Evaluation of Efficacy and Safety of Symbicort® as an add-on Treatment to Spiriva® in Patients With Severe COPD.

A 12-week, Double-blind, Randomised, Parallel Group, Multi-centre, Study to Evaluate Efficacy and Safety of Budesonide/Formoterol (Symbicort Turbuhaler®) 320/9 µg One Inhalation Twice Daily on Top of Tiotropium (Spiriva®) 18 µg One Inhalation Once Daily

The purpose of this study is to investigate the effect of combined treatment with Symbicort and Spiriva, in terms of improvement of lung function, symptoms and inflammatory markers, in patients with severe COPD.

Study Overview

• Status: Completed
• Conditions: Chronic Obstructive Pulmonary Disease, COPD
• Intervention / Treatment: Drug: Symbicort (budesonide/formoterol turbuhaler 320/9ug); Drug: Spiriva (tiotropium bromide 18ug)

• Study Type: Interventional
• Enrollment (Actual): 660
• Phase: Phase 4

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Concord, New South Wales, Australia
      • Research Site
    • Sydney, New South Wales, Australia
      • Research Site
  • Queensland
    • Auchenflower, Queensland, Australia
      • Research Site
    • Carina Heights, Queensland, Australia
      • Research Site
    • North Mackay, Queensland, Australia
      • Research Site
  • South Australia
    • Adelaide, South Australia, Australia
      • Research Site
    • Daw Park, South Australia, Australia
      • Research Site
  • Victoria
    • Clayton, Victoria, Australia
      • Research Site
    • Malvern, Victoria, Australia
      • Research Site
  • Western Australia
    • Nedlands, Western Australia, Australia
      • Research Site
• Canada
  • Quebec, Canada
    • Research Site
  • Alberta
    • Calgary, Alberta, Canada
      • Research Site
  • British Columbia
    • Vancouver, British Columbia, Canada
      • Research Site
  • Manitoba
    • Winnipeg, Manitoba, Canada
      • Research Site
  • Newfoundland and Labrador
    • St. John's, Newfoundland and Labrador, Canada
      • Research Site
  • Nova Scotia
    • Halifax, Nova Scotia, Canada
      • Research Site
  • Ontario
    • Mississauga, Ontario, Canada
      • Research Site
    • Toronto, Ontario, Canada
      • Research Site
  • Quebec
    • La Malbaie, Quebec, Canada
      • Research Site
    • Trois-rivires, Quebec, Canada
      • Research Site
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada
      • Research Site
• France
  • Chamalieres, France
    • Research Site
  • Creil, France
    • Research Site
  • Ferolles Attilly, France
    • Research Site
  • Grasse, France
    • Research Site
  • Lille, France
    • Research Site
  • Marseille Cedex 06, France
    • Research Site
  • Metz, France
    • Research Site
  • Montpellier, France
    • Research Site
  • Perpignan, France
    • Research Site
  • Poitiers Cedex, France
    • Research Site
  • Selestat, France
    • Research Site
  • St Laurent Du Var, France
    • Research Site
  • Strasbourg Cedex, France
    • Research Site
  • Toulouse Cedex 9, France
    • Research Site
• Germany
  • Berlin, Germany
    • Research Site
  • Gelsenkirchen, Germany
    • Research Site
  • Hagen, Germany
    • Research Site
  • Hannover, Germany
    • Research Site
  • Kassel, Germany
    • Research Site
  • Koblenz, Germany
    • Research Site
  • Leipzig, Germany
    • Research Site
  • Marburg, Germany
    • Research Site
  • Potsdam, Germany
    • Research Site
• Hungary
  • Aszod, Hungary
    • Research Site
  • Baja, Hungary
    • Research Site
  • Balassagyarmat, Hungary
    • Research Site
  • Budapest, Hungary
    • Research Site
  • Cegled, Hungary
    • Research Site
  • Debrecen, Hungary
    • Research Site
  • Fuzesabony, Hungary
    • Research Site
  • Jaszbereny, Hungary
    • Research Site
  • Komlo, Hungary
    • Research Site
  • Nyiregyhaza, Hungary
    • Research Site
  • Torokbalint, Hungary
    • Research Site
  • Vásárosnamény, Hungary
    • Research Site
• Poland
  • Bydgoszcz, Poland
    • Research Site
  • Chrzanów, Poland
    • Research Site
  • Ilawa, Poland
    • Research Site
  • Krakow, Poland
    • Research Site
  • Lomza, Poland
    • Research Site
  • Piekary Slaskie, Poland
    • Research Site
  • Tarnow, Poland
    • Research Site
  • Turek, Poland
    • Research Site
  • Zawadzkie, Poland
    • Research Site
• Slovakia
  • Kosice, Slovakia
    • Research Site
  • Liptovsky Hradok, Slovakia
    • Research Site
  • Lucenec, Slovakia
    • Research Site
  • Nove Mesto Nad Vahom, Slovakia
    • Research Site
  • Nove Zamky, Slovakia
    • Research Site
  • Piestany, Slovakia
    • Research Site
  • Poprad, Slovakia
    • Research Site
  • Povazska Bystrica, Slovakia
    • Research Site
  • Presov, Slovakia
    • Research Site
  • Prievidza, Slovakia
    • Research Site
  • Revuca, Slovakia
    • Research Site
  • Trnava, Slovakia
    • Research Site
  • Zilina, Slovakia
    • Research Site
• Spain
  • Cataluna
    • Barcelona, Cataluna, Spain
      • Research Site
    • Reus (tarragona), Cataluna, Spain
      • Research Site
  • Comunidad Valenciana
    • Requena (valencia), Comunidad Valenciana, Spain
      • Research Site
    • Valencia, Comunidad Valenciana, Spain
      • Research Site
  • Comunidad de Madrid
    • Madrid, Comunidad de Madrid, Spain
      • Research Site
  • Galicia
    • Pontevedra, Galicia, Spain
      • Research Site
• Sweden
  • Atvidaberg, Sweden
    • Research Site
  • Hollviken, Sweden
    • Research Site
  • Limhamn, Sweden
    • Research Site
  • Lund, Sweden
    • Research Site
  • Malmo, Sweden
    • Research Site
  • Motala, Sweden
    • Research Site
  • Stockholm, Sweden
    • Research Site
  • Uppsala, Sweden
    • Research Site
  • Orebro Lan
    • Lindesberg, Orebro Lan, Sweden
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 38 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• >=40 years of age, diagnosed COPD with symptoms >=2 years, pre-bronchodilatory FEV1 <=50% of PN

Exclusion Criteria:

• Current respiratory tract disorder other than COPD, history of asthma or rhinitis, significant or unstable cardiovascular disorder

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Symbicort+TIO; Symbicort Turbuhaler® (budesonide/formoterol) 320/9 mcg, one inhalation twice daily and Spiriva® (tiotropium) 18 mcg, one inhalation once daily	Drug: Symbicort (budesonide/formoterol turbuhaler 320/9ug); Symbicort (budesonide/formoterol turbuhaler 320/9ug)
Active Comparator: Spiriva® + Placebo Turbuhaler; Spiriva® (tiotropium) 18 mcg, one inhalation once daily and placebo Turbuhaler one inhalation once daily	Drug: Spiriva (tiotropium bromide 18ug); Spiriva (tiotropium bromide 18ug)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Forced Expiratory Volume in 1 Second (FEV1) Pre-dose	Change in the pre-dose FEV1from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12)	Baseline to 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Forced Expiratory Volume in 1 Second (FEV1) 5 Min Post-dose	Change in the 5 min post-dose FEV1from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12)	Baseline to 12 weeks
Forced Expiratory Volume in 1 Second (FEV1) 60 Min Post-dose	Change in the 60 min post-dose FEV1from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12)	Baseline to 12 weeks
Forced Vital Capacity (FVC) Pre-dose	Change in the pre-dose FVC from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12)	Baseline to 12 weeks
Forced Vital Capacity (FVC) 5 Minutes Post-dose	Change in the 5 min post-dose FVC from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12)	Baseline to 12 weeks
Forced Vital Capacity (FVC) 60 Minutes Post-dose	Change in the 60 min post-dose FVC from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12	Baseline to 12 weeks
Inspiratory Capacity (IC) Pre-dose	Change in the pre-dose IC from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12)	Baseline to 12 weeks
Inspiratory Capacity (IC) 60 Minutes Post-dose	Change in the 60 min post-dose IC from baseline to week 12 (calculated as a mean using all available data of treatment period between week 1 and week 12)	Baseline to 12 weeks
St George's Respiratory Questionnaire for COPD Patients (SGRQ-C) Score	Change in total score from baseline (Visit 3) to end of treatment (Visit 6, or last available visit). SGRQ-C is a health related quality of life questionnaire consisting of 40 items divided into two components: 1) symptoms, 2) activity& impacts. The lowest possible value is zero and the highest 100. Higher values correspond to greater impairment in quality of life.	Baseline and 12 weeks
Morning Peak Expiratory Flow (PEF) Pre-dose	Daily diary record. Change in average values from run-in to the full treatment period	Baseline to 12 weeks
Evening Peak Expiratory Flow (PEF) Pre-dose	Daily diary record. Change in average values from run-in to the full treatment period	Baseline to 12 weeks
Morning Peak Expiratory Flow (PEF) 5 Min Post-dose	Daily diary record. Change in average values from run-in to the full treatment period	Baseline to 12 weeks
Morning Peak Expiratory Flow (PEF) 15 Min Post-dose	Daily diary record. Change in average values from run-in to the full treatment period	Baseline to 12 weeks
Morning Diary FEV1 Pre-dose	Daily diary record. Change in average values from run-in to the full treatment period	Baseline to 12 weeks
Evening Diary FEV1, Pre-dose	Daily diary record. Change in average values from run-in to the full treatment period	Baseline to 12 weeks
Morning Diary FEV1, 5 Minutes Post-dose	Daily diary record. Change in average values from run-in to the full treatment period	Baseline to 12 weeks
Morning Diary FEV1, 15 Minutes Post-dose	Daily diary record. Change in average values from run-in to the full treatment period	Baseline to 12 weeks
Global Chest Symptoms Questionnaire (GCSQ) Score, Pre-dose	Daily diary record. Change in average values from run-in to the full treatment period. The GCSQ consisted of two questions that required the patient to rate shortness of breath and feelings of chest tightness. The patients recorded their response on a five-point Likert-type scale ranging from 0 (not at all) to 4 (extremely), the total score being calculated as the average score of the two questions.	Baseline to 12 weeks
GCSQ Score, 5 Minutes Post-dose	Daily diary record. Change in average values from run-in to the full treatment period. The GCSQ consisted of two questions that required the patient to rate shortness of breath and feelings of chest tightness. The patients recorded their response on a five-point Likert-type scale ranging from 0 (not at all) to 4 (extremely), the total score being calculated as the average score of the two questions.	Baseline to 12 weeks
GCSQ Score, 15 Minutes Post-dose	Daily diary record. Change in average values from run-in to the full treatment period. The GCSQ consisted of two questions that required the patient to rate shortness of breath and feelings of chest tightness. The patients recorded their response on a five-point Likert-type scale ranging from 0 (not at all) to 4 (extremely), the total score being calculated as the average score of the two questions.	Baseline to 12 weeks
Capacity of Day Living in the Morning (CDLM) Score	Daily diary record. Change in average values from run-in to the full treatment period. The CDLM questionnaire is as a questionnaire to report on patient's ability to carry out each of six different morning activities (score ranging from 0 "not performed" to 1"performed") and rank the difficulty of performing each of those activities (score ranging from 0 "so difficult that the activity could not be carried out by the patient on their own" to 5 "activity was not at all difficult to carry out". Total score for each morning activity range from 0-6. Total score for whole CDLM questionnaire range from 0-36.	Baseline to 12 weeks
Use of Rescue Medication, Night	Daily diary record - Night, after evening measurement till morning. Change in average values from run-in to the full treatment period	Baseline to 12 weeks
Use of Rescue Medication, Morning	Daily diary record - Morning, after morning measurement till midday. Change in average values from run-in to the full treatment period	Baseline to 12 weeks
Use of Rescue Medication, Day	Daily diary record - Day, after morning measurement till evening. Change in average values from run-in to the full treatment period	Baseline to 12 weeks
Use of Rescue Medication, Total	Daily diary record - Total, 24 hours, during the night, and during the day. Change in average values from run-in to the full treatment period	Baseline to 12 weeks
COPD Symptoms, Breathing Score	Daily diary record. Change in average values from run-in to the full treatment period. Symptom scale 0 - 4 (0) None (1) Mild (2) Moderate (3) Marked (4) Severe	Baseline to 12 weeks
COPD Symptoms, Sleeping Score	Daily diary record. Change in average values from run-in to the full treatment period. Symptom scale 0 - 4 (0) None (1) Mild (2) Moderate (3) Marked (4) Severe	Baseline to 12 weeks
COPD Symptoms, Chest Score	Daily diary record. Change in average values from run-in to the full treatment period. Symptom scale 0 - 4 (0) None (1) Mild (2) Moderate (3) Marked (4) Severe	Baseline to 12 weeks
COPD Symptoms, Cough Score	Daily diary record. Change in average values from run-in to the full treatment period. Symptom scale 0 - 4 (0) None (1) Mild (2) Moderate (3) Marked (4) Severe	Baseline to 12 weeks
Severe COPD Exacerbations	Patients with worsening of COPD leading to treatment with systemic steroids (oral or parenteral), emergency room treatment or hospitalisation	12 weeks
Serum High-sensitivity C-reactive Protein (hsCRP)	Ratio of treatment period mean to run-in value	Baseline to 12 weeks
Serum Interleukin 6 (IL-6)	Ratio of treatment period mean to run-in value	Baseline to 12 weeks
Serum Interleukin 8 (IL-8)	Ratio of treatment period mean to run-in value	Baseline to 12 weeks
Serum Monocyte Chemoattractant Protein-1 (MCP-1)	Ratio of treatment period mean to run-in value	Baseline to 12 weeks
Serum Soluble Tumor Necrosis Factor-alpha (sTNF-alpha)	Ratio of treatment period mean to run-in value	Baseline to 12 weeks
Serum Tumor Necrosis Factor-alpha (TNF-alpha)	Ratio of treatment period mean to run-in value	Baseline to 12 weeks
Serum Vascular Cell Adhesion Molecule-1 (VCAM-1)	Ratio of treatment period mean to run-in value	Baseline to 12 weeks

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Principal Investigator: Tobias Welte, MD, Hannover Medical School

Publications and helpful links

General Publications

• Nielsen R, Kankaanranta H, Bjermer L, Lange P, Arnetorp S, Hedegaard M, Stenling A, Mittmann N. Cost effectiveness of adding budesonide/formoterol to tiotropium in COPD in four Nordic countries. Respir Med. 2013 Nov;107(11):1709-21. doi: 10.1016/j.rmed.2013.06.007. Epub 2013 Jul 13.
• Mittmann N, Hernandez P, Mellstrom C, Brannman L, Welte T. Cost effectiveness of budesonide/formoterol added to tiotropium bromide versus placebo added to tiotropium bromide in patients with chronic obstructive pulmonary disease: Australian, Canadian and Swedish healthcare perspectives. Pharmacoeconomics. 2011 May;29(5):403-14. doi: 10.2165/11590380-000000000-00000.
• Partridge MR, Miravitlles M, Stahl E, Karlsson N, Svensson K, Welte T. Development and validation of the Capacity of Daily Living during the Morning questionnaire and the Global Chest Symptoms Questionnaire in COPD. Eur Respir J. 2010 Jul;36(1):96-104. doi: 10.1183/09031936.00123709. Epub 2009 Nov 6.
• Welte T, Miravitlles M, Hernandez P, Eriksson G, Peterson S, Polanowski T, Kessler R. Efficacy and tolerability of budesonide/formoterol added to tiotropium in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2009 Oct 15;180(8):741-50. doi: 10.1164/rccm.200904-0492OC. Epub 2009 Jul 30.

Study record dates

Study Major Dates

• Study Start: May 1, 2007
• Primary Completion (Actual): June 1, 2008
• Study Completion (Actual): June 1, 2008

Study Registration Dates

• First Submitted: July 3, 2007
• First Submitted That Met QC Criteria: July 3, 2007
• First Posted (Estimate): July 4, 2007

Study Record Updates

• Last Update Posted (Estimate): November 9, 2012
• Last Update Submitted That Met QC Criteria: October 10, 2012
• Last Verified: October 1, 2012

More Information

Terms related to this study

• Keywords: Chronic Obstructive Pulmonary Disease, COPD
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Antagonists; Cholinergic Agents; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Adrenergic Agonists; Anticonvulsants; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Budesonide; Tiotropium Bromide; Bromides; Formoterol Fumarate; Budesonide, Formoterol Fumarate Drug Combination
• Other Study ID Numbers: D5892C00015; Eudract no:2006-006796-21