Trial Outcomes & Findings for Study of Efficacy and Safety of LOU064 in Inadequately Controlled Asthma Patients (NCT NCT03944707)

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

76 participants

Primary outcome timeframe

Baseline, Week 12

Results posted on

2021-10-11

Participant Flow

Participants took part in 19 investigative sites in 5 countries.

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.

Participant milestones

Participant milestones
Measure	LOU064 LOU064 100 mg once daily orally	Placebo Placebo once daily orally
Overall Study STARTED	47	29
Overall Study PK Analysis Set	33	0
Overall Study PD Analysis Set	47	29
Overall Study COMPLETED	35	19
Overall Study NOT COMPLETED	12	10

Reasons for withdrawal

Reasons for withdrawal
Measure	LOU064 LOU064 100 mg once daily orally	Placebo Placebo once daily orally
Overall Study Adverse Event	0	2
Overall Study Study terminated by sponsor	12	7
Overall Study Subject decision	0	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	LOU064 n=47 Participants LOU064 100 mg once daily orally	Placebo n=29 Participants Placebo once daily orally	Total n=76 Participants Total of all reporting groups
Age, Continuous	49.2 years STANDARD_DEVIATION 10.96 • n=5 Participants	53.2 years STANDARD_DEVIATION 10.40 • n=7 Participants	50.7 years STANDARD_DEVIATION 10.85 • n=5 Participants
Sex: Female, Male Female	28 Participants n=5 Participants	22 Participants n=7 Participants	50 Participants n=5 Participants
Sex: Female, Male Male	19 Participants n=5 Participants	7 Participants n=7 Participants	26 Participants n=5 Participants
Race/Ethnicity, Customized Caucasian	42 Participants n=5 Participants	27 Participants n=7 Participants	69 Participants n=5 Participants
Race/Ethnicity, Customized Black	4 Participants n=5 Participants	2 Participants n=7 Participants	6 Participants n=5 Participants
Race/Ethnicity, Customized Asian	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline, Week 12

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

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.

Outcome measures

Outcome measures
Measure	LOU064 n=32 Participants LOU064 100 mg once daily orally	Placebo n=20 Participants Placebo once daily orally
Change From Baseline in Pre-dose FEV1 at Week 12	0.105 liters Standard Deviation 0.0494	0.075 liters Standard Deviation 0.0497

SECONDARY outcome

Timeframe: pre-dose, 0.5, 1, 2, 3 and 4 hours after dosing on Days 15 and 85

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

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.

Outcome measures

Outcome measures
Measure	LOU064 n=33 Participants LOU064 100 mg once daily orally	Placebo Placebo once daily orally
Maximum Observed Blood Concentrations (Cmax) of LOU064 at Steady State Day 15	239 ng/mL Standard Deviation 152	—
Maximum Observed Blood Concentrations (Cmax) of LOU064 at Steady State Day 85	222 ng/mL Standard Deviation 142	—

SECONDARY outcome

Timeframe: pre-dose, 0.5, 1, 2, 3 and 4 hours after dosing on Days 15 and 85

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

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.

Outcome measures

Outcome measures
Measure	LOU064 n=33 Participants LOU064 100 mg once daily orally	Placebo Placebo once daily orally
Time to Reach Maximum Blood Concentrations (Tmax) of LOU064 at Steady State Day 15	1.00 hours (hr) Interval 0.483 to 2.0	—
Time to Reach Maximum Blood Concentrations (Tmax) of LOU064 at Steady State Day 85	1.00 hours (hr) Interval 0.5 to 3.0	—

SECONDARY outcome

Timeframe: pre-dose, 0.5, 1, 2, 3 and 4 hours after dosing on Days 15 and 85

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

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.

Outcome measures

Outcome measures
Measure	LOU064 n=33 Participants LOU064 100 mg once daily orally	Placebo Placebo once daily orally
Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC0-24h) of LOU064 at Steady State Day 15	471 hr*ng/mL Standard Deviation 285	—
Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC0-24h) of LOU064 at Steady State Day 85	517 hr*ng/mL Standard Deviation 342	—

SECONDARY outcome

Timeframe: Baseline, Week 12

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

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.

Outcome measures

Outcome measures
Measure	LOU064 n=33 Participants LOU064 100 mg once daily orally	Placebo n=20 Participants Placebo once daily orally
Change From Baseline in Asthma Symptom Questionnaire-5 Score (ACQ-5) at Week 12	-0.95 score on scale Standard Deviation 0.133	-0.86 score on scale Standard Deviation 0.164

SECONDARY outcome

Timeframe: Baseline, Weeks 9-12

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

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.

Outcome measures

Outcome measures
Measure	LOU064 n=47 Participants LOU064 100 mg once daily orally	Placebo n=29 Participants Placebo once daily orally
Change From Baseline in Mean Morning and Mean Evening Peak Expiratory Flow (PEF) Change from baseline in mean morning PEF	-2.4 liters/minute Standard Deviation 4.30	-2.6 liters/minute Standard Deviation 5.59
Change From Baseline in Mean Morning and Mean Evening Peak Expiratory Flow (PEF) Change from baseline in mean evening PEF	-9.7 liters/minute Standard Deviation 5.58	-6.3 liters/minute Standard Deviation 7.23

SECONDARY outcome

Timeframe: Baseline, 12 weeks

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

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.

Outcome measures

Outcome measures
Measure	LOU064 n=41 Participants LOU064 100 mg once daily orally	Placebo n=26 Participants Placebo once daily orally
Change From Baseline in Number of Puffs of SABA Taken Per Day During the Treatment Period	-0.192 puffs of SABA Standard Deviation 0.0946	-0.059 puffs of SABA Standard Deviation 0.1224

SECONDARY outcome

Timeframe: Baseline, Weeks 9-12

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

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.

Outcome measures

Outcome measures
Measure	LOU064 n=47 Participants LOU064 100 mg once daily orally	Placebo n=29 Participants Placebo once daily orally
Change From Baseline in Daytime and Nighttime Asthma Symptom Score Change from baseline in daytime asthma symptom score	-0.225 score on scale Standard Deviation 0.0962	-0.175 score on scale Standard Deviation 0.1237
Change From Baseline in Daytime and Nighttime Asthma Symptom Score Change from baseline in nighttime asthma symptom score	-0.120 score on scale Standard Deviation 0.0488	-0.195 score on scale Standard Deviation 0.0651

Adverse Events

LOU064

Serious events: 0 serious events

Other events: 8 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 10 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	LOU064 n=47 participants at risk LOU064 100 mg once daily orally	Placebo n=29 participants at risk Placebo once daily orally
Infections and infestations Nasopharyngitis	8.5% 4/47 • From first dose of study treatment until last dose of study treatment plus 30 days post treatment, up to Day 115. Any sign or symptom that occurs during the study treatment plus 30 days post treatment.	20.7% 6/29 • From first dose of study treatment until last dose of study treatment plus 30 days post treatment, up to Day 115. Any sign or symptom that occurs during the study treatment plus 30 days post treatment.
Infections and infestations Upper respiratory tract infection	8.5% 4/47 • From first dose of study treatment until last dose of study treatment plus 30 days post treatment, up to Day 115. Any sign or symptom that occurs during the study treatment plus 30 days post treatment.	13.8% 4/29 • From first dose of study treatment until last dose of study treatment plus 30 days post treatment, up to Day 115. Any sign or symptom that occurs during the study treatment plus 30 days post treatment.
Respiratory, thoracic and mediastinal disorders Asthma	0.00% 0/47 • From first dose of study treatment until last dose of study treatment plus 30 days post treatment, up to Day 115. Any sign or symptom that occurs during the study treatment plus 30 days post treatment.	6.9% 2/29 • From first dose of study treatment until last dose of study treatment plus 30 days post treatment, up to Day 115. Any sign or symptom that occurs during the study treatment plus 30 days post treatment.

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER