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Comparing the Efficacy of Symbicort® pMDI and Formoterol Turbuhaler in Reducing Exacerbations in Patients With Cronic Obstructive Pulmonary Disease (RISE)

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ClinicalTrials.gov Identifier: NCT02157935
Recruitment Status : Completed
First Posted : June 6, 2014
Results First Posted : June 12, 2017
Last Update Posted : November 7, 2017
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Tracking Information
First Submitted Date  ICMJE June 5, 2014
First Posted Date  ICMJE June 6, 2014
Results First Submitted Date  ICMJE December 15, 2016
Results First Posted Date  ICMJE June 12, 2017
Last Update Posted Date November 7, 2017
Actual Study Start Date  ICMJE June 27, 2014
Actual Primary Completion Date February 8, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 12, 2017)
The Rate of Moderate and Severe COPD Exacerbations Defined as: Worsening of ≥2 Major Symptoms or Worsening of 1 Major Symptom Together With ≥1 Minor Symptom for ≥2 Consecutive Days [ Time Frame: Randomization at Week 0 to End of Treatment (EoT) W 26 ]
The annual COPD exacerbation rate was analyzed and compared between two arms. Annual exacerbation rate for each subject is defined as number of exacerbations divided by duration of randomized treatment period in years. The annual COPD exacerbation rate of Symbicort group was compared with annual rate of Formoterol group. The rate ratio of Symbicort vs. Formoteroal was assessed by a negative binomial model. Exacerbations, that met the modified Anthonisen criteria and duration ≥2 days were classified as moderate and severe exacerbations. Moderate exacerbation: treatment of symptoms with systemic corticosteroids (≥3 days) and/or antibiotics. Severe exacerbation: symptoms that require hospitalization (including >24 hours in ED/urgent care setting).
Original Primary Outcome Measures  ICMJE
 (submitted: June 5, 2014)
The Rate of Moderate and Severe COPD Exacerbations Defined as: Worsening of ≥2 Major Symptoms or Worsening of 1 Major Symptom Together With ≥1 Minor Symptom for ≥2 Consecutive Days [ Time Frame: Enrolment Week (W) -5, Run-in W -4, Randomization W 0, Treatment W 4, 8, 17, End of Treatment (EoT) W 26 ]
Moderate exacerbation: treatment of symptoms with systemic corticosteroids (≥3 days) and/or antibiotics. Severe exacerbation: symptoms that require hospitalization (including >24 hours in ED/urgent care setting). Major symptom: Dyspnea
  • Increase in sputum volume
  • Increase in sputum color/purulence
Minor symptoms:
  • Sore throat
  • Colds (nasal discharge and/or nasal congestion)
  • Fever without other cause
  • Increased cough
  • Increased wheeze
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 12, 2017)
  • Number of Patients With Moderate or Severe COPD Exacerbation. [ Time Frame: From randomzation to EoT W 26 ]
    The number of patients who developed moderate or severe COPD exacerbation during treatment period were reported. Cox proportional hazards regression model was fitted to data to compare the two treatment arms . The hazard ratio and 95% CI were estimated.
  • St. George's Respiratory Questionnaire (SGRQ) [ Time Frame: From Run-in W -4 to EoT W 26 ]
    SGRQ is a standardized, self-administered tool for measuring impaired health and perceived wellbeing in respiratory diseases; a validated electronic version of the questionnaire in the relevant validated languages was used in this study. The questionnaire contains 50 items divided into three dimensions (Symptoms, Activity and Impact). Each of the three dimensions of the questionnaire is scored separately in the range from 0 to 100: zero (0) score indicating no impairment of quality of life. The total SGRQ score ranging from 0 to 100 is a summary score utilizing responses to all items calculated using weights attached to each item of the questionnaire. Higher scores indicate poorer health and change of 4 units in the SGRQ has been determined to be the threshold for a clinically relevant change in health status. The change from baseline was statistically summarized and compared between two arms in a mixed model.
  • Pre-dose/Pre-bronchodilator FEV1 at the Study Site [ Time Frame: From Run-in W -4 to EoT W 26 ]
    FEV1 from pre-dose spirometry is a measurement of lung function. The change from baseline on pre-dose FEV1 was summarized and compared between Symbicort and Formoterol groups using a mixed model.
  • Total Rescue Medication Use (Average Puffs/Day) [ Time Frame: From Run-in W -4 to EoT W 26 ]
    Use of rescue medication is a measure of symptoms that need to be treated with a short-acting bronchodilator. The average daily use across the observation period was used for analysis. Change from baseline was summarized and compared between two arms using a mixed model.
  • Nights With Awakening Due to COPD [ Time Frame: From Run-in W -4 to EoT W 26 ]
    Nighttime awakening due to COPD symptoms correspond to the severity of nocturnal symptoms from COPD. The average number of awakening per night over the treatment period was analyzed. It was derived as the number of night with awakening divided by the total number of nights with data in the recording period. Change from baseline period on awakening was summarized and compared between two arms using a mixed model.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 5, 2014)
  • Time to first moderate or severe COPD exacerbation [ Time Frame: From randomzation to EoT W 26 ]
    Mean time to first COPD exacerbation in the different treatment arms
  • St. George's Respiratory Questionnaire (SGRQ) [ Time Frame: From Run-in W -4 to EoT W 26 ]
    St. George's Respiratory Questionnaire for measurement of quality of life in patients with diseases of airways obstruction
  • Pre-dose/Pre-bronchodilator FEV1 at the Study Site [ Time Frame: From Run-in W -4 to EoT W 26 ]
    Measurement of lung function
  • Total Rescue Medication Use (Average Puffs/Day) [ Time Frame: From Run-in W -4 to EoT W 26 ]
    Use of rescue medication is a measure of symptoms that need to be treated with a short-acting bronchodilator
  • Nights With Awakening Due to COPD [ Time Frame: From Run-in W -4 to EoT W 26 ]
    Number of nights awakened due to COPD symptoms correspond to the severity of nocturnal symptoms from COPD
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Comparing the Efficacy of Symbicort® pMDI and Formoterol Turbuhaler in Reducing Exacerbations in Patients With Cronic Obstructive Pulmonary Disease
Official Title  ICMJE A Phase IIIB, 6-Month, Double-blind, Double-dummy, Randomized, Parallel-group, Multicenter Exacerbation Study of Symbicort® Pressurized Metered-Dose Inhaler (pMDI) 160/4.5 μg x 2 Actuations Twice-daily Compared to Formoterol Turbuhaler 4.5 μg x 2 Inhalations Twice-daily in Cronic Obstructive Pulmonary Disease (COPD) Patients.
Brief Summary Comparing the efficacy of Symbicort® pMDI and Formoterol Turbuhaler in reducing exacerbations in patients with Chronic Obstructive Pulmonary Disease (COPD).
Detailed Description A Phase IIIB, 6-Month, Double-blind, Double-dummy, Randomized, Parallel-group, Multicenter Exacerbation Study of Symbicort® pMDI 160/4.5 μg x 2 Actuations Twice-daily Compared to Formoterol Turbuhaler 4.5 μg x 2 Inhalations Twice-daily in COPD Patients.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE COPD Patients
Intervention  ICMJE
  • Drug: Symbicort
    Budesonide/formoterol pMDI, 160/4.5 μg x 2 actuations BID, for oral inhalation, 120 doses
  • Drug: Formoterol turbohaler
    Formoterol Turbuhaler 4.5 μg x 2 actuations BID, for oral inhalation, 60 doses
  • Other: Placebo for Symbicort pMDI
    pMDI, aerosol for oral inhalation, placebo, 120 doses
  • Other: Placebo for Formoterol Turbohaler
    PLacebo powder for oral inhalation, 60 doses
Study Arms  ICMJE
  • Active Comparator: Symbicort pMDI
    Symbicort pMDI, budesonide/formoterol, 160/4.5 μg x 2 actuations BID, for oral inhalation
    Interventions:
    • Drug: Symbicort
    • Other: Placebo for Symbicort pMDI
  • Active Comparator: Formoterol Turbuhaler
    Formoterol Turbuhaler, 4.5 μg x 2 actuations BID, for oral inhalation
    Interventions:
    • Drug: Formoterol turbohaler
    • Other: Placebo for Formoterol Turbohaler
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 11, 2016)
2026
Original Estimated Enrollment  ICMJE
 (submitted: June 5, 2014)
1700
Actual Study Completion Date  ICMJE February 8, 2016
Actual Primary Completion Date February 8, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

3. A current clinical diagnosis of COPD with COPD symptoms for more than 1 year, according to the GOLD guidelines.

4. Current or previous smoker with a smoking history equivalent to 10 or more pack years (1 pack year = 20 cigarettes smoked per day for 1 year).

5. Post-bronchodilator FEV1/forced vital capacity (FVC) <0.7 (70%) and FEV1 ≤70% of predicted normal (PN) value.

6. Documented use of a short-acting inhaled bronchodilator (β2-agonists or anticholinergics) as rescue medication within 6 months prior to study start.

7. A score of ≥2 on the modified medical research council (MMRC) dyspnea scale. 8. Documented history of ≥1 moderate or severe COPD exacerbation(s) that required treatment with systemic (oral, IM, IV) corticosteroids (a minimum 3 day course of an oral corticosteroid treatment or single depot corticosteroid injection), or hospitalization (defined as an inpatient stay or >24 hour stay in an observation area in the emergency department or other equivalent facility depending on the country and healthcare system) within 2-52 weeks before Visit 1 (i.e., not within the 14 days prior to Visit 1). A history of an exacerbation treated exclusively with antibiotics will not be considered adequate.

Exclusion Criteria:

  1. A history of asthma at or after 18 years of age.
  2. Subjects with significant or unstable ischemic heart disease, arrhythmia, cardiomyopathy, heart failure (including significant cor pulmonale), uncontrolled hypertension as defined by the Investigator, or any other relevant cardiovascular disorder as judged by the Investigator.
  3. Known homozygous alpha-1 antitrypsin deficiency.
  4. Any significant disease or disorder (e.g., gastrointestinal, liver, renal, neurological, musculoskeletal, endocrine, metabolic, malignant, psychiatric, major physical impairment) which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results of the study, or the subject's ability to participate in the study.
  5. A history of malignancy (except basal cell carcinoma) within the past 5 years.
  6. Active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, primary pulmonary hypertension, interstitial lung disease, or other active pulmonary diseases.
  7. Subjects who have needed additions or alterations to their usual maintenance or change in formulation of rescue therapy for COPD due to worsening symptoms within the 14 days prior to Visit 1 and up to Visit 3.
  8. CXR (frontal and lateral) with suspicion of pneumonia or other condition/abnormality that will require additional investigation/treatment, or put the subject at risk because of participation in the study.
  9. Risk factors for pneumonia: immune suppression (HIV, lupus) or other risk for pneumonia (e.g. neurological disorders affecting control of the upper airway, such as Parkinson's disease, myasthenia gravis, etc.).
  10. Pneumonia not resolved within 14 days of Visit 1.
  11. Moderate or severe COPD exacerbation that has not resolved within 14 days prior to Visit 1 or a moderate or severe COPD exacerbation that occurs between Visit 1 and Visit 2.
  12. Long-term oxygen therapy (LTOT) or nocturnal oxygen therapy required for greater than 12 hours a day.
  13. Subjects who are currently in the intensive rehabilitation phase or scheduled to begin new participation (intensive rehabilitation phase) in a pulmonary rehabilitation program during the study or have started a new pulmonary rehabilitation program within 60 days of Visit 1. Subjects in the maintenance phase of pulmonary rehabilitation program are not excluded.
  14. Treatment with oral, parenteral, or intra-articular corticosteroids within 4 weeks prior to Visit 1.
  15. Omalizumab or any other monoclonal or polyclonal antibody therapy taken for any reason within 6 months prior to Visit 1.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 40 Years to 95 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Bulgaria,   Chile,   Czechia,   Germany,   Mexico,   Poland,   Puerto Rico,   South Africa,   Spain,   United States
Removed Location Countries Czech Republic
 
Administrative Information
NCT Number  ICMJE NCT02157935
Other Study ID Numbers  ICMJE D589UC00001
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party AstraZeneca
Study Sponsor  ICMJE AstraZeneca
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Gary T Ferguson, MD Pulmonary Research Insititute of Southeast Michigan
PRS Account AstraZeneca
Verification Date October 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP