Study to Evaluate the Effect on Lung Function and ECG When a Combination of Tiotropium Plus Olodaterol is Administered to Patients With COPD Either From a Single Inhaler or Each Compound is Administered After Each Other From Two Different Inhalers

A Randomised, Placebo-controlled, Double-blind, Single Dose, Cross-over Study to Evaluate the Efficacy and Safety of Orally Inhaled Tiotropium + Olodaterol as Both a Fixed Dose Combination and a Free Combination (Both Delivered by the Respimat® Inhaler) in Patients With Chronic Obstructive Pulmonary Disease (COPD)

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02030535

Enrollment

Registered

2014-01-08

Start date

2014-01-31

Completion date

2014-06-30

Last updated

2015-07-16

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Pulmonary Disease, Chronic Obstructive

Brief summary

The primary objective of this study is to evaluate the efficacy and safety of orally inhaled tiotropium and olodaterol as both a fixed dose combination and a free combination with respect to lung function and ECG parameters

Interventions

DRUGolodaterol

free combination with tiotropium

DRUGtiotropium

free combination with olodaterol

DRUGPlacebo

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

TREATMENT

Masking

DOUBLE

Eligibility

Sex/Gender

ALL

Age

40 Years to No maximum

Healthy volunteers

Inclusion criteria

* patients must sign informed consent consistent with ICH-GCP guidelines prior to participation in the trial, which includes medication washout and restrictions. * Patients must have a diagnosis of COPD and must meet the following spirometric criteria: Patients must have relatively stable airway obstruction with a post-bronchodilator (10 to 45 minutes after 400mcg salbutamol) FEV1\>30% and \< 80% of predicted normal (ECSC, GOLD II - III) and a post-bronchodilator FEV1/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 technically acceptable pulmonary function tests according to ATS/ERS guidelines and maintain records in a paper diary * Patients must be able to inhale medication in a competent manner from the RESPIMAT inhaler and from a metered dose inhaler (MDI).

Exclusion criteria

* Significant disease other than COPD * Clinically relevant abnormal lab values. * History of asthma. * Diagnosis of thyrotoxicosis * Diagnosis of paroxysmal tachycardia * History of myocardial infarction within 1 year of screening visit * Unstable or life-threatening cardiac arrhythmia * Hospitalization for heart failure within the past year * Known active tuberculosis * Malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years * History of life-threatening pulmonary obstruction and patients with chronic respiratory failure * History of cystic fibrosis * Clinically evident bronchiectasis * History of significant alcohol or drug abuse * Thoracotomy with pulmonary resection * Patients treated with oral or patch ß-adrenergics * Patients treated with oral corticosteroid medication at unstable doses or at doses in excess of 10mg prednisolone per day or equivalent * Regular use of daytime oxygen therapy for more than one hour per day * Pulmonary rehabilitation program in the six weeks prior to the screening visit or patients currently in a pulmonary rehabilitation program * Investigational drug within one month or six half lives (whichever is greater) prior to screening visit * Known hypersensitivity to ß-adrenergic and/or anticholinergic drugs, BAC, EDTA * Pregnant or nursing women * Women of childbearing potential not using a highly effective method of birth control * Patient 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

Design outcomes

Primary

Measure	Time frame	Description
Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) (0-3hours) Response After Single-dose Administration	1 hour (h) and 10 min pre-dose and at 15 min, 30 min, 1 h, 2 h and 3 h post-dose	The response was defined as the change from patient baseline. Patient baseline was the average of the mean pre-dose values (period baseline) on each test day (Visit 2 (Day 1), Visit 3 (Day 22 (±7days)), and Visit 4 (Day 43±7days)). For patients who did not complete all periods, patient baseline was the average of the available period baselines. The means presented are the adjusted means.

Secondary

Measure	Time frame	Description
Peak QTcF Interval Change From Patient Baseline Over All Post-dose Time Points	40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose	Peak QTcF interval change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)
Mean Heart Rate Change From Patient Baseline Over All Post-dose Time Points	40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose	Mean heart rate change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)
Peak Heart Rate Change From Patient Baseline Over All Post-dose Time Points	40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose	Peak heart rate change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)
Heart Rate Change From Patient Baseline at Individual Post-dose Time Points	40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose	Heart rate change from patient baseline at individual post-dose time points
Mean RR (Time Interval of ECG) Change From Patient Baseline Over All Post-dose Time Points	40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose	Mean RR change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)
Peak RR Change From Patient Baseline Over All Post-dose Time Points	40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose	Peak RR change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)
RR Change From Patient Baseline at Individual Post-dose Time Points	40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose	RR change from patient baseline at individual post-dose time points
Mean QT (Time Interval of ECG) Change From Patient Baseline Over All Post-dose Time Points	40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose	Mean QT change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)
Peak QT (Time Interval of ECG) Change From Patient Baseline Over All Post-dose Time Points	40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose	Peak QT change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)
Mean (Heart Rate Corrected QT Interval (Using Fredericia Adjustment)) QTcF Interval Change From Patient Baseline Over All Post-dose Time Points	40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose	Mean QTcF interval change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)
Mean QTcB (Heart Rate Corrected QT Interval (Using Bazett Adjustment)) Change From Patient Baseline Over All Post-dose Time Points	40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose	Mean QTcB (Heart Rate Corrected QT Interval (Using Bazett Adjustment))change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)
Peak QTcB (Heart Rate Corrected QT Interval (Using Bazett Adjustment)) Change From Patient Baseline Over All Post-dose Time Points	40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose	Peak QTcB (Heart Rate Corrected QT Interval (Using Bazett Adjustment))change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)
QTcB Change From Patient Baseline at Individual Post-dose Time Points	40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose	QTcB change from patient baseline at individual post-dose time points
Mean PR (Time Interval of ECG) Change From Patient Baseline Over All Post-dose Time Points	40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose	Mean PR change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)
Peak PR (Time Interval of ECG) Change From Patient Baseline Over All Post-dose Time Points	40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose	Peak PR change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)
PR Change From Patient Baseline at Individual Post-dose Time Points	40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose	PR change from patient baseline at individual post-dose time points
Mean QRS (Time Interval of ECG) Change From Patient Baseline Over All Post-dose Time Points	40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose	Mean QRS change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)
Peak QRS (Time Interval of ECG) Change From Patient Baseline Over All Post-dose Time Points	40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose	Peak QRS change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)
QRS Change From Patient Baseline at Individual Post-dose Time Points	40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose	QRS change from patient baseline at individual post-dose time points
QT Change From Patient Baseline at Individual Post-dose Time Points	40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose	QT change from patient baseline at individual post-dose time points

Countries

Germany

Participant flow

Participants by arm

Arm	Count
Overall Study Total number of patients randomised and treated in the study.	53
Total	53

Withdrawals & dropouts

Period	Reason	FG000
Washout Period 1 (21 Days)	Adverse Event	1

Baseline characteristics

Characteristic	Overall Study
Age, Continuous	64.4 years STANDARD_DEVIATION 6.8
Sex: Female, Male Female	22 Participants
Sex: Female, Male Male	31 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —
other Total, other adverse events	3 / 53	1 / 52	2 / 52
serious Total, serious adverse events	0 / 53	0 / 52	2 / 52

Outcome results

Primary

Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) (0-3hours) Response After Single-dose Administration

The response was defined as the change from patient baseline. Patient baseline was the average of the mean pre-dose values (period baseline) on each test day (Visit 2 (Day 1), Visit 3 (Day 22 (±7days)), and Visit 4 (Day 43±7days)). For patients who did not complete all periods, patient baseline was the average of the available period baselines. The means presented are the adjusted means.

Time frame: 1 hour (h) and 10 min pre-dose and at 15 min, 30 min, 1 h, 2 h and 3 h post-dose

Population: Full Analysis Set (FAS): This patient set included all patients in the TS who had at least 1 visit (Visit 2(Day1), Visit 3(Day22), or Visit 4(Day43)) with both the period baseline value plus any evaluable post-dose spirometry measurement from the same visit.

Arm	Measure	Value (MEAN)	Dispersion
Placebo	Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) (0-3hours) Response After Single-dose Administration	0.014 Litres	Standard Error 0.016
Tio+Olo 5/5μg	Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) (0-3hours) Response After Single-dose Administration	0.233 Litres	Standard Error 0.016
Tiotropium 5μg + Olodaterol 5μg	Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) (0-3hours) Response After Single-dose Administration	0.266 Litres	Standard Error 0.016

p-value: <0.000195% CI: [0.187, 0.252]Mixed models repeated measures analysis

p-value: <0.000195% CI: [0.22, 0.284]Mixed models repeated measures analysis

Comparison: Descriptive comparison. Statistical Analyses 1 \& 2 were included in the hierarchical testing sequence (alpha protected), and analysis 3 was not included in the hierarchical testing sequence (not alpha protected)95% CI: [-0.065, -0.001]

Secondary