Co-administration of Olodaterol Respimat® and Tiotropium Handihaler®

Pulmonary Disease, Chronic Obstructive Clinical Trial

Official title:

A Randomised, Double Blind, Parallel Group Study to Assess the Efficacy and Safety of 12 Weeks of Once Daily, Orally Inhaled, Co-administration of Olodaterol 5µg (Delivered by the Respimat® Inhaler) and Tiotropium 18µg (Delivered by the HandiHaler®) Compared to Once Daily, Orally Inhaled, Co-administration of Placebo (Delivered by the Respimat® Inhaler) and Tiotropium 18µg (Delivered by the HandiHaler®) in Patients With Chronic Obstructive Pulmonary Disease (COPD)[ANHELTO TM 2]

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01696058
• Other study ID #: 1222.52
• Status: Completed
• Phase: Phase 3
• First received: September 26, 2012
• Last updated: November 13, 2014
• Start date: September 2012
• Est. completion date: October 2013

Study information

• Verified date: November 2014
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

The overall objective of this study is to assess efficacy and safety of 12 weeks, once daily, orally inhaled co-administration of olodaterol 5 µg (delivered by the Respimat® Inhaler) and tiotropium (delivered by the Handihaler® as Spiriva Handihaler®), compared to tiotropium (Spiriva Handihaler®) monotherapy on lung function in patients with COPD.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1137
• Est. completion date: October 2013
• Est. primary completion date: October 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 40 Years and older

Eligibility

Inclusion criteria:

1. All patients must sign an informed consent consistent with International Conference on Harmonization-Good Clinical Practice (ICH-GCP) guidelines prior to participation in the trial, which includes medication washout and restrictions.

2. All patients must have a diagnosis of chronic obstructive pulmonary disease and must meet the following spirometric criteria: Patients must have a relatively stable airway obstruction with a post-bronchodilator FEV1 = 30 % and < 80% of predicted normal and a post-bronchodilator FEV1/FVC <70% at Visit 1.

3. Male or female patients, 40 years of age or older.

4. Patients must be current or ex-smokers with a smoking history of more than 10 pack years

5. Patients must be able to: perform technically acceptable pulmonary function tests, and maintain records(paper diary).

6. Patients must be able to inhale medication in a competent manner from the Respimat Inhaler as well as the Handihaler.

Exclusion criteria:

1. Patients with a significant disease other than 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 patients ability to participate in the study.

2. Patients with clinically relevant abnormal baseline haematology, blood chemistry, or urinalysis; all patients with an AST >x2 ULN, ALT >x2 ULN, bilirubin >x2 ULN or creatinine >x2 ULN will be excluded regardless of clinical condition (a repeat laboratory evaluation will not be conducted in these patients).

3. 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 non-asthmatic condition.

4. A diagnosis of thyrotoxicosis (due to the known class side effect profile of ß2-agonists).

5. A diagnosis of paroxysmal tachycardia (>100 beats per minute) (due to the known class side effect profile of ß2-agonists).

6. A history of myocardial infarction within 1 year of screening visit (Visit 1).

7. Unstable or life-threatening cardiac arrhythmia.

8. Hospitalization for heart failure within the past year.

9. Known active tuberculosis.

10. A malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years (patients with treated basal cell carcinoma are allowed).

11. A history of life-threatening pulmonary obstruction.

12. A history of cystic fibrosis.

13. Clinically evident bronchiectasis.

14. A history of significant alcohol or drug abuse.

15. Patients who have undergone thoracotomy with pulmonary resection (patients with a history of thoracotomy for other reasons should be evaluated as per exclusion criterion No. 1).

16. Patients being treated with oral or patch ß-adrenergics.

17. Patients being treated with oral corticosteroid medication at unstable doses (i.e., less than six weeks on a stable dose) or at doses in excess of the equivalent of 10 mg of prednisone per day or 20 mg every other day.

18. Patients who regularly use daytime oxygen therapy for more than one hour per day and in the investigators opinion will be unable to abstain from the use of oxygen therapy during clinic visits.

19. 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.

20. Patients who have taken an investigational drug within one month or six half lives (whichever is greater) prior to screening visit (Visit 1).

21. Patients with known hypersensitivity to ß-adrenergic drugs, BAC, EDTA, or any other component of the Respimat® inhalation solution.

22. Patients with known hypersensitivity to anticholinergic drugs, lactose, or any other components of the HandiHaler®.

23. Pregnant or nursing women.

24. Women of childbearing potential not using a highly effective method of birth control*. Female patients will be considered to be of childbearing potential unless surgically sterilised by hysterectomy or bilateral tubal ligation, or post-menopausal for at least two years.

• as per ICH M3(R2) a highly effective method of birth control is defined as those which result in a low failure rate (i.e. less than 1% per year).

25. Patients who have previously been randomised in this study or are currently participating in another study.

26. Patients who are unable to comply with pulmonary medication restrictions prior to randomisation.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Disease
• Lung Diseases
• Pulmonary Disease, Chronic Obstructive

Intervention

Drug:
• Tiotropium
marketed product
• Placebo matching Olodaterol
one dose
• Tiotropium
marketed product
• Olodaterol
one dose

Locations

Country	Name	City	State
United States	1222.52.02071 Boehringer Ingelheim Investigational Site	Albuquerque	New Mexico
United States	1222.52.02092 Boehringer Ingelheim Investigational Site	Anchorage	Alaska
United States	1222.52.02090 Boehringer Ingelheim Investigational Site	Anniston	Alabama
United States	1222.52.02086 Boehringer Ingelheim Investigational Site	Arlington	Texas
United States	1222.52.02044 Boehringer Ingelheim Investigational Site	Austin	Texas
United States	1222.52.02005 Boehringer Ingelheim Investigational Site	Baltimore	Maryland
United States	1222.52.02050 Boehringer Ingelheim Investigational Site	Billings	Montana
United States	1222.52.02046 Boehringer Ingelheim Investigational Site	Birmingham	Alabama
United States	1222.52.02009 Boehringer Ingelheim Investigational Site	Blue Ridge	Georgia
United States	1222.52.02061 Boehringer Ingelheim Investigational Site	Boulder	Colorado
United States	1222.52.02018 Boehringer Ingelheim Investigational Site	Brentwood	Tennessee
United States	1222.52.02076 Boehringer Ingelheim Investigational Site	Calabash	North Carolina
United States	1222.52.02072 Boehringer Ingelheim Investigational Site	Chandler	Arizona
United States	1222.52.02100 Boehringer Ingelheim Investigational Site	Charleston	South Carolina
United States	1222.52.02003 Boehringer Ingelheim Investigational Site	Chelsea	Michigan
United States	1222.52.02068 Boehringer Ingelheim Investigational Site	Chesterfield	Missouri
United States	1222.52.02062 Boehringer Ingelheim Investigational Site	Cincinnati	Ohio
United States	1222.52.02094 Boehringer Ingelheim Investigational Site	Clearwater	Florida
United States	1222.52.02029 Boehringer Ingelheim Investigational Site	Columbia	Maryland
United States	1222.52.02039 Boehringer Ingelheim Investigational Site	Columbus	Ohio
United States	1222.52.02081 Boehringer Ingelheim Investigational Site	Columbus	Ohio
United States	1222.52.02093 Boehringer Ingelheim Investigational Site	Columbus	Ohio
United States	1222.52.02048 Boehringer Ingelheim Investigational Site	Duluth	Georgia
United States	1222.52.02096 Boehringer Ingelheim Investigational Site	Easley	South Carolina
United States	1222.52.02041 Boehringer Ingelheim Investigational Site	El Paso	Texas
United States	1222.52.02054 Boehringer Ingelheim Investigational Site	Fort Collins	Colorado
United States	1222.52.02022 Boehringer Ingelheim Investigational Site	Fort Lauderdale	Florida
United States	1222.52.02008 Boehringer Ingelheim Investigational Site	Fort Mitchell	Kentucky
United States	1222.52.02027 Boehringer Ingelheim Investigational Site	Fort Worth	Texas
United States	1222.52.02077 Boehringer Ingelheim Investigational Site	Gainsville	Georgia
United States	1222.52.02063 Boehringer Ingelheim Investigational Site	Glendale	Arizona
United States	1222.52.02085 Boehringer Ingelheim Investigational Site	Greenville	South Carolina
United States	1222.52.02101 Boehringer Ingelheim Investigational Site	Greenville	South Carolina
United States	1222.52.02001 Boehringer Ingelheim Investigational Site	Hartford	Connecticut
United States	1222.52.02035 Boehringer Ingelheim Investigational Site	Henderson	Nevada
United States	1222.52.02065 Boehringer Ingelheim Investigational Site	Hodges	South Carolina
United States	1222.52.02036 Boehringer Ingelheim Investigational Site	Hollywood	Maryland
United States	1222.52.02056 Boehringer Ingelheim Investigational Site	Houston	Texas
United States	1222.52.02010 Boehringer Ingelheim Investigational Site	Huntersville	North Carolina
United States	1222.52.02006 Boehringer Ingelheim Investigational Site	Huntington Beach	California
United States	1222.52.02064 Boehringer Ingelheim Investigational Site	Johnson City	New York
United States	1222.52.02020 Boehringer Ingelheim Investigational Site	Kalamazoo	Michigan
United States	1222.52.02025 Boehringer Ingelheim Investigational Site	Louisville	Kentucky
United States	1222.52.02030 Boehringer Ingelheim Investigational Site	Marlton	New Jersey
United States	1222.52.02026 Boehringer Ingelheim Investigational Site	Medford	Oregon
United States	1222.52.02097 Boehringer Ingelheim Investigational Site	Medford	Oregon
United States	1222.52.02057 Boehringer Ingelheim Investigational Site	Midvale	Utah
United States	1222.52.02047 Boehringer Ingelheim Investigational Site	Minneapolis	Minnesota
United States	1222.52.02049 Boehringer Ingelheim Investigational Site	Minneapolis	Minnesota
United States	1222.52.02014 Boehringer Ingelheim Investigational Site	Mobile	Alabama
United States	1222.52.02017 Boehringer Ingelheim Investigational Site	Montgomery	Alabama
United States	1222.52.02099 Boehringer Ingelheim Investigational Site	Morgantown	West Virginia
United States	1222.52.02002 Boehringer Ingelheim Investigational Site	Muncie	Indiana
United States	1222.52.02042 Boehringer Ingelheim Investigational Site	Myrtle Beach	South Carolina
United States	1222.52.02089 Boehringer Ingelheim Investigational Site	New Orleans	Louisiana
United States	1222.52.02087 Boehringer Ingelheim Investigational Site	New Windsor	New York
United States	1222.52.02034 Boehringer Ingelheim Investigational Site	North Dartmouth	Massachusetts
United States	1222.52.02037 Boehringer Ingelheim Investigational Site	Norwalk	Connecticut
United States	1222.52.02024 Boehringer Ingelheim Investigational Site	O'Fallon	Illinois
United States	1222.52.02059 Boehringer Ingelheim Investigational Site	Oklahoma City	Oklahoma
United States	1222.52.02074 Boehringer Ingelheim Investigational Site	Orlando	Florida
United States	1222.52.02088 Boehringer Ingelheim Investigational Site	Peoria	Arizona
United States	1222.52.02075 Boehringer Ingelheim Investigational Site	Philadelphia	Pennsylvania
United States	1222.52.02102 Boehringer Ingelheim Investigational Site	Philadelphia	Pennsylvania
United States	1222.52.02012 Boehringer Ingelheim Investigational Site	Phoenix	Arizona
United States	1222.52.02080 Boehringer Ingelheim Investigational Site	Pittsburgh	Pennsylvania
United States	1222.52.02079 Boehringer Ingelheim Investigational Site	Plymouth	Minnesota
United States	1222.52.02016 Boehringer Ingelheim Investigational Site	Ponte Verda	Florida
United States	1222.52.02045 Boehringer Ingelheim Investigational Site	Raleigh	North Carolina
United States	1222.52.02023 Boehringer Ingelheim Investigational Site	Richmond	Virginia
United States	1222.52.02040 Boehringer Ingelheim Investigational Site	Rincon	Georgia
United States	1222.52.02083 Boehringer Ingelheim Investigational Site	Rock Hill	South Carolina
United States	1222.52.02038 Boehringer Ingelheim Investigational Site	Salisbury	North Carolina
United States	1222.52.02007 Boehringer Ingelheim Investigational Site	San Antonio	Texas
United States	1222.52.02060 Boehringer Ingelheim Investigational Site	San Antonio	Texas
United States	1222.52.02031 Boehringer Ingelheim Investigational Site	San Jose	California
United States	1222.52.02069 Boehringer Ingelheim Investigational Site	Selah	Washington
United States	1222.52.02051 Boehringer Ingelheim Investigational Site	Shelby	North Carolina
United States	1222.52.02066 Boehringer Ingelheim Investigational Site	Spartanburg	South Carolina
United States	1222.52.02095 Boehringer Ingelheim Investigational Site	Spartanburg	South Carolina
United States	1222.52.02028 Boehringer Ingelheim Investigational Site	St. Louis	Missouri
United States	1222.52.02053 Boehringer Ingelheim Investigational Site	St. Louis	Missouri
United States	1222.52.02084 Boehringer Ingelheim Investigational Site	St. Petersberg	Florida
United States	1222.52.02078 Boehringer Ingelheim Investigational Site	Sugar Land	Texas
United States	1222.52.02091 Boehringer Ingelheim Investigational Site	Syracuse	New York
United States	1222.52.02058 Boehringer Ingelheim Investigational Site	Tabor City	North Carolina
United States	1222.52.02019 Boehringer Ingelheim Investigational Site	Tacoma	Washington
United States	1222.52.02043 Boehringer Ingelheim Investigational Site	Tampa	Florida
United States	1222.52.02011 Boehringer Ingelheim Investigational Site	Torrance	California
United States	1222.52.02015 Boehringer Ingelheim Investigational Site	Townson	Maryland
United States	1222.52.02098 Boehringer Ingelheim Investigational Site	Union	South Carolina
United States	1222.52.02082 Boehringer Ingelheim Investigational Site	Waco	Texas
United States	1222.52.02055 Boehringer Ingelheim Investigational Site	Waterbury	Connecticut
United States	1222.52.02013 Boehringer Ingelheim Investigational Site	Winston Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	FEV1 AUC0-3h Response at 12 Weeks; Defined as Change From Baseline to Week 12	FEV1 (Forced expiratory volume in 1 second) AUC0-3h (area under the curve) response at 12 weeks; defined as change from baseline to Week 12. AUC was standardized by dividing by time unit.	baseline and 12 weeks	No
Primary	Trough FEV1 Response at 12 Weeks; Defined as Change From Baseline to Week 12	Trough FEV1 (Forced expiratory volume in 1 second) response at 12 weeks; defined as change from baseline to Week 12	baseline and 12 weeks	No
Secondary	Saint George Respiratory Questionnaire - (Total Score) Based on Combined 1222.51 and 1222.52 Data	The Saint George Respiratory Questionnaire (SGRQ) is designed to measure health impairment in patients with asthma and chronic obstructive pulmonary disease (COPD). It is divided into two parts. Part I produces the Symptoms score (several scales), and Part II the Activity and Impacts scores [dichotomous (true/false) except last question (4-point Likert scale)]. A Total score is also produced with scores ranging from 0 to 100, with higher scores indicating more limitations. Since the SGRQ analysis is based on the combined data from both this study and protocol 1222.51 (NCT01694771), only combined SGRQ results will be included in the latest clinical trial report. Hence there will only be one SGRQ analysis from both studies, which will not appear in the first clinical trial report. For this same reason, another covariate - study - will also be included in the MMRM for SGRQ analysis. The combined data for this outcome measure was pre-specified in both protocols.	12 weeks	No
Secondary	Peak FEV1 Response at 12 Weeks - Defined as Change From Baseline	Peak FEV1 (Forced Expiratory Volume in 1 second) response at 12 Weeks - defined as change from baseline. All p-values for these measures are only descriptive.	baseline and 12 weeks	No
Secondary	FVC AUC0-3h Response at 12 Weeks; Defined as Change From Baseline	Forced Vital Capacity (FVC) AUC0-3h response at 12 weeks - defined as change from baseline. AUC was standardized by dividing by time unit.	baseline and 12 Weeks	No
Secondary	Peak FVC Response at 12 Weeks; Defined as Change From Baseline	Peak FVC response at 12 weeks - defined as change from baseline.	baseline and 12 weeks	No
Secondary	Trough FVC Response at 12 Weeks; Defined as Change From Baseline	Trough Forced Vital Capacity (FVC) response at 12 weeks- defined as change from baseline.	baseline and 12 weeks	No
Secondary	Rescue Medication Usage - Percentage of Rescue Free Days	Rescue medication usage - the percentage of rescue free days. The percentage of rescue free days is defined as: number of rescue free days divided by total exposure, multiplied by 100%. The baseline for the number of rescue-free days was defined as the number of rescue-free days observed during the last week of the baseline period (i.e., the 7 days prior to administration of the first dose of randomized treatment).; Results are from non-MMRM ANCOVA models by week with LOCF up to each week. Fixed effects include treatment and baseline.; Number of patients contributing to models: Tio+Placebo (559), Tio+Olo 5ug (552)	over 12 weeks	No
Secondary	Rescue Medication Usage - Mean Weekly Rescue Usage (Total Daily)	Rescue medication usage - mean weekly rescue usage (total daily). The baseline for the rescue use was the mean of the observations during the last week of the baseline period. Administration of rescue medication could occur at any point during the trial as deemed necessary by the patient or the investigator. Open label albuterol metered dose inhaler (MDI) (100 µg per puff) was provided as rescue medication . Daily, between clinic visits, patients recorded the number of puffs of albuterol in a paper diary.; Results are from non-MMRM ANCOVA models by week with LOCF up to each week. Fixed effects include treatment and baseline.; Number of patients contributing to models: Tio+Placebo (559), Tio+Olo 5ug (555)	over 12 weeks	No
Secondary	Rescue Medication Usage - Mean Weekly Rescue Usage (Daytime)	Rescue medication usage - Mean weekly rescue usage during daytime hours. Administration of rescue medication could occur at any point during the trial as deemed necessary by the patient or the investigator. Open label albuterol MDI (100 µg per puff) was provided as rescue medication by BI, and only the albuterol MDI provided by BI was allowed for rescue medication use. Daily, between clinic visits, patients recorded the number of puffs of albuterol in a paper diary.; Results are from non-MMRM ANCOVA models by week with LOCF up to each week. Fixed effects include treatment and baseline.; Number of patients contributing to models: Tio+Placebo (559), Tio+Olo 5ug (555)	over 12 weeks	No
Secondary	Rescue Medication Usage - Mean Weekly Rescue Usage (Nighttime)	Rescue medication usage - Mean weekly rescue usage during nighttime hours. Administration of rescue medication could occur at any point during the trial as deemed necessary by the patient or the investigator. Open label albuterol MDI (100 µg per puff) was provided as rescue medication by BI, and only the albuterol MDI provided by BI was allowed for rescue medication use. Daily, between clinic visits, patients recorded the number of puffs of albuterol in a paper diary.; Results are from non-MMRM ANCOVA models by week with LOCF up to each week. Fixed effects include treatment and baseline.; Number of patients contributing to models: Tio+Placebo (559), Tio+Olo 5ug (555)	over 12 weeks	No

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