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A Study to Evaluate the Effect of Ustekinumab on Cytochrome P450 Enzyme Activities Following Induction and Maintenance Dosing in Participants With Moderate to Severe Crohn's Disease

This study is not yet open for participant recruitment.
Verified November 2017 by Janssen Research & Development, LLC
Sponsor:
ClinicalTrials.gov Identifier:
NCT03358706
First Posted: December 1, 2017
Last Update Posted: December 1, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
Janssen Research & Development, LLC
  Purpose
The purpose of this study is to evaluate the potential effects of an intravenous (IV) induction and subcutaneous (SC) maintenance administration of ustekinumab on the pharmacokinetic (PK) of a cocktail of representative probe substrates of cytochrome P450 (CYP) enzymes (CYP3A4, CYP2C9, CYP2C19, CYP2D6, and CYP1A2) in participants with moderate to severe Crohn's disease (CD).

Condition Intervention Phase
Crohn Disease Drug: Ustekinumab IV Infusion Drug: Ustekinumab SC Injection Drug: Midazolam 2 mg Drug: Warfarin 10 mg Drug: Vitamin K 10 mg Drug: Omeprazole 20 mg Drug: Dextromethorphan 30 mg Drug: Caffeine 100 mg Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: A Phase 1, Open-label, Drug Interaction Study to Evaluate the Effect of Ustekinumab on Cytochrome P450 Enzyme Activities Following Induction and Maintenance Dosing in Participants With Moderate to Severe Crohn's Disease.

Resource links provided by NLM:


Further study details as provided by Janssen Research & Development, LLC:

Primary Outcome Measures:
  • Geometric Mean Ratio (Day 22/ Day 1) of the Maximum Plasma Concentration (Cmax) of Cytochrome P450 Probe Substrates (Midazolam, Omeprazole, Dextromethorphan, S-warfarin and Caffeine) [ Time Frame: Day 1 and 22: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post dose ]
    Cmax is defined as maximum observed plasma concentrations. The geometric mean ratio of Cmax will be defined as the Cmax of probe substrates on Day 22/Cmax of probe substrates on Day 1.

  • Geometric Mean Ratio (Day 113/ Day 1) of the Maximum Plasma Concentration (Cmax) of Cytochrome P450 Probe Substrates (Midazolam, Omeprazole, Dextromethorphan, S-warfarin and Caffeine) [ Time Frame: Day 1 and 113: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post dose ]
    Cmax is defined as maximum observed plasma concentrations. The geometric mean ratio of Cmax will be defined as the Cmax of probe substrates on Day 113/Cmax of probe substrates on Day 1.

  • Geometric Mean Ratio (Day 22/ Day 1) of the Area Under the Plasma Concentration-time Curve From 0 to Infinity (AUC [0-inf]) of Cytochrome P450 Probe Substrates (Midazolam, Omeprazole, Dextromethorphan, S-warfarin and Caffeine) [ Time Frame: Day 1 and 22: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post dose ]
    (AUC [0-inf]) is defined as area under the plasma concentration versus time curve from time 0 to infinity with extrapolation of the terminal phase. The geometric mean ratio of Cmax will be defined as the (AUC [0-inf]) of probe substrates on Day 22/(AUC [0-inf]) of probe substrates on Day 1.

  • Geometric Mean Ratio (Day 113/ Day 1) of the Area Under the Plasma Concentration-time Curve From 0 to Infinity (AUC [0-inf]) of Cytochrome P450 Probe Substrates (Midazolam, Omeprazole, Dextromethorphan, S-warfarin and Caffeine) [ Time Frame: Day 1 and 113: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post dose ]
    (AUC [0-inf]) is defined as area under the plasma concentration versus time curve from time 0 to infinity with extrapolation of the terminal phase. The geometric mean ratio of (AUC [0-inf]) will be defined as the (AUC [0-inf]) of probe substrates on Day 113/(AUC [0-inf]) of probe substrates on Day 1.

  • Geometric Mean Ratio (Day 22/ Day 1) of the Area Under the Plasma Concentration-time Curve From 0 to Last Time (AUC [0-last]) of Cytochrome P450 Probe Substrates (Midazolam, Omeprazole, Dextromethorphan, S-warfarin and Caffeine) [ Time Frame: Day 1 and 22: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post dose ]
    (AUC [0-last]) is defined as the area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. The geometric mean ratio of (AUC [0-last]) will be defined as the (AUC [0-last]) of probe substrates on Day 22/(AUC [0-last]) of probe substrates on Day 1.

  • Geometric Mean Ratio (Day 113/ Day 1) of the Area Under the Plasma Concentration-time Curve From 0 to Last Time (AUC [0-last]) of Cytochrome P450 Probe Substrates (Midazolam, Omeprazole, Dextromethorphan, S-warfarin and Caffeine) [ Time Frame: Day 1 and 113: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post dose ]
    (AUC [0-last]) is defined as the area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. The geometric mean ratio of (AUC [0-last]) will be defined as the (AUC [0-last]) of probe substrates on Day 113/(AUC [0-last]) of probe substrates on Day 1.

  • Geometric Mean Ratio (Day 22/ Day 1) of the Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC [0-24]) of Cytochrome P450 Probe Substrates (Midazolam, Omeprazole, Dextromethorphan, and Caffeine) [ Time Frame: Day 1 and 22: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post dose ]
    (AUC [0-24]) is defined as area under the plasma concentration-time curve from time 0 to 24 hours. The geometric mean ratio of (AUC [0-24]) will be defined as the (AUC [0-24]) of probe substrates on Day 22/(AUC [0-24]) of probe substrates on Day 1.

  • Geometric Mean Ratio (Day 113/ Day 1) of the Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC [0-24]) of Cytochrome P450 Probe Substrates (Midazolam, Omeprazole, Dextromethorphan, and Caffeine) [ Time Frame: Day 1 and 113: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post dose ]
    (AUC [0-24]) is defined as area under the plasma concentration-time curve from time 0 to 24 hours. The geometric mean ratio of (AUC [0-24]) will be defined as the (AUC [0-24]) of probe substrates on Day 113/(AUC [0-24]) of probe substrates on Day 1.

  • Geometric Mean Ratio (Day 22/ Day 1) of the Area Under the Plasma Concentration-time Curve From 0 to 96 Hours (AUC [0-96]) of Cytochrome P450 Probe Substrate (S-warfarin) [ Time Frame: Day 1 and 22: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post dose ]
    (AUC [0-96]) is defined as area under the plasma concentration-time curve from time 0 to 96 hours. The geometric mean ratio of (AUC [0-96]) will be defined as the (AUC [0-96]) of probe substrates on Day 22/(AUC [0-96]) of probe substrates on Day 1.

  • Geometric Mean Ratio (Day 113/ Day 1) of the Area Under the Plasma Concentration-time Curve From 0 to 96 Hours (AUC [0-96]) of Cytochrome P450 Probe Substrate (S-warfarin) [ Time Frame: Day 1 and 113: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post dose ]
    (AUC [0-96]) is defined as area under the plasma concentration-time curve from time 0 to 96 hours. The geometric mean ratio of (AUC [0-96]) will be defined as the (AUC [0-96]) of probe substrates on Day 113/(AUC [0-96]) of probe substrates on Day 1.


Secondary Outcome Measures:
  • Time to Reach the Maximum Observed Plasma Concentration (Tmax) of Cytochrome P450 Probe Substrates (Midazolam, Omeprazole, Dextromethorphan, S-warfarin and Caffeine) [ Time Frame: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 (only for dextromethorphan and S-warfarin), 72 (only for S-warfarin) and 96 hours (only for S-warfarin) on Days 1, 22, and 113 postdose administration of cytochrome P450 probe substrates ]
    Tmax is defined as time to reach the maximum observed plasma concentration of Cytochrome P450 Probe Substrates.

  • Terminal Half-Life (T1/2) of Cytochrome P450 Probe Substrates (Midazolam, Omeprazole, Dextromethorphan, S-warfarin and Caffeine) [ Time Frame: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 (only for dextromethorphan and S-warfarin), 72 (only for S-warfarin) and 96 hours (only for S-warfarin) on Days 1, 22, and 113 postdose administration of cytochrome P450 probe substrates ]
    T1/2 is defined as the time measured for the plasma concentration to decrease by 1 half to its original concentration. It is associated with the terminal slope of the semi logarithmic drug concentration-time curve, and is calculated as 0.693/lambda(z).

  • Apparent Total Systemic Clearance (CL/F) of Cytochrome P450 Probe Substrates (Midazolam, Omeprazole, Dextromethorphan, S-warfarin and Caffeine) [ Time Frame: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 (only for dextromethorphan and S-warfarin), 72 (only for S-warfarin) and 96 hours (only for S-warfarin) on Days 1, 22, and 113 postdose administration of cytochrome P450 probe substrates ]
    CL/F after extravascular administration is defined as the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.

  • Apparent Volume of Distribution (Vz/F) of Cytochrome P450 Probe Substrates (Midazolam, Omeprazole, Dextromethorphan, S-warfarin and Caffeine) [ Time Frame: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 (only for dextromethorphan and S-warfarin), 72 (only for S-warfarin) and 96 hours (only for S-warfarin) on Days 1, 22, and 113 postdose administration of cytochrome P450 probe substrates ]
    Vz/F based on terminal phase after extravascular administration is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. Apparent volume of distribution after subcutaneous dose (Vz/F) is influenced by the fraction absorbed.

  • Twelve Hour Urine Dextromethorphan to Dextrorphan Ratio [ Time Frame: Pre-dose and for 12 hours after probe cocktail administration on Day 1, 22 and 113 ]
    Urine samples will be analyzed to determine 12 hour urine dextromethorphan to dextrorphan ratio.

  • Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: Up to Day 176 ]
    An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were events between administration of study drug and up to Day 176 that were absent before treatment or that worsened relative to pre-treatment state.


Estimated Enrollment: 51
Anticipated Study Start Date: January 8, 2018
Estimated Study Completion Date: September 10, 2021
Estimated Primary Completion Date: September 24, 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Crohn's Disease Participants: Ustekinumab + Probe Cocktail
Participants will receive a single Intravenous (IV) infusion dose of ustekinumab (dosage to be decided based on body weight) on Day 8 and a ustekinumab 90 milligram (mg) maintenance dose via subcutaneous (SC) route on Day 64. A second optional maintenance dose may be administered on Day 120 based on participants clinical response assessed by investigator. The probe cocktail (2 milligram [mg] of midazolam, 10 mg of warfarin plus 10 mg of vitamin K, 20 mg of omeprazole, 30 mg dextromethorphan, and 100 mg of caffeine) will be administered orally on Days 1, 22, and 113.
Drug: Ustekinumab IV Infusion
Participants will receive a single IV infusion dose of ustekinumab (dosage to be decided based on body weight) on Day 8.
Drug: Ustekinumab SC Injection
Participants will receive a Ustekinumab 90 mg SC maintenance dose on Day 64. A second optional maintenance dose may be administered on Day 120 based on participants clinical response assessed by investigator.
Drug: Midazolam 2 mg
Participants will receive 2 milligram per milliliter (mg/ml) syrup of midazolam as a component of the Cytochrome P 450 probe cocktail orally.
Drug: Warfarin 10 mg
Participants will receive 10 mg tablet of warfarin as a component of the Cytochrome P 450 probe cocktail orally.
Drug: Vitamin K 10 mg
Participants will receive 10 mg tablet of vitamin K as a component of the Cytochrome P 450 probe cocktail orally.
Drug: Omeprazole 20 mg
Participants will receive 20 mg capsule of omeprazole as a component of the Cytochrome P 450 probe cocktail orally.
Drug: Dextromethorphan 30 mg
Participants will receive 30 mg capsule of dextromethorphan as a component of the Cytochrome P 450 probe cocktail orally.
Drug: Caffeine 100 mg
Participants will receive 100 mg tablet of caffeine as a component of the Cytochrome P 450 probe cocktail orally.
Experimental: Healthy Participants: Probe Cocktail
Participants will receive the probe cocktail (2 mg of midazolam, 10 mg of warfarin plus 10 mg of vitamin K, 20 mg of omeprazole, 30 mg dextromethorphan, and 100 mg of caffeine) orally on Day 1.
Drug: Midazolam 2 mg
Participants will receive 2 milligram per milliliter (mg/ml) syrup of midazolam as a component of the Cytochrome P 450 probe cocktail orally.
Drug: Warfarin 10 mg
Participants will receive 10 mg tablet of warfarin as a component of the Cytochrome P 450 probe cocktail orally.
Drug: Vitamin K 10 mg
Participants will receive 10 mg tablet of vitamin K as a component of the Cytochrome P 450 probe cocktail orally.
Drug: Omeprazole 20 mg
Participants will receive 20 mg capsule of omeprazole as a component of the Cytochrome P 450 probe cocktail orally.
Drug: Dextromethorphan 30 mg
Participants will receive 30 mg capsule of dextromethorphan as a component of the Cytochrome P 450 probe cocktail orally.
Drug: Caffeine 100 mg
Participants will receive 100 mg tablet of caffeine as a component of the Cytochrome P 450 probe cocktail orally.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria For Crohn's Disease (CD) Participants

  • Participant must have a body weight in the range of 45 to 110 kilogram (kg) inclusive and have a body mass index (BMI) of 18 to 35 kilogram per meter square (kg/m^2) inclusive
  • Have moderate to severe CD or fistulizing CD of at least 3 months duration, with colitis, ileitis, or ileocolitis, confirmed at any time in the past by histology, and/or endoscopy

For Healthy Volunteers

  • Healthy on the basis of physical examination, medical history, vital signs, and 12-lead electrocardiogram (ECG) performed at screening
  • Healthy on the basis of clinical laboratory tests performed at screening and Day-1
  • If a woman of childbearing potential, she must have a negative serum beta-human chorionic gonadotropin (hCG) pregnancy test at screening; and a negative urine pregnancy test at Day -1

Exclusion Criteria For CD Participants

  • Has complications of CD such as symptomatic strictures or stenoses, short gut syndrome, or any other manifestation that might be anticipated to require surgery in the next 3 months, could preclude the use of the Crohn's Disease Activity Index (CDAI) to assess response to therapy, would possibly confound the ability to assess the effect of treatment with ustekinumab, or would alter the absorption of the probe cocktail
  • Currently has or is suspected to have an abscess. Recent cutaneous and perianal abscesses are not exclusionary if drained and adequately treated at least 3 weeks prior to baseline, or 8 weeks prior to baseline for intra-abdominal abscesses, provided that there is no anticipated need for any further surgery. Participants with active fistulas may be included if there is no anticipation of a need for surgery and there are currently no abscesses identified

For Healthy Volunteers Participants

  • Has an abnormal C-reactive protein (CRP) greater than (>) 2* upper limit of normal (ULN)
  • Has had major surgery (example, requiring general anesthesia) within 8 weeks before screening, or will not have fully recovered from surgery, or has surgery planned during the time the participant is in screening or is expected to participate in the study (5 weeks)
  • Is pregnant, nursing, or planning a pregnancy (both men and women) during the study
  Contacts and Locations
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): NCT03358706


Contacts
Contact: Study Contact 844-434-4210 JNJ.CT@sylogent.com

Locations
United States, California
WCCT Global, LLC Not yet recruiting
Cypress, California, United States, 90630
United States, Florida
Accel Research Sites Not yet recruiting
DeLand, Florida, United States, 32720
Ocean Blue Medical Research Center Inc. Not yet recruiting
Miami Springs, Florida, United States, 33166
Advanced Pharma CR, LLC Withdrawn
Miami, Florida, United States, 33147
Belgium
Az Sint-Maarten Not yet recruiting
Mechelen, Belgium, 2800
Clinical Pharmacology Unit Not yet recruiting
Merksem, Belgium, 2170
Germany
Universitatsklinikum Bonn Not yet recruiting
Bonn, Germany, 53127
Universitatsklinikum Essen Not yet recruiting
Essen, Germany, 45147
CTC North GmbH & Co. KG, Am Universitätsklinikum Hamburg-Eppendorf Not yet recruiting
Hamburg, Germany, 20251
Clinical Research Center Hannover Not yet recruiting
Hannover, Germany, 30625
University Hospital Heidelberg Not yet recruiting
Heidelberg, Germany, 69120
Sponsors and Collaborators
Janssen Research & Development, LLC
Investigators
Study Director: Janssen Research & Development, LLC Clinical Trial Janssen Research & Development, LLC
  More Information

Responsible Party: Janssen Research & Development, LLC
ClinicalTrials.gov Identifier: NCT03358706     History of Changes
Other Study ID Numbers: CR108352
2017-000831-16 ( EudraCT Number )
CNTO1275CRD1003 ( Other Identifier: Janssen Research & Development, LLC )
First Submitted: November 27, 2017
First Posted: December 1, 2017
Last Update Posted: December 1, 2017
Last Verified: November 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Omeprazole
Crohn Disease
Inflammatory Bowel Diseases
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Intestinal Diseases
Vitamins
Vitamin K
Midazolam
Caffeine
Dextromethorphan
Warfarin
Ustekinumab
Micronutrients
Growth Substances
Physiological Effects of Drugs
Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action