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Completed

NCT Number: NCT02617810

A Study to Assess the Effect of Multiple-Dose Administration of JNJ-42847922 on Midazolam and Warfarin in Healthy Participants

The purpose of this study is to evaluate effect of multiple-dose administration of JNJ-42847922 on the single-dose pharmacokinetics of oral midazolam and single-dose pharmacokinetics and pharmacodynamics of (R)- and (S)-warfarin after oral administration of racemic warfarin.

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Key information

Conditions

Healthy

Age range

18 year–60 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1

Primary location

Overland Park, Kansas, United States

About this study

This is an open-label (all people know the identity of the intervention), single-center, fixed-sequence, study of JNJ-42847922 in healthy participants. The study consists of 3 Phases: Screening Phase (28 Days), open-label treatment Phase (40 Days) and follow up visit (7 to 14 Days after last study procedure). The duration of participation in the study for each participant is approximately 82 Days. Participants' safety will be monitored throughout the study.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Signed an informed consent document indicating they understand the purpose of and procedures required for the study and are willing to participate in the study
  • Willing to adhere to the prohibitions and restrictions specified in protocol
  • If a woman, must be not of child-bearing potential: postmenopausal [greater than or equal to (>=) 45 years of age with amenorrhea for at least 2 years, or any age with amenorrhea for at least 6 months and a serum stimulating hormone (FSH) greater than (>) 40 International units per liter (IU/L), or surgically sterile (example, hysterectomy, oophorectomy, tubal ligation or tubal occlusion)
  • If a woman, must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction for at least 3 months after the last dose of study drug
  • If a man who is sexually active with a woman of childbearing potential and has not had a vasectomy, must agree to use an adequate contraception method as deemed appropriate by the Investigator (example, vasectomy, double-barrier, partner using effective contraception) and to not donate sperm during the study and for 3 months after receiving the last dose of study drug
  • Body mass index (BMI) between 18 and 30 kilogram (kg)/meter^2 (m^2), and body weight not less than 50 kg

Exclusion criteria

  • History of or current clinically significant medical illness including (but not limited to) cardiac arrhythmias or other cardiac disease, hematologic disease, coagulation disorders (including any abnormal bleeding or blood dyscrasias), syncope, hypotension, hypertension or vascular disorders, lipid abnormalities, significant pulmonary disease, including bronchospastic respiratory disease, diabetes mellitus, hepatic or renal insufficiency, kidney or urinary tract disturbances, thyroid disease, neurologic disease, significant psychiatric disorder, epilepsy, or fits of unexplained black-outs, infection, or any other illness that the Investigator considers should exclude the participant or that could interfere with the interpretation of the study results
  • Clinically significant abnormal values for hematology, clinical chemistry, urinalysis, or thyroid stimulating hormone (TSH) at Screening or at Day -1 of the first treatment period as deemed appropriate by the Investigator. In addition, participants must have coagulation test results [(prothrombin time (PT), international normalized ratio (INR), and activated partial thromboplastin time (aPTT)] within clinically acceptable limits at Screening as deemed appropriate by the Investigator
  • Clinically significant abnormal physical examination, vital signs, or 12 lead electrocardiogram (ECG) at Screening or Day -1 of the first treatment period as deemed appropriate by the Investigator
  • Participants who are homozygous or heterozygous for CYP2C9*2 or CYP2C9*3 alleles
  • Use of any prescription or nonprescription medication (including vitamins and herbal supplements), except for acetaminophen, within 14 days before the first dose of the study drug is scheduled until completion of the study. In addition, participants will be excluded if they have used medications known to affect coagulation or modulate CYP2C9 or VKORC1 within 28 days of study admission

Treatment and study plan

JNJ-42847922

Drug

Participants will receive JNJ-42847922 20 milligram (mg) tablet orally once daily from Day 1 to Day 9.

midazolam

Drug

Participants will receive midazolam 4 milligram (mg) syrup orally once on Day 1 during treatment A and on Day 7 during treatment B.

Warfarin

Drug

Participants will receive warfarin 25 milligram (mg) tablet orally once on Day 3 during treatment A and on Day 9 during treatment B.

Primary outcomes

  1. Maximum Plasma Concentration (Cmax) of Midazolam

    Time frame: Predose, 0.5, 1, 1.5, 2, 3 , 4, 6, 8, 10, 12, 16, 24, 30, 36 and 48 hours postdose on Day 1 during Treatment A and on Day 7 during Treatment B

    The Cmax is the maximum observed plasma concentration of Midazolam.

  2. Maximum Plasma Concentration (Cmax) of 1-Hydroxymidazolam

    Time frame: Predose, 0.5, 1, 1.5, 2, 3 , 4, 6, 8, 10, 12, 16, 24, 30, 36 and 48 hours postdose on Day 1 during Treatment A and on Day 7 during Treatment B

    The Cmax is the maximum observed plasma concentration of 1-Hydroxymidazolam.

  3. Maximum Plasma Concentration (Cmax) of Warfarin

    Time frame: Predose, 0.5, 1, 2 , 4, 6, 9, 12, 16, 24, 36, 48, 72, 96, 120, 144 and 168 hours postdose on Day 3 during Treatment A and on Day 9 during Treatment B

    The Cmax is the maximum observed plasma concentration of Warfarin.

  4. Time to Reach the Maximum Plasma Concentration (Tmax) of Midazolam

    Time frame: Predose, 0.5, 1, 1.5, 2, 3 , 4, 6, 8, 10, 12, 16, 24, 30, 36 and 48 hours postdose on Day 1 during Treatment A and on Day 7 during Treatment B

    The Tmax is the time to reach the maximum observed plasma concentration of Midazolam.

  5. Time to Reach the Maximum Plasma Concentration (Tmax) of 1-Hydroxymidazolam

    Time frame: Predose, 0.5, 1, 1.5, 2, 3 , 4, 6, 8, 10, 12, 16, 24, 30, 36 and 48 hours postdose on Day 1 during Treatment A and on Day 7 during Treatment B

    The Tmax is the time to reach the maximum observed plasma concentration of 1-Hydroxymidazolam.

  6. Time to Reach the Maximum Plasma Concentration (Tmax) of Warfarin

    Time frame: Predose, 0.5, 1, 2 , 4, 6, 9, 12, 16, 24, 36, 48, 72, 96, 120, 144 and 168 hours postdose on Day 3 during Treatment A and on Day 9 during Treatment B

    The Tmax is the time to reach the maximum observed plasma concentration of Warfarin.

  7. Time of Last Measurable Plasma Concentration (Tlast) of Midazolam

    Time frame: Predose, 0.5, 1, 1.5, 2, 3 , 4, 6, 8, 10, 12, 16, 24, 30, 36 and 48 hours postdose on Day 1 during Treatment A and on Day 7 during Treatment B

    Time to last measurable plasma concentration is evaluated.

  8. Time of Last Measurable Plasma Concentration (Tlast) of 1-Hydroxymidazolam

    Time frame: Predose, 0.5, 1, 1.5, 2, 3 , 4, 6, 8, 10, 12, 16, 24, 30, 36 and 48 hours postdose on Day 1 during Treatment A and on Day 7 during Treatment B

    Time to last measurable plasma concentration is evaluated.

  9. Time of Last Measurable Plasma Concentration (Tlast) of Warfarin

    Time frame: Predose, 0.5, 1, 2 , 4, 6, 9, 12, 16, 24, 36, 48, 72, 96, 120, 144 and 168 hours postdose on Day 3 during Treatment A and on Day 9 during Treatment B

    Time to last measurable plasma concentration is evaluated.

  10. Area Under the Plasma Concentration-Time Curve From 0 to Last Quantifiable Concentration (AUC[0-last]) Post Dose of Midazolam

    Time frame: Predose, 0.5, 1, 1.5, 2, 3 , 4, 6, 8, 10, 12, 16, 24, 30, 36 and 48 hours postdose on Day 1 during Treatment A and on Day 7 during Treatment B

    The AUC(0-last) is the area under the plasma concentration-time curve from 0 to time of the last quantifiable concentration.

  11. Area Under the Plasma Concentration-Time Curve From 0 to Last Quantifiable Concentration (AUC[0-last]) Post Dose of 1-Hydroxymidazolam

    Time frame: Predose, 0.5, 1, 1.5, 2, 3 , 4, 6, 8, 10, 12, 16, 24, 30, 36 and 48 hours postdose on Day 1 during Treatment A and on Day 7 during Treatment B

    The AUC(0-last) is the area under the plasma concentration-time curve from 0 to time of the last quantifiable concentration.

  12. Area Under the Plasma Concentration-Time Curve From 0 to Last Quantifiable Concentration (AUC[0-last]) Post Dose of Warfarin

    Time frame: Predose, 0.5, 1, 2 , 4, 6, 9, 12, 16, 24, 36, 48, 72, 96, 120, 144 and 168 hours postdose on Day 3 during Treatment A and on Day 9 during Treatment B

    The AUC(0-last) is the area under the plasma concentration-time curve from 0 to time of the last quantifiable concentration.

  13. Area Under the Plasma Concentration-Time Curve From 0 to Infinite Time (AUC[0-infinity]) Post Dose of Midazolam

    Time frame: Predose, 0.5, 1, 1.5, 2, 3 , 4, 6, 8, 10, 12, 16, 24, 30, 36 and 48 hours postdose on Day 1 during Treatment A and on Day 7 during Treatment B

    The AUC (0-infinity) is the area under the plasma Midazolam concentration-time curve from time 0 to infinite time, calculated as the sum of AUC (0-last) and C(last)/lambda(z), in which AUC(0-last) is area under the plasma Midazolam concentration-time curve from time zero to time of the last quantifiable concentration, C(last) is the last observed quantifiable concentration and lambda(z) is elimination rate constant.

  14. Area Under the Plasma Concentration-Time Curve From 0 to Infinite Time (AUC[0-infinity]) Post Dose of 1-Hydroxymidazolam

    Time frame: Predose, 0.5, 1, 1.5, 2, 3 , 4, 6, 8, 10, 12, 16, 24, 30, 36 and 48 hours postdose on Day 1 during Treatment A and on Day 7 during Treatment B

    The AUC (0-infinity) is the area under the plasma 1-Hydroxymidazolam concentration-time curve from time 0 to infinite time, calculated as the sum of AUC (0-last) and C(last)/lambda(z), in which AUC(0-last) is area under the plasma 1-Hydroxymidazolam concentration-time curve from time zero to time of the last quantifiable concentration, C(last) is the last observed quantifiable concentration and lambda(z) is elimination rate constant.

  15. Area Under the Plasma Concentration-Time Curve From 0 to Infinite Time (AUC[0-infinity]) Post Dose of Warfarin

    Time frame: Predose, 0.5, 1, 2 , 4, 6, 9, 12, 16, 24, 36, 48, 72, 96, 120, 144 and 168 hours postdose on Day 3 during Treatment A and on Day 9 during Treatment B

    The AUC (0-infinity) is the area under the plasma Warfarin concentration-time curve from time 0 to infinite time, calculated as the sum of AUC (0-last) and C(last)/lambda(z), in which AUC(0-last) is area under the plasma Warfarin concentration-time curve from time zero to time of the last quantifiable concentration, C(last) is the last observed quantifiable concentration and lambda(z) is elimination rate constant.

  16. Terminal Half-life (t[1/2]) of Midazolam

    Time frame: Predose, 0.5, 1, 1.5, 2, 3 , 4, 6, 8, 10, 12, 16, 24, 30, 36 and 48 hours postdose on Day 1 during Treatment A and on Day 7 during Treatment B

    Elimination half-life associated with the terminal slope Lambda (z) of the semi logarithmic drug concentration-time curve, calculated as 0.693/Lambda (z).

  17. Terminal Half-life (t[1/2]) of 1-Hydroxymidazolam

    Time frame: Predose, 0.5, 1, 1.5, 2, 3 , 4, 6, 8, 10, 12, 16, 24, 30, 36 and 48 hours postdose on Day 1 during Treatment A and on Day 7 during Treatment B

    Elimination half-life associated with the terminal slope Lambda (z) of the semi logarithmic drug concentration-time curve, calculated as 0.693/Lambda (z).

  18. Terminal Half-life (t[1/2]) of Warfarin

    Time frame: Predose, 0.5, 1, 2 , 4, 6, 9, 12, 16, 24, 36, 48, 72, 96, 120, 144 and 168 hours postdose on Day 3 during Treatment A and on Day 9 during Treatment B

    Elimination half-life associated with the terminal slope Lambda (z) of the semi logarithmic drug concentration-time curve, calculated as 0.693/Lambda (z).

  19. Total Apparent Clearance (CL/F) of Midazolam

    Time frame: Predose, 0.5, 1, 1.5, 2, 3 , 4, 6, 8, 10, 12, 16, 24, 30, 36 and 48 hours postdose on Day 1 during Treatment A and on Day 7 during Treatment B

    The CL/F is defined as Dose/AUC (0-infinity).

  20. Total Apparent Clearance (CL/F) of 1-Hydroxymidazolam

    Time frame: Predose, 0.5, 1, 1.5, 2, 3 , 4, 6, 8, 10, 12, 16, 24, 30, 36 and 48 hours postdose on Day 1 during Treatment A and on Day 7 during Treatment B

    The CL/F is defined as Dose/AUC (0-infinity).

  21. Total Apparent Clearance (CL/F) of Warfarin

    Time frame: Predose, 0.5, 1, 2 , 4, 6, 9, 12, 16, 24, 36, 48, 72, 96, 120, 144 and 168 hours postdose on Day 3 during Treatment A and on Day 9 during Treatment B

    The CL/F is defined as Dose/AUC (0-infinity).

  22. Apparent Volume of Distribution (Vd/F) of Midazolam

    Time frame: Predose, 0.5, 1, 1.5, 2, 3 , 4, 6, 8, 10, 12, 16, 24, 30, 36 and 48 hours postdose on Day 1 during Treatment A and on Day 7 during Treatment B

    The Vd/F is defined as Dose/[Lambda (z)*AUC (0-infinity)].

  23. Apparent Volume of Distribution (Vd/F) of 1-Hydroxymidazolam

    Time frame: Predose, 0.5, 1, 1.5, 2, 3 , 4, 6, 8, 10, 12, 16, 24, 30, 36 and 48 hours postdose on Day 1 during Treatment A and on Day 7 during Treatment B

    The Vd/F is defined as Dose/[Lambda (z)*AUC (0-infinity)].

  24. Apparent Volume of Distribution (Vd/F) of Warfarin

    Time frame: Predose, 0.5, 1, 2 , 4, 6, 9, 12, 16, 24, 36, 48, 72, 96, 120, 144 and 168 hours postdose on Day 3 during Treatment A and on Day 9 during Treatment B

    The Vd/F is defined as Dose/[Lambda (z)*AUC (0-infinity)].

  25. Maximum Observed Effect (Emax) for Prothrombin Time (PT)

    Time frame: Predose, 2 , 6, 12, 16, 24, 30, 36, 40, 48, 54, 60, 66, 72, 96, 120, 144 and 168 hours postdose on Day 3 during Treatment A and on Day 9 during Treatment B

    The Emax for prothrombin time (PT) will be assessed.

  26. Maximum Observed Effect (Emax) for activated Partial Thromboplastin Time (aPTT)

    Time frame: Predose, 2 , 6, 12, 16, 24, 30, 36, 40, 48, 54, 60, 66, 72, 96, 120, 144 and 168 hours postdose on Day 3 during Treatment A and on Day 9 during Treatment B

    The Emax for activated partial thromboplastin time (aPTT) will be assessed.

  27. Maximum Observed Effect (Emax) for International Normalized Ratio (INR)

    Time frame: Predose, 2 , 6, 12, 16, 24, 30, 36, 40, 48, 54, 60, 66, 72, 96, 120, 144 and 168 hours postdose on Day 3 during Treatment A and on Day 9 during Treatment B

    The Emax for international normalized ratio (INR) will be assessed.

  28. Time to Reach the Maximum Plasma Concentration (Tmax) of JNJ-42847922

    Time frame: 2 hours postdose on Day 1 to Day 6; 2 and 26 hours postdose on Day 7; 2 hours postdose on Day 9 during Treatment B

    The Tmax is the time to reach the maximum observed plasma concentration of JNJ-42847922.

  29. Area Under the Plasma Concentration-Time Curve From 0 to 168 Hours (AUC[0-168]) Post Dose of Warfarin

    Time frame: Predose, 0.5, 1, 2 , 4, 6, 9, 12, 16, 24, 36, 48, 72, 96, 120, 144 and 168 hours postdose on Day 3 during Treatment A and on Day 9 during Treatment B

    The AUC(0-168hrs) is the area under the plasma concentration-time curve from 0 to 168 hours post dosing.

  30. Area Under the Plasma Concentration-Time Curve From 0 to 168 Hours (AUC[0-168]) Post Dose of JNJ-42847922

    Time frame: 2 hours postdose on Day 1 to Day 6; 2 and 26 hours postdose on Day 7; 2 hours postdose on Day 9 during Treatment B

    The AUC(0-168hrs) is the area under the plasma concentration-time curve from 0 to 168 hours post dosing.

  31. Pharmacodynamic Effect by Using Bond and Lader Visual Analogue Scale (B and L VAS)

    Time frame: Day -1 of Treatment A dosing

    The B and L VAS will be performed to measure effects of a JNJ-42847922 on the duration of the pharmacodynamic effect of midazolam. The B and L VAS includes 16 questions with VAS scales to rate subjective feelings.

  32. Pharmacodynamic Effect by Using Bond and Lader Visual Analogue Scale (B and L VAS)

    Time frame: 4 hours postdose on Day 1 during Treatment A

    The B and L VAS will be performed to measure effects of a JNJ-42847922 on the duration of the pharmacodynamic effect of midazolam. The B and L VAS includes 16 questions with VAS scales to rate subjective feelings.

  33. Pharmacodynamic Effect by Using Bond and Lader Visual Analogue Scale (B and L VAS)

    Time frame: 8 hours postdose on Day 1 during Treatment A

    The B and L VAS will be performed to measure effects of a JNJ-42847922 on the duration of the pharmacodynamic effect of midazolam. The B and L VAS includes 16 questions with VAS scales to rate subjective feelings.

  34. Pharmacodynamic Effect by Using Bond and Lader Visual Analogue Scale (B and L VAS)

    Time frame: Day -1 of Treatment B dosing

    The B and L VAS will be performed to measure effects of a JNJ-42847922 on the duration of the pharmacodynamic effect of midazolam. The B and L VAS includes 16 questions with VAS scales to rate subjective feelings.

  35. Pharmacodynamic Effect by Using Bond and Lader Visual Analogue Scale (B and L VAS)

    Time frame: 4 hours postdose on Day 7 during Treatment B

    The B and L VAS will be performed to measure effects of a JNJ-42847922 on the duration of the pharmacodynamic effect of midazolam. The B and L VAS includes 16 questions with VAS scales to rate subjective feelings.

  36. Pharmacodynamic Effect by Using Bond and Lader Visual Analogue Scale (B and L VAS)

    Time frame: 8 hours postdose on Day 7 during Treatment B

    The B and L VAS will be performed to measure effects of a JNJ-42847922 on the duration of the pharmacodynamic effect of midazolam. The B and L VAS includes 16 questions with VAS scales to rate subjective feelings.

Secondary outcomes

  1. Number of Participants with Adverse Events (AEs) and Serious AEs

    Time frame: Screening up to follow-up visit (7 to 14 days after last study procedure)

    An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.

Sponsors and collaborators

Lead sponsor

Janssen Research & Development, LLC

Industry

Registry information

Official study title

An Open-Label Drug Interaction Study to Assess the Effect of Multiple-Dose Administration of JNJ-42847922 on the Single-Dose Pharmacokinetics of Midazolam and the Single Dose Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Subjects

Important dates

Study start
2015
Primary completion
2016
Study completion
2016
First posted
Dec 1, 2015
Registry last updated
Feb 23, 2016

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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