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

• ClinicalTrials.gov Identifier: NCT02867761
• Recruitment Status: Completed
• First Posted: August 16, 2016
• Results First Posted: August 30, 2022
• Last Update Posted: April 13, 2023
• Sponsor: University of Michigan
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): MeiLan Han, University of Michigan

Study Description

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.

Condition or disease	Intervention/treatment	Phase
COPD (Chronic Obstructive Pulmonary Disease)	Drug: Indacaterol/Glycopyrrolate; Drug: Placebo	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 780 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: RETHINC: REdefining THerapy In Early COPD for the Pulmonary Trials Cooperative
• Actual Study Start Date: August 29, 2017
• Actual Primary Completion Date: July 7, 2021
• Actual Study Completion Date: July 7, 2021

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. 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 [ Time Frame: 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 :

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

Eligibility Criteria

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

Criteria

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).

Contacts and Locations

Locations

United States, Alabama

Universityof Alabama

Birmingham, Alabama, United States, 35294

United States, California

University of California

Los Angeles, California, United States, 90095

University of California

San Francisco, California, United States, 94143

LABIOMED at Harbor-UCLA Medical Center

Torrance, California, United States, 90502

United States, Illinois

University of Illinois

Chicago, Illinois, United States, 60608

Northwestern University

Chicago, Illinois, United States, 60657

United States, Iowa

University of Iowa

Iowa City, Iowa, United States, 52242

United States, Maryland

Johns Hopkins University

Baltimore, Maryland, United States, 21224

United States, Michigan

University of Michigan

Ann Arbor, Michigan, United States, 48109

United States, Minnesota

Minneapolis VA Medical Center

Minneapolis, Minnesota, United States, 55417

Minnesota Health partners

Saint Paul, Minnesota, United States, 55130

United States, New York

Cornell University

New York, New York, United States, 10021

United States, North Carolina

Duke University

Durham, North Carolina, United States, 27705

United States, Pennsylvania

Temple University

Philadelphia, Pennsylvania, United States, 19140

University of Pittsburgh

Pittsburgh, Pennsylvania, United States, 15213

United States, Utah

University of Utah

Salt Lake City, Utah, United States, 84132

Sponsors and Collaborators

University of Michigan

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: MeiLan Han, MD, MS; University of Michigan
• Principal Investigator: Prescott Woodruff, MD, MPH; University of California, San Francisco

  Study Documents (Full-Text)

Documents provided by MeiLan Han, University of Michigan:

Study Protocol and Statistical Analysis Plan  [PDF] July 27, 2020

More Information

Additional Information:

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

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Han MK, Ye W, Wang D, White E, Arjomandi M, Barjaktarevic IZ, Brown SA, Buhr RG, Comellas AP, Cooper CB, Criner GJ, Dransfield MT, Drescher F, Folz RJ, Hansel NN, Kalhan R, Kaner RJ, Kanner RE, Krishnan JA, Lazarus SC, Maddipati V, Martinez FJ, Mathews A, Meldrum C, McEvoy C, Nyunoya T, Rogers L, Stringer WW, Wendt CH, Wise RA, Wisniewski SR, Sciurba FC, Woodruff PG; RETHINC Study Group. Bronchodilators in Tobacco-Exposed Persons with Symptoms and Preserved Lung Function. N Engl J Med. 2022 Sep 29;387(13):1173-1184. doi: 10.1056/NEJMoa2204752. Epub 2022 Sep 4.

• Responsible Party: MeiLan Han, Professor, Department of Internal Medicine, University of Michigan
• ClinicalTrials.gov Identifier: NCT02867761
• Other Study ID Numbers: 1U01HL128952-01 ( U.S. NIH Grant/Contract ); 1U01HL128952 ( U.S. NIH Grant/Contract )
• First Posted: August 16, 2016
• Results First Posted: August 30, 2022
• Last Update Posted: April 13, 2023
• Last Verified: April 2023

• 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

Keywords provided by MeiLan Han, University of Michigan:

COPD; Chronic Obstructive Pulmonary Disease; Pulmonary Function Tests; Current Smoker; Former Smoker; Chronic Obstructive Airway Disease; Respiratory Symptoms

Additional relevant MeSH terms:

Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Respiratory Tract Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Glycopyrrolate; Adjuvants, Anesthesia; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs