Primary objectiveTo evaluate if tralokinumab after 14 weeks of treatment (at steady state) changes the metabolism of substrates of CYP 1A2, 2C9, 2C19, 2D6, or 3A4 pathways in subjects with moderate-tosevere atopic dermatitisSecondary objectivesTo…
ID
Source
Brief title
Condition
- Skin and subcutaneous tissue disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- Ratio of the AUClast at Week 15 (after multiple doses of tralokinumab,
AUClast,MD) to that on Day -7 (at baseline, AUClast,Base) for each of the 5
substrates
- Ratio of the Cmax at Week 15 (Cmax,MD) to that on Day -7 (Cmax,Base) for each
of the 5 substrates
Secondary outcome
- Ratio of the AUClast on Day 8 (after a single dose of tralokinumab,
AUClast,SD) to that on Day -7 (AUClast,Base) for each of the 5 substrates
- Ratio of the Cmax on Day 8 (Cmax,SD) to that on Day -7 (Cmax,Base) for each
of the 5 substrates
- Ratio of the AUCinf on Day 8 (AUCinf,SD) to that on Day -7 (AUCinf,Base) for
each of the 5 substrates
Background summary
Because AD is associated with elevated proinflammatory cytokines, and because
increased levels of certain cytokines during chronic inflammation can alter the
formation of cytochrome P450 (CYP) enzymes, there is potential for AD
disease-drug-drug interaction.
The current draft guidance for drug interaction studies (FDA 2017) recommends
conducting clinical trials to determine the effect of a therapeutic protein on
CYP enzymes in the target patient population if the investigational therapeutic
protein is a cytokine or cytokine modulator. This is the case with
tralokinumab, the investigational medicinal product (IMP) in this trial.
Study objective
Primary objective
To evaluate if tralokinumab after 14 weeks of treatment (at steady state)
changes the metabolism of substrates of CYP 1A2, 2C9, 2C19, 2D6, or 3A4
pathways in subjects with moderate-tosevere atopic dermatitis
Secondary objectives
To evaluate if a single dose of tralokinumab changes the metabolism of
substrates of CYP 1A2, 2C9, 2C19, 2D6, or 3A4 pathways in subjects with
moderate-to-severe atopic dermatitis
To evaluate the safety and tolerability of tralokinumab in subjects with
moderate-to-severe atopic dermatitis
Study design
The trial will consist of a screening period of 2*5 weeks (Week -6 to Day -7),
a 1-week pre-IMP period (Day -7 to Day 1), a 16-week treatment period (Day 1 to
Week 16), and a 14-week safety follow-up period (Week 16 to Week 30).
Eligible subjects may enter the open-label, long-term extension trial
(LP0162-1337, ECZTEND) at Week 16 or later.
Following the pre-IMP period, all subjects will be dosed with tralokinumab 600
mg (4 mL) on Day 1, then with tralokinumab 300 mg (2 mL) every 2 weeks. The
last dose of tralokinumab will be administered at Week 14.
After administration of the 5 substrates (caffeine, warfarin, omeprazole,
metoprolol, and midazolam [CYP cocktail]) on Day -7, Day 8, and Week 15, plasma
samples will be collected for up to 7 days after the cocktail dosing for
measurement of plasma concentrations of the substrates.
For each of the 5 substrates, the pharmacokinetic (PK) parameters on Day -7
(baseline) will be compared with the PK parameters on Day 8 (after a single
dose of tralokinumab) and at Week 15 (after multiple doses of tralokinumab).
Plasma concentrations of tralokinumab will be measured at the cocktail dosing
visits on Day 8 and at Week 15. Additionally, plasma concentrations of
tralokinumab will be measured before administration of tralokinumab at Weeks 4
and 14, and 2 weeks after the last administration of tralokinumab, that is, at
Week 16.
All subjects will use an emollient twice daily (or more, as needed) for at
least 14 days before baseline and will continue this treatment throughout the
trial (including the safety follow-up period).
Intervention
Tralokinumab
CYP cocktail:
- Caffeine
- Warfarin
- Omeprazole
- Metoprolol
- Midazolam
Study burden and risks
There is an unmet medical need for new therapies for use in subjects with
moderate-to-severe AD because current immunosuppressive medications, such as
cyclosporine, methotrexate, and azathioprine, are associated with long-term
toxicities. Although dupilumab exhibits an acceptable benefit/risk ratio in
clinical trials in AD, the long-term efficacy and safety experience with
dupilumab is currently limited.
Tralokinumab has already demonstrated efficacy in moderate-to-severe AD in
phase 2 trials, and has shown an acceptable safety profile in AD, asthma,
ulcerative colitis, idiopathic pulmonary fibrosis, and in trials with healthy
subjects. The evidence discussed further supports the hypothesis that
individuals with AD may benefit from treatment with tralokinumab.
In the clinical trials completed to date, tralokinumab was well tolerated. A
number of theoretical potential risks have been identified that are described
in the current version of the Investigator*s Brochure, including
hypersensitivity reactions, immune complex disease, severe infections,
malignancies, and interference with reproductive function.
Zernikedreef 8
Leiden 2333CL
NL
Zernikedreef 8
Leiden 2333CL
NL
Listed location countries
Age
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:
o ±7 days within each cocktail dosing visit (that is, between the Day -14 and Day 15 visits and between the Week 14 and Week 16 visits): 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, including but not limited to broccoli, cabbage, cauliflower, kale, Brussels sprout, radish, turnip, horseradish.
- Chargrilled meat.
o ±48 hours within each cocktail dosing visit: caffeinated beverages, foods/drugs that contain caffeine, including coffee, tea (black and green), coca cola, energy drinks, and chocolate.
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:
o From Day -14 (±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, including but not limited to broccoli, cabbage, cauliflower, kale, Brussels sprout, radish, turnip, horseradish.
- Chargrilled meat.
o From Day -9 (±48 hours within each cocktail dosing visit):
caffeinated beverages, foods/drugs that contain caffeine, including coffee, tea (black and green), coca cola, energy drinks, and chocolate.
* 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 (that is, immunoglobulin or anti-immunoglobulin E) including dupilumab or investigational biologic agents:
o Any cell-depleting agents, including but not limited to rituximab: within 6 months prior to baseline (Day -7), or until lymphocyte count returns to normal, whichever is longer.
o Other biologics: within 3 months or 5 half-lives, whichever is longer, prior to baseline (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 the 12 months prior to screening.
* Known primary immunodeficiency disorder.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | 2018-000534-35 |
| ClinicalTrials.gov | NCT03556592 |
| CCMO | NL68628.056.18 |