictions specified in this protocol through the Day 113 visit Exclusion Criteria: Acute illness, including an upper respiratory infection (with or without fever), within 7 days prior to study drug administration or have had a major illness or hospitalization within 1 month prior to study drug administration Clinically significant abnormal values for coagulation, hematology, clinical chemistry or urinalysis at screening or on Day -1 (at admission to the clinical research unit) as determined by the investigator or appropriate designee Have smoked tobacco or nicotine-related products within 6 months prior to dosing or does not agree to refrain through Day 113 Donated blood or blood products or had substantial loss of blood [more than 500 milliliter (mL)] within 3 months before the first administration of study drug or intends to donate or donates blood or blood products during the study until 30 days after completion History of or current clinically significant medical illness including (but not limited to) cardiac arrhythmias or other cardiac disease, hematologic disease, bleeding or thrombotic disorders

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Male

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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Cohort 1 (0.03 mg/kg of JNJ-64179375 or Placebo)<br>Participants in a ratio of 3:1 will receive a single 0.03 milligram per kilogram (mg/kg) intravenous (IV) dose of JNJ-64179375 or matching placebo on Day 1. | Drug: JNJ-64179375<br>* During part 1, participants will receive a single ascending Intravenous dose of JNJ-64179375 ranging from (0.03 mg/kg to 5.0 mg/kg). In Part 2, participants will receive a 2.5 mg/kg or highest tolerable dose if lower than 2.5 mg/kg of JNJ-64179375. In Part 3, participants will receive a Single Subcutaneous (SC) dose of 1.0 mg/kg or highest tolerable dose if less than 1.0 mg/kg of JNJ-64179375.<br>Drug: Placebo<br>* Participants will randomly receive matching placebo in all 3 Parts on day 1 administered via IV Route (for Part 1 and 2) and SC route (for Part 3).<br>|
| Experimental: Part 1: Cohort 2 (0.1 mg/kg of JNJ-64179375 or Placebo)<br>Participants in a ratio of 3:1 will receive a single 0.1 mg/kg IV dose of JNJ-64179375 or matching placebo on Day 1. | Drug: JNJ-64179375<br>* During part 1, participants will receive a single ascending Intravenous dose of JNJ-64179375 ranging from (0.03 mg/kg to 5.0 mg/kg). In Part 2, participants will receive a 2.5 mg/kg or highest tolerable dose if lower than 2.5 mg/kg of JNJ-64179375. In Part 3, participants will receive a Single Subcutaneous (SC) dose of 1.0 mg/kg or highest tolerable dose if less than 1.0 mg/kg of JNJ-64179375.<br>Drug: Placebo<br>* Participants will randomly receive matching placebo in all 3 Parts on day 1 administered via IV Route (for Part 1 and 2) and SC route (for Part 3).<br>|
| Experimental: Part 1: Cohort 3 (0.3 mg/kg of JNJ-64179375 or Placebo)<br>Participants in a ratio of 3:1 will receive a single 0.3 mg/kg IV dose of JNJ-64179375 or matching placebo on Day 1. | Drug: JNJ-64179375<br>* During part 1, participants will receive a single ascending Intravenous dose of JNJ-64179375 ranging from (0.03 mg/kg to 5.0 mg/kg). In Part 2, participants will receive a 2.5 mg/kg or highest tolerable dose if lower than 2.5 mg/kg of JNJ-64179375. In Part 3, participants will receive a Single Subcutaneous (SC) dose of 1.0 mg/kg or highest tolerable dose if less than 1.0 mg/kg of JNJ-64179375.<br>Drug: Placebo<br>* Participants will randomly receive matching placebo in all 3 Parts on day 1 administered via IV Route (for Part 1 and 2) and SC route (for Part 3).<br>|
| Experimental: Part 1: Cohort 4 (1.0 mg/kg of JNJ-64179375 or Placebo)<br>Participants in a ratio of 3:1 will receive a single 1.0 mg/kg IV dose of JNJ-64179375 or matching placebo on Day 1. | Drug: JNJ-64179375<br>* During part 1, participants will receive a single ascending Intravenous dose of JNJ-64179375 ranging from (0.03 mg/kg to 5.0 mg/kg). In Part 2, participants will receive a 2.5 mg/kg or highest tolerable dose if lower than 2.5 mg/kg of JNJ-64179375. In Part 3, participants will receive a Single Subcutaneous (SC) dose of 1.0 mg/kg or highest tolerable dose if less than 1.0 mg/kg of JNJ-64179375.<br>Drug: Placebo<br>* Participants will randomly receive matching placebo in all 3 Parts on day 1 administered via IV Route (for Part 1 and 2) and SC route (for Part 3).<br>|
| Experimental: Part 1: Cohort 5 (2.5 mg/kg of JNJ-64179375 or Placebo)<br>Participants in a ratio of 3:1 will receive a single 2.5 mg/kg IV dose of JNJ-64179375 or matching placebo on Day 1. | Drug: JNJ-64179375<br>* During part 1, participants will receive a single ascending Intravenous dose of JNJ-64179375 ranging from (0.03 mg/kg to 5.0 mg/kg). In Part 2, participants will receive a 2.5 mg/kg or highest tolerable dose if lower than 2.5 mg/kg of JNJ-64179375. In Part 3, participants will receive a Single Subcutaneous (SC) dose of 1.0 mg/kg or highest tolerable dose if less than 1.0 mg/kg of JNJ-64179375.<br>Drug: Placebo<br>* Participants will randomly receive matching placebo in all 3 Parts on day 1 administered via IV Route (for Part 1 and 2) and SC route (for Part 3).<br>|
| Experimental: Part 1: Cohort 6 (5.0 mg/kg of JNJ-64179375 or Placebo)<br>Participants in a ratio of 3:1 will receive a single 5.0 mg/kg IV dose of JNJ-64179375 or matching placebo on Day 1. | Drug: JNJ-64179375<br>* During part 1, participants will receive a single ascending Intravenous dose of JNJ-64179375 ranging from (0.03 mg/kg to 5.0 mg/kg). In Part 2, participants will receive a 2.5 mg/kg or highest tolerable dose if lower than 2.5 mg/kg of JNJ-64179375. In Part 3, participants will receive a Single Subcutaneous (SC) dose of 1.0 mg/kg or highest tolerable dose if less than 1.0 mg/kg of JNJ-64179375.<br>Drug: Placebo<br>* Participants will randomly receive matching placebo in all 3 Parts on day 1 administered via IV Route (for Part 1 and 2) and SC route (for Part 3).<br>|
| Experimental: Part 1: Cohort 7 (Escalation Dose of JNJ-64179375 or Placebo)<br>Dose escalation will proceed until the toxicology study exposure limits or a highest tolerable dose will be reached. | Drug: JNJ-64179375<br>* During part 1, participants will receive a single ascending Intravenous dose of JNJ-64179375 ranging from (0.03 mg/kg to 5.0 mg/kg). In Part 2, participants will receive a 2.5 mg/kg or highest tolerable dose if lower than 2.5 mg/kg of JNJ-64179375. In Part 3, participants will receive a Single Subcutaneous (SC) dose of 1.0 mg/kg or highest tolerable dose if less than 1.0 mg/kg of JNJ-64179375.<br>Drug: Placebo<br>* Participants will randomly receive matching placebo in all 3 Parts on day 1 administered via IV Route (for Part 1 and 2) and SC route (for Part 3).<br>|
| Experimental: Part 1: Cohort 8 (Escalation Dose of JNJ-64179375 or Placebo)<br>Dose escalation will proceed until the toxicology study exposure limits or a highest tolerable dose will be reached. | Drug: JNJ-64179375<br>* During part 1, participants will receive a single ascending Intravenous dose of JNJ-64179375 ranging from (0.03 mg/kg to 5.0 mg/kg). In Part 2, participants will receive a 2.5 mg/kg or highest tolerable dose if lower than 2.5 mg/kg of JNJ-64179375. In Part 3, participants will receive a Single Subcutaneous (SC) dose of 1.0 mg/kg or highest tolerable dose if less than 1.0 mg/kg of JNJ-64179375.<br>Drug: Placebo<br>* Participants will randomly receive matching placebo in all 3 Parts on day 1 administered via IV Route (for Part 1 and 2) and SC route (for Part 3).<br>|
| Experimental: Part 2: Reversal Cohort :(50 IU/kg of 4-factor PCC)<br>Participants will receive a 2.5 mg/kg of JNJ-64179375 or highest tolerable dose if lower than 2.5 mg/kg followed by administration of a single IV 50 International Unit per kilogram (IU/Kg) dose of a 4 factor prothrombin complex concentrate (PCC) or matching placebo on Day 1. | Drug: JNJ-64179375<br>* During part 1, participants will receive a single ascending Intravenous dose of JNJ-64179375 ranging from (0.03 mg/kg to 5.0 mg/kg). In Part 2, participants will receive a 2.5 mg/kg or highest tolerable dose if lower than 2.5 mg/kg of JNJ-64179375. In Part 3, participants will receive a Single Subcutaneous (SC) dose of 1.0 mg/kg or highest tolerable dose if less than 1.0 mg/kg of JNJ-64179375.<br>Drug: Placebo<br>* Participants will randomly receive matching placebo in all 3 Parts on day 1 administered via IV Route (for Part 1 and 2) and SC route (for Part 3).<br>Drug: 4 Factor Prothrombin Complex Concentrate (PCC)<br>* Following a single dose of JNJ-64179375, participants will receive a single IV dose of 4 factor-PCC.<br>|
| Experimental: Part 3: Subcutaneous Cohort (1.0 mg/kg of JNJ-64179375)<br>Participants will receive a Single Subcutaneous (SC) dose of 1.0 mg.kg or highest tolerable dose if less than 1.0 mg/kg of JNJ-64179375 or matching placebo on Day 1. | Drug: JNJ-64179375<br>* During part 1, participants will receive a single ascending Intravenous dose of JNJ-64179375 ranging from (0.03 mg/kg to 5.0 mg/kg). In Part 2, participants will receive a 2.5 mg/kg or highest tolerable dose if lower than 2.5 mg/kg of JNJ-64179375. In Part 3, participants will receive a Single Subcutaneous (SC) dose of 1.0 mg/kg or highest tolerable dose if less than 1.0 mg/kg of JNJ-64179375.<br>Drug: Placebo<br>* Participants will randomly receive matching placebo in all 3 Parts on day 1 administered via IV Route (for Part 1 and 2) and SC route (for Part 3).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of Participants With Adverse Events (AE) as a Measure of Safety and Tolerability |  | Up to Day 113 | 
| Part 3: Number of Participants With Adverse Events (AE) as a Measure of Safety and Tolerability |  | Up to Day 113 | 
| Part 2: Change From Baseline in Potential for Reversibility of the JNJ-64179375 Induced Pharmacodynamic Effects on Coagulation Parameters | Change in Potential for Reversibility of the JNJ-64179375 will be assessed by assessing the change in thrombin time as coagulation parameter. | Baseline and Day 1 | 
| Part 2: Change From Baseline in Potential for Reversibility of the JNJ-64179375 Induced Pharmacodynamic Effects on Platelet Function | Platelet function will be assessed by measuring platelet activation and aggregation in response to thrombin and other agonists and with the platelet function analyzer (PFA)100. | Baseline and Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 and 3: Maximum Observed Plasma Concentration (Cmax) of JNJ-64179375 | Cmax is defined as maximum observed plasma concentration of JNJ-64179375. | Predose, Day 1, 2, 4, 7, 10, 14, 22, 29, 43, 57, 85 and 113 | 
| Part 1 and 3: Area Under the Plasma Concentration-Time Curve From Time Zero to Time of the Last Quantifiable Concentration (AUClast) of JNJ-64179375 | The (AUC [0-last]) is defined as Area under the plasma concentration versus time curve from time 0 to the time corresponding to the last quantifiable serum concentration of JNJ-64179375. | Predose, Day 1, 2, 4, 7, 10, 14, 22, 29, 43, 57, 85 and 113 | 
| Part 1 and 3: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC [0-infinity]) of JNJ-64179375 | The (AUC [0-infinity]) is defined as Area under the plasma concentration versus time curve from time 0 to infinity with extrapolation of the terminal phase. | Predose, Day 1, 2, 4, 7, 10, 14, 22, 29, 43, 57, 85 and 113 | 
| Part 1 and 3: Terminal Half-Life (t1/2) of JNJ-64179375 | Half-life (t[1/2]) is associated with the terminal slope (lambda [z]) of the semi-logarithmic drug concentration-time curve, calculated as 0.693/lambda(z). | Predose, Day 1, 2, 4, 7, 10, 14, 22, 29, 43, 57, 85 and 113 | 
| Part 1: Total Systemic Clearance (CL) of JNJ-64179375 | CL is defined as total systemic clearance after intravenous administration of JNJ-64179375. | Predose, Day 1, 2, 4, 7, 10, 14, 22, 29, 43, 57, 85 and 113 | 
| Part 1: Apparent Volume of Distribution at Terminal Phase After Intravenous Administration (Vz) of JNJ-64179375 | Vz is defined as the Apparent volume of distribution at terminal phase after intravenous administration. | Predose, Day 1, 2, 4, 7, 10, 14, 22, 29, 43, 57, 85 and 113 | 
| Part 3: Time to Reach Maximum Observed Concentration (Tmax) of JNJ-64179375 | Tmax is defined as time to the maximum observed plasma concentration of JNJ-64179375. | Predose, Day 1, 2, 4, 7, 10, 14, 22, 29, 43, 57, 85 and 113 | 
| Part 3: Total Systemic Clearance Over Bioavailability After Subcutaneous (SC) Administration (CL/F) of JNJ-64179375 | CL/F is defined as total systemic clearance over bioavailability after SC administration. | Predose, Day 1, 2, 4, 7, 10, 14, 22, 29, 43, 57, 85 and 113 | 
| Part 3: Apparent Volume of Distribution at Terminal Phase Over Bioavailability After Subcutaneous Administration (Vz/F) of JNJ-64179375 | (Vz/F) is defined as Apparent Volume of distribution at terminal phase over bioavailability after SC administration of JNJ-64179375. | Predose, Day 1, 2, 4, 7, 10, 14, 22, 29, 43, 57, 85 and 113 | 
| Part 3: Absolute Bioavailability (F) After Subcutaneous Administration of JNJ-64179375 | F is defined as absolute bioavailability after SC administration of JNJ-64179375. | Predose, Day 1, 2, 4, 7, 10, 14, 22, 29, 43, 57, 85 and 113 | 
| Part 1 and 3: Immunogenicity of JNJ-64179375 | Plasma samples will be collected and screened for antibodies binding to JNJ-64179375 and the titer of confirmed positive samples will be reported. | Predose, Day 7, 14, 29, 57, 85 and 113 | 
| Part 2: Maximum Observed Plasma Concentration (Cmax) of JNJ-64179375 in presence of 4-factor prothrombin complex concentrate (PCC) | Cmax is defined as maximum observed plasma concentration of JNJ-64179375. | Predose, Day 1, 2, 4, 7, 10, 14, 22, 29, 43, 57, 85 and 113 | 
| Part 2: Area Under the Plasma ConcentrationTime Curve From Time Zero to Time of the Last Quantifiable Concentration (AUC [0-last]) of JNJ-64179375 in the presence of 4-factor PCC | The (AUC [0-last]) is defined as Area under the plasma concentration versus time curve from time 0 to the time corresponding to the last quantifiable serum concentration of JNJ-64179375 | Predose, Day 1, 2, 4, 7, 10, 14, 22, 29, 43, 57, 85 and 113 | 
| Part 2: Area Under the Plasma ConcentrationTime Curve From Time Zero to Infinite Time (AUC [0-infinity]) of JNJ-64179375 in the presence of 4-factor PCC | The (AUC [0-infinity]) is defined as Area under the plasma concentration versus time curve from time 0 to infinity with extrapolation of the terminal phase. | Predose, Day 1, 2, 4, 7, 10, 14, 22, 29, 43, 57, 85 and 113 | 
| Part 2: Terminal Half Life [t(1/2)] of JNJ-64179375 in the presence of 4-factor PCC | Half life [t(1/2)] is associated with the terminal slope (lambda [z]) of the semilogarithmic drug concentration time curve, calculated as 0.693/lambda(z). | Predose, Day 1, 2, 4, 7, 10, 14, 22, 29, 43, 57, 85 and 113 | 
| Part 2: Total Systemic Clearance (CL) of JNJ-64179375 in the presence of 4-factor PCC | CL is defined as total systemic clearance after intravenous administration of JNJ-64179375. | Predose, Day 1, 2, 4, 7, 10, 14, 22, 29, 43, 57, 85 and 113 | 
| Part 2: Apparent Volume of Distribution at Terminal Phase After Intravenous Administration (Vz) of JNJ-64179375 in the presence of 4-factor PCC | Vz is defined as the Apparent volume of distribution at terminal phase after intravenous administration. | Predose, Day 1, 2, 4, 7, 10, 14, 22, 29, 43, 57, 85 and 113 | 
| Part 2: Immunogenicity of JNJ-64179375 in the presence of 4-factor PCC | Plasma samples will be collected and screened for antibodies binding to JNJ-64179375 and the titer of confirmed positive samples will be reported. | Predose, Day 7, 14, 29, 57, 85 and 113 | 
| Part 2: Number of Participants With Adverse Events (AE) as a Measure of Safety and Tolerability |  | Baseline to End of treatment (Day 113) | 
| Part 1 and 3: Pharmacodynamic Effect of JNJ-64179375 on Platelet Function | Platelet function will be assessed by measuring platelet activation and aggregation in response to thrombin and other agonists and with the platelet function analyzer (PFA)-100. | Predose, Day 1, 2, 4, 7, 14, 29, 57 and 113 | 
| Part 1 and 3: Pharmacodynamic Effect of JNJ-64179375 on Coagulation Parameters | The pharmacodynamic effect of JNJ-64179375 on coagulation parameters will be assessed by measuring the change in thrombin time. | Predose, Day 1, 2, 4, 7, 14, 29, 57 and 113 |