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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03944707
• Collaborator: (none)
• Enrollment: 76
• Locations: 19
• Arms: 2
• Actual Duration (Months): 9.3
• Patients Per Site: 4
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Asthma	Drug: LOU064 100 mg; Drug: Placebo	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 76 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Subject- and Investigator-blinded, Placebo-controlled Study to Assess the Efficacy and Safety of LOU064 in Patients With Inadequately Controlled Asthma
• Actual Study Start Date: Jul 18, 2019
• Actual Primary Completion Date: Apr 27, 2020
• Actual Study Completion Date: Apr 27, 2020

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Pre-dose FEV1 at Week 12 [Baseline, 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.

Secondary Outcome Measures

1. Maximum Observed Blood Concentrations (Cmax) of LOU064 at Steady State [pre-dose, 0.5, 1, 2, 3 and 4 hours after dosing on Days 15 and 85]

   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.

2. Time to Reach Maximum Blood Concentrations (Tmax) of LOU064 at Steady State [pre-dose, 0.5, 1, 2, 3 and 4 hours after dosing on Days 15 and 85]

   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.

3. Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC0-24h) of LOU064 at Steady State [pre-dose, 0.5, 1, 2, 3 and 4 hours after dosing on Days 15 and 85]

   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.

4. Change From Baseline in Asthma Symptom Questionnaire-5 Score (ACQ-5) at Week 12 [Baseline, 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.

5. Change From Baseline in Mean Morning and Mean Evening Peak Expiratory Flow (PEF) [Baseline, Weeks 9-12]

   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.

6. Change From Baseline in Number of Puffs of SABA Taken Per Day During the Treatment Period [Baseline, 12 weeks]

   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.

7. Change From Baseline in Daytime and Nighttime Asthma Symptom Score [Baseline, Weeks 9-12]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Denver	Colorado	United States	80230
2	Novartis Investigative Site	North Dartmouth	Massachusetts	United States	02747
3	Novartis Investigative Site	Saint Louis	Missouri	United States	63141
4	Novartis Investigative Site	Raleigh	North Carolina	United States	27607
5	Novartis Investigative Site	Caba	Buenos Aires	Argentina	C1056ABJ
6	Novartis Investigative Site	Caba	Buenos Aires	Argentina	C1425BEN
7	Novartis Investigative Site	Rosario	Santa Fe	Argentina	S2000DBS
8	Novartis Investigative Site	Rosario	Santa Fe	Argentina	S2000JKR
9	Novartis Investigative Site	Berlin		Germany	10787
10	Novartis Investigative Site	Berlin		Germany	12159
11	Novartis Investigative Site	Frankfurt		Germany	60596
12	Novartis Investigative Site	Hamburg		Germany	20354
13	Novartis Investigative Site	Hannover		Germany	30173
14	Novartis Investigative Site	Biaystok		Poland	15-430
15	Novartis Investigative Site	Grudziadz		Poland	86-300
16	Novartis Investigative Site	Krakow		Poland	30033
17	Novartis Investigative Site	Poznan		Poland	60 823
18	Novartis Investigative Site	Saint-Petersburg		Russian Federation	196143
19	Novartis Investigative Site	Ulyanovsk		Russian Federation	432063

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Mar 18, 2020
• Statistical Analysis Plan - Aug 24, 2020

More Information

Additional Information:

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

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03944707
• Other Study ID Numbers: CLOU064D12201; 2018-003609-24
• First Posted: May 9, 2019
• Last Update Posted: Oct 11, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: asthma; LOU064
• Additional relevant MeSH terms: Asthma

Study Results

Participant Flow

Recruitment Details	Participants took part in 19 investigative sites in 5 countries.
Pre-assignment Detail	After the screening, participants went through a Run-in period of 3-5 weeks where they discontinued their current asthma therapy and were placed on budesonide 80 μg/formoterol 4.5 μg delivered by dry powder inhaler. Afterwards, patients were randomized in 3:2 ratio to receive LOU064 or placebo and continued to use the budesonide/formoterol inhaler.

Arm/Group Title	LOU064	Placebo
Arm/Group Description	LOU064 100 mg once daily orally	Placebo once daily orally
Period Title: Overall Study
STARTED	47	29
PK Analysis Set	33	0
PD Analysis Set	47	29
COMPLETED	35	19
NOT COMPLETED	12	10

Baseline Characteristics

Arm/Group Title	LOU064	Placebo	Total
Arm/Group Description	LOU064 100 mg once daily orally	Placebo once daily orally	Total of all reporting groups
Overall Participants	47	29	76
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	49.2 (10.96)	53.2 (10.40)	50.7 (10.85)
Sex: Female, Male (Count of Participants)
Female	28 59.6%	22 75.9%	50 65.8%
Male	19 40.4%	7 24.1%	26 34.2%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	42 89.4%	27 93.1%	69 90.8%
Black	4 8.5%	2 6.9%	6 7.9%
Asian	1 2.1%	0 0%	1 1.3%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Pre-dose FEV1 at Week 12
Description	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.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

PD analysis set including participants with a valid measurement for the outcome measure.

Arm/Group Title	LOU064	Placebo
Arm/Group Description	LOU064 100 mg once daily orally	Placebo once daily orally
Measure Participants	32	20
Mean (Standard Deviation) [liters]	0.105 (0.0494)	0.075 (0.0497)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LOU064, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6643
	Comments	Probability LOU064 better than placebo
	Method	Bayesian model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.030
	Confidence Interval	(2-Sided) 80%; -0.060 to 0.119
	Parameter Dispersion	Type: Standard Deviation; Value: 0.0698
	Estimation Comments	Posterior mean difference (LOU064 - placebo) and 80% credible interval are presented.

2. Secondary Outcome

Title	Maximum Observed Blood Concentrations (Cmax) of LOU064 at Steady State
Description	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.
Time Frame	pre-dose, 0.5, 1, 2, 3 and 4 hours after dosing on Days 15 and 85

Outcome Measure Data

Analysis Population Description

PK analysis set including participants with a valid measurement for the outcome measure.

Arm/Group Title	LOU064	Placebo
Arm/Group Description	LOU064 100 mg once daily orally	Placebo once daily orally
Measure Participants	33	0
Day 15	239 (152)
Day 85	222 (142)

3. Secondary Outcome

Title	Time to Reach Maximum Blood Concentrations (Tmax) of LOU064 at Steady State
Description	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.
Time Frame	pre-dose, 0.5, 1, 2, 3 and 4 hours after dosing on Days 15 and 85

Outcome Measure Data

Analysis Population Description

PK analysis set including participants with a valid measurement for the outcome measure.

Arm/Group Title	LOU064	Placebo
Arm/Group Description	LOU064 100 mg once daily orally	Placebo once daily orally
Measure Participants	33	0
Day 15	1.00
Day 85	1.00

4. Secondary Outcome

Title	Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC0-24h) of LOU064 at Steady State
Description	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.
Time Frame	pre-dose, 0.5, 1, 2, 3 and 4 hours after dosing on Days 15 and 85

Outcome Measure Data

Analysis Population Description

PK analysis set including participants with a valid measurement for the outcome measure.

Arm/Group Title	LOU064	Placebo
Arm/Group Description	LOU064 100 mg once daily orally	Placebo once daily orally
Measure Participants	33	0
Day 15	471 (285)
Day 85	517 (342)

5. Secondary Outcome

Title	Change From Baseline in Asthma Symptom Questionnaire-5 Score (ACQ-5) at Week 12
Description	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.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

PD analysis set including participants with a valid measurement for the outcome measure.

Arm/Group Title	LOU064	Placebo
Arm/Group Description	LOU064 100 mg once daily orally	Placebo once daily orally
Measure Participants	33	20
Mean (Standard Deviation) [score on scale]	-0.95 (0.133)	-0.86 (0.164)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LOU064, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6609
	Comments	Probability LOU064 better than placebo
	Method	Bayesian model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	-0.09
	Confidence Interval	(2-Sided) 80%; -0.35 to 0.18
	Parameter Dispersion	Type: Standard Deviation; Value: 0.210
	Estimation Comments	Posterior mean difference (LOU064 - placebo) and 80% credible interval are presented.

6. Secondary Outcome

Title	Change From Baseline in Mean Morning and Mean Evening Peak Expiratory Flow (PEF)
Description	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.
Time Frame	Baseline, Weeks 9-12

Outcome Measure Data

Analysis Population Description

PD analysis set including participants with a valid measurement for the outcome measure.

Arm/Group Title	LOU064	Placebo
Arm/Group Description	LOU064 100 mg once daily orally	Placebo once daily orally
Measure Participants	47	29
Change from baseline in mean morning PEF	-2.4 (4.30)	-2.6 (5.59)
Change from baseline in mean evening PEF	-9.7 (5.58)	-6.3 (7.23)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LOU064, Placebo
	Comments	Change from baseline in mean morning PEF
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5107
	Comments	Probability LOU064 better than placebo
	Method	Bayesian model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 80%; -9.0 to 9.1
	Parameter Dispersion	Type: Standard Deviation; Value: 7.13
	Estimation Comments	Posterior mean difference (LOU064 - placebo) and 80% credible interval are presented.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LOU064, Placebo
	Comments	Change from baseline in mean evening PEF
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3611
	Comments	Probability LOU064 better than placebo
	Method	Bayesian model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-3.4
	Confidence Interval	(2-Sided) 80%; -15.2 to 8.1
	Parameter Dispersion	Type: Standard Deviation; Value: 9.15
	Estimation Comments	Posterior mean difference (LOU064 - placebo) and 80% credible interval are presented.

7. Secondary Outcome

Title	Change From Baseline in Number of Puffs of SABA Taken Per Day During the Treatment Period
Description	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.
Time Frame	Baseline, 12 weeks

Outcome Measure Data

Analysis Population Description

PD analysis set including participants with a valid measurement for the outcome measure.

Arm/Group Title	LOU064	Placebo
Arm/Group Description	LOU064 100 mg once daily orally	Placebo once daily orally
Measure Participants	41	26
Mean (Standard Deviation) [puffs of SABA]	-0.192 (0.0946)	-0.059 (0.1224)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LOU064, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8022
	Comments	Probability LOU064 better than placebo
	Method	Bayesian model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.133
	Confidence Interval	(2-Sided) 80%; -0.336 to 0.071
	Parameter Dispersion	Type: Standard Deviation; Value: 0.1588
	Estimation Comments	Posterior mean difference (LOU064 - placebo) and 80% credible interval are presented.

8. Secondary Outcome

Title	Change From Baseline in Daytime and Nighttime Asthma Symptom Score
Description	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.
Time Frame	Baseline, Weeks 9-12

Outcome Measure Data

Analysis Population Description

PD analysis set including participants with a valid measurement for the outcome measure.

Arm/Group Title	LOU064	Placebo
Arm/Group Description	LOU064 100 mg once daily orally	Placebo once daily orally
Measure Participants	47	29
Change from baseline in daytime asthma symptom score	-0.225 (0.0962)	-0.175 (0.1237)
Change from baseline in nighttime asthma symptom score	-0.120 (0.0488)	-0.195 (0.0651)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LOU064, Placebo
	Comments	Change from baseline in daytime asthma symptom score
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6312
	Comments	Probability LOU064 better than placebo
	Method	Bayesian model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.050
	Confidence Interval	(2-Sided) 80%; -0.251 to 0.149
	Parameter Dispersion	Type: Standard Deviation; Value: 0.1573
	Estimation Comments	Posterior mean difference (LOU064 - placebo) and 80% credible interval are presented.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LOU064, Placebo
	Comments	Change from baseline in nighttime asthma symptom score
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1752
	Comments	Probability LOU064 better than placebo
	Method	Bayesian model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.075
	Confidence Interval	(2-Sided) 80%; -0.028 to 0.180
	Parameter Dispersion	Type: Standard Deviation; Value: 0.0819
	Estimation Comments	Posterior mean difference (LOU064 - placebo) and 80% credible interval are presented.

Adverse Events

Time Frame	From first dose of study treatment until last dose of study treatment plus 30 days post treatment, up to Day 115.
Adverse Event Reporting Description	Any sign or symptom that occurs during the study treatment plus 30 days post treatment.
Arm/Group Title	LOU064		Placebo
Arm/Group Description	LOU064 100 mg once daily orally		Placebo once daily orally
All Cause Mortality
	LOU064		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/47 (0%)		0/29 (0%)
Serious Adverse Events
	LOU064		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/47 (0%)		0/29 (0%)
Other (Not Including Serious) Adverse Events
	LOU064		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/47 (17%)		10/29 (34.5%)
Infections and infestations
Nasopharyngitis	4/47 (8.5%)		6/29 (20.7%)
Upper respiratory tract infection	4/47 (8.5%)		4/29 (13.8%)
Respiratory, thoracic and mediastinal disorders
Asthma	0/47 (0%)		2/29 (6.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. Novartis does not prohibit any investigator from publishing. Any publications from a single site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.