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

Phase 3

Completed

• Conditions: COPD (Chronic Obstructive Pulmonary Disease)
• Interventions: Drug: Indacaterol/Glycopyrrolate; Drug: Placebo

• Registration Number: NCT02867761
• Lead Sponsor: University of Michigan

Brief Summary

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.

Detailed Description

RETHINC is a 12-week multicenter, randomized, double-blind, placebo-controlled, parallel-group study to assess the efficacy and safety of indacaterol/glycopyrrolate 27.5/15.6 mcg inhaled twice daily in symptomatic current and former smokers with respiratory symptoms despite preserved spirometry as defined by CAT ≥ 10 and post-bronchodilator FEV1/FVC ratio ≥0.70, respectively.

Study Timeline

• Study First Submitted: 2016-08-12
• Study First Submitted QC: 2016-08-12
• Study First Posted: 2016-08-16
• Study Start: 2017-08-29
• Primary Completion: 2021-07-07
• Study Completion: 2021-07-07
• Results First Submitted: 2022-07-07
• Results First Submitted QC: 2022-08-08
• Results First Posted: 2022-08-30
• Status Verified: 2023-04
• Last Update Submitted: 2023-04-11
• Last Update Posted: 2023-04-13

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 780

Inclusion Criteria

1. Subject must be able to understand and provide informed consent
2. Age 40-80
3. ≥10 pack-year smoking history
4. Post-bronchodilator FEV1/FVC ratio ≥0.70
5. Baseline CAT≥10

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Exclusion Criteria

1. Inability or unwillingness of a participant to give written informed consent or comply with study protocol.
2. Subject is pregnant, breast-feeding, or plans to become pregnant.
3. Active pulmonary infection or prior pulmonary infection where antibiotic and/or steroid treatment was completed ≤4 weeks prior to enrollment.
4. Post-BD FVC < 70% predicted
5. A primary diagnosis of asthma established by each study investigator based on ATS/ERS criteria as previously implemented in the MACRO clinical trial.
6. Known concomitant lung disease, pulmonary tuberculosis (unless confirmed by chest x-ray to be no longer active), or clinically significant bronchiectasis.
7. History (or family history) of long QT syndrome.
8. History of paroxysmal (intermittent) atrial fibrillation will be considered an exclusion. Patients with persistent atrial fibrillation as defined by continuous atrial fibrillation for at least 6 months and controlled with a rate control strategy (i.e., selective beta blocker, calcium channel blocker, pacemaker placement, digoxin or ablation therapy) for at least 6 months may be considered for inclusion. In such patients, heart rate at enrollment must be < 100/min.
9. Patients with BMI < 15 or more than 40 kg/m2.
10. Patients with diabetes Type I or uncontrolled diabetes Type II.
11. Patients who, in the judgment of the investigator, have a clinically relevant laboratory abnormality or a clinically significant condition such as (but not limited to) significant renal disease, psychiatric disease, gastrointestinal disease, unstable ischemic heart disease, arrhythmia (excluding chronic stable atrial fibrillation), uncontrolled hypertension or any other condition which in the opinion of investigator might compromise patient safety or compliance, interfere with evaluation, or preclude completion of the study.
12. Patients with any history of lung cancer.
13. Patients with narrow-angle glaucoma, symptomatic benign prostatic hyperplasia or bladder-neck obstruction or severe renal impairment or urinary retention. Benign Prostatic Hyperplasia (BPH) patients who are stable on treatment can be considered.
14. Any other past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study.
15. Patients with a history of hypersensitivity to any of the study drugs or to drugs from similar chemical classification, including untoward reactions to sympathomimetic amines or inhaled medication or any component thereof.
16. Patients unable to successfully use a dry powder inhaler device or perform spirometry measurements.
17. Use of other investigational drugs at the time of enrollment or within 30 days or 5 half-lives of enrollment, whichever is longer.
18. Patients receiving any protocol-specified prohibited medications..
19. Patients receiving any protocol-specified prohibited COPD related medications (will be required to undergo a required washout period prior to enrollment).

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Indacaterol/Glycopyrrolate	Indacaterol/Glycopyrrolate	indacaterol/glycopyrrolate 27.5/15.6 mcg inhaled twice daily for 12 weeks
Placebo	Placebo	Placebo 27.5/15.6 mcg inhaled twice daily for 12 weeks

Primary Outcome Measures

Name	Time	Method
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	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).

Secondary Outcome Measures

Name	Time	Method
Mean Change in Baseline Dyspnea Index (BDI)/Transition Dyspnea Index (TDI)	12 Weeks	Value at 12 Weeks Minus Baseline.
Symptoms and Rescue Medication Use Based on Daily Diary	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
Change in FEF25-75%	Baseline to 12 weeks	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.
Proportion of Individuals With a 2 Unit Improvement in CAT Without Treatment Failure	12 weeks	Proportion of individuals with a 2 unit improvement in CAT without treatment failure
Proportion of Individuals With a 1 Unit Improvement in the BDI/TDI Without Treatment Failure	12 weeks	Proportion of individuals with a 1 unit improvement in the BDI/TDI without treatment failure
Proportion of Individuals With Both a 4 Unit Improvement in SGRQ and a 1 Unit Improvement in BDI/TDI Without Treatment Failure	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).
Mean Change in COPD Assessment Test (CAT)	Baseline, 12 weeks	Value at 12 Weeks Minus Baseline. 0 - 40; 0 as low symptoms (feeling better) and 40 as high symptoms (feeling worse).
Change From Baseline in Trough Forced Expiratory Volume Per 1 Second (FEV1) - Absolute Value	Baseline to 12 Weeks	Trough FEV1 at 12 week minus trough FEV1 at baseline.
Change From Baseline in Trough FEV1 - % Predicted	Baseline to 12 Weeks	Trough FEV1 at 12 week minus trough FEV1 at baseline.
Mean Change in St. George's Respiratory Questionnaire (SGRQ)	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).
Area Under the Curve (AUC) 0-3 Hours for FEV1	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.
Change From Baseline in 12 Hour Trough Inspiratory Capacity - Absolute Value	Baseline	Change from baseline in 12 hour trough inspiratory capacity - absolute value
Treatment Failure Defined by Increase in Lower Respiratory Symptoms Necessitating Treatment With Active, Long-acting Inhaled Bronchodilator, Corticosteroids or Antibiotics	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

Trial Locations

Locations (15)

Universityof Alabama; 🇺🇸 Birmingham, Alabama, United States

LABIOMED at Harbor-UCLA Medical Center; 🇺🇸 Torrance, California, United States

University of California; 🇺🇸 San Francisco, California, United States

University of Illinois; 🇺🇸 Chicago, Illinois, United States

Northwestern University; 🇺🇸 Chicago, Illinois, United States

University of Iowa; 🇺🇸 Iowa City, Iowa, United States

Johns Hopkins University; 🇺🇸 Baltimore, Maryland, United States

University of Michigan; 🇺🇸 Ann Arbor, Michigan, United States

Minneapolis VA Medical Center; 🇺🇸 Minneapolis, Minnesota, United States

Minnesota Health partners; 🇺🇸 Saint Paul, Minnesota, United States

Cornell University; 🇺🇸 New York, New York, United States

Duke University; 🇺🇸 Durham, North Carolina, United States

Temple University; 🇺🇸 Philadelphia, Pennsylvania, United States

University of Pittsburgh; 🇺🇸 Pittsburgh, Pennsylvania, United States

University of Utah; 🇺🇸 Salt Lake City, Utah, United States