Company decision

This was a proof-of-concept study to evaluate the efficacy of LOU064 in patients with inadequately controlled asthma. All subjects were randomized with 3:2 ratio to receive LOU064 100 mg once daily or LOU064 matching placebo for 12 weeks with standard background therapy of budesonide 80 µg/formoterol 4.5 µg two inhalations twice a day (b.i.d).

This was a non-confirmatory, multi-center, randomized, placebo-controlled, subject- and investigator-blinded, parallel-group study to evaluate the efficacy and safety of LOU064 in patients with inadequately controlled asthma who were on a standardized background therapy of inhaled corticosteroid plus long acting beta-2 agonist (ICS/LABA).

The study included:

• a Screening period of up to 2 weeks to assess eligibility.
• a Run-in period of minimum 3 weeks and maximum 5 weeks where patients discontinued their current asthma therapy and were placed on budesonide 80 μg/formoterol 4.5 μg delivered by dry powder inhaler, two inhalations twice a day (b.i.d).
• a Treatment period of 12 weeks. All subjects were randomized 3:2 to receive LOU064 100 mg once daily or placebo for 12 weeks with standard background therapy of budesonide 80 μg/formoterol 4.5 μg, two inhalations b.i.d.
• a Follow-up period of 3 weeks following the last dose of study drug. Results from the interim analysis did not provide sufficient evidence of efficacy of LOU064 in inadequately controlled asthma and the sponsor decided to terminate early the study in April 2020. The median duration of exposure (12.0 weeks for LOU064 and 11.7 weeks for placebo) was close to the treatment target, as most of the subjects had completed treatment when the study was terminated.

Inclusion Criteria:

• Male and female adult patients aged ≥ 18 to ≤ 70 years at screening.

• Patients must weigh at least 40 kg to participate in the study, and must have a body mass index (BMI) <35 kg/m2. BMI = Body weight (kg) / [Height (m)]2 at screening

• Patients with a physician-diagnosed history of asthma (according to GINA 2018) for a period of at least 6 months prior to screening.

• Patients who have been treated with:

  • Medium or high dose inhaled corticosteroids (ICS), or
  • ICS plus long-acting beta agonist (LABA), or
  • ICS plus leukotriene receptor antagonist (LTRA), or
  • ICS plus long-acting beta agonist (LABA) and long lasting muscarinic antagonist (LAMA) for at least 1 month prior to screening and on the same doses of the above mentioned medications over at least 2 weeks prior to start of the run-in period.

• Post-bronchodilator reversibility of FEV1 ≥ 12% and ≥ 200 mL at screening. If reversibility is not demonstrated at screening, then two additional attempts are permitted (one at the run-in visit and the last one during the run-in period between the run-in visit and baseline visit if needed)

• Spirometry with pre-bronchodilator FEV1 ≥ 40% of predicted (at screening and baseline) and ≤ 85% of predicted at the baseline visit.

• ACQ-5 score ≥ 1.5 at baseline visit

• ≥ 80% compliance with peak expiratory flow measurement and recording of symptoms in the eDiary during the run-in period.

Exclusion Criteria:

• Patients who have had an asthma exacerbation requiring systemic corticosteroids, hospitalization, or emergency room visit within 6 weeks prior to screening or during the screening period.

• Patients who have smoked or inhaled any substance other than asthma medications within the 6 month period prior to screening, or who have a smoking history of greater than 10 pack years (e.g. 10 pack years = 1 pack/day x 10 years or ½ pack/day x 20 years, etc.).

• History of life-threatening asthma event such as significant hypercarbia (pCO2 > 45 mmHg), endotracheal intubation, non-invasive positive pressure ventilation (NIPPV), respiratory arrest, or seizure as a result of asthma.

• Patients with chronic lung diseases other than asthma, including (but not limited to) chronic obstructive pulmonary disease, clinically significant bronchiectasis, sarcoidosis, interstitial lung disease, cystic fibrosis, Churg-Strauss syndrome, allergic broncho-pulmonary aspergillosis, or clinically significant chronic lung diseases related to a history of tuberculosis or asbestosis.

• History or current diagnosis of ECG abnormalities indicating significant risk of safety for subjects participating in the study such as:

  • Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker
  • History of familial long QT syndrome or known family history of Torsades de Pointes
  • Resting heart rate (physical exam or 12 lead ECG) < 50 bpm at screening
  • Resting QTcF ≥ 450 msec (male) or ≥ 460 msec (female) at screening or inability to determine the QTcF interval
  • Use of agents known to prolong the QT interval unless they can be permanently discontinued for the duration of study

• At screening and/or run-in period, any severe, progressive or uncontrolled, acute or chronic, medical or psychiatric condition, or other factors such as abnormal vital signs, ECG or physical findings, or clinically relevant abnormal laboratory values, that in the judgment of the investigator may increase the risk associated with study participation/treatment or may interfere with interpretation of study results, and thus would make the patient inappropriate for entry into or continuing the study.

• Major surgery within 8 weeks prior to screening or surgery planned prior to end of study.

• History of live attenuated vaccine within 6 weeks prior to randomization or requirement to receive vaccinations at any time during the study.

• Hematology parameters at screening:

  • Hemoglobin: < 10 g/dl
  • Platelets: < 100 000/mm3
  • White blood cells: < 3 000/mm3
  • Neutrophils: < 1 500/mm3

• Significant bleeding risk or coagulation disorders.

• History of gastrointestinal bleeding, e.g. in association with use of Nonsteroidal Anti-Inflammatory Drug (NSAID).

• Requirement for anti-platelet or anticoagulant medication (e.g., warfarin, or clopidogrel or Novel Oral Anti-Coagulant (NOAC)) other than acetylsalicylic acid (up to 100 mg/d).

• History or presence of thrombotic or thromboembolic event, or increased risk for thrombotic or thromboembolic event.

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.