Clinical trial NCT02867761: RETHINC: REdefining THerapy In Early COPD for the Pulmonary Trials Cooperative
Official title: RETHINC: REdefining THerapy In Early COPD for the Pulmonary Trials Cooperative
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: COPD (Chronic Obstructive Pulmonary Disease)
Keywords: COPD
Chronic Obstructive Pulmonary Disease
Pulmonary Function Tests
Current Smoker
Former Smoker
Chronic Obstructive Airway Disease
Respiratory Symptoms
Lead sponsor: University of Michigan
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2016-08-16
Enrollment: 780
Sex: ALL
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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 Known concomitant lung disease, pulmonary tuberculosis (unless confirmed by chest x-ray to be no longer active), or clinically significant bronchiectasis.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).

Primary outcomes:
measure: 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
timeFrame: Baseline and 12 weeks
Secondary outcomes:
measure: Proportion of Individuals With a 2 Unit Improvement in CAT Without Treatment Failure
timeFrame: 12 weeks
measure: Proportion of Individuals With a 1 Unit Improvement in the BDI/TDI Without Treatment Failure
timeFrame: 12 weeks
measure: Proportion of Individuals With Both a 4 Unit Improvement in SGRQ and a 1 Unit Improvement in BDI/TDI Without Treatment Failure
timeFrame: 12 weeks
measure: Mean Change in St. George's Respiratory Questionnaire (SGRQ)
timeFrame: Baseline, 12 weeks
measure: Mean Change in COPD Assessment Test (CAT)
timeFrame: Baseline, 12 weeks
measure: Mean Change in Baseline Dyspnea Index (BDI)/Transition Dyspnea Index (TDI)
timeFrame: 12 Weeks
measure: Area Under the Curve (AUC) 0-3 Hours for FEV1
timeFrame: At 12 weeks, FEV1 is measured at 1-hour intervals for 3 hours
measure: Change From Baseline in Trough Forced Expiratory Volume Per 1 Second (FEV1) - Absolute Value
timeFrame: Baseline to 12 Weeks
measure: Change From Baseline in 12 Hour Trough Inspiratory Capacity - Absolute Value
timeFrame: Baseline
measure: Symptoms and Rescue Medication Use Based on Daily Diary
timeFrame: During study follow-up (Baseline to 12 weeks)
measure: Treatment Failure Defined by Increase in Lower Respiratory Symptoms Necessitating Treatment With Active, Long-acting Inhaled Bronchodilator, Corticosteroids or Antibiotics
timeFrame: During study follow-up (baseline to 12 Weeks)
measure: Change From Baseline in Trough FEV1 - % Predicted
timeFrame: Baseline to 12 Weeks
measure: Change in FEF25-75%
timeFrame: Baseline to 12 weeks
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Universityof Alabama
state: Alabama
city: Los Angeles
country: United States
facility: University of California
state: California
city: San Francisco
country: United States
facility: University of California
state: California
city: Torrance
country: United States
facility: LABIOMED at Harbor-UCLA Medical Center
state: California
city: Chicago
country: United States
facility: University of Illinois
state: Illinois
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Minneapolis
country: United States
facility: Minneapolis VA Medical Center
state: Minnesota
city: Saint Paul
country: United States
facility: Minnesota Health partners
state: Minnesota
city: New York
country: United States
facility: Cornell University
state: New York
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Philadelphia
country: United States
facility: Temple University
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
Study officials:
affiliation: University of Michigan
name: MeiLan Han, MD, MS
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Francisco
name: Prescott Woodruff, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.