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

Study Overview
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Brief Summary
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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

Official Title
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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

Conditions
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Atopic Dermatitis

Intervention / Treatment
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* Drug: Tralokinumab
* Drug: Caffeine
* Drug: Warfarin
* Drug: Omeprazole
* Drug: Metoprolol
* Drug: Midazolam Hydrochloride


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: All subjects<br>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<br>* 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.<br>Drug: Caffeine<br>* 1x 100 mg tablet<br>Drug: Warfarin<br>* 2x 5 mg tablets<br>Drug: Omeprazole<br>* 1x 20 mg capsule<br>Drug: Metoprolol<br>* 1x 100 mg tablet<br>Drug: Midazolam Hydrochloride<br>* 1 mL of 2 mg/mL oral solution/syrup<br>|

What is the study measuring?
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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 |