FSS-AS-30017

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., 1 215-591-3000, ustevatrials@tevapharm.com

Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 1 215-591-3000, ustevatrials@tevapharm.com

No

No

No

Final

16 Feb 2016

No

Yes

26 Sep 2015

No

The primary objective of this study was to evaluate the efficacy of Fp MDPI and 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.

30 Jun 2014

No

No

Canada: 3

United States: 540

South Africa: 17

Russian Federation: 46

Ukraine: 36

Poland: 137

Czech Republic: 5

Hungary: 98

882

240

0

0

0

0

0

64

722

96

0

Run-In Period

Non-randomised - controlled

All patients replace their current inhaled corticosteroid and instead take 1 inhalation twice a day from a single-blinded fluticasone propionate 50 mcg multidose dry powder inhaler device.

Fluticasone propionate

Inhalation powder

Inhalation use

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

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.

Treatment Period

Randomised - controlled

Patients were randomly assigned to one of 5 treatments; a permanent unique randomization number and treatment kit number was generated using interactive response technology (IRT). Patients and investigators remained blinded to treatment assignment during the study. The sponsor’s clinical personnel involved in the study were blinded until the database was locked for analysis.

Yes

Placebo

Inhalation powder

Inhalation use

The placebo multidose dry powder inhaler was identical to the devices used to deliver active drug, and indistinguishable from the active treatments. Patients took one inhalation twice a day (approximately 12 hours apart). Patients were instructed to rinse their mouth and expectorate (not swallow) after study drug administration.

Fluticasone propionate

Inhalation powder

Inhalation use

Fluticasone propionate multidose dry powder inhaler (Fp MDPI) 100 mcg in the morning and evening for a total daily dose of 200 mcg. Patients were instructed to rinse their mouth and expectorate (not swallow) after study drug administration.

Fluticasone propionate

Inhalation powder

Inhalation use

Fluticasone propionate multidose dry powder inhaler (Fp MDPI) 200 mcg in the morning and evening for a total daily dose of 400 mcg. Patients were instructed to rinse their mouth and expectorate (not swallow) after study drug administration.

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. Patients were instructed to rinse their mouth and expectorate (not swallow) after study drug administration.

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. Patients were instructed to rinse their mouth and expectorate (not swallow) after study drug administration.

Fluticasone propionate

Inhalation powder

Inhalation use

Fluticasone propionate (combined with salmeterol) multidose dry powder inhaler 200 mcg in the morning and evening for a total daily dose of 400 mcg. Patients were instructed to rinse their mouth and expectorate (not swallow) after study drug administration.

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. Patients were instructed to rinse their mouth and expectorate (not swallow) after study drug administration.

Placebo MDPI

Fp MDPI 100 mcg

Fp MDPI 200 mcg

FS MDPI 100 / 12.5 mcg

FS MDPI 200 / 12.5 mcg

Fluticasone Propionate 50 mcg BID

Placebo MDPI

Fp MDPI 100 mcg

Fp MDPI 200 mcg

FS MDPI 100 / 12.5 mcg

FS MDPI 200 / 12.5 mcg

FS MDPI 200 / 12.5 mcg

Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 200 mcg (for a total daily dose of 400 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. The full analysis set included intent-to-treat patients with >=1 dose of study drug and >=1 postbaseline trough FEV1.

FS MDPI 100 / 12.5 mcg

Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 100 mcg (for a total daily dose of 200 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. The full analysis set included intent-to-treat patients with >=1 dose of study drug and >=1 postbaseline trough FEV1.

Fp MDPI 200 mcg

Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate for a total daily dose of 400 mcg for 12 weeks. The full analysis set included intent-to-treat patients with >=1 dose of study drug and >=1 postbaseline trough FEV1.

Fp MDPI 100 mcg

Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate for a total daily dose of 200 mcg for 12 weeks. The full analysis set included intent-to-treat patients with >=1 dose of study drug and >=1 postbaseline trough FEV1.

Placebo MDPI

Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of placebo for 12 weeks. The full analysis set included intent-to-treat patients with >=1 dose of study drug and >=1 postbaseline trough FEV1.

Serial Spirometry Subset:FS MDPI 200 / 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 200 mcg and salmeterol 12.5 mcg/dose BID treatment group.

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: Fp MDPI 200 mcg

A subset of patients who performed postdose serial spirometry at the baseline visit and week 12, and were randomized to the fluticasone propionate 200 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: 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 patients performed postdose serial spirometry. 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 200 / 12.5 mcg v Serial Spirometry Subset: Fp MDPI 200 mcg

129

Pre-specified

0.179

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

122

Pre-specified

0.182

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 200 / 12.5 mcg v Serial Spirometry Subset: Placebo MDPI

129

Pre-specified

0.326

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 100 / 12.5 mcg v Serial Spirometry Subset: Placebo MDPI

119

Pre-specified

0.322

2-sided

Trough FEV1 is 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 200 / 12.5 mcg v Placebo MDPI

286

Pre-specified

0.276

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 100 / 12.5 mcg v Placebo MDPI

283

Pre-specified

0.274

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 200 mcg v Placebo MDPI

288

Pre-specified

0.183

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 100 mcg v Placebo MDPI

287

Pre-specified

0.123

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, baseline), 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 200 mcg v Placebo MDPI

288

Pre-specified

18.45

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 100 mcg v Placebo MDPI

287

Pre-specified

16.718

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 200 / 12.5 mcg v Placebo MDPI

287

Pre-specified

31.221

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

283

Pre-specified

29.597

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 200 / 12.5 mcg v Fp MDPI 200 mcg

291

Pre-specified

12.771

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

286

Pre-specified

12.879

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 200 mcg

287

Pre-specified

11.146

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 200 mcg v Placebo MDPI

288

Pre-specified

-0.156

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 100 mcg v Placebo MDPI

287

Pre-specified

-0.195

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 200 / 12.5 mcg v Placebo MDPI

287

Pre-specified

-0.304

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

283

Pre-specified

-0.277

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 200 / 12.5 mcg v Fp MDPI 200 mcg

291

Pre-specified

-0.149

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

286

Pre-specified

-0.082

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 200 mcg

287

Pre-specified

-0.121

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 200 mcg v Placebo MDPI

289

Pre-specified

-0.702

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 100 mcg v Placebo MDPI

288

Pre-specified

-0.607

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 200 / 12.5 mcg v Placebo MDPI

288

Pre-specified

-1.066

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

284

Pre-specified

-0.989

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 200 / 12.5 mcg v Fp MDPI 200 mcg

291

Pre-specified

-0.364

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

286

Pre-specified

-0.382

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 200 mcg

287

Pre-specified

-0.287

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 200 mcg v Placebo MDPI

289

Pre-specified

Fp MDPI 100 mcg v Placebo MDPI

288

Pre-specified

FS MDPI 200 / 12.5 mcg v Placebo MDPI

288

Pre-specified

FS MDPI 100 / 12.5 mcg v Placebo MDPI

284

Pre-specified

FS MDPI 200 / 12.5 mcg v Fp MDPI 200 mcg

291

Pre-specified

FS MDPI 100 / 12.5 mcg v Fp MDPI 100 mcg

286

Pre-specified

FS MDPI 100 / 12.5 mcg v Fp MDPI 200 mcg

287

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 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 200 mcg v Placebo MDPI

261

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).

Fp MDPI 100 mcg v Placebo MDPI

262

Pre-specified

0.428

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 200 / 12.5 mcg v Placebo MDPI

260

Pre-specified

0.623

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

264

Pre-specified

0.681

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 200 / 12.5 mcg v Fp MDPI 200 mcg

263

Pre-specified

0.15

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

268

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 Fp MDPI 200 mcg

267

Pre-specified

0.209

2-sided

The baseline forced expiratory volume in 1 second (FEV1) was the average of the 2 predose 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, the baseline trough FEV1 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. Relation 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 14

17.0

Placebo MDPI

Fp MDPI 100 mcg

Fp MDPI 200 mcg

FS MDPI 100 / 12.5 mcg

FS MDPI 200 / 12.5 mcg