NCT02867761: RETHINC

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

Completed Phase 3 Results posted Last updated 13 April 2023

What this trial tests

Phase 3 trial testing Indacaterol/Glycopyrrolate in COPD (Chronic Obstructive Pulmonary Disease) in 780 participants. Completed in 7 July 2021.

Timeline

29 August 2017

Primary endpoint
7 July 2021

7 July 2021

Quick facts

Lead sponsor	University of Michigan
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	780
Start date	29 August 2017
Primary completion	7 July 2021
Estimated completion	7 July 2021
Sites	16 locations across United States

Drugs / interventions tested

• Indacaterol/Glycopyrrolate — full drug profile →
• Placebo

Conditions studied

• COPD (Chronic Obstructive Pulmonary Disease) — all drugs for COPD (Chronic Obstructive Pulmonary Disease) →

Sponsor

University of Michigan

Who can join

Adults 40 to 80, any sex, with COPD (Chronic Obstructive Pulmonary Disease). Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

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 Primary · Baseline and 12 weeks

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).

Group	Value	95% CI
Indacaterol/Glycopyrrolate	128
Placebo	144

Proportion of Individuals With a 2 Unit Improvement in CAT Without Treatment Failure Secondary · 12 weeks

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

Group	Value	95% CI
Indacaterol/Glycopyrrolate	169
Placebo	166

Proportion of Individuals With a 1 Unit Improvement in the BDI/TDI Without Treatment Failure Secondary · 12 weeks

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

Group	Value	95% CI
Indacaterol/Glycopyrrolate	80
Placebo	80

Proportion of Individuals With Both a 4 Unit Improvement in SGRQ and a 1 Unit Improvement in BDI/TDI Without Treatment Failure Secondary · 12 weeks

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).

Group	Value	95% CI
Indacaterol/Glycopyrrolate	55
Placebo	60

Mean Change in St. George's Respiratory Questionnaire (SGRQ) Secondary · Baseline, 12 weeks

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).

Group	Value	95% CI
Indacaterol/Glycopyrrolate	-7.7	-9.4 – -5.9
Placebo	-8.9	-10.6 – -7.2

Mean Change in COPD Assessment Test (CAT) Secondary · Baseline, 12 weeks

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

Group	Value	95% CI
Indacaterol/Glycopyrrolate	-4.5	-5.4 – -3.5
Placebo	-4.8	-5.8 – -3.9

Mean Change in Baseline Dyspnea Index (BDI)/Transition Dyspnea Index (TDI) Secondary · 12 Weeks

Value at 12 Weeks Minus Baseline.

Group	Value	95% CI
Indacaterol/Glycopyrrolate	0.93	0.59 – 1.27
Placebo	0.92	0.59 – 1.26

Area Under the Curve (AUC) 0-3 Hours for FEV1 Secondary · At 12 weeks, FEV1 is measured at 1-hour intervals for 3 hours

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.

Group	Value	95% CI
Indacaterol/Glycopyrrolate	8.09	7.99 – 8.20
Placebo	7.82	7.72 – 7.92

Change From Baseline in Trough Forced Expiratory Volume Per 1 Second (FEV1) - Absolute Value Secondary · Baseline to 12 Weeks

Trough FEV1 at 12 week minus trough FEV1 at baseline.

Group	Value	95% CI
Indacaterol/Glycopyrrolate	0.04	0.01 – 0.08
Placebo	-0.01	-0.04 – 0.02

Change From Baseline in 12 Hour Trough Inspiratory Capacity - Absolute Value Secondary · Baseline

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

Group	Value	95% CI
Indacaterol/Glycopyrrolate	0.12	0.07 – 0.18
Placebo	0.02	-0.03 – 0.08

Symptoms and Rescue Medication Use Based on Daily Diary Secondary · During study follow-up (Baseline to 12 weeks)

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

Group	Value	95% CI
Indacaterol/Glycopyrrolate	67.0	59.0 – 75.0
Placebo	63.6	55.7 – 71.5

Treatment Failure Defined by Increase in Lower Respiratory Symptoms Necessitating Treatment With Active, Long-acting Inhaled Bronchodilator, Corticosteroids or Antibiotics Secondary · During study follow-up (baseline to 12 Weeks)

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

Group	Value	95% CI
Indacaterol/Glycopyrrolate	5
Placebo	9

Adverse events — posted to ClinicalTrials.gov

Time frame: During the trial, approximately 12 weeks.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Indacaterol/Glycopyrrolate

Serious: 4/261 (2%)

Deaths: 0/261

Placebo

Serious: 8/274 (3%)

Deaths: 0/274

Serious adverse events (19 terms)

Reaction	System	Indacaterol/Glycopyrrolate	Placebo
Motor Vehicle Accident	Musculoskeletal and connective tissue disorders	—	—
Abdominal Pain	Gastrointestinal disorders	—	—
Anastomotic Ulcer	Gastrointestinal disorders	—	—
Breakthrough Seizures	Psychiatric disorders	—	—
Gastric GJ junction ulcer and posterior wall perforation	Gastrointestinal disorders	—	—
Postprocedural Intraabdominal Abscess	Gastrointestinal disorders	—	—
Chest Pain	Cardiac disorders	—	—
Sigmoid diverticulitis with small abscess	Gastrointestinal disorders	—	—
Suicide Attempt	Psychiatric disorders	—	—
Diarrhea	Gastrointestinal disorders	—	—
Respiratory Exacerbation	Respiratory, thoracic and mediastinal disorders	—	—
Uncontrolled hypertension	Psychiatric disorders	—	—
Acute Cholecystitis	Gastrointestinal disorders	—	—
Vitamin B12 Deficiency	Psychiatric disorders	—	—
Acute Pancreatitis	Gastrointestinal disorders	—	—
Portal Hypertension	Gastrointestinal disorders	—	—
Community Acquired Pneumonia	Respiratory, thoracic and mediastinal disorders	—	—
Non-displaced Fibular Fracture	Musculoskeletal and connective tissue disorders	—	—
Kidney stone with obstruction	Renal and urinary disorders	—	—

Most-reported serious reactions: Motor Vehicle Accident, Abdominal Pain, Anastomotic Ulcer, Breakthrough Seizures, Gastric GJ junction ulcer and posterior wall perforation, Postprocedural Intraabdominal Abscess, Chest Pain, Sigmoid diverticulitis with small abscess.

Data from ClinicalTrials.gov NCT02867761 adverse events section.

Sponsor's own description

The study hypothesis is that symptomatic current and former smokers with spirometric values within the normal range (post-bronchodilator FEV1/FVC≥0.70 and post-BD FVC ≥ 70% predicted will still derive symptomatic benefit from long-acting bronchodilator therapy even though they are excluded from current GOLD guideline recommendations.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Advances in Chronic Obstructive Pulmonary Disease.
   Ferrera MC, Labaki WW, Han MK. · · 2021 · cited 110× · PMID 33502902 · DOI 10.1146/annurev-med-080919-112707
2. Bronchodilators in Tobacco-Exposed Persons with Symptoms and Preserved Lung Function.
   Han MK, Ye W, Wang D, White E, et al · · 2022 · cited 75× · PMID 36066078 · DOI 10.1056/nejmoa2204752
3. Pectoralis muscle area and mortality in smokers without airflow obstruction.
   Diaz AA, Martinez CH, Harmouche R, Young TP, et al · · 2018 · cited 50× · PMID 29636050 · DOI 10.1186/s12931-018-0771-6
4. Improving Detection of Early Chronic Obstructive Pulmonary Disease.
   Labaki WW, Han MK. · · 2018 · cited 33× · PMID 30759006 · DOI 10.1513/annalsats.201808-529mg
5. Diagnosis and Treatment of Early Chronic Obstructive Lung Disease (COPD).
   Choi JY, Rhee CK. · · 2020 · cited 32× · PMID 33114502 · DOI 10.3390/jcm9113426
6. Early diagnosis of COPD: myth or a true perspective.
   Laucho-Contreras ME, Cohen-Todd M. · · 2020 · cited 19× · PMID 33268437 · DOI 10.1183/16000617.0131-2020
7. Design and rationale of a multi-center, pragmatic, open-label randomized trial of antimicrobial therapy - the study of clinical efficacy of antimicrobial therapy strategy using pragmatic design in Idiopathic Pulmonary Fibrosis (CleanUP-IPF) clinical trial.
   Anstrom KJ, Noth I, Flaherty KR, Edwards RH, et al · · 2020 · cited 19× · PMID 32164673 · DOI 10.1186/s12931-020-1326-1
8. Rethinking Chronic Obstructive Pulmonary Disease. Chronic Pulmonary Insufficiency and Combined Cardiopulmonary Insufficiency.
   Barr RG. · · 2018 · cited 11× · PMID 29461894 · DOI 10.1513/annalsats.201708-667kv