FSS-AS-301

Teva Branded Pharmaceutical Products R&D, Inc

41 Moores Road, Frazer, Pennsylvania, United States, 19355

Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 215-591-3000, ustevatrials@tevapharm.com

Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 215-591-3000, ustevatrials@tevapharm.com

No

No

No

Final

15 Feb 2016

No

Yes

21 Sep 2015

No

The primary objective of this study was to evaluate the efficacy of fluticasone propionate multidose dry powder inhaler (Fp MDPI) and fluticasone propionate/salmeterol xinafoate multidose dry powder inhaler (FS MDPI) when administered over 12 weeks in patients 12 years of age and older with persistent asthma.

This study was conducted in full accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline (E6) and any applicable national and local laws and regulations (eg, Code of Federal Regulations [CFR] Title 21, Parts 50, 54, 56, 312, and 314; European Union [EU] Directive 2001/20/EC on the approximation of the laws, regulations, and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use). Information regarding any investigational centers participating in this study that could not comply with these standards was documented. Written and/or oral information about the study was provided to all patients (or, in the case of minor patients [age 12 to 17 years or per local regulations], to patients and their parents/legally authorized representatives) in a language understandable by the patients (to the extent practical for minor patients) and/or representatives. The information included an adequate explanation of the aims, methods, anticipated benefits, potential hazards, and insurance arrangements in force. Written informed consent was obtained before any study procedures or assessments were done. It was explained that patients were free to refuse entry into the study and free to withdraw from the study at any time without prejudice to future treatment. Each patient’s willingness to participate in the study was documented in writing in an informed consent form (ICF) that was signed by the patient (or legally acceptable representative) with the date of that signature indicated. Each investigator kept the original ICFs, and copies were given to the patients. Analogous procedures applied to assent forms.

25 Jun 2014

No

No

Poland: 107

Hungary: 68

Canada: 3

Russian Federation: 94

Ukraine: 43

United States: 456

South Africa: 16

787

175

0

0

0

0

0

112

595

79

1

Run-In Period

Non-randomised - controlled

Patients discontinued their current inhaled corticosteroid and instead took 1 inhalation twice a day of a single-blinded placebo multidose dry powder inhaler (MDPI) device and 1 puff twice a day of an open-label QVAR® (beclomethasone dipropionate 40 mcg metered-dose inhaler, or equivalent). Placebo, manufactured by Teva, was supplied in a MDPI device that was identical to the devices used to deliver active drug, and indistinguishable from the active treatments.

Albuterol/Salbutamol

ProAir

Inhalation solution

Inhalation use

Albuterol/salbutamol hydrofluoroalkane (specifically, HFA 134a) metered dose inhaler (MDI), for use on an as-needed basis for the immediate relief of asthma symptoms. Albuterol/salmeterol HFA MDI was supplied to all patients for use as rescue medication throughout the run-in and treatment periods.

Placebo MDPI

Inhalation powder

Inhalation use

Placebo administered via a multidose dry powder inhaler (MDPI) one puff in the morning and one puff in the evening for the duration of the Run-in Period (14-21 days).

Beclomethasone dipropionate

QVAR

Inhalation solution

Inhalation use

QVAR (beclomethasone dipropionate) 40 mcg Inhalation Aerosol is a pressurized MDI that contains a Food and Drug Administration (FDA)-approved formulation of beclomethasone dipropionate. Patients took 1 puff twice a day from open-label QVAR 40 mcg hydrofluoroalkane (specifically, HFA-134a) metered-dose inhaler (MDI). A clinically equivalent dose of inhaled corticosteroid (ICS) was substituted in countries where QVAR 40 mcg was not available.

Treatment Period

Randomised - controlled

Patients were randomized 1:1:1:1:1 to receive Fp MDPI 50 mcg, Fp MDPI 100 mcg, FS MDPI 50/12.5 mcg, FS MDPI 100/12.5 mcg, or placebo MDPI for the entire treatment period. Patients and investigators remained blinded to treatment assignment during the study. The sponsor’s clinical personnel involved in the study were also blinded to the study drug identity until the database was locked for analysis and the treatment assignment revealed.

Yes

Fluticasone propionate

Inhalation powder

Inhalation use

Fluticasone propionate (combined with salmeterol) multidose dry powder inhaler 100 mcg in the morning and evening for a total daily dose of 200 mcg.

Salmeterol

Inhalation powder

Inhalation use

Salmeterol (combined with fluticasone propionate) multidose dry powder inhaler 12.5 mcg in the morning and evening for a total daily dose of 25 mcg.

Fluticasone propionate

Inhalation powder

Inhalation use

Fluticasone propionate (combined with salmeterol) multidose dry powder inhaler 50 mcg in the morning and evening for a total daily dose of 100 mcg.

Salmeterol

Inhalation powder

Inhalation use

Salmeterol (combined with fluticasone propionate) multidose dry powder inhaler 12.5 mcg in the morning and evening for a total daily dose of 25 mcg.

Fluticasone propionate

Inhalation powder

Inhalation use

Fluticasone propionate multidose dry powder inhaler 100 mcg in the morning and evening for a total daily dose of 200 mcg.

Fluticasone propionate

Inhalation powder

Inhalation use

Fluticasone propionate multidose dry powder inhaler 50 mcg in the morning and evening for a total daily dose of 100 mcg.

Placebo MDPI

Inhalation powder

Inhalation use

Placebo administered via a multidose dry powder inhaler (MDPI) one puff in the morning and one puff in the evening for12 weeks.

FS MDPI 100 / 12.5 mcg

FS MDPI 50 / 12.5 mcg

Fp MDPI 100 mcg

Fp MDPI 50 mcg

Placebo MDPI

Enrolled Patients

FS MDPI 100 / 12.5 mcg

FS MDPI 50 / 12.5 mcg

Fp MDPI 100 mcg

Fp MDPI 50 mcg

Placebo MDPI

Serial Spirometry Subset:FS MDPI 100 / 12.5 mcg

A subset of patients who performed postdose serial spirometry at the baseline visit and week 12, and were randomized to the fluticasone propionate 100 mcg and salmeterol 12.5 mcg/dose BID treatment group.

Serial Spirometry Subset:FS MDPI 50 / 12.5 mcg

A subset of patients who performed postdose serial spirometry at the baseline visit and week 12, and were randomized to the fluticasone propionate 50 mcg and salmeterol 12.5 mcg/dose BID treatment group.

Serial Spirometry Subset: Fp MDPI 100 mcg

A subset of patients who performed postdose serial spirometry at the baseline visit and week 12, and were randomized to the fluticasone propionate 100 mcg/dose BID treatment group.

Serial Spirometry Subset: Fp MDPI 50 mcg

A subset of patients who performed postdose serial spirometry at the baseline visit and week 12, and were randomized to the fluticasone propionate 50 mcg/dose BID treatment group.

Serial Spirometry Subset: Placebo MDPI

A subset of patients who performed postdose serial spirometry at the baseline visit and week 12, and were randomized to the placebo treatment group.

A subset of approximately 300 patients who performed postdose serial spirometry is based on sample size calculation. Data from these assessments were used to analyze the primary endpoint of baseline-adjusted FEV1 AUEC0-12h at week 12 using the trapezoidal rule based on actual time of measurement. It was standardized by dividing it by the number of hours between the start time of dose administration and the end time of the last nonmissing FEV1 measurement. The baseline FEV1 was the average of the 2 predose FEV1 measurements (30 and 10 minutes predose). If 1 of these was missing, the nonmissing value was used; if both were missing, baseline was treated as missing. Baseline-adjusted FEV1 was calculated as postdose FEV1 after subtracting the baseline FEV1 value.

Primary

Day 1 (predose, baseline), Week 12 and was performed at the following times relative to the administration of study drug (±5 minutes): 15 and 30 minutes and 1, 2, 3, 4, 6, 8, 10, and 12 hours.

A fixed-sequence multiple testing procedure was used to control the overall Type I error rate at the 0.05 level (2-sided) for the primary endpoints analyses. Analyses appear in the defined sequence. This is the first in the sequence.

Serial Spirometry Subset:FS MDPI 100 / 12.5 mcg v Serial Spirometry Subset: Fp MDPI 100 mcg

133

Pre-specified

0.154

2-sided

A fixed-sequence multiple testing procedure was used to control the overall Type I error rate at the 0.05 level (2-sided) for the primary endpoints analyses. Analyses appear in the defined sequence. This is the second in the sequence.

Serial Spirometry Subset:FS MDPI 50 / 12.5 mcg v Serial Spirometry Subset: Fp MDPI 50 mcg

119

Pre-specified

0.131

2-sided

A fixed-sequence multiple testing procedure was used to control the overall Type I error rate at the 0.05 level (2-sided) for the primary endpoints analyses. Analyses appear in the defined sequence. This is the third in the sequence.

Serial Spirometry Subset:FS MDPI 100 / 12.5 mcg v Serial Spirometry Subset: Placebo MDPI

121

Pre-specified

0.335

2-sided

A fixed-sequence multiple testing procedure was used to control the overall Type I error rate at the 0.05 level (2-sided) for the primary endpoints analyses. Analyses appear in the defined sequence. This is the fourth in the sequence.

Serial Spirometry Subset:FS MDPI 50 / 12.5 mcg v Serial Spirometry Subset: Placebo MDPI

116

Pre-specified

0.325

2-sided

Trough FEV1 was a morning spirometry taken predose and pre-rescue bronchodilator. If the patient inadvertently administered asthma medication/study drug at home on the AM of the visit, or if the patient took rescue medication within 6 hours of testing, the visit was rescheduled. The baseline for predose FEV1 was defined as the average of the 30-minute and 10-minute predose measurements obtained at the randomization visit (Day 1).

Primary

Day 1 (predose, baseline), Week 12

A fixed-sequence multiple testing procedure was used to control the overall Type I error rate at the 0.05 level (2-sided) for the primary endpoints analyses. Analyses appear in the defined sequence. This is the fifth in the sequence.

FS MDPI 100 / 12.5 mcg v Placebo MDPI

255

Pre-specified

0.262

2-sided

A fixed-sequence multiple testing procedure was used to control the overall Type I error rate at the 0.05 level (2-sided) for the primary endpoints analyses. Analyses appear in the defined sequence. This is the sixth in the sequence.

FS MDPI 50 / 12.5 mcg v Placebo MDPI

257

Pre-specified

0.266

2-sided

A fixed-sequence multiple testing procedure was used to control the overall Type I error rate at the 0.05 level (2-sided) for the primary endpoints analyses. Analyses appear in the defined sequence. This is the seventh in the sequence.

Fp MDPI 100 mcg v Placebo MDPI

258

Pre-specified

0.151

2-sided

A fixed-sequence multiple testing procedure was used to control the overall Type I error rate at the 0.05 level (2-sided) for the primary endpoints analyses. Analyses appear in the defined sequence. This is the eighth in the sequence.

Fp MDPI 50 mcg v Placebo MDPI

257

Pre-specified

0.119

2-sided

Morning PEF tests were performed before administration of study drug or rescue medications (data were excluded if the time of PEF measurement was more than 5 minutes after the dose time). The patient recorded the highest value of 3 measurements obtained in the patient diary. The baseline PEF was the average value of recorded (nonmissing) morning assessments over the 7 days prior to randomization on Day 1. For efficacy analyses of weekly average morning PEF measurements, values were the averages based on available data for that week.

Secondary

Days -6 to Day 1 (predose), Day 1 (postdose) daily until Week 12

The analysis of change from baseline in weekly average of daily (AM predose and pre-rescue bronchodilator) PEF over the 12-week treatment period was performed using an mixed model for repeated measures (MMRM) with an unstructured covariance matrix and with effects due to baseline weekly average of daily AM PEF, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.

Fp MDPI 100 mcg v Placebo MDPI

257

Pre-specified

10.926

2-sided

The analysis of change from baseline in weekly average of daily (AM predose and pre-rescue bronchodilator) PEF over the 12-week treatment period was performed using an mixed model for repeated measures (MMRM) with an unstructured covariance matrix and with effects due to baseline weekly average of daily AM PEF, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.

Fp MDPI 50 mcg v Placebo MDPI

256

Pre-specified

7.018

2-sided

The analysis of change from baseline in weekly average of daily (AM predose and pre-rescue bronchodilator) PEF over the 12-week treatment period was performed using an mixed model for repeated measures (MMRM) with an unstructured covariance matrix and with effects due to baseline weekly average of daily AM PEF, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.

FS MDPI 100 / 12.5 mcg v Placebo MDPI

253

Pre-specified

20.824

2-sided

The analysis of change from baseline in weekly average of daily (AM predose and pre-rescue bronchodilator) PEF over the 12-week treatment period was performed using an mixed model for repeated measures (MMRM) with an unstructured covariance matrix and with effects due to baseline weekly average of daily AM PEF, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.

FS MDPI 50 / 12.5 mcg v Placebo MDPI

256

Pre-specified

21.273

2-sided

The analysis of change from baseline in weekly average of daily (AM predose and pre-rescue bronchodilator) PEF over the 12-week treatment period was performed using an mixed model for repeated measures (MMRM) with an unstructured covariance matrix and with effects due to baseline weekly average of daily AM PEF, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.

FS MDPI 100 / 12.5 mcg v Fp MDPI 100 mcg

254

Pre-specified

9.898

2-sided

The analysis of change from baseline in weekly average of daily (AM predose and pre-rescue bronchodilator) PEF over the 12-week treatment period was performed using an mixed model for repeated measures (MMRM) with an unstructured covariance matrix and with effects due to baseline weekly average of daily AM PEF, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.

FS MDPI 50 / 12.5 mcg v Fp MDPI 50 mcg

256

Pre-specified

14.255

2-sided

The analysis of change from baseline in weekly average of daily (AM predose and pre-rescue bronchodilator) PEF over the 12-week treatment period was performed using an mixed model for repeated measures (MMRM) with an unstructured covariance matrix and with effects due to baseline weekly average of daily AM PEF, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.

FS MDPI 50 / 12.5 mcg v Fp MDPI 100 mcg

257

Pre-specified

10.347

2-sided

The total daily asthma symptom score is the average of the daytime and nighttime scores as recorded in the patient diary. Daytime Symptom Score: 0=No symptoms 1=Symptoms for 1 short period 2=Symptoms for 2+ short periods 3=Symptoms for most of the day - did not affect normal daily activities 4=Symptoms for most of the day - did affect normal daily activities 5=Symptoms so severe that I could not go to work or perform normal daily activities Nighttime Symptom Score (determined in the AM): 0=No symptoms 1=Symptoms causing me to wake once (or wake early) 2=Symptoms causing me to wake twice or more (including waking early) 3=Symptoms causing me to be awake for most of the night 4=Symptoms so severe that I did not sleep Baseline was the average of recorded scores over the 7 days before randomization. The change from baseline in the weekly average over weeks 1 to 12 was analyzed using an mixed model for repeated measures (MMRM).

Secondary

Days -6 to Day 1 (predose, baseline) to Week 12

The change from baseline in the weekly average of the total daily asthma symptom scores over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.

Fp MDPI 100 mcg v Placebo MDPI

257

Pre-specified

-0.165

2-sided

The change from baseline in the weekly average of the total daily asthma symptom scores over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.

Fp MDPI 50 mcg v Placebo MDPI

256

Pre-specified

-0.143

2-sided

The change from baseline in the weekly average of the total daily asthma symptom scores over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.

FS MDPI 100 / 12.5 mcg v Placebo MDPI

253

Pre-specified

-0.23

2-sided

The change from baseline in the weekly average of the total daily asthma symptom scores over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.

FS MDPI 50 / 12.5 mcg v Placebo MDPI

256

Pre-specified

-0.194

2-sided

The change from baseline in the weekly average of the total daily asthma symptom scores over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.

FS MDPI 100 / 12.5 mcg v Fp MDPI 100 mcg

254

Pre-specified

-0.064

2-sided

The change from baseline in the weekly average of the total daily asthma symptom scores over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.

FS MDPI 50 / 12.5 mcg v Fp MDPI 50 mcg

256

Pre-specified

-0.051

2-sided

The change from baseline in the weekly average of the total daily asthma symptom scores over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.

FS MDPI 50 / 12.5 mcg v Fp MDPI 100 mcg

257

Pre-specified

-0.029

2-sided

Patients recorded the number of inhalations of rescue medication (albuterol/salbutamol HFA MDI) each AM and PM in the diary. The average number of daily inhalations over the 7 days before the randomization visit was the baseline value. The weekly average was based on the available data for the 7 days before each analysis week. The change from baseline in the weekly average of total daily (24-hour) use of albuterol/ salbutamol inhalation aerosol (number of inhalations) over weeks 1 to 12 was analyzed using a mixed model for repeated measures.

Secondary

Days -6 to Day 1 (predose, baseline), up to week 12

The change from baseline in the weekly average of total daily (24-hour) use of albuterol/ salbutamol inhalation aerosol (number of inhalations) over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline value, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.

Fp MDPI 100 mcg v Placebo MDPI

258

Pre-specified

-0.463

2-sided

The change from baseline in the weekly average of total daily (24-hour) use of albuterol/ salbutamol inhalation aerosol (number of inhalations) over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline value, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.

Fp MDPI 50 mcg v Placebo MDPI

257

Pre-specified

-0.464

2-sided

The change from baseline in the weekly average of total daily (24-hour) use of albuterol/ salbutamol inhalation aerosol (number of inhalations) over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline value, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.

FS MDPI 100 / 12.5 mcg v Placebo MDPI

255

Pre-specified

-0.675

2-sided

The change from baseline in the weekly average of total daily (24-hour) use of albuterol/ salbutamol inhalation aerosol (number of inhalations) over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline value, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.

FS MDPI 50 / 12.5 mcg v Placebo MDPI

257

Pre-specified

-0.704

2-sided

The change from baseline in the weekly average of total daily (24-hour) use of albuterol/ salbutamol inhalation aerosol (number of inhalations) over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline value, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.

FS MDPI 100 / 12.5 mcg v Fp MDPI 100 mcg

255

Pre-specified

-0.212

2-sided

The change from baseline in the weekly average of total daily (24-hour) use of albuterol/ salbutamol inhalation aerosol (number of inhalations) over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline value, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.

FS MDPI 50 / 12.5 mcg v Fp MDPI 50 mcg

256

Pre-specified

-0.239

2-sided

The change from baseline in the weekly average of total daily (24-hour) use of albuterol/ salbutamol inhalation aerosol (number of inhalations) over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline value, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.

FS MDPI 50 / 12.5 mcg v Fp MDPI 100 mcg

257

Pre-specified

-0.241

2-sided

The analysis of probability of remaining in the study at Week 12 used the time to patient withdrawal for worsening asthma, defined as the number of days elapsed from the date of randomization to the date of withdrawal due to worsening asthma. Patients who were lost to follow-up, who had not withdrawn due to worsening asthma by week 12, or who had withdrawn due to reasons other than worsening asthma were right-censored at the date of last assessment.

Secondary

up to Week 12 of the Treatment Period

Fp MDPI 100 mcg v Placebo MDPI

258

Pre-specified

Fp MDPI 50 mcg v Placebo MDPI

257

Pre-specified

FS MDPI 100 / 12.5 mcg v Placebo MDPI

255

Pre-specified

FS MDPI 50 / 12.5 mcg v Placebo MDPI

257

Pre-specified

FS MDPI 100 / 12.5 mcg v Fp MDPI 100 mcg

255

Pre-specified

FS MDPI 50 / 12.5 mcg v Fp MDPI 50 mcg

256

Pre-specified

FS MDPI 50 / 12.5 mcg v Fp MDPI 100 mcg

257

Pre-specified

The AQLQ(S) (September 2010 version; patients aged ≥18 years) was self-administered by the patients at the investigational center at the randomization visit and at Week 12 or end of trial. The questionnaire is a tool to measure the impact of asthma on a patient’s quality of life (physical, emotional, social, and occupational) with a recall period of 2 weeks. The AQLQ(S) was administered only to patients 18 years and older. The 32 individual questions in the AQLQ were equally weighted. The overall AQLQ score was the mean of the responses to each of the 32 questions, and ranged from 1 to 7. A score of 7.0 indicated that the patient had no impairments due to asthma and a score of 1.0 indicated severe impairment. Positive change from baseline scores indicate improved quality of life.

Secondary

Day 1 (predose, baseline), end of trial (up to week 12)

The change from baseline in AQLQ(S) score (patients ≥18 years of age) at endpoint (ie, last postbaseline observation) was analyzed using an ANCOVA model with effects due to baseline AQLQ(S) score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), and treatment, imputing missing data via last observation carried forward (LOCF).

Fp MDPI 100 mcg v Placebo MDPI

200

Pre-specified

0.301

2-sided

The change from baseline in AQLQ(S) score (patients ≥18 years of age) at endpoint (ie, last postbaseline observation) was analyzed using an ANCOVA model with effects due to baseline AQLQ(S) score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), and treatment, imputing missing data via last observation carried forward (LOCF).

Fp MDPI 50 mcg v Placebo MDPI

205

Pre-specified

0.253

2-sided

The change from baseline in AQLQ(S) score (patients ≥18 years of age) at endpoint (ie, last postbaseline observation) was analyzed using an ANCOVA model with effects due to baseline AQLQ(S) score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), and treatment, imputing missing data via last observation carried forward (LOCF).

FS MDPI 100 / 12.5 mcg v Placebo MDPI

206

Pre-specified

0.473

2-sided

The change from baseline in AQLQ(S) score (patients ≥18 years of age) at endpoint (ie, last postbaseline observation) was analyzed using an ANCOVA model with effects due to baseline AQLQ(S) score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), and treatment, imputing missing data via last observation carried forward (LOCF).

FS MDPI 50 / 12.5 mcg v Placebo MDPI

199

Pre-specified

0.23

2-sided

The change from baseline in AQLQ(S) score (patients ≥18 years of age) at endpoint (ie, last postbaseline observation) was analyzed using an ANCOVA model with effects due to baseline AQLQ(S) score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), and treatment, imputing missing data via last observation carried forward (LOCF).

FS MDPI 100 / 12.5 mcg v Fp MDPI 100 mcg

212

Pre-specified

0.172

2-sided

The change from baseline in AQLQ(S) score (patients ≥18 years of age) at endpoint (ie, last postbaseline observation) was analyzed using an ANCOVA model with effects due to baseline AQLQ(S) score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), and treatment, imputing missing data via last observation carried forward (LOCF).

FS MDPI 50 / 12.5 mcg v Fp MDPI 50 mcg

210

Pre-specified

-0.023

2-sided

The change from baseline in AQLQ(S) score (patients ≥18 years of age) at endpoint (ie, last postbaseline observation) was analyzed using an ANCOVA model with effects due to baseline AQLQ(S) score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), and treatment, imputing missing data via last observation carried forward (LOCF).

FS MDPI 50 / 12.5 mcg v Fp MDPI 100 mcg

205

Pre-specified

-0.071

2-sided

A subset of approximately 300 patients who performed postdose serial spirometry is based on sample size calculation. Baseline FEV1 was the average of 2 FEV1 measurements (30 and 10 minutes predose) on Day 1. If one of these was missing, the other measurement was used as baseline value. If both were missing, baseline was treated as missing. Time to target improvement (15% or 12%) was defined as the time elapsed from the time of first dose to the first time the target improvement in FEV1 was achieved. If an exact target increase was not achieved at a measured timepoint, then the time was estimated by linear interpolation between the timepoint when target was reached and the timepoint immediately before. Patients who did not achieve the target improvement were censored at the time of last serial spirometry assessment. Values of 9999 indicate the values could not be estimated which happened when the estimated probability of not achieving target is more than 50%.

Secondary

Day 1 of the Treatment Period (predose and postdose)

An adverse event was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an AE which prevents normal daily activities. Relationship of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.

Secondary

Day 1 to Week 12 of the Treatment Period

Day 1 up to Week 12

17.0

FS MDPI 100 / 12.5 mcg

FS MDPI 50 / 12.5 mcg

Fp MDPI 100 mcg

Fp MDPI 50 mcg

Placebo MDPI