A Multicentre, Randomized, Double-blind, Parallel Group, Placebo Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Tralokinumab in Reducing Oral Corticosteroid Use in Adults and Adolescents with Oral Corticosteroids dependent Asthma (TROPOS)

Asthma is a syndrome characterized by airway inflammation, reversible airway
obstruction and airway hyperresponsiveness, with a global prevalence of
approximately 300 million patients (GINA 2014). Approximately 5% to 10% of
asthma patients have severe asthma, many of whom may be inadequately controlled
by inhaled corticosteroids (ICS) and long-acting β2-agonists (LABA)in
combination with additional controller therapies (Bateman et al 2010).
The observed variability in clinical response to currently available asthma
therapies appears to be related, in part, to distinctive inflammatory
phenotypes (Wenzel 2012). There is considerable evidence that interleukin-13
(IL-13) is a key mediator in the pathogenesis of asthma. Tralokinumab is a
human recombinant monoclonal antibody (MAb) that specifically binds human
IL-13, blocking interactions with the IL-13 receptor.
OCS are effective agents for controlling airway inflammation in asthma and are
indicated for severe persistent asthma, as outlined in Step 5 of the Global
Initiative for Asthma (GINA 2014) guidelines. Since long-term treatment with
OCS use can result in adverse reactions such as osteoporosis, diabetes,
cataract and growth retardation in children, a major objective in this
population is to reduce their overall exposure to OCS thereby minimising
adverse events. Given the need to reduce the requirement of OCS in patients
with severe asthma, treatments that may allow tapering of OCS without loss of
control are needed.

Primary objective:
• To evaluate the effect of tralokinumab compared to placebo in reducing the
prescribed, OCS maintenance dose in adult and adolescent subjects with asthma
requiring chronic treatment with maintenance OCS in addition to ICS/LABA.

Secundary objective:
• To evaluate the effect of tralokinumab compared to placebo on the proportion
of subjects with the prescribed, OCS maintenance dose <=5 mg (daily) in adult
and adolescent subjects with asthma requiring chronic treatment with
maintenance OCS in addition to ICS/LABA.

• To evaluate the effect of tralokinumab compared to placebo on the proportion
of subjects with at least 50% reduction in their prescribed, OCS maintenance
dose in adult and adolescent subjects with asthma requiring chronic treatment
with maintenance OCS in addition to ICS/LABA.

Safety objective:
• To evaluate the safety and tolerability of tralokinumab

Exploratory objectives:
• To evaluate the effect of tralokinumab versus placebo in overall OCS exposure

• To evaluate the effect of tralokinumab versus placebo in the proportion of
subjects that have decreased their daily average prescribed, OCS dose

• To evaluate the effect of tralokinumab compared with placebo on asthma
exacerbations.

• To evaluate the effect of tralokinumab compared with placebo on lung function

• To evaluate the effect of tralokinumab compared with placebo on asthma
symptoms and other asthma control metrics

• To evaluate the effect of tralokinumab compared with placebo with regards to
asthma specific health-related quality of life

• To evaluate the effect of tralokinumab compared with placebo with regards to
health related quality of life

• To evaluate the effect of tralokinumab compared with placebo with regards to
HRU and productivity loss due to asthma

• To evaluate the pharmacokinetics and immunogenicity of tralokinumab

• To evaluate the change from baseline of biomarkers that may be associated
with upregulation of IL-13

• To evaluate the relationship between baseline biomarkers and the effect of
tralokinumab on OCS dose reduction and clinical efficacy

• To evaluate the impact of OCS optimization on biomarkers

Randomized, double-blind, parallel group, placebo-controlled phase III study.
Approximately 120 subjects will be randomized to tralokinumab or placebo (1:1
ratio). Subjects will be stratified at randomization by the baseline OCS dose
(<=10 mg versus >10 mg prednisone or prednisolone) and age group (adults versus
adolescents). (NB: only adults in the Netherlands)

- Run-in period (2 weeks)
- OCS optimization period (maximum 8 weeks), except for patients with
documented failure of OCS reduction within 6 months prior to visit 1 and only
after approval of the study physician.

Once subjects have completed the run-in or run-in/optimization period, subjects
will be randomised to receive tralokinumab or placebo over a 40-week treatment
period.

Treatment period consists of 3 phases:
- Induction phase (12 weeks), needed to ensure maximal effect on FEV1
- OCS reduction phase (20 weeks), needed to reach the lowest possible dose
based on the titration schedule (CSP table 4)
- Maintenance phase (8 weeks)

Post-treatment safety follow-up visits will be performed at week 44 and week 54.

Subjects will be maintained on their currently prescribed ICS/LABA therapy and
any additional asthma controller medications, without changes, from enrollment
throughout the run-in/optimization and treatment periods.

Subjects will be administered 300 mg tralokinumab (2 x 150mg, 1mL injections)
or placebo (2 x 1mL injections) every 2 weeks

The subject visits the hospital 28 times maximally. Subjects with documented
OCS reduction failure prior to visit 1, visit the hospital 24 times maximally.
These visits to the hospital will take 30 minutes up to 4.5 hours each,
depending on the assessments per visit.

The following will be done during the hospital visits:
- Physical examination
- Check of vital functions, assessment of length and weight
- ECG
- Collection of blood for clinical chemistry, hematology and exploratory
research
- Urinalysis
- Assessment of exhaled nitric oxide (NO)
- Pre- and post-bronchodilator spirometry
- Subject will be asked about health care resource utilization, asthma
symptoms, adverse events and medication
- Subject will be asked to complete several questionnaires (ACQ-6, AQLQ(S)+12,
WPAI+CIQ, EQ-5D-5L)
- Pregnancy test will be done (women of child baring potential only)
- FSH test done only for female subjects to confirm post-menopausal status in
women<50 years who have been ammenorrheic for >12 months
- Test for Hepatitis B and C, and HIV and concentration levels maintenance
treatment.

Subjects will be asked to complete an electronic diary (eDiary) every morning
and evening and determine morning and evening peakflow. This will take
approximately 10 minutes per day.

In addition, the subject should complete questionnaires several times at home:
- ACQ-6: every 2 weeks from visit 1 till visit 26
- AQLQ(S)+12: every 14 days from visit 1 till 6, from visit 6 every 28 days
till visit 26
- WPAI+CIQ: every 2 weeks from visit 6 till visit 26
- EQ-5D-5L: every week from visit 6 till visit 26

Patients using OCS other than prednisone or prednisolone, will be switched to
an equivalent dose of prednisone or prednisolone at visit 1. During the
optimalization period (visit 2-5) OCS dose will be optimized without loss of
asthma control. The treatment period starts at randomization (visit 6) and OCS
dose will remain constant for 8 weeks (induction phase, visit 6-11). During the
reduction phase (visit 12-21) attempts will be made to reduce OCS dose. During
the maintenance phase (visit 22-25) the OCS dose will remain constant again.
During the treatment period (visit 6-26) patients will receive tralokinumab or
placebo (1:1) every 2 weeks via subcutaneous injections (2 subcutaneous
injections each time).

Subjects will continue using their current ICS/LABA and additional asthma
controller medication. The costs for this asthma medication will be reimbursed
by AstraZeneca.