A randomized, placebo-controlled, dose-ranging, multi-centre trial of QAW039 (1-450 mg p.o.) to investigate the effect on FEV1 and ACQ in patients with moderate-to-severe, persistent, allergic asthma, inadequately controlled with ICS therapy (CQAW039A2206)

Many adults with asthma have inadequate control of symptoms when receiving a
low-to-medium dose of an inhaled corticosteroid. Treatment options include the
addition of a leukotriene modifier (Montelukast), the addition of an inhaled
long-acting beta-agonist (LABA) or an increased dose of an inhaled
corticosteroid. There are weaknesses with the current treatments namely,
patients have trouble accurately dosing with the ICS/LABA inhalers and
compliance with these devices is less than that seen with oral medications.
Further the efficacy of montelukast is lower than ICS. Thus there is a need for
a new oral therapy that is more efficacious than montelukast and that would
provide added benefit when added to ICS.
QAW039 is a highly selective and potent oral antagonist of prostaglandin D2
(PGD2) that binds to the CRTH2 receptor (CRTH2 is also known as the DP2
receptor). QAW039 is expected to work by binding CRTH2 receptors on eosinophils
and CRTH2+ T lymphocytes in the blood. At high levels of receptor inhibition,
the migration of eosinophils and CRTH2+ CD4+ lymphocytes into the airway
tissues will be blocked. Since both cell types are thought to be major effector
cells that drive the allergic inflammation associated with asthma, the control
of the signs and symptoms of the disease should be improved.
The purpose of this Phase IIb study is to support the dose selection decision
by finding the dose and/or regimen of QAW039 that will provide the optimal
benefit/risk ratio in patients with moderate to severe allergic asthma
inadequately controlled by ICS therapy.

Primary objective: To demonstrate a clinically significant improvement in
morning FEV1 in moderate to severe allergic asthmatics inadequately controlled
by ICS therapy treated with QAW039 for 12 weeks compared to placebo.
Secondary objectives: asthmatic symptoms (ACQ and Juniper diary), other
spirometry parameters, dose response (trough FEV1), safety and tolerability,
efficacy vs montelukast.

Randomized, double-blind parallel group, phase IIB dose-ranging study.
Screening, thereafter switch to inhaled budesonide, to be stepped down (2-4
weeks) to a low dose (200 ug bid). Washout of prohibited co-medication during
washout period. Thereafter randomization to 12 weeks of treatment with:
• QAW039: 13 dosing groups 1-150 mg 1-2 times daily and 450 mg qd.
• Montelukast 10 mg qd (chance 1:9).
• Placebo (chance 1:9).
All treatments oral (7 capsules daily), in combination with inhaled budesonide.
After the treatment period all patients will be given placebo for 4 weeks.
Salbutamol rescue medication.
Total study duration 18-21 weeks.
Approx. 950 patients.

Treatment with QAW039 in various doses, montelukast or placebo.

Risk: Adverse effects of study medication. Changes in current asthma
medication. Stepping down budesonide.
Burden: 10 visits in 18-21 weeks. 3 visits 7-8 h, 7 visits 2-3 h.
Physical examination 3 times.
Blood tests 9 times (8-54 ml/occasion, 150 ml in total).
Pregnancy test 7 times.
Skin prick test once.
Lung function (reversibility) once.
Lung function 4 times 1 test, 1 time 2 tests.
FENO test 4 times 1 test, 1 time 2 tests.
ECG 3 times 1 ECG, 4 times 4 ECGs.
Questionnaires (1-2) 9 times.
Daily diary and peak flow measurements.
Optional substudy: pharmacogenetic blood test (10 ml).