Trial Outcomes & Findings for RETHINC: REdefining THerapy In Early COPD for the Pulmonary Trials Cooperative (NCT NCT02867761)

Results Overview

Measured by units of improvement in SGRQ scores at Baseline and 12 weeks, as well as review of treatment failure status at 4 weeks and 12 weeks of treatment (treatment failure is defined by an increase in lower respiratory symptoms necessitating treatment with active, long-acting inhaled bronchodilator, corticosteroids or antibiotics). A 4 unit change is the minimum clinically important difference. SGRQ has a 0 - 100 score; 0 as low symptoms (feeling better) and 100 as high symptoms (feeling worse).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

780 participants

Primary outcome timeframe

Baseline and 12 weeks

Results posted on

2023-04-13

Participant Flow

Of the 780 consented, 242 were screen fails and 3 dropped out before randomization, so 535 were randomized.

Participant milestones

Participant milestones
Measure	Indacaterol/Glycopyrrolate indacaterol/glycopyrrolate 27.5/15.6 mcg inhaled twice daily for 12 weeks Indacaterol/Glycopyrrolate: 27.5/15.6 mcg active indacaterol/glycopyrrolate	Placebo Placebo 27.5/15.6 mcg inhaled twice daily for 12 weeks Placebo: 27.5/15.6 mcg placebo
Overall Study STARTED	261	274
Overall Study COMPLETED	233	248
Overall Study NOT COMPLETED	28	26

Reasons for withdrawal

Reasons for withdrawal
Measure	Indacaterol/Glycopyrrolate indacaterol/glycopyrrolate 27.5/15.6 mcg inhaled twice daily for 12 weeks Indacaterol/Glycopyrrolate: 27.5/15.6 mcg active indacaterol/glycopyrrolate	Placebo Placebo 27.5/15.6 mcg inhaled twice daily for 12 weeks Placebo: 27.5/15.6 mcg placebo
Overall Study Participant withdrawn by investigator	0	1
Overall Study Lost to Follow-up	25	18
Overall Study Unable to complete protocol	3	7

Baseline Characteristics

RETHINC: REdefining THerapy In Early COPD for the Pulmonary Trials Cooperative

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Indacaterol/Glycopyrrolate n=261 Participants indacaterol/glycopyrrolate 27.5/15.6 mcg inhaled twice daily for 12 weeks Indacaterol/Glycopyrrolate: 27.5/15.6 mcg active indacaterol/glycopyrrolate	Placebo n=274 Participants Placebo 27.5/15.6 mcg inhaled twice daily for 12 weeks Placebo: 27.5/15.6 mcg placebo	Total n=535 Participants Total of all reporting groups
Age, Continuous	58.6 years STANDARD_DEVIATION 9.6 • n=99 Participants	59.1 years STANDARD_DEVIATION 9.8 • n=107 Participants	58.8 years STANDARD_DEVIATION 9.7 • n=206 Participants
Sex: Female, Male Female	134 Participants n=99 Participants	140 Participants n=107 Participants	274 Participants n=206 Participants
Sex: Female, Male Male	127 Participants n=99 Participants	134 Participants n=107 Participants	261 Participants n=206 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	25 Participants n=99 Participants	22 Participants n=107 Participants	47 Participants n=206 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	236 Participants n=99 Participants	252 Participants n=107 Participants	488 Participants n=206 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) American Indian or Alaska Native	2 Participants n=99 Participants	1 Participants n=107 Participants	3 Participants n=206 Participants
Race (NIH/OMB) Asian	1 Participants n=99 Participants	1 Participants n=107 Participants	2 Participants n=206 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=99 Participants	2 Participants n=107 Participants	2 Participants n=206 Participants
Race (NIH/OMB) Black or African American	92 Participants n=99 Participants	99 Participants n=107 Participants	191 Participants n=206 Participants
Race (NIH/OMB) White	148 Participants n=99 Participants	154 Participants n=107 Participants	302 Participants n=206 Participants
Race (NIH/OMB) More than one race	7 Participants n=99 Participants	5 Participants n=107 Participants	12 Participants n=206 Participants
Race (NIH/OMB) Unknown or Not Reported	11 Participants n=99 Participants	12 Participants n=107 Participants	23 Participants n=206 Participants
Region of Enrollment United States	261 participants n=99 Participants	274 participants n=107 Participants	535 participants n=206 Participants
COPD Assessment Test (CAT) Score	17.5 units on a scale STANDARD_DEVIATION 6.7 • n=99 Participants	17.6 units on a scale STANDARD_DEVIATION 6 • n=107 Participants	17.6 units on a scale STANDARD_DEVIATION 6.4 • n=206 Participants
St. George's Respiratory Questionnaire (SGRQ) Score	37.9 units on a scale STANDARD_DEVIATION 21 • n=99 Participants	38.4 units on a scale STANDARD_DEVIATION 19.3 • n=107 Participants	38.2 units on a scale STANDARD_DEVIATION 20.2 • n=206 Participants
Post bronchodilator FEV1 percent predicted	93.8 percent predicted STANDARD_DEVIATION 14.0 • n=99 Participants	94.9 percent predicted STANDARD_DEVIATION 12.6 • n=107 Participants	94.2 percent predicted STANDARD_DEVIATION 13.3 • n=206 Participants

PRIMARY outcome

Timeframe: Baseline and 12 weeks

Population: In the treatment arm, 5 subjects had primary efficacy assessment \>=4 weeks after the last visit that were not included in the mITT (233 - 5 = 228). One additional subject was missing SGRQ at final visit (228 - 1 = 227). In the placebo arm, 5 subjects had primary efficacy assessment \>=4 weeks after the last visit that were not included in the mITT (248 - 5 = 243). An additional person did not complete final visit but had treatment failure so are still included in mITT (243 + 1 = 244).

Measured by units of improvement in SGRQ scores at Baseline and 12 weeks, as well as review of treatment failure status at 4 weeks and 12 weeks of treatment (treatment failure is defined by an increase in lower respiratory symptoms necessitating treatment with active, long-acting inhaled bronchodilator, corticosteroids or antibiotics). A 4 unit change is the minimum clinically important difference. SGRQ has a 0 - 100 score; 0 as low symptoms (feeling better) and 100 as high symptoms (feeling worse).

Outcome measures

Outcome measures
Measure	Indacaterol/Glycopyrrolate n=227 Participants indacaterol/glycopyrrolate 27.5/15.6 mcg inhaled twice daily for 12 weeks Indacaterol/Glycopyrrolate: 27.5/15.6 mcg active indacaterol/glycopyrrolate	Placebo n=244 Participants Placebo 27.5/15.6 mcg inhaled twice daily for 12 weeks Placebo: 27.5/15.6 mcg placebo
Proportion (Percentage) of Individuals Who Experience a 4 Unit Improvement in St. George's Respiratory Questionnaire (SGRQ) at 12 Weeks and do Not Meet Criteria for Treatment Failure During the 12 Week Treatment Period	128 Participants	144 Participants

SECONDARY outcome

Timeframe: 12 weeks

Population: In the treatment arm, 5 subjects had primary efficacy assessment \>=4 weeks after the last visit that were not included in the mITT (233 - 5 = 228). One additional subject was missing SGRQ at final visit (228 - 1 = 227). In the placebo arm, 5 subjects had primary efficacy assessment \>=4 weeks after the last visit that were not included in the mITT (248 - 5 = 243). An additional person did not complete final visit but had treatment failure so are still included in mITT (243 + 1 = 244).

Proportion of individuals with a 2 unit improvement in CAT without treatment failure

Outcome measures

Outcome measures
Measure	Indacaterol/Glycopyrrolate n=227 Participants indacaterol/glycopyrrolate 27.5/15.6 mcg inhaled twice daily for 12 weeks Indacaterol/Glycopyrrolate: 27.5/15.6 mcg active indacaterol/glycopyrrolate	Placebo n=244 Participants Placebo 27.5/15.6 mcg inhaled twice daily for 12 weeks Placebo: 27.5/15.6 mcg placebo
Proportion of Individuals With a 2 Unit Improvement in CAT Without Treatment Failure	169 Participants	166 Participants

SECONDARY outcome

Timeframe: 12 weeks

Population: Not all participants had all measures measured.

Proportion of individuals with a 1 unit improvement in the BDI/TDI without treatment failure

Outcome measures

Outcome measures
Measure	Indacaterol/Glycopyrrolate n=220 Participants indacaterol/glycopyrrolate 27.5/15.6 mcg inhaled twice daily for 12 weeks Indacaterol/Glycopyrrolate: 27.5/15.6 mcg active indacaterol/glycopyrrolate	Placebo n=234 Participants Placebo 27.5/15.6 mcg inhaled twice daily for 12 weeks Placebo: 27.5/15.6 mcg placebo
Proportion of Individuals With a 1 Unit Improvement in the BDI/TDI Without Treatment Failure	80 Participants	80 Participants

SECONDARY outcome

Timeframe: 12 weeks

Population: Not all participants had all measures measured.

Measured by units of improvement in SGRQ scores at Baseline and 12 weeks, as well as review of treatment failure status at 4 weeks and 12 weeks of treatment (treatment failure is defined by an increase in lower respiratory symptoms necessitating treatment with active, long-acting inhaled bronchodilator, corticosteroids or antibiotics).

Outcome measures

Outcome measures
Measure	Indacaterol/Glycopyrrolate n=220 Participants indacaterol/glycopyrrolate 27.5/15.6 mcg inhaled twice daily for 12 weeks Indacaterol/Glycopyrrolate: 27.5/15.6 mcg active indacaterol/glycopyrrolate	Placebo n=234 Participants Placebo 27.5/15.6 mcg inhaled twice daily for 12 weeks Placebo: 27.5/15.6 mcg placebo
Proportion of Individuals With Both a 4 Unit Improvement in SGRQ and a 1 Unit Improvement in BDI/TDI Without Treatment Failure	55 Participants	60 Participants

SECONDARY outcome

Timeframe: Baseline, 12 weeks

Population: In the treatment arm, 5 subjects had primary efficacy assessment \>=4 weeks after the last visit that were not included in the mITT (233 - 5 = 228). One additional subject was missing SGRQ at final visit (228 - 1 = 227). In the placebo arm, 5 subjects had primary efficacy assessment \>=4 weeks after the last visit that were not included in the mITT (248 - 5 = 243). .

Value at 12 Weeks Minus Baseline. SGRQ has a 0 - 100 score; 0 as low symptoms (feeling better) and 100 as high symptoms (feeling worse).

Outcome measures

Outcome measures
Measure	Indacaterol/Glycopyrrolate n=227 Participants indacaterol/glycopyrrolate 27.5/15.6 mcg inhaled twice daily for 12 weeks Indacaterol/Glycopyrrolate: 27.5/15.6 mcg active indacaterol/glycopyrrolate	Placebo n=243 Participants Placebo 27.5/15.6 mcg inhaled twice daily for 12 weeks Placebo: 27.5/15.6 mcg placebo
Mean Change in St. George's Respiratory Questionnaire (SGRQ)	-7.7 score on a scale Interval -9.4 to -5.9	-8.9 score on a scale Interval -10.6 to -7.2

SECONDARY outcome

Timeframe: Baseline, 12 weeks

Population: In the treatment arm, 5 subjects had primary efficacy assessment \>=4 weeks after the last visit that were not included in the mITT (233 - 5 = 228). One additional subject was missing CAT at final visit (228 - 1 = 227). In the placebo arm, 5 subjects had primary efficacy assessment \>=4 weeks after the last visit that were not included in the mITT (248 - 5 = 243).

Value at 12 Weeks Minus Baseline. 0 - 40; 0 as low symptoms (feeling better) and 40 as high symptoms (feeling worse).

Outcome measures

Outcome measures
Measure	Indacaterol/Glycopyrrolate n=227 Participants indacaterol/glycopyrrolate 27.5/15.6 mcg inhaled twice daily for 12 weeks Indacaterol/Glycopyrrolate: 27.5/15.6 mcg active indacaterol/glycopyrrolate	Placebo n=243 Participants Placebo 27.5/15.6 mcg inhaled twice daily for 12 weeks Placebo: 27.5/15.6 mcg placebo
Mean Change in COPD Assessment Test (CAT)	-4.5 score on a scale Interval -5.4 to -3.5	-4.8 score on a scale Interval -5.8 to -3.9

SECONDARY outcome

Timeframe: 12 Weeks

Population: Not all participants had these measures taken.

Value at 12 Weeks Minus Baseline.

Outcome measures

Outcome measures
Measure	Indacaterol/Glycopyrrolate n=219 Participants indacaterol/glycopyrrolate 27.5/15.6 mcg inhaled twice daily for 12 weeks Indacaterol/Glycopyrrolate: 27.5/15.6 mcg active indacaterol/glycopyrrolate	Placebo n=233 Participants Placebo 27.5/15.6 mcg inhaled twice daily for 12 weeks Placebo: 27.5/15.6 mcg placebo
Mean Change in Baseline Dyspnea Index (BDI)/Transition Dyspnea Index (TDI)	0.93 ratio Interval 0.59 to 1.27	0.92 ratio Interval 0.59 to 1.26

SECONDARY outcome

Timeframe: At 12 weeks, FEV1 is measured at 1-hour intervals for 3 hours

Population: Not all persons completed their lung function tests.

FEV1 AUC0-3h was calculated as the area under the FEV1-time curve from 0 to 3h post-dose using the trapezoidal rule, divided by the duration (3h) to report in liters.

Outcome measures

Outcome measures
Measure	Indacaterol/Glycopyrrolate n=175 Participants indacaterol/glycopyrrolate 27.5/15.6 mcg inhaled twice daily for 12 weeks Indacaterol/Glycopyrrolate: 27.5/15.6 mcg active indacaterol/glycopyrrolate	Placebo n=199 Participants Placebo 27.5/15.6 mcg inhaled twice daily for 12 weeks Placebo: 27.5/15.6 mcg placebo
Area Under the Curve (AUC) 0-3 Hours for FEV1	8.09 liters Interval 7.99 to 8.2	7.82 liters Interval 7.72 to 7.92

SECONDARY outcome

Timeframe: Baseline to 12 Weeks

Population: Not all participants had all measures measured.

Trough FEV1 at 12 week minus trough FEV1 at baseline.

Outcome measures

Outcome measures
Measure	Indacaterol/Glycopyrrolate n=198 Participants indacaterol/glycopyrrolate 27.5/15.6 mcg inhaled twice daily for 12 weeks Indacaterol/Glycopyrrolate: 27.5/15.6 mcg active indacaterol/glycopyrrolate	Placebo n=205 Participants Placebo 27.5/15.6 mcg inhaled twice daily for 12 weeks Placebo: 27.5/15.6 mcg placebo
Change From Baseline in Trough Forced Expiratory Volume Per 1 Second (FEV1) - Absolute Value	0.04 Liters Interval 0.01 to 0.08	-0.01 Liters Interval -0.04 to 0.02

SECONDARY outcome

Timeframe: Baseline

Population: Not all participants had all measures measured.

Change from baseline in 12 hour trough inspiratory capacity - absolute value

Outcome measures

Outcome measures
Measure	Indacaterol/Glycopyrrolate n=194 Participants indacaterol/glycopyrrolate 27.5/15.6 mcg inhaled twice daily for 12 weeks Indacaterol/Glycopyrrolate: 27.5/15.6 mcg active indacaterol/glycopyrrolate	Placebo n=203 Participants Placebo 27.5/15.6 mcg inhaled twice daily for 12 weeks Placebo: 27.5/15.6 mcg placebo
Change From Baseline in 12 Hour Trough Inspiratory Capacity - Absolute Value	0.12 Liters Interval 0.07 to 0.18	0.02 Liters Interval -0.03 to 0.08

SECONDARY outcome

Timeframe: During study follow-up (Baseline to 12 weeks)

Population: Not all participants submitted complete diaries.

Percentage of days with symptoms (shortness of breath, chest tightness, wheezing, cough, or sputum) or use of albuterol

Outcome measures

Outcome measures
Measure	Indacaterol/Glycopyrrolate n=198 Participants indacaterol/glycopyrrolate 27.5/15.6 mcg inhaled twice daily for 12 weeks Indacaterol/Glycopyrrolate: 27.5/15.6 mcg active indacaterol/glycopyrrolate	Placebo n=210 Participants Placebo 27.5/15.6 mcg inhaled twice daily for 12 weeks Placebo: 27.5/15.6 mcg placebo
Symptoms and Rescue Medication Use Based on Daily Diary	67.0 percentage of days Interval 59.0 to 75.0	63.6 percentage of days Interval 55.7 to 71.5

SECONDARY outcome

Timeframe: During study follow-up (baseline to 12 Weeks)

Population: In the treatment arm, 5 subjects had primary efficacy assessment \>=4 weeks after the last visit that were not included in the mITT (233 - 5 = 228). One additional subject was missing SGRQ at final visit (228 - 1 = 227). In the placebo arm, 5 subjects had primary efficacy assessment \>=4 weeks after the last visit that were not included in the mITT (248 - 5 = 243). An additional person did not complete final visit but had treatment failure so are still included in mITT (243 + 1 = 244).

Treatment failure defined by increase in lower respiratory symptoms necessitating treatment with active, long-acting inhaled bronchodilator, corticosteroids or antibiotics

Outcome measures

Outcome measures
Measure	Indacaterol/Glycopyrrolate n=227 Participants indacaterol/glycopyrrolate 27.5/15.6 mcg inhaled twice daily for 12 weeks Indacaterol/Glycopyrrolate: 27.5/15.6 mcg active indacaterol/glycopyrrolate	Placebo n=244 Participants Placebo 27.5/15.6 mcg inhaled twice daily for 12 weeks Placebo: 27.5/15.6 mcg placebo
Treatment Failure Defined by Increase in Lower Respiratory Symptoms Necessitating Treatment With Active, Long-acting Inhaled Bronchodilator, Corticosteroids or Antibiotics	5 Participants	9 Participants

SECONDARY outcome

Timeframe: Baseline to 12 Weeks

Population: Not all participants had all measures measured.

Trough FEV1 at 12 week minus trough FEV1 at baseline.

Outcome measures

Outcome measures
Measure	Indacaterol/Glycopyrrolate n=198 Participants indacaterol/glycopyrrolate 27.5/15.6 mcg inhaled twice daily for 12 weeks Indacaterol/Glycopyrrolate: 27.5/15.6 mcg active indacaterol/glycopyrrolate	Placebo n=205 Participants Placebo 27.5/15.6 mcg inhaled twice daily for 12 weeks Placebo: 27.5/15.6 mcg placebo
Change From Baseline in Trough FEV1 - % Predicted	2.48 percentage of predicted number Interval 1.49 to 3.47	-0.09 percentage of predicted number Interval -1.06 to 0.89

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: Not all participants had pulmonary function tests.

FEF25-75%-Forced expiratory flow over the middle one half of the FVC; the average flow from the point at which 25 percent of the FVC has been exhaled to the point at which 75 percent of the FVC has been exhaled.

Outcome measures

Outcome measures
Measure	Indacaterol/Glycopyrrolate n=198 Participants indacaterol/glycopyrrolate 27.5/15.6 mcg inhaled twice daily for 12 weeks Indacaterol/Glycopyrrolate: 27.5/15.6 mcg active indacaterol/glycopyrrolate	Placebo n=205 Participants Placebo 27.5/15.6 mcg inhaled twice daily for 12 weeks Placebo: 27.5/15.6 mcg placebo
Change in FEF25-75%	0.07 Liters per second Interval 0.0 to 0.15	-0.08 Liters per second Interval -0.15 to 0.0

Adverse Events

Indacaterol/Glycopyrrolate

Serious events: 4 serious events

Other events: 0 other events

Deaths: 0 deaths

Placebo

Serious events: 8 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Adverse event data not reported

Additional Information

Meilan K. Han

University of Michigan

Phone: 734 615-9772

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Indacaterol/Glycopyrrolate n=261 participants at risk indacaterol/glycopyrrolate 27.5/15.6 mcg inhaled twice daily for 12 weeks Indacaterol/Glycopyrrolate: 27.5/15.6 mcg active indacaterol/glycopyrrolate	Placebo n=274 participants at risk Placebo 27.5/15.6 mcg inhaled twice daily for 12 weeks Placebo: 27.5/15.6 mcg placebo
Musculoskeletal and connective tissue disorders Motor Vehicle Accident	0.38% 1/261 • During the trial, approximately 12 weeks.	0.36% 1/274 • During the trial, approximately 12 weeks.
Gastrointestinal disorders Abdominal Pain	0.38% 1/261 • During the trial, approximately 12 weeks.	0.36% 1/274 • During the trial, approximately 12 weeks.
Gastrointestinal disorders Anastomotic Ulcer	0.38% 1/261 • During the trial, approximately 12 weeks.	0.00% 0/274 • During the trial, approximately 12 weeks.
Psychiatric disorders Breakthrough Seizures	0.38% 1/261 • During the trial, approximately 12 weeks.	0.00% 0/274 • During the trial, approximately 12 weeks.
Gastrointestinal disorders Gastric GJ junction ulcer and posterior wall perforation	0.38% 1/261 • During the trial, approximately 12 weeks.	0.00% 0/274 • During the trial, approximately 12 weeks.
Gastrointestinal disorders Postprocedural Intraabdominal Abscess	0.38% 1/261 • During the trial, approximately 12 weeks.	0.00% 0/274 • During the trial, approximately 12 weeks.
Cardiac disorders Chest Pain	0.38% 1/261 • During the trial, approximately 12 weeks.	0.00% 0/274 • During the trial, approximately 12 weeks.
Gastrointestinal disorders Sigmoid diverticulitis with small abscess	0.00% 0/261 • During the trial, approximately 12 weeks.	0.36% 1/274 • During the trial, approximately 12 weeks.
Psychiatric disorders Suicide Attempt	0.38% 1/261 • During the trial, approximately 12 weeks.	0.00% 0/274 • During the trial, approximately 12 weeks.
Gastrointestinal disorders Diarrhea	0.38% 1/261 • During the trial, approximately 12 weeks.	0.00% 0/274 • During the trial, approximately 12 weeks.
Respiratory, thoracic and mediastinal disorders Respiratory Exacerbation	0.00% 0/261 • During the trial, approximately 12 weeks.	0.36% 1/274 • During the trial, approximately 12 weeks.
Psychiatric disorders Uncontrolled hypertension	0.00% 0/261 • During the trial, approximately 12 weeks.	0.36% 1/274 • During the trial, approximately 12 weeks.
Gastrointestinal disorders Acute Cholecystitis	0.38% 1/261 • During the trial, approximately 12 weeks.	0.00% 0/274 • During the trial, approximately 12 weeks.
Psychiatric disorders Vitamin B12 Deficiency	0.00% 0/261 • During the trial, approximately 12 weeks.	0.36% 1/274 • During the trial, approximately 12 weeks.
Gastrointestinal disorders Acute Pancreatitis	0.00% 0/261 • During the trial, approximately 12 weeks.	0.36% 1/274 • During the trial, approximately 12 weeks.
Gastrointestinal disorders Portal Hypertension	0.00% 0/261 • During the trial, approximately 12 weeks.	0.36% 1/274 • During the trial, approximately 12 weeks.
Respiratory, thoracic and mediastinal disorders Community Acquired Pneumonia	0.00% 0/261 • During the trial, approximately 12 weeks.	0.36% 1/274 • During the trial, approximately 12 weeks.
Musculoskeletal and connective tissue disorders Non-displaced Fibular Fracture	0.00% 0/261 • During the trial, approximately 12 weeks.	0.36% 1/274 • During the trial, approximately 12 weeks.
Renal and urinary disorders Kidney stone with obstruction	0.00% 0/261 • During the trial, approximately 12 weeks.	0.36% 1/274 • During the trial, approximately 12 weeks.