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This was an exploratory, randomized, subject- and investigator-blind, placebo-controlled, parallel group, proof-of-mechanism study of multiple oral doses of fevipiprant (QAW039) in chronic obstructive pulmonary disease (COPD) patients with eosinophilia.

This was an exploratory, randomized, subject- and investigator-blind, placebo-controlled, parallel group, proof-of-mechanism study in COPD subjects with eosinophilia, on standard of care therapy. Standard of care (SoC) treatment in subjects with COPD typically includes a regimen of inhaled corticosteroid (ICS) plus one or more long acting bronchodilator (long-acting beta2-agonist (LABA) or long-acting antimuscarinic antagonist (LAMA)).

The study consisted of a screening period (including an optional pre-screen visit) during which the subject's phenotype and eligibility for the study were assessed. All subjects who met the eligibility criteria after the screening visit were to undergo induction of their sputum to examine the baseline sputum cell counts. Subjects were required to demonstrate both blood and sputum eosinophilia to be eligible for participation in the study.

Eligible subjects were randomized 3:2 to active (fevipiprant 450 mg oral daily) vs. placebo arms. Randomization was stratified by current smoking status (current vs. ex-smoker). Subjects were to continue their COPD standard of care and other medications during the entire course of the study. Subjects were to receive multiple doses of fevipiprant or placebo for six weeks.

Sputum induction was to be repeated at the end of the treatment period and at the end of the study (approximately 4 weeks after the last dose).

The primary purpose of the proof-of-mechanism study was to determine whether fevipiprant (QAW039), when administered to COPD patients with eosinophilic airway inflammation on standard of care therapy, reduced the burden of sputum eosinophilia. Data from other trials did not confirm efficacy of fevipiprant and did not warrant the continuation of treatment in this study. As a result, this study was terminated early.

Inclusion Criteria:

1. Acceptable and reproducible spirometry with post-bronchodilator FEV1/FVC < 0.7 and post-bronchodilator FEV1≥ 30 and ≤ 80% of predicted at the screening and baseline visits (GOLD stage II or III COPD).
2. Patients with a physician-diagnosed history of COPD for at least 1 year prior to screening visit, and a documented history of at least one COPD exacerbation within the year prior to screening visit and on a stable therapy regimen for COPD for at least 4 weeks prior to screening visit with inhaled glucocorticoid + one or more long acting bronchodilator.
3. Current or ex-smokers who have a smoking history of at least 10 pack-years (10 pack-years are defined as 20 cigarettes a day for 10 years, or 10 cigarettes a day for 20 years, or equivalent).
4. Circulating eosinophils ≥ 300 cells/µL blood AND sputum eosinophils ≥ 3% of total cell count during screening period.

Exclusion Criteria:

1. Patients with a past or current medical history of asthma.

2. Patients with a past or current medical history of conditions other than COPD or allergic rhinitis that could result in elevated sputum eosinophils (e.g., asthma, hypereosinophilic syndrome, Churg-Strauss Syndrome). Patients with known parasitic infestation within 6 months prior to screening are also excluded.

3. Patients who have had a respiratory tract infection or COPD worsening or systemic steroid use within 4 weeks prior to screening visit or between screening and randomization visits.

4. Patients with history of concomitant chronic or severe pulmonary disease (e.g., sarcoidosis, interstitial lung disease, cystic fibrosis, tuberculosis). Exception: patients with concomitant mild or moderate pulmonary hypertension or bronchiectasis are permitted to participate.

5. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective contraception (also called basic contraception)methods during the study.

6. Patients on any statin therapy with a CK level > 2 X ULN at screening.

7. Patients who have a clinically significant laboratory abnormality at the screening visit including (but not limited to):

   • Total white blood cell count <2500 cells/uL
   • AST or ALT > 2.0 X ULN or total bilirubin > 1.3 X ULN
   • Estimated Glomerular Filtration Rate (eGFR) by the Modification of Diet in Renal Disease (MDRD) equation or Bedside Schwartz equation <55 mL/minute/1.73 m2.

8. Patients with any of the following cardiac related concerns:

   • A resting QTcF (Fridericia) ≥450 msec (male) or ≥460 msec (female) at screening visit
   • A history of familial long QT syndrome or known family history of Torsades de Pointe
   • Receiving any medications or other agents known to prolong the QT interval
   • patients with a history of moderate or severe uncontrolled tachyarrhythmias
   • History of a clinically significant cardiovascular event within 1 year prior to the screening visit, such as acute myocardial infarction, congestive heart failure, unstable arrhythmia
   • Patients who, in the judgment of the investigator have a clinically significant ECG abnormality such as (but not limited to) sustained ventricular tachycardia, or clinically significant second or third degree AV block without a pacemaker

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.

Adverse events were collected from first dose of study treatment until last dose plus 30 days, up to a maximum of 72 days.

Any signs or symptoms that occurs during study treatment plus the 30 days post treatment.

This was a subject and investigator-blinded study. Subjects, investigators and all site staff remained blinded to study treatment throughout the study.

The identity of the treatments was concealed by the use of study drugs that were all identical in packaging, labeling, schedule of administration, appearance, and odor.

The sponsor could be unblinded to the study treatment at any time, especially in case of a safety concern.