Trial Outcomes & Findings for Comparative Study of Umeclidinium/Vilanterol (UMEC/VI) in a Fixed Dose Combination With Indacaterol Plus Tiotropium (NCT NCT02257385)

Last Updated: 2018-03-01

Results Overview

FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in 1 second. BL was the mean of the 2 assessments made 30 and 5 minutes (min) pre-dose (PD) on Day 1. Trough FEV1 measurements were taken electronically by spirometry on Days 2, 28, 56, 84 and 85. Trough FEV1 on Day 85 is defined as the mean of the FEV1 values obtained at 23 and 24 hours (hr) after dosing on Day 84 (at Week 12 + 1 day). Analysis was performed using mixed model repeated measures (RM) with covariates of trt, BL FEV1 (mean of values measured at 30 and 5 min PD on Day 1), center group, day, day by BL interaction and day by trt interaction, where day was nominal.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

967 participants

Primary outcome timeframe

Baseline (BL) and Day 85

Results posted on

2018-03-01

Participant Flow

Eligible participants (par) completed a 5-7 day run-in period, and were randomized to blinded study medication for 12 weeks. Supplemental albuterol/salbutamol was provided to all par, to be used on an as-needed basis during run-in and up to Day 85.

A total of 1190 par were screened; 967 par randomized and 961 par comprised the Intent-to-Treat (ITT) Population (Pop), comprised of all par randomized to treatment (trt) who received at least 1 dose of randomized study medication in the trt period.

Participant milestones

Participant milestones
Measure	Umeclidinium/Vilanterol 62.5/25 µg Participants self-administered one dose each morning from each of the following three inhalers for 12 weeks: ELLIPTA dry powder inhaler containing umeclidinium/vilanterol inhalation powder 62.5/25 micrograms (µg), BREEZHALER containing placebo, and HANDIHALER containing placebo. Each inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.	Indacaterol 150 µg + Tiotropium Bromide 18 µg Participants self-administered one dose each morning from each of the following three inhalers for 12 weeks: ELLIPTA dry powder inhaler containing placebo, BREEZHALER containing indacaterol 150 µg, and HANDIHALER containing tiotropium bromide 18 µg. The inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.
Overall Study STARTED	482	479
Overall Study COMPLETED	460	457
Overall Study NOT COMPLETED	22	22

Reasons for withdrawal

Reasons for withdrawal
Measure	Umeclidinium/Vilanterol 62.5/25 µg Participants self-administered one dose each morning from each of the following three inhalers for 12 weeks: ELLIPTA dry powder inhaler containing umeclidinium/vilanterol inhalation powder 62.5/25 micrograms (µg), BREEZHALER containing placebo, and HANDIHALER containing placebo. Each inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.	Indacaterol 150 µg + Tiotropium Bromide 18 µg Participants self-administered one dose each morning from each of the following three inhalers for 12 weeks: ELLIPTA dry powder inhaler containing placebo, BREEZHALER containing indacaterol 150 µg, and HANDIHALER containing tiotropium bromide 18 µg. The inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.
Overall Study Adverse Event	12	8
Overall Study Lack of Efficacy	1	2
Overall Study Protocol Violation	5	7
Overall Study Lost to Follow-up	0	1
Overall Study Withdrawal by Subject	4	4

Baseline Characteristics

Comparative Study of Umeclidinium/Vilanterol (UMEC/VI) in a Fixed Dose Combination With Indacaterol Plus Tiotropium

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Umeclidinium/Vilanterol 62.5/25 µg n=482 Participants Participants self-administered one dose each morning from each of the following three inhalers for 12 weeks: ELLIPTA dry powder inhaler containing umeclidinium/vilanterol inhalation powder 62.5/25 micrograms (µg), BREEZHALER containing placebo, and HANDIHALER containing placebo. Each inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.	Indacaterol 150 µg + Tiotropium Bromide 18 µg n=479 Participants Participants self-administered one dose each morning from each of the following three inhalers for 12 weeks: ELLIPTA dry powder inhaler containing placebo, BREEZHALER containing indacaterol 150 µg, and HANDIHALER containing tiotropium bromide 18 µg. The inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.	Total n=961 Participants Total of all reporting groups
Age, Continuous	64.4 Years STANDARD_DEVIATION 7.75 • n=5 Participants	64.0 Years STANDARD_DEVIATION 8.44 • n=7 Participants	64.2 Years STANDARD_DEVIATION 8.10 • n=5 Participants
Sex: Female, Male Female	127 Participants n=5 Participants	138 Participants n=7 Participants	265 Participants n=5 Participants
Sex: Female, Male Male	355 Participants n=5 Participants	341 Participants n=7 Participants	696 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	24 Participants n=5 Participants	27 Participants n=7 Participants	51 Participants n=5 Participants
Race/Ethnicity, Customized Asian - Central/South Asian Heritage	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Asian - East Asian Heritage	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Asian - Japanese Heritage	4 Participants n=5 Participants	1 Participants n=7 Participants	5 Participants n=5 Participants
Race/Ethnicity, Customized White - Arabic/North African Heritage	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized White -White/Caucasian/European Heritage	453 Participants n=5 Participants	449 Participants n=7 Participants	902 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline (BL) and Day 85

Population: Per Protocol (PP) Pop: all ITT Pop par who were not full protocol deviators considered to impact efficacy. Only par with data available at the specified time points (TP) were analyzed but all par without (w/o) missing covariate information and with \>= 1 post BL measurement were included in the analysis.

Outcome measures

Outcome measures
Measure	Umeclidinium/Vilanterol 62.5/25 µg n=392 Participants Participants self-administered one dose each morning from each of the following three inhalers for 12 weeks: ELLIPTA dry powder inhaler containing umeclidinium/vilanterol inhalation powder 62.5/25 micrograms (µg), BREEZHALER containing placebo, and HANDIHALER containing placebo. Each inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.	Indacaterol 150 µg + Tiotropium Bromide 18 µg n=392 Participants Participants self-administered one dose each morning from each of the following three inhalers for 12 weeks: ELLIPTA dry powder inhaler containing placebo, BREEZHALER containing indacaterol 150 µg, and HANDIHALER containing tiotropium bromide 18 µg. The inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.
Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) on Treatment Day 85 (Visit 8)	0.172 Liters Standard Error 0.0107	0.171 Liters Standard Error 0.0108

SECONDARY outcome

Timeframe: Baseline and Day 84

Population: ITT Population

BL FEV1 was the mean of the 2 assessments made 30 and 5 min PD on Day 1. WM FEV1 derived by calculating the area under the FEV1/time curve (AUC) using the trapezoidal rule, and then dividing the value by the time interval over which the AUC was calculated. The WM was calculated at Days 1 and 84 using the 0-6 hr post-dose FEV1 measurements collected on that day, which included PD FEV1 (taken 30 and 5 min prior to dosing on Day 1 and the 30 and 5 min reading prior to dosing on Day 84) and post-dose FEV1 measurements at 1, 3 and 6 hr post-dose.WM change from BL was the WM at at the visit minus the BL value. Analysis was performed using a RM model with covariates of trt, BL FEV1 (mean of values measured at 30 and 5 min PD on Day 1) center group, day, day by BL and day by trt interaction, where day was nominal. Only par with data available at the specified TP were analyzed but all par w/o missing covariate information and with \>=1 post-BL measurement were included in the analysis.

Outcome measures

Outcome measures
Measure	Umeclidinium/Vilanterol 62.5/25 µg n=455 Participants Participants self-administered one dose each morning from each of the following three inhalers for 12 weeks: ELLIPTA dry powder inhaler containing umeclidinium/vilanterol inhalation powder 62.5/25 micrograms (µg), BREEZHALER containing placebo, and HANDIHALER containing placebo. Each inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.	Indacaterol 150 µg + Tiotropium Bromide 18 µg n=452 Participants Participants self-administered one dose each morning from each of the following three inhalers for 12 weeks: ELLIPTA dry powder inhaler containing placebo, BREEZHALER containing indacaterol 150 µg, and HANDIHALER containing tiotropium bromide 18 µg. The inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.
Change From Baseline in Weighted Mean (WM) FEV1 Over 0-6 Hour Post-dose at Day 84	0.235 Liters Standard Error 0.0111	0.258 Liters Standard Error 0.0111

Adverse Events

Umeclidinium/Vilanterol 62.5/25 µg

Serious events: 21 serious events

Other events: 76 other events

Deaths: 0 deaths

Indacaterol 150 µg + Tiotropium Bromide 18 µg

Serious events: 16 serious events

Other events: 65 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Umeclidinium/Vilanterol 62.5/25 µg n=482 participants at risk Participants self-administered one dose each morning from each of the following three inhalers for 12 weeks: ELLIPTA dry powder inhaler containing umeclidinium/vilanterol inhalation powder 62.5/25 micrograms (µg), BREEZHALER containing placebo, and HANDIHALER containing placebo. Each inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.	Indacaterol 150 µg + Tiotropium Bromide 18 µg n=479 participants at risk Participants self-administered one dose each morning from each of the following three inhalers for 12 weeks: ELLIPTA dry powder inhaler containing placebo, BREEZHALER containing indacaterol 150 µg, and HANDIHALER containing tiotropium bromide 18 µg. The inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.
Nervous system disorders Headache	7.5% 36/482 • Number of events 56 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected over a period of a maximum of 96 days starting from Day 1 of treatment until the follow-up contact. On-treatment SAEs and non-serious AEs were reported for members of the ITT Population, comprised of all participants randomized to treatment who received at least one dose of randomized study medication in the treatment period.	5.8% 28/479 • Number of events 60 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected over a period of a maximum of 96 days starting from Day 1 of treatment until the follow-up contact. On-treatment SAEs and non-serious AEs were reported for members of the ITT Population, comprised of all participants randomized to treatment who received at least one dose of randomized study medication in the treatment period.
Infections and infestations Nasopharyngitis	6.6% 32/482 • Number of events 34 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected over a period of a maximum of 96 days starting from Day 1 of treatment until the follow-up contact. On-treatment SAEs and non-serious AEs were reported for members of the ITT Population, comprised of all participants randomized to treatment who received at least one dose of randomized study medication in the treatment period.	5.6% 27/479 • Number of events 31 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected over a period of a maximum of 96 days starting from Day 1 of treatment until the follow-up contact. On-treatment SAEs and non-serious AEs were reported for members of the ITT Population, comprised of all participants randomized to treatment who received at least one dose of randomized study medication in the treatment period.
Respiratory, thoracic and mediastinal disorders Cough	3.3% 16/482 • Number of events 18 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected over a period of a maximum of 96 days starting from Day 1 of treatment until the follow-up contact. On-treatment SAEs and non-serious AEs were reported for members of the ITT Population, comprised of all participants randomized to treatment who received at least one dose of randomized study medication in the treatment period.	3.5% 17/479 • Number of events 18 • On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected over a period of a maximum of 96 days starting from Day 1 of treatment until the follow-up contact. On-treatment SAEs and non-serious AEs were reported for members of the ITT Population, comprised of all participants randomized to treatment who received at least one dose of randomized study medication in the treatment period.

Additional Information

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GlaxoSmithKline

Phone: 866-435-7343

Results disclosure agreements

Principal investigator is a sponsor employee GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
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