The ENERGITO® 2 Study Compares 2 Inhaled Medicines for Chronic Obstructive Pulmonary Disease (COPD). One Medicine is a Combination of Tiotropium and Olodaterol (Stiolto®) Taken Using the Respimat® Inhaler and the Other Medicine is a Combination of Fluticasone and Salmeterol Taken Using the Diskus

• Tiotropium (Drug), also known as INSPIOLTO, SPIOLTO, STIOLTO, VAHELVA, YANIMO: Fixed Dose Combination
• Olodaterol (Drug), also known as INSPIOLTO, SPIOLTO, STIOLTO, VAHELVA, YANIMO: Fixed Dose Combination
• Fluticasone propionate (Drug): Fixed Dose Combination
• Salmeterol (Drug): Fixed Dose Combination

Primary outcomes

• Forced Expiratory Volume in One Second (FEV1) Area Under the Curve From 0 to 24 Hours (AUC0-24) Response (Change From Baseline) [L] After 12 Weeks of Treatment [1 hours (h) and 10 minutes (min) before first dose at day1 of weeks 1 for baseline.10 min before and 30 min, 1 h, 2h, 3h, 4h, 6h, 8h, 10h, 11h 50min, 12h 30 min, 13h, 14h, 22h, 23h, and 24h post morning dose at week 12.]: Forced Expiratory Volume in one second (FEV1) Area under the Curve from 0 to 24 hours (AUC0-24) response (change from baseline) \[L\] after 12 weeks of treatment. FEV1 AUC0-24 was calculated as the area under the FEV1-time curve from 0-24 hours post-dose using the trapezoidal rule, divided by the duration (24 hours) and reported in liters. FEV1 AUC0-24 response (change from baseline) was defined as FEV1 AUC0-24 mius baseline FEV1.

Secondary outcomes

• Forced Expiratory Volume in One Second (FEV1) Area Under the Curve From 0 to 12 Hours (AUC0-12) Response (Change From Baseline) [L] After 12 Weeks of Treatment [1 hours (h) and 10 minutes (min) before first dose at day1 of weeks 1 for baseline. 10 min before and 30 min, 1 h, 2h, 3h, 4h, 6h, 8h, 10h, 11h 50min post morning dose at week 12.]: Forced Expiratory Volume in one second (FEV1) Area under the Curve from 0 to 12 hours (AUC0-12) response (change from baseline) \[L\] after 12 weeks of treatment. FEV1 AUC0-12 was calculated as the area under the FEV1-time curve from 0-12 hours post-dose using the trapezoidal rule, divided by the duration (12 hours) and reported in liters. FEV1 AUC0-12 response (change from baseline) was defined as FEV1 AUC0-12 minus baseline FEV1.
• Trough Forced Expiratory Volume in One Second (FEV1) Response (Change From Baseline) [L] After 12 Weeks Treatment [At 23 h and 24 h post dose at baseline and at 23h and 24 h post dose at week 12.]: Trough Forced Expiratory Volume in one second (FEV1) response (change from baseline) \[L\] after 12 weeks treatment. Trough FEV1 was defined as the mean of the FEV1 value measured at 23 hours and at 24 hours after the trial medication administration. Through FEV1 response (change from baseline) was defined as trough FEV1 minus baseline FEV1.
• Peak 0-3 Hours Forced Expiratory Volume in One Second (FEV1) Response (Change From Baseline) [L] After 12 Weeks Treatment [30 minutes, 1 h, 2h and 3h post dose at baseline and week 12.]: Peak 0-3 hours Forced Expiratory Volume in one second (FEV1) response (change from baseline) \[L\] after 12 weeks treatment. Peak 0-3h was defined as the maximum value measured within the first three hours post doing.

Sex: All, ages: 40 Years to any

Inclusion Criteria:

* All patients must sign an informed consent consistent with FDA regulations prior to participation in the trial, which includes medication washout and restrictions.
* All patients must have a diagnosis of chronic obstructive pulmonary disease and must meet the following spirometric criteria:

  \-- Patients with a post-bronchodilator 30% ≤ Forced Expiratory Volume in one second (FEV1) <80% of predicted normal (European Coal and Steel Community( ECSC)); and a post-bronchodilator FEV1/Forced Vital Capacity (FVC) <70% at Visit 1
* Male or female patients, 40 years of age or older.
* Patients must be current or ex-smokers with a smoking history of more than 10 pack years. Patients who have never smoked cigarettes must be excluded.
* Patients must be able to perform, according to investigator's judgment, all trial related procedures including:

  * Technically acceptable pulmonary function tests (spirometry)
  * Completion of study questionnaires
* Patients must be able to inhale medication in a competent manner (in the opinion of the investigator) from the Respimat® and Diskus® inhalers and from a metered dose inhaler (MDI).

Exclusion Criteria:

* Patients with a significant disease other than Chronic Obstructive Pulmonary Disease (COPD); a significant disease is defined as a disease which, in the opinion of the investigator, may (i) put the patient at risk because of participation in the study, (ii) influence the results of the study, or (iii) cause concern regarding the patient's ability to participate in the study.
* Patients who have had a COPD exacerbation that required treatment with antibiotics, systemic steroids (oral or intravenous) or hospitalization in the last 3 months prior to Visit 1 and/or between Visit 1 and Visit 2.
* Patients with a history of asthma. For patients with allergic rhinitis or atopy, source documentation is required to verify that the patient does not have asthma. If a patient has a total blood eosinophil count ≥ 600/mm3, source documentation is required to verify that the increased eosinophil count is related to a nonasthmatic condition.

Patients with any of the following conditions:

* A diagnosis of thyrotoxicosis (due to the known class side effect profile of ß2-agonists).
* A diagnosis of paroxysmal tachycardia (>100 beats per minute) (due to the known class side effect profile of ß2-agonists).
* A history of myocardial infarction within 1 year of screening visit (Visit 1).
* Unstable or life-threatening cardiac arrhythmia.
* Hospitalization for heart failure within the past year.
* Known active tuberculosis.
* A malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years (patients with treated basal cell carcinoma are allowed).
* A history of life-threatening pulmonary obstruction.
* A history of cystic fibrosis.
* Clinically evident bronchiectasis.
* A history of significant alcohol or drug abuse.
* Patients who have undergone thoracotomy with pulmonary resection (patients with a history of thoracotomy for other reasons should be evaluated as per the first exclusion criterion).
* Patients being treated with oral or patch β-adrenergics.
* Patients being treated with oral corticosteroid medication within 6 weeks prior to Visit 1.
* Patients who regularly use daytime oxygen therapy for more than one hour per day and in the investigator's opinion will be unable to abstain from the use of oxygen therapy during clinic visits.
* Patients who have completed a pulmonary rehabilitation program in the six weeks prior to the screening visit (Visit 1) or patients who are currently in a pulmonary rehabilitation program.
* Patients who have taken an investigational drug within one month, six half-lives or within the wash out period (whichever is greater) prior to screening visit (Visit 1).
* Patients with known hypersensitivity to β-adrenergic drugs, BAC, EDTA, or any other component of the Respimat® inhalation solution. In addition, patients with known hypersensitivity to Lactose monohydrate (which contains milk proteins).
* Pregnant or nursing women.
* Women of childbearing potential not using a method of birth control classified at least as "acceptable". Female patients will be considered to be of childbearing potential unless surgically sterilized by hysterectomy, bilateral salpingectomy, bilateral oophorectomy, or post-menopausal (defined as no menses for 12 months without an alternative medical cause). Tubal ligation is NOT a method of permanent sterilisation.
* Patients who have previously been randomized in this study or are currently participating in another study.
* Patients who are unable to comply with pulmonary medication restrictions prior to randomization.

Participant flow

Outcome results

• Forced Expiratory Volume in One Second (FEV1) Area Under the Curve From 0 to 24 Hours (AUC0-24) Response (Change From Baseline) [L] After 12 Weeks of Treatment (Primary), Mean, Litre*hours (L*h): Tiotropium+Olodaterol (5μg/5μg) - Main Study 0.174 +/- 0.019; Fluticasone Propionate+Salmeterol (500μg/100μg) - Main Study 0.122 +/- 0.019; Tiotropium+Olodaterol (5μg/5μg) - DH-study NA +/- NA; Fluticasone Propionate+Salmeterol (500μg/100μg) - DH-study NA +/- NA (p 0.0543)
• Forced Expiratory Volume in One Second (FEV1) Area Under the Curve From 0 to 12 Hours (AUC0-12) Response (Change From Baseline) [L] After 12 Weeks of Treatment (Secondary), Mean, Litre*hours (L*h): Tiotropium+Olodaterol (5μg/5μg) - Main Study 0.237 +/- 0.019; Fluticasone Propionate+Salmeterol (500μg/100μg) - Main Study 0.147 +/- 0.020; Tiotropium+Olodaterol (5μg/5μg) - DH-study NA +/- NA; Fluticasone Propionate+Salmeterol (500μg/100μg) - DH-study NA +/- NA (p 0.0011)
• Trough Forced Expiratory Volume in One Second (FEV1) Response (Change From Baseline) [L] After 12 Weeks Treatment (Secondary), Mean, Litre (L): Tiotropium+Olodaterol (5μg/5μg) - Main Study 0.118 +/- 0.019; Fluticasone Propionate+Salmeterol (500μg/100μg) - Main Study 0.114 +/- 0.019; Tiotropium+Olodaterol (5μg/5μg) - DH-study NA +/- NA; Fluticasone Propionate+Salmeterol (500μg/100μg) - DH-study NA +/- NA (p 0.8593)
• Peak 0-3 Hours Forced Expiratory Volume in One Second (FEV1) Response (Change From Baseline) [L] After 12 Weeks Treatment (Secondary), Mean, Litre (L): Tiotropium+Olodaterol (5μg/5μg) - Main Study 0.341 +/- 0.021; Fluticasone Propionate+Salmeterol (500μg/100μg) - Main Study 0.243 +/- 0.021; Tiotropium+Olodaterol (5μg/5μg) - DH-study NA +/- NA; Fluticasone Propionate+Salmeterol (500μg/100μg) - DH-study NA +/- NA (p 0.0010)

Adverse events

Time frame: From screening visit (28 days before treatment start) until end of follow up period (up to 105 days).

Serious adverse events by term

Other adverse events by term

Limitations and caveats: The objectives of the DH-study were exploratory. The DH-study aimed to gather information and experience about the feasibility of a remote trial in this indication, and was not designed to support treatment comparisons.

• Statistical Analysis Plan (PDF, 2018-05-14)
• Study Protocol (PDF, 2018-03-06)