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

Tracking Information

• First Submitted Date: August 12, 2016
• First Posted Date: August 16, 2016
• Results First Submitted Date: July 7, 2022
• Results First Posted Date: August 30, 2022
• Last Update Posted Date: April 13, 2023
• Actual Study Start Date: August 29, 2017
• Actual Primary Completion Date: July 7, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 8, 2022)

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).

Original Primary Outcome Measures (submitted: August 12, 2016)

Proportion of individuals who experience a 4 unit improvement in 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).

Current Secondary Outcome Measures (submitted: August 8, 2022)

• 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
• 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
• 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).
• 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).
• 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).
• Mean Change in Baseline Dyspnea Index (BDI)/Transition Dyspnea Index (TDI) [ Time Frame: 12 Weeks ]
  Value at 12 Weeks Minus Baseline.
• 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.
• 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.
• 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
• 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
• 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
• Change From Baseline in Trough FEV1 - % Predicted [ Time Frame: Baseline to 12 Weeks ]
  Trough FEV1 at 12 week minus trough FEV1 at baseline.
• 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.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: RETHINC: REdefining THerapy In Early COPD for the Pulmonary Trials Cooperative
• Official Title: RETHINC: REdefining THerapy In Early COPD for the Pulmonary Trials Cooperative
• 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 Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: COPD (Chronic Obstructive Pulmonary Disease)

Intervention

• Drug: Indacaterol/Glycopyrrolate
  27.5/15.6 mcg active indacaterol/glycopyrrolate
• Drug: Placebo
  27.5/15.6 mcg placebo

Study Arms

• Active Comparator: Indacaterol/Glycopyrrolate
  indacaterol/glycopyrrolate 27.5/15.6 mcg inhaled twice daily for 12 weeks
  Intervention: Drug: Indacaterol/Glycopyrrolate
• Placebo Comparator: Placebo
  Placebo 27.5/15.6 mcg inhaled twice daily for 12 weeks
  Intervention: Drug: Placebo

• Publications *: 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 7, 2022): 780
• Original Estimated Enrollment (submitted: August 12, 2016): 580
• Actual Study Completion Date: July 7, 2021
• Actual Primary Completion Date: July 7, 2021 (Final data collection date for primary outcome measure)

Eligibility 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).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 40 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02867761
• Other Study ID Numbers: 1U01HL128952-01( U.S. NIH Grant/Contract ); 1U01HL128952 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

• IPD Sharing Statement: Not Provided
• Current Responsible Party: MeiLan Han, University of Michigan
• Original Responsible Party: MeiLan Han, University of Michigan, Associate Professor, Department of Internal Medicine
• Current Study Sponsor: University of Michigan
• Original Study Sponsor: Same as current
• Collaborators: 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

• PRS Account: University of Michigan
• Verification Date: April 2023