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

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

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.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: JNJ-64179375; Drug: Placebo; Drug: 4 Factor Prothrombin Complex Concentrate (PCC)

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Merksem, Belgium

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

10

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1: Cohort 1 (0.03 mg/kg of JNJ-64179375 or Placebo); 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; 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.; Drug: Placebo; 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).
Experimental: Part 1: Cohort 2 (0.1 mg/kg of JNJ-64179375 or Placebo); 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; 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.; Drug: Placebo; 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).
Experimental: Part 1: Cohort 3 (0.3 mg/kg of JNJ-64179375 or Placebo); 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; 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.; Drug: Placebo; 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).
Experimental: Part 1: Cohort 4 (1.0 mg/kg of JNJ-64179375 or Placebo); 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; 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.; Drug: Placebo; 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).
Experimental: Part 1: Cohort 5 (2.5 mg/kg of JNJ-64179375 or Placebo); 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; 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.; Drug: Placebo; 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).
Experimental: Part 1: Cohort 6 (5.0 mg/kg of JNJ-64179375 or Placebo); 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; 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.; Drug: Placebo; 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).
Experimental: Part 1: Cohort 7 (Escalation Dose of JNJ-64179375 or Placebo); Dose escalation will proceed until the toxicology study exposure limits or a highest tolerable dose will be reached.	Drug: JNJ-64179375; 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.; Drug: Placebo; 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).
Experimental: Part 1: Cohort 8 (Escalation Dose of JNJ-64179375 or Placebo); Dose escalation will proceed until the toxicology study exposure limits or a highest tolerable dose will be reached.	Drug: JNJ-64179375; 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.; Drug: Placebo; 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).
Experimental: Part 2: Reversal Cohort :(50 IU/kg of 4-factor PCC); 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; 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.; Drug: Placebo; 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).; Drug: 4 Factor Prothrombin Complex Concentrate (PCC); Following a single dose of JNJ-64179375, participants will receive a single IV dose of 4 factor-PCC.
Experimental: Part 3: Subcutaneous Cohort (1.0 mg/kg of JNJ-64179375); 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; 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.; Drug: Placebo; 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).

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Janssen Research & Development, LLC

Study record dates

Study Major Dates

• Study Start (Actual): November 14, 2016
• Primary Completion (Actual): August 9, 2017
• Study Completion (Actual): August 9, 2017

Study Registration Dates

• First Submitted: October 27, 2016
• First Submitted That Met QC Criteria: October 27, 2016
• First Posted (Estimate): October 31, 2016

Study Record Updates

• Last Update Posted (Actual): September 25, 2017
• Last Update Submitted That Met QC Criteria: September 22, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hemostatics; Coagulants; Thrombin
• Other Study ID Numbers: CR108238; 64179375EDI1001 (Other Identifier: Janssen Research & Development, LLC); 2016-003006-13 (EudraCT Number)

Drug and device information, study documents

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