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

NCT03358706 | Terminated Phase 1 FDA Drug

• 3 other identifiers: CR108352CNTO1275CRD10032017-000831-16
• Study Type: interventional
• Target: 28
• Locations: 4 countries
• Sites: 16

Brief Summary

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 Active Crohn's disease (CD) or Ulcerative Colitis (UC).

Conditions

Crohn Disease; Ulcerative Colitis

Outcome Measures

Primary Outcomes (10)

• For Crohn's disease (CD) or Ulcerative Colitis (UC) Participants: 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)

  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.

  Day 1 and 22: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post dose

• For CD or UC Participants: Geometric Mean Ratio (Day 113/ Day 1) of the Cmax of Cytochrome P450 Probe Substrates (Midazolam, Omeprazole, Dextromethorphan, S-warfarin and Caffeine)

  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.

  Day 1 and 113: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post dose

• For CD or UC Participants: 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)

  (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.

  Day 1 and 22: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post dose

• For CD or UC Participants: Geometric Mean Ratio (Day 113/ Day 1) of AUC (0-inf) of Cytochrome P450 Probe Substrates (Midazolam, Omeprazole, Dextromethorphan, S-warfarin and Caffeine)

  (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.

  Day 1 and 113: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post dose

• For CD or UC Participants: Geometric Mean Ratio (Day 22/ Day 1) of 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)

  (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.

  Day 1 and 22: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post dose

• For CD or UC Participants: Geometric Mean Ratio (Day 113/ Day 1) of AUC (0-last) of Cytochrome P450 Probe Substrates (Midazolam, Omeprazole, Dextromethorphan, S-warfarin and Caffeine)

  (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.

  Day 1 and 113: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post dose

• For CD or UC Participants: 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)

  (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.

  Day 1 and 22: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post dose

• For CD or UC Participants: 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)

  (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.

  Day 1 and 113: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post dose

• For CD or UC Participants: 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)

  (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.

  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

• For CD or UC Participants: 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)

  (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.

  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

Secondary Outcomes (6)

• CD and UC Participants: Time to Reach the Maximum Observed Plasma Concentration (Tmax) of Cytochrome P450 Probe Substrates (Midazolam, Omeprazole, Dextromethorphan, S-warfarin and Caffeine)

  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

• CD and UC Participants: Terminal Half-Life (T1/2) of Cytochrome P450 Probe Substrates (Midazolam, Omeprazole, Dextromethorphan, S-warfarin and Caffeine)

  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

• CD and UC Participants: Apparent Total Systemic Clearance (CL/F) of Cytochrome P450 Probe Substrates (Midazolam, Omeprazole, Dextromethorphan, S-warfarin and Caffeine)

  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

• CD and UC Participants: Apparent Volume of Distribution (Vz/F) of Cytochrome P450 Probe Substrates (Midazolam, Omeprazole, Dextromethorphan, S-warfarin and Caffeine)

  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

• CD and UC Participants: Twelve Hour Urine Dextromethorphan to Dextrorphan Ratio

  Pre-dose and for 12 hours after probe cocktail administration on Day 1, 22 and 113

Study Arms (2)

Crohn's Disease or Ulcerative Colitis Participants: Ustekinumab + Probe Cocktail

EXPERIMENTAL

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; 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

Healthy Participants: Probe Cocktail

EXPERIMENTAL

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; Drug: Warfarin 10 mg; Drug: Vitamin K 10 mg; Drug: Omeprazole 20 mg; Drug: Dextromethorphan 30 mg; Drug: Caffeine 100 mg

Interventions

Ustekinumab IV Infusion DRUG

Participants will receive a single IV infusion dose of ustekinumab (dosage to be decided based on body weight) on Day 8.

Crohn's Disease or Ulcerative Colitis Participants: Ustekinumab + Probe Cocktail

Ustekinumab SC Injection DRUG

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.

Crohn's Disease or Ulcerative Colitis Participants: Ustekinumab + Probe Cocktail

Midazolam 2 mg DRUG

Participants will receive 2 milligram per milliliter (mg/ml) syrup of midazolam as a component of the Cytochrome P 450 probe cocktail orally.

Crohn's Disease or Ulcerative Colitis Participants: Ustekinumab + Probe Cocktail; Healthy Participants: Probe Cocktail

Warfarin 10 mg DRUG

Participants will receive 10 mg tablet of warfarin as a component of the Cytochrome P 450 probe cocktail orally.

Crohn's Disease or Ulcerative Colitis Participants: Ustekinumab + Probe Cocktail; Healthy Participants: Probe Cocktail

Vitamin K 10 mg DRUG

Participants will receive 10 mg tablet of vitamin K as a component of the Cytochrome P 450 probe cocktail orally.

Crohn's Disease or Ulcerative Colitis Participants: Ustekinumab + Probe Cocktail; Healthy Participants: Probe Cocktail

Omeprazole 20 mg DRUG

Participants will receive 20 mg capsule of omeprazole as a component of the Cytochrome P 450 probe cocktail orally.

Crohn's Disease or Ulcerative Colitis Participants: Ustekinumab + Probe Cocktail; Healthy Participants: Probe Cocktail

Dextromethorphan 30 mg DRUG

Participants will receive 30 mg capsule of dextromethorphan as a component of the Cytochrome P 450 probe cocktail orally.

Crohn's Disease or Ulcerative Colitis Participants: Ustekinumab + Probe Cocktail; Healthy Participants: Probe Cocktail

Caffeine 100 mg DRUG

Participants will receive 100 mg tablet of caffeine as a component of the Cytochrome P 450 probe cocktail orally.

Crohn's Disease or Ulcerative Colitis Participants: Ustekinumab + Probe Cocktail; Healthy Participants: Probe Cocktail

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 had 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Janssen Research & Development, LLC: lead

Study Sites (16)

WCCT Global, LLC

Cypress, California, 90630, United States

Location

Ocean Blue Medical Research Center Inc.

Miami Springs, Florida, 33166, United States

Location

Duke University

Durham, North Carolina, 27710, United States

Location

Ghent University Hospital

Ghent, 9000, Belgium

Location

Centre Hospitalier Universitaire de Liege Domaine Universitaire du Sart Tilman

Liège, 4000, Belgium

Location

Az Sint-Maarten

Mechelen, 2800, Belgium

Location

Clinical Pharmacology Unit

Merksem, 2170, Belgium

Location

Universitatsklinikum Bonn

Bonn, 53127, Germany

Location

Universitatsklinikum Essen

Essen, 45147, Germany

Location

Universitatsklinikum Freiburg

Freiburg im Breisgau, 79106, Germany

Location

CTC North GmbH & Co. KG, Am Universitätsklinikum Hamburg-Eppendorf

Hamburg, 20251, Germany

Location

Clinical Research Center Hannover

Hanover, 30625, Germany

Location

University Hospital Heidelberg

Heidelberg, 69120, Germany

Location

Wythenshawe Hospital

Greater Manchester, M23 9LT, United Kingdom

Location

Royal Liverpool University Hospital

Liverpool, L7 8XP, United Kingdom

Location

Guy's Hospital

London, SE1 9RT, United Kingdom

Location

MeSH Terms

Conditions

Crohn Disease; Colitis, Ulcerative

Interventions

Midazolam; Warfarin; Vitamin K; Omeprazole; Dextromethorphan; Caffeine

Condition Hierarchy (Ancestors)

Inflammatory Bowel Diseases; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Intestinal Diseases; Colitis; Colonic Diseases

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; 4-Hydroxycoumarins; Coumarins; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Naphthoquinones; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Phytol; Diterpenes; Terpenes; Polycyclic Compounds; 2-Pyridinylmethylsulfinylbenzimidazoles; Sulfoxides; Sulfur Compounds; Pyridines; Benzimidazoles; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Phenanthrenes; Xanthines; Purinones; Purines

Study Officials

• Janssen Research & Development, LLC Clinical Trial

  Janssen Research & Development, LLC

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 27, 2017
• First Posted: December 2, 2017
• Study Start: February 2, 2018
• Primary Completion: November 22, 2021
• Study Completion: November 22, 2021
• Last Updated: August 21, 2025

Record last verified: 2025-08

Locations

BE (4); US (3); DE (6); GB (3)