A randomised, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy and safety of tralokinumab in combination with topical corticosteroids in subjects with moderate-to-severe atopic dermatitis who are candidates for systemic therapy

Treatment recommendations for AD include topical therapies, the main being TCS.
Unfortunately, TCS and topical calcineurin inhibitors (TCIs) have limited
efficacy in patients with moderate to severe disease. TCS and non-biologic
systemic therapies (e.g. cyclosporine, azathioprine) are all associated with
toxicities with long-term use (*16-*18). The recently approved biological agent
dupilumab exhibits an acceptable benefit-risk ratio in clinical trials
investigating subjects with moderate to-severe AD, however there is limited
experience with long-term dupilumab use in the post marketing setting.
The purpose of this phase 3 trial is to provide evidence of the efficacy and
safety of tralokinumab in combination with TCS in the treatment of subjects
with moderate-to-severe AD inadequately controlled with topical therapies. Such
subjects would be candidates for systemic therapy.
Since TCS represent the mainstay of pharmacological treatment of AD, many
patients may use tralokinumab in combination with TCS and this trial is
intended to inform about treatment and maintenance with concomitant use of
tralokinumab and TCS. After a 16 week initial treatment period, the trial will
evaluate 2 different treatment options for additional 16-weeks of maintenance
therapy in the continuation treatment period (tralokinumab 300 mg Q2W and 300
mg every 4 weeks [Q4W]).
The primary objective of this trial is to demonstrate that tralokinumab in
combination with TCS provides more effective control of the skin manifestations
of AD than placebo in combination with TCS. The trial will evaluate the
percentage of subjects achieving IGA response of 0 (clear) or 1 (almost clear)
and the percentage of subjects achieving at least 75% reduction in EASI score
(EASI75) at Week 16, with secondary endpoints addressing symptom scores and
extent of AD (SCORAD), itch severity, and health-related quality of life
(HRQoL) measures related to AD.
Thus, the trial will further contribute to the characterisation of the
benefit-risk profile of tralokinumab.

Primary objective:
To demonstrate that tralokinumab in combination with TCS is superior to placebo
in combination with TCS in treating moderate-to-severe AD.
Secondary objectives:
To evaluate the efficacy of tralokinumab in combination with TCS on severity
and extent of AD, itch, and health-related quality of life compared with
placebo in combination with TCS.
To assess safety of tralokinumab in combination with TCS when used to treat
moderate-to-severe AD for 32 weeks.

The trial will consist of a screening period of 2 to 6 weeks (Weeks 6/ 2 to
0), an initial treatment period of 16 weeks (Weeks 0 to 16), a continuation
treatment period of 16 weeks (Weeks 16 to 32), and a 14-week off treatment
follow-up period for the assessment of safety (Weeks 32 to 46).
Subjects will be randomised in a 2:1 ratio to receive multiple subcutaneous
(SC) doses of tralokinumab (300 mg) or placebo every 2 weeks (Q2W) following a
loading dose of 600 mg on Day 0 (or 4 mL placebo). Randomisation will be
stratified by region and baseline disease severity.
At Week 16, subjects will continue into continuation treatment until Week 32
(the last dose of investigational medicinal product [IMP] will be given at Week
30). The treatment during the continuation treatment period will depend on the
regimen received in the initial treatment period and on the subject*s clinical
response at Week 16 (defined as IGA of 0 or 1 on a 5 point scale ranging from 0
[clear] to 4 [severe], or EASI75).
Subjects randomised to tralokinumab in the initial treatment period and with a
clinical response at Week 16 will be re-randomised 1:1 to one of the following
Q2W maintenance regimens stratified by region and IGA response at Week 16 (IGA
0/1 or IGA >1):
* Tralokinumab 300 mg Q2W.
* Alternating dose administrations tralokinumab 300 mg and placebo
(tralokinumab Q4W).
Subjects randomised to placebo in the initial treatment period and with a
clinical response at Week 16 will receive placebo Q2W in the continuation
treatment period. Non responders at Week 16 in the tralokinumab and placebo
groups will receive tralokinumab 300 mg Q2W.
The primary endpoints are assessed at Week 16, and the final efficacy
assessment will be conducted at Week 32.
Starting on Day 0 (baseline), all subjects will be allowed to initiate
treatment once daily with a supplied TCS on lesional skin and continue as
needed throughout the treatment period. TCS use will be monitored throughout
the trial.
All subjects will use an emollient twice daily (or more, as needed) for at
least 14 days before randomisation and will continue this treatment throughout
the trial (including safety follow-up). On lesional skin, emollients should
only be applied at a time where TCS is not applied; on TCS-untreated areas, the
emollients may be applied at all times.

Tralokinumab (human recombinant IL 13 monoclonal antibody)
150 mg/mL solution for SC injection in an accessorised pre filled syringe, 1.0
mL fill volume. Each kit contains 1 syringe.
Placebo
Placebo solution for SC injection in an accessorised pre-filled syringe, 1.0 mL
fill volume. Each kit contains 1 syringe.

There is an unmet medical need for new therapies for use in subjects with
moderate-to-severe AD as current immunosuppressive medications, such as
cyclosporine, methotrexate, and azathioprine, have associated long-term
toxicities. Albeit 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 both moderate-to-severe AD as
well as in a severe asthma population 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
in Section *5.2 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; measures are in
place in this trial to protect participating subjects as follows:
* Close monitoring of subjects during the trial with trial visits every 2 weeks
during the treatment period (see the schedule of procedures in Section *4).
* Close monitoring of subjects during the post dosing period at the first 3
investigational medicinal product (IMP) dosing visits in the initial treatment
period (i.e., Weeks 0, 2, and 4) and after re-randomisation (i.e., Weeks 16,
18, and 20) as a precautionary measure against hypersensitivity reactions
(further details are given in Section *9.1.3.1).
* Monitoring of subjects for clinical manifestations that may be associated
with the development of specific antibodies to tralokinumab (i.e., immune
complex disease).
* Exclusion of subjects with untreated systemic helminth infestations or
subjects who have failed to respond to standard of care therapy; neutralisation
of IL 13 might theoretically cause a worsening of parasitic infestation, in
particular prevention of expulsion of gastrointestinal worms (helminths) (*19).
* Exclusion of subjects with a history of tuberculosis requiring treatment
within 12 months prior to the screening visit.
* Exclusion of subjects with a history of a clinically significant infection
(defined as a systemic or serious skin infection requiring parenteral
antibiotics, antiviral, or anti-fungal medication; see Section *8.3) within 4
weeks prior to baseline which, in the opinion of the investigator or sponsor*s
medical expert, may compromise the safety of the subject in the trial.
In conclusion, previous clinical experience with tralokinumab shows no major
safety or tolerability concerns and appropriate measures have been instituted
in this trial to protect subjects from potential risks that have been
previously identified and to closely monitor each subject. The current
risk/benefit ratio is favourable and supports the administration of
tralokinumab in combination with TCS therapy for the purposes of achieving the
objectives of this trial.