Drug-drug Interaction Trial With Tralokinumab in Moderate to Severe Atopic Dermatitis - ECZTRA 4

An Open-label, Multi Centre Drug-drug Interaction Trial to Investigate the Effects of Tralokinumab on the Pharmacokinetics of Selected Cytochrome P450 Substrates in Adult Subjects With Moderate-to-severe Atopic Dermatitis

The purpose of this trial is to investigate if tralokinumab changes the metabolism of selected CYP substrates in adults with moderate-to-severe AD after:

• 14 weeks of treatment with tralokinumab
• a single dose of tralokinumab

Study Overview

• Status: Completed
• Conditions: Atopic Dermatitis
• Intervention / Treatment: Drug: Tralokinumab; Drug: Caffeine; Drug: Warfarin; Drug: Omeprazole; Drug: Metoprolol; Drug: Midazolam Hydrochloride

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 1

Contacts and Locations

Study Locations

• France
  • Nice, France, 06202
    • LEO Pharma Investigational Site
  • Paris, France, 75010
    • LEO Pharma Investigational Site
• Netherlands
  • Leiden, Netherlands, 2333 ZC
    • LEO Pharma Investigational Site
• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72212
      • LEO Pharma Investigational Site
    • Rogers, Arkansas, United States, 72758
      • LEO Pharma Investigational Site
  • California
    • San Diego, California, United States, 92119
      • LEO Pharma Investigational Site
  • Florida
    • Doral, Florida, United States, 33122
      • LEO Pharma Investigational Site
    • Miami, Florida, United States, 33015
      • LEO Pharma Investigational Site
    • Miami, Florida, United States, 33144
      • LEO Pharma Investigational Site
  • Massachusetts
    • Quincy, Massachusetts, United States, 02169
      • LEO Pharma Investigational Site
  • South Carolina
    • Spartanburg, South Carolina, United States, 29303
      • LEO Pharma Investigational Site
  • Virginia
    • Norfolk, Virginia, United States, 23502
      • LEO Pharma Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 18 and above.
• Diagnosis of AD as defined by the Hanifin and Rajka 1980 criteria for AD.
• History of AD for ≥1 year.
• Subjects who have a recent history of inadequate response to treatment with topical medications or for whom topical treatments are otherwise medically inadvisable.
• AD involvement of ≥10% body surface area at screening and baseline.
• Stable dose of emollient twice daily (or more, as needed) for at least 14 days before baseline.

• Willingness to abstain from consumption of any 1 or more of the following items in the periods specified:

  • ±7 days within each cocktail dosing visit: foods/beverages that affect the CYP system:

    • Grapefruit or grapefruit juice, Seville oranges or orange juice, starfruit, pomegranate and cranberry juices, red wine, red grape extract.
    • Cruciferous vegetables (for example broccoli).
    • Chargrilled meat.
  • ±48 hours within each cocktail dosing visit: caffeinated beverages and foods/drugs that contain caffeine.

Exclusion Criteria:

• Administration, within 14 days or 5 half-lives (whichever is longer) prior to Day -7, of any medication that is a known inducer or inhibitor of 1 or more of the following CYP enzymes: CYP3A, CYP2C19, CYP2C9, CYD2D6, and CYP1A2.
• Subjects who are poor metabolisers of CYP2C9, CYP2C19, or CYP2D6, based on genotyping.
• Any contraindication to 1 or more of the following drugs, according to the applicable labelling: caffeine, warfarin, omeprazole, metoprolol, or midazolam.

• Consumption of any 1 or more of the following items in the periods specified:

  • ±7 days within each cocktail dosing visit: foods/beverages that affect the CYP system:

    • Grapefruit or grapefruit juice, Seville oranges or orange juice, starfruit, pomegranate and cranberry juices, red wine, red grape extract.
    • Cruciferous vegetables (for example broccoli).
    • Chargrilled meat.
  • ±48 hours within each cocktail dosing visit: caffeinated beverages and foods/drugs that contain caffeine.
• Nausea or diarrhoea 1 week prior to Day -7.
• Active dermatologic conditions that may confound the diagnosis of AD.
• Use of tanning beds or phototherapy within 5 weeks prior to Day -7.
• Treatment with systemic immunosuppressive/immunomodulating drugs and/or systemic corticosteroid within 3 weeks prior to Day -7.
• Treatment with topical corticosteroids, topical calcineurin inhibitors, or topical phosphodiesterase 4 inhibitors within 1 week prior to Day -7.

• Receipt of any marketed biological therapy or investigational biologic agent (including immunoglobulin, anti-IgE, or dupilumab):

  • Any cell-depleting agents, including but not limited to rituximab: within 6 months prior to Day -7, or until lymphocyte count returns to normal, whichever is longer.
  • Other biologics: within 3 months or 5 half-lives, whichever is longer, prior to Day -7.
• Active skin infection within 1 week prior to Day -7.
• Clinically significant infection within 4 weeks prior to Day -7.
• A helminth parasitic infection within 6 months prior to the date informed consent is obtained.
• Tuberculosis requiring treatment within 12 months prior to screening.
• Known primary immunodeficiency disorder.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: All subjects; Tralokinumab - investigational medicinal product: Week 0: subcutaneous (SC) injection of tralokinumab loading dose. Week 2 to Week 14: SC injection of tralokinumab maintenance dose. CYP substrates - non-investigational medicinal products: Week -1, Week 1, and Week 15: oral administration of caffeine 100 mg, warfarin sodium 5 mg x2, omeprazole 20 mg, metoprolol tartrate 100 mg, and midazolam hydrochloride 2 mg.

Drug: Tralokinumab; Human recombinant monoclonal antibody of the IgG4 subclass that specifically binds to human IL-13 and blocks interaction with the IL-13 receptors. Presented as a liquid formulation for subcutaneous injection.; Drug: Caffeine; 1x 100 mg tablet; Drug: Warfarin; 2x 5 mg tablets; Drug: Omeprazole; 1x 20 mg capsule; Drug: Metoprolol; 1x 100 mg tablet; Drug: Midazolam Hydrochloride; 1 mL of 2 mg/mL oral solution/syrup

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ratio of the AUC-last at Week 15 (after multiple doses of tralokinumab) to that on Day -7 (at baseline) for each of the 5 substrates	AUC-last = area under the plasma concentration curve from time 0 to the last quantifiable observation	Day -7 and Week 15
Ratio of the Cmax at Week 15 (after multiple doses of tralokinumab) to that on Day -7 (at baseline) for each of the 5 substrates	Cmax = maximum observed plasma concentration	Day -7 and Week 15

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ratio of the AUC-last on Day 8 (after a single dose of tralokinumab) to that on Day -7 (at baseline) for each of the 5 substrates	AUC-last = area under the plasma concentration curve from time 0 to the last quantifiable observation	Day -7 and Day 8
Ratio of the Cmax on Day 8 (after a single dose of tralokinumab) to that on Day -7 (at baseline) for each of the 5 substrates	Cmax = maximum observed plasma concentration	Day -7 and Day 8
Ratio of the AUC-inf on Day 8 (after a single dose of tralokinumab) to that on Day -7 (at baseline) for each of the 5 substrates	AUC-inf = area under the plasma concentration curve from time 0 to infinity	Day -7 and Day 8
Number of adverse events		From Day 1 up to Week 30
Presence of anti-drug antibodies (yes/no)		From Day 1 up to Week 30

Collaborators and Investigators

• Sponsor: LEO Pharma

Study record dates

Study Major Dates

• Study Start (Actual): August 13, 2018
• Primary Completion (Actual): March 16, 2020
• Study Completion (Actual): June 20, 2020

Study Registration Dates

• First Submitted: May 30, 2018
• First Submitted That Met QC Criteria: June 13, 2018
• First Posted (Actual): June 14, 2018

Study Record Updates

• Last Update Posted (Actual): October 26, 2020
• Last Update Submitted That Met QC Criteria: October 23, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Immune System Diseases; Hypersensitivity, Immediate; Genetic Diseases, Inborn; Skin Diseases, Genetic; Hypersensitivity; Skin Diseases, Eczematous; Dermatitis; Eczema; Dermatitis, Atopic; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Purinergic Antagonists; Purinergic Agents; Gastrointestinal Agents; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Anticoagulants; Anti-Ulcer Agents; Proton Pump Inhibitors; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Central Nervous System Stimulants; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Midazolam; Warfarin; Metoprolol; Caffeine; Omeprazole
• Other Study ID Numbers: LP0162-1342; 2018-000534-35 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

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