Trial Outcomes & Findings for The Effect of STIOLTO™ RESPIMAT® on Fatigue in Chronic Obstructive Pulmonary Disease (NCT NCT02845752)

NCT ID: NCT02845752

Last Updated: 2020-08-06

Results Overview

Constant work rate (CWR) exercise causes fatigue. Fatigue is measured by the difference between pre-CWR and post-CWR maximal voluntary isokinetic power i.e. how much maximal voluntary isokinetic power declines during CWR. The magnitude of fatigue is measured in watts at the time of the shortest exercise duration in either study arm, which is termed "isotime". A smaller value (in watts) of performance fatigue means that the intervention was associated with less fatigue after a given CWR exercise duration (i.e. at isotime).

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 14 participants
• Primary outcome timeframe: Baseline and day 7 of each treatment period
• Results posted on: 2020-08-06

Participant Flow

Participant milestones

Measure	Stiolto Respimat, Then Placebo Respimat Participants first received Stiolto Respimat inhaler (two actuations, once daily for 7 days). After a washout period of 14 days, participants will then received Placebo Respimat inhaler (two actuations, once daily for 7 days).	Placebo Respimat, Then Stiolto Respimat Participants first received Placebo Respimat inhaler (two actuations, once daily for 7 days). After a washout period of 14 days, participants will then received Stiolto Respimat inhaler (two actuations, once daily for 7 days).
First Intervention (7 Days) STARTED	7	7
First Intervention (7 Days) COMPLETED	7	7
First Intervention (7 Days) NOT COMPLETED	0	0
Washout (14 Days) STARTED	7	7
Washout (14 Days) COMPLETED	7	7
Washout (14 Days) NOT COMPLETED	0	0
Second Intervention (7 Days) STARTED	7	7
Second Intervention (7 Days) COMPLETED	7	7
Second Intervention (7 Days) NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

The Effect of STIOLTO™ RESPIMAT® on Fatigue in Chronic Obstructive Pulmonary Disease

Baseline characteristics by cohort

Measure	Stiolto Respimat, Then Placebo Respimat n=7 Participants Participants first received Stiolto Respimat inhaler (two actuations, once daily for 7 days). After a washout period of 14 days, participants will then received Placebo Respimat inhaler (two actuations, once daily for 7 days).	Placebo Respimat, Then Stiolto Respimat n=7 Participants Participants first received Placebo Respimat inhaler (two actuations, once daily for 7 days). After a washout period of 14 days, participants will then received Stiolto Respimat inhaler (two actuations, once daily for 7 days).	Total n=14 Participants Total of all reporting groups
Age, Continuous	63 years n=5 Participants	71 years n=7 Participants	64 years n=5 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants
Sex: Female, Male Male	5 Participants n=5 Participants	5 Participants n=7 Participants	10 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	3 Participants n=5 Participants	4 Participants n=7 Participants	7 Participants n=5 Participants
Race (NIH/OMB) White	4 Participants n=5 Participants	3 Participants n=7 Participants	7 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	7 participants n=5 Participants	7 participants n=7 Participants	14 participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and day 7 of each treatment period

Constant work rate (CWR) exercise causes fatigue. Fatigue is measured by the difference between pre-CWR and post-CWR maximal voluntary isokinetic power i.e. how much maximal voluntary isokinetic power declines during CWR. The magnitude of fatigue is measured in watts at the time of the shortest exercise duration in either study arm, which is termed "isotime". A smaller value (in watts) of performance fatigue means that the intervention was associated with less fatigue after a given CWR exercise duration (i.e. at isotime).

Outcome measures

Measure	Stiolto Respimat n=14 Participants Stiolto Respimat inhaler (two actuations, taken once daily for 7 days).	Placebo Respimat n=14 Participants Placebo Respimat inhaler (two actuations, taken once daily for 7 days).
The Magnitude of Change in Isokinetic Power (Performance Fatigue, PF) Associated With Stiolto Respimat Compared With Placebo Respimat at Isotime During Constant Work Rate Exercise (CWR)	75 watts Interval 53.0 to 103.0	77 watts Interval 61.0 to 117.0

SECONDARY outcome

Timeframe: Baseline and day 7 of each treatment period

Constant work rate (CWR) exercise causes fatigue and reduces muscle activation. The relationship between muscle activation and power is measured at baseline (unfatigued condition). Fatigue is measured by the difference between pre-CWR and post-CWR maximal voluntary isokinetic power i.e. how much maximal voluntary isokinetic power declines during CWR. The fraction of fatigue that is ascribed to reduced muscle activity is then calculated. The magnitude of activation fatigue is measured in EMG activity and expressed in watts at the time of the shortest exercise duration in either study arm, which is termed "isotime". A smaller value (in watts) of activation fatigue means that the intervention was associated with a less reduction in EMG activity after a given CWR exercise duration (i.e. at isotime).

Outcome measures

Measure	Stiolto Respimat n=14 Participants Stiolto Respimat inhaler (two actuations, taken once daily for 7 days).	Placebo Respimat n=14 Participants Placebo Respimat inhaler (two actuations, taken once daily for 7 days).
The Magnitude of Change Electromyographic (EMG) Muscle Activity (Activation Fatigue, AF) Associated With Stiolto Respimat Compared With Placebo Respimat at Isotime During Constant Work Rate Exercise (CWR)	58 watts Interval 33.0 to 74.0	50 watts Interval 27.0 to 80.0

SECONDARY outcome

Timeframe: Baseline and day 7 of each treatment period

The duration in seconds for which constant work rate (CWR) cycling exercise could be tolerated prior to voluntary termination of exercise.

Outcome measures

Measure	Stiolto Respimat n=14 Participants Stiolto Respimat inhaler (two actuations, taken once daily for 7 days).	Placebo Respimat n=14 Participants Placebo Respimat inhaler (two actuations, taken once daily for 7 days).
Exercise Endurance Time During CWR Cycling Exercise	297 seconds Interval 253.0 to 352.0	274 seconds Interval 222.0 to 326.0

SECONDARY outcome

Timeframe: Baseline and day 7 of each treatment period

Inspiratory reserve volume (IRV) measured during CWR cycling exercise at the time of the shortest duration of each intervention arm (isotime). A greater IRV would reflect a beneficial response to intervention.

Outcome measures

Measure	Stiolto Respimat n=14 Participants Stiolto Respimat inhaler (two actuations, taken once daily for 7 days).	Placebo Respimat n=14 Participants Placebo Respimat inhaler (two actuations, taken once daily for 7 days).
Change From Period Baseline in the Exercise-isotime Inspiratory Reserve Volume During CWR	0.54 Liters Interval 0.26 to 0.86	0.46 Liters Interval 0.31 to 0.6

SECONDARY outcome

Timeframe: Baseline and day 7 of each treatment period

Inspiratory capacity (IC) measured during constant work rate (CWR) cycling exercise at the time of the shortest duration of each intervention arm (isotime). A greater IC would reflect a beneficial response to the intervention.

Outcome measures

Measure	Stiolto Respimat n=14 Participants Stiolto Respimat inhaler (two actuations, taken once daily for 7 days).	Placebo Respimat n=14 Participants Placebo Respimat inhaler (two actuations, taken once daily for 7 days).
Change From Period Baseline in the Exercise-isotime Inspiratory Capacity During CWR	1.91 Liters Interval 1.64 to 2.48	1.88 Liters Interval 1.71 to 2.25

SECONDARY outcome

Timeframe: Baseline and day 7 of each treatment period

This outcome describes the the effect of the intervention on forced expiratory volume in 1 second (FEV1) during resting spirometry. A greater FEV1 would reflect a positive benefit of the intervention.

Outcome measures

Measure	Stiolto Respimat n=14 Participants Stiolto Respimat inhaler (two actuations, taken once daily for 7 days).	Placebo Respimat n=14 Participants Placebo Respimat inhaler (two actuations, taken once daily for 7 days).
Change From Period Baseline in the Forced Expiratory Volume in 1 Second (FEV1)	1.81 Liters Interval 1.58 to 1.98	1.72 Liters Interval 1.29 to 1.99

SECONDARY outcome

Timeframe: Baseline and day 7 of each treatment period

Percentage of arterial hemoglobin that is saturated with oxygen, measured using pulse oximetry during constant work rate (CWR) cycling exercise at the time of the shortest duration of each intervention arm (isotime). A greater pulse oximeter oxygen saturation would reflect a beneficial response to the intervention.

Outcome measures

Measure	Stiolto Respimat n=14 Participants Stiolto Respimat inhaler (two actuations, taken once daily for 7 days).	Placebo Respimat n=14 Participants Placebo Respimat inhaler (two actuations, taken once daily for 7 days).
Change From Period Baseline in the Exercise-isotime in Pulse Oximeter Oxygen Saturation During CWR	99.0 percent of hemoglobin saturated with O2 Interval 97.3 to 100.0	98.5 percent of hemoglobin saturated with O2 Interval 97.8 to 100.0

SECONDARY outcome

Timeframe: Baseline and day 7 of each treatment period

Minute ventilation (VE) measured during constant work rate (CWR) cycling exercise at the time of the shortest duration of each intervention arm (isotime). A lesser VE would reflect a beneficial response to the intervention.

Outcome measures

Measure	Stiolto Respimat n=14 Participants Stiolto Respimat inhaler (two actuations, taken once daily for 7 days).	Placebo Respimat n=14 Participants Placebo Respimat inhaler (two actuations, taken once daily for 7 days).
Change From Period Baseline in the Exercise-isotime Ventilation During CWR	50.20 Liters/minute Interval 44.65 to 55.45	45.25 Liters/minute Interval 42.95 to 55.43

SECONDARY outcome

Timeframe: Baseline and day 7 of each treatment period

Pulmonary oxygen uptake (VO2) measured during constant work rate (CWR) cycling exercise at the time of the shortest duration of each intervention arm (isotime). A lesser VO2 would reflect a beneficial response to the intervention.

Outcome measures

Measure	Stiolto Respimat n=14 Participants Stiolto Respimat inhaler (two actuations, taken once daily for 7 days).	Placebo Respimat n=14 Participants Placebo Respimat inhaler (two actuations, taken once daily for 7 days).
Change From Period Baseline in the Exercise-isotime Oxygen Uptake (VO2) During CWR	1.279 Liters/minute Interval 0.996 to 1.462	1.219 Liters/minute Interval 1.07 to 1.452

SECONDARY outcome

Timeframe: Baseline and day 7 of each treatment period

Tissue saturation of hemoglobin with oxygen is measured by spatially resolved near-infrared spectroscopy from the frontal lobe during constant work rate (CWR) cycling exercise at the time of the shortest duration of each intervention arm (isotime). A greater frontal lobe oxygen saturation at isotime would reflect a beneficial response to the intervention.

Outcome measures

Measure	Stiolto Respimat n=14 Participants Stiolto Respimat inhaler (two actuations, taken once daily for 7 days).	Placebo Respimat n=14 Participants Placebo Respimat inhaler (two actuations, taken once daily for 7 days).
Change From Period Baseline in the Exercise-isotime Frontal Lobe Oxygen Saturation During CWR	62.5 Percent of hemoglobin saturated with O2 Interval 58.0 to 67.0	62.8 Percent of hemoglobin saturated with O2 Interval 56.6 to 65.9

SECONDARY outcome

Timeframe: Baseline and day 7 of each treatment period

Tissue saturation of hemoglobin plus myoglobin with oxygen is measured by spatially resolved near-infrared spectroscopy from the vastus lateralis muscle during constant work rate (CWR) cycling exercise at the time of the shortest duration of each intervention arm (isotime). A greater muscle oxygen saturation at isotime would reflect a beneficial response to the intervention.

Outcome measures

Measure	Stiolto Respimat n=14 Participants Stiolto Respimat inhaler (two actuations, taken once daily for 7 days).	Placebo Respimat n=14 Participants Placebo Respimat inhaler (two actuations, taken once daily for 7 days).
Change From Period Baseline in the Exercise-isotime Muscle Oxygen Saturation During CWR	54.5 % of O2 saturated hemoglobin+myoglobin Interval 43.9 to 60.8	53.4 % of O2 saturated hemoglobin+myoglobin Interval 44.2 to 58.7

SECONDARY outcome

Timeframe: Baseline and day 7 of each treatment period

Borg rating of perceived shortness of breath (dyspnea) were measured on a category-ratio scale from 0 to 10 (CR-10) during constant work rate (CWR) cycling exercise at the time of the shortest duration of each intervention arm (isotime). A lower CR-10 score for dyspnea at isotime would reflect a beneficial response to the intervention.

Outcome measures

Measure	Stiolto Respimat n=14 Participants Stiolto Respimat inhaler (two actuations, taken once daily for 7 days).	Placebo Respimat n=14 Participants Placebo Respimat inhaler (two actuations, taken once daily for 7 days).
Change From Period Baseline in the Exercise-isotime Borg CR-10 Rating of Perceived Dyspnea During CWR	3 scores on a scale Interval 2.0 to 4.0	2.5 scores on a scale Interval 1.0 to 4.0

SECONDARY outcome

Timeframe: Baseline and day 7 of each treatment period

Borg rating of perceived tiredness on the legs (leg fatigue) were measured on a category-ratio scale from 0 to 10 (CR-10) during constant work rate (CWR) cycling exercise at the time of the shortest duration of each intervention arm (isotime). A lower CR-10 score for leg fatigue at isotime would reflect a beneficial response to the intervention.

Outcome measures

Measure	Stiolto Respimat n=14 Participants Stiolto Respimat inhaler (two actuations, taken once daily for 7 days).	Placebo Respimat n=14 Participants Placebo Respimat inhaler (two actuations, taken once daily for 7 days).
Change From Period Baseline in the Exercise-isotime Borg CR-10 Rating of Perceived Leg Fatigue During CWR	3 scores on a scale Interval 2.0 to 4.0	2.5 scores on a scale Interval 1.0 to 4.0

SECONDARY outcome

Timeframe: Baseline and day 7 of each treatment period

Constant work rate (CWR) exercise causes muscle fatigue (MF) and reduces muscle activation (activation fatigue; AF). The relationship between muscle activity (using EMG) and power is measured at baseline (unfatigued condition). Fatigue is measured by the difference between pre-CWR and post-CWR maximal voluntary isokinetic power i.e. how much maximal voluntary isokinetic power declines during CWR. The fraction of the total fall in voluntary isokinetic power (total fatigue) that is ascribed to reduced muscle activity is then calculated from the reduction in EMG activity. The remainder is ascribed to muscle fatigue (MF) and expressed as a percentage of total fatigue. This measurement was made at peak exercise. A smaller value (%) of MF would be associated with a beneficial response to the intervention.

Outcome measures

Measure	Stiolto Respimat n=14 Participants Stiolto Respimat inhaler (two actuations, taken once daily for 7 days).	Placebo Respimat n=14 Participants Placebo Respimat inhaler (two actuations, taken once daily for 7 days).
Change From Period Baseline in the Pre/Post Exercise-induced Decline in Peak Isokinetic Power Normalized to the Measured Muscle Activity (Muscle Fatigue, MF) During CWR	20.9 percentage of total fatigue Interval 0.0 to 51.9	25.4 percentage of total fatigue Interval 14.0 to 68.41

Adverse Events

Stiolto Respimat

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Placebo Respimat

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Adverse event data not reported

Additional Information

Dr. Harry Rossiter

The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center

Phone: 3102228200

Email: hrossiter@lundquist.org

Results disclosure agreements

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

Restriction type: LTE60