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

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.

Study Overview

• Status: Completed
• Conditions: COPD (Chronic Obstructive Pulmonary Disease)
• Intervention / Treatment: Drug: Indacaterol/Glycopyrrolate; Drug: Placebo

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 Type: Interventional
• Enrollment (Actual): 780
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Universityof Alabama
  • California
    • Los Angeles, California, United States, 90095
      • University of California
    • San Francisco, California, United States, 94143
      • University of California
    • Torrance, California, United States, 90502
      • LABIOMED at Harbor-UCLA Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60657
      • Northwestern University
    • Chicago, Illinois, United States, 60608
      • University of Illinois
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • Johns Hopkins University
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • Minnesota
    • Minneapolis, Minnesota, United States, 55417
      • Minneapolis VA Medical Center
    • Saint Paul, Minnesota, United States, 55130
      • Minnesota Health partners
  • New York
    • New York, New York, United States, 10021
      • Cornell University
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Indacaterol/Glycopyrrolate; indacaterol/glycopyrrolate 27.5/15.6 mcg inhaled twice daily for 12 weeks	Drug: Indacaterol/Glycopyrrolate; 27.5/15.6 mcg active indacaterol/glycopyrrolate
Placebo Comparator: Placebo; Placebo 27.5/15.6 mcg inhaled twice daily for 12 weeks	Drug: Placebo; 27.5/15.6 mcg placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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).	Baseline and 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Individuals With a 2 Unit Improvement in CAT Without Treatment Failure	Proportion of individuals with a 2 unit improvement in CAT without treatment failure	12 weeks
Proportion of Individuals With a 1 Unit Improvement in the BDI/TDI Without Treatment Failure	Proportion of individuals with a 1 unit improvement in the BDI/TDI without treatment failure	12 weeks
Proportion of Individuals With Both a 4 Unit Improvement in SGRQ and a 1 Unit Improvement in BDI/TDI Without Treatment Failure	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).	12 weeks
Mean Change in St. George's Respiratory Questionnaire (SGRQ)	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).	Baseline, 12 weeks
Mean Change in COPD Assessment Test (CAT)	Value at 12 Weeks Minus Baseline. 0 - 40; 0 as low symptoms (feeling better) and 40 as high symptoms (feeling worse).	Baseline, 12 weeks
Mean Change in Baseline Dyspnea Index (BDI)/Transition Dyspnea Index (TDI)	Value at 12 Weeks Minus Baseline.	12 Weeks
Area Under the Curve (AUC) 0-3 Hours for FEV1	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.	At 12 weeks, FEV1 is measured at 1-hour intervals for 3 hours
Change From Baseline in Trough Forced Expiratory Volume Per 1 Second (FEV1) - Absolute Value	Trough FEV1 at 12 week minus trough FEV1 at baseline.	Baseline to 12 Weeks
Change From Baseline in 12 Hour Trough Inspiratory Capacity - Absolute Value	Change from baseline in 12 hour trough inspiratory capacity - absolute value	Baseline
Symptoms and Rescue Medication Use Based on Daily Diary	Percentage of days with symptoms (shortness of breath, chest tightness, wheezing, cough, or sputum) or use of albuterol	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	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)
Change From Baseline in Trough FEV1 - % Predicted	Trough FEV1 at 12 week minus trough FEV1 at baseline.	Baseline to 12 Weeks
Change in FEF25-75%	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.	Baseline to 12 weeks

Collaborators and Investigators

• Sponsor: University of Michigan
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)

Publications and helpful links

General Publications

• Souto LR, Serrao PRMDS, Pisani GK, Tessarin BM, da Silva HF, Machado EM, de Oliveira Sato T, Serrao FV. Immediate effects of hip strap and foot orthoses on self-reported measures and lower limb kinematics during functional tasks in individuals with patellofemoral osteoarthritis: protocol for a randomised crossover clinical trial. Trials. 2022 Sep 5;23(1):746. doi: 10.1186/s13063-022-06676-0.

Helpful Links

• Pulmonary Trials Cooperative website, containing information regarding RETHINC and other studies included in the Pulmonary Trials Cooperative

Study record dates

Study Major Dates

• Study Start (Actual): August 29, 2017
• Primary Completion (Actual): July 7, 2021
• Study Completion (Actual): July 7, 2021

Study Registration Dates

• First Submitted: August 12, 2016
• First Submitted That Met QC Criteria: August 12, 2016
• First Posted (Estimate): August 16, 2016

Study Record Updates

• Last Update Posted (Actual): April 13, 2023
• Last Update Submitted That Met QC Criteria: April 11, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: COPD; Chronic Obstructive Pulmonary Disease; Current Smoker; Former Smoker; Pulmonary Function Tests; Chronic Obstructive Airway Disease; Respiratory Symptoms
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Adjuvants, Anesthesia; Glycopyrrolate
• Other Study ID Numbers: 1U01HL128952-01 (U.S. NIH Grant/Contract); 1U01HL128952 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No