Study of Efficacy and Safety of LOU064 in Inadequately Controlled Asthma Patients

A Randomized, Subject- and Investigator-blinded, Placebo-controlled Study to Assess the Efficacy and Safety of LOU064 in Patients With Inadequately Controlled Asthma

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).

Study Overview

• Status: Terminated
• Conditions: Asthma
• Intervention / Treatment: Drug: LOU064 100 mg; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 76
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires
    • Caba, Buenos Aires, Argentina, C1056ABJ
      • Novartis Investigative Site
    • Caba, Buenos Aires, Argentina, C1425BEN
      • Novartis Investigative Site
  • Santa Fe
    • Rosario, Santa Fe, Argentina, S2000DBS
      • Novartis Investigative Site
    • Rosario, Santa Fe, Argentina, S2000JKR
      • Novartis Investigative Site
• Germany
  • Berlin, Germany, 10787
    • Novartis Investigative Site
  • Berlin, Germany, 12159
    • Novartis Investigative Site
  • Frankfurt, Germany, 60596
    • Novartis Investigative Site
  • Hamburg, Germany, 20354
    • Novartis Investigative Site
  • Hannover, Germany, 30173
    • Novartis Investigative Site
• Poland
  • Biaystok, Poland, 15-430
    • Novartis Investigative Site
  • Grudziadz, Poland, 86-300
    • Novartis Investigative Site
  • Krakow, Poland, 30033
    • Novartis Investigative Site
  • Poznan, Poland, 60 823
    • Novartis Investigative Site
• Russian Federation
  • Saint-Petersburg, Russian Federation, 196143
    • Novartis Investigative Site
  • Ulyanovsk, Russian Federation, 432063
    • Novartis Investigative Site
• United States
  • Colorado
    • Denver, Colorado, United States, 80230
      • Novartis Investigative Site
  • Massachusetts
    • North Dartmouth, Massachusetts, United States, 02747
      • Novartis Investigative Site
  • Missouri
    • Saint Louis, Missouri, United States, 63141
      • Novartis Investigative Site
  • North Carolina
    • Raleigh, North Carolina, United States, 27607
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo once daily orally	Drug: Placebo; Placebo once daily administered orally as capsules
Experimental: LOU064; LOU064 100 mg once daily orally	Drug: LOU064 100 mg; LOU064 100 mg once daily orally administered as two 50 mg capsules

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Pre-dose FEV1 at Week 12	FEV1 (forced expiratory volume in one second) is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation, measured through spirometry testing. Pre-dose FEV1 is defined as average of the two FEV1 measurements taken 45 min and 15 min pre-dose. The baseline pre-dose FEV1 is defined as the average of the FEV1 measurements performed 45 min and 15 min prior to dosing on Day 1. A positive change from baseline in pre-dose FEV1 is considered a favorable outcome. Change from baseline in pre-dose FEV1 was analyzed using a Bayesian model for repeated measures, adjusting for effects of treatment*visit interaction and baseline pre-dose FEV1. A weakly informative prior was considered for the placebo response.	Baseline, Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Observed Blood Concentrations (Cmax) of LOU064 at Steady State	Pharmacokinetic (PK) parameters were calculated based on LOU064 blood concentrations determined by a validated liquid chromatography and tandem mass spectrometry (LC-MS/MS) method with a lower limit of quantification of 1 ng/mL. Cmax was determined using non-compartmental methods.	pre-dose, 0.5, 1, 2, 3 and 4 hours after dosing on Days 15 and 85
Time to Reach Maximum Blood Concentrations (Tmax) of LOU064 at Steady State	PK parameters were calculated based on LOU064 blood concentrations determined by a validated LC-MS/MS method with a lower limit of quantification of 1 ng/mL. Tmax was determined using non-compartmental methods.	pre-dose, 0.5, 1, 2, 3 and 4 hours after dosing on Days 15 and 85
Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC0-24h) of LOU064 at Steady State	PK parameters were calculated based on LOU064 blood concentrations determined by a validated LC-MS/MS method with a lower limit of quantification of 1 ng/mL. AUC0-24h was determined using non-compartmental methods. The linear trapezoidal rule was used for AUC0-24h calculation.	pre-dose, 0.5, 1, 2, 3 and 4 hours after dosing on Days 15 and 85
Change From Baseline in Asthma Symptom Questionnaire-5 Score (ACQ-5) at Week 12	The ACQ-5 is a five-item, self-completed questionnaire, which is used as a measure of asthma control of a participant. Patients were asked to recall how their asthma had been during the previous week and to respond to the symptom questions on a 7-point scale (0=no impairment, 6=maximum impairment). The questions are equally weighted and the overall ACQ-5 score is the mean of all 5 questions, therefore between 0 (totally controlled) and 6 (severely uncontrolled). The baseline values of ACQ-5 were collected at the baseline visit. A negative change from baseline in ACQ-5 is considered a favorable outcome. Change from baseline in ACQ-5 score was analyzed using a Bayesian model for repeated measures, adjusting for effects of treatment*visit interaction and baseline ACQ-5 score. Non-informative priors were considered.	Baseline, Week 12
Change From Baseline in Mean Morning and Mean Evening Peak Expiratory Flow (PEF)	PEF (Peak Expiratory Flow) is a person's maximum speed of expiration. All participants were instructed to record PEF twice daily before taking any medication using an electronic peak expiratory flow device (ePEF), once in the morning and once approximately 12 h later in the evening at home. At each timepoint, the participant was instructed to perform 3 consecutive manoeuvres within 10 minutes. These PEF values were captured in the e-PEF/diary. For each day the best value in the morning and in the evening were considered and mean values on 4-week intervals were derived. The baseline values of PEF were the mean values in the run-in period. A positive change from baseline in PEF is considered a favorable outcome. Change from baseline in mean morning and mean evening PEF were analyzed using a Bayesian model for repeated measures, adjusting for effects of treatment*weeks interaction and baseline PEF values. Non-informative priors were considered.	Baseline, Weeks 9-12
Change From Baseline in Number of Puffs of SABA Taken Per Day During the Treatment Period	Participants were given a short acting β2-agonist (SABA; salbutamol, known also as albuterol) to use as rescue medication throughout the study along with an electronic diary (eDiary) to record rescue medication use. Participants recorded in the eDiary, once in the morning and once in the evening, the use of rescue medication (number of puffs of SABA taken in the previous 12 hours). The total number of puffs of SABA taken per day was calculated and the mean daily use of puffs of SABA over 12 weeks was derived. The baseline values of number of puffs of SABA taken per day were defined as the average from all non-missing records taken during the run-in period. A negative change from baseline is considered a favorable outcome. Change from baseline in number of puffs of SABA taken per day was analyzed using a Bayesian model, adjusting for effects of baseline SABA use, baseline FEV1, baseline asthma daytime symptom score and treatment. Non-informative priors were considered.	Baseline, 12 weeks
Change From Baseline in Daytime and Nighttime Asthma Symptom Score	Participants recorded asthma symptoms twice daily in the eDiary. Daytime asthma symptoms were assessed before bed and nighttime symptoms on awakening.; Daytime asthma symptom score included 4 questions. Overall score (0 to 6) was calculated as the average of the 4 questions with higher values indicating more asthma symptoms.; Nighttime asthma symptom score included 2 questions. Overall score (0 to 3.5) was calculated as the average of the 2 questions with higher values indicating more asthma symptoms. Mean values of both scores were calculated over 4-week intervals during the treatment period. The baseline values of both asthma symptoms scores were defined as the average score during the run-in period. A negative change from baseline is a favorable outcome. Change from baseline in daytime and nighttime asthma symptom score were analyzed using a Bayesian model for repeated measures, adjusting for effects of treatment*weeks and baseline scores. Non-informative priors were considered.	Baseline, Weeks 9-12

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• A Plain Language Trial Summary is available on novartisclinicaltrials.com

Study record dates

Study Major Dates

• Study Start (Actual): July 18, 2019
• Primary Completion (Actual): April 27, 2020
• Study Completion (Actual): April 27, 2020

Study Registration Dates

• First Submitted: May 2, 2019
• First Submitted That Met QC Criteria: May 8, 2019
• First Posted (Actual): May 9, 2019

Study Record Updates

• Last Update Posted (Actual): October 11, 2021
• Last Update Submitted That Met QC Criteria: October 7, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: asthma; LOU064
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma
• Other Study ID Numbers: CLOU064D12201; 2018-003609-24 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No