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Benralizumab Efficacy in Moderate to Very Severe Chronic Obstructive Pulmonary Disease (COPD) With Exacerbation History (GALATHEA)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02138916
Recruitment Status : Completed
First Posted : May 15, 2014
Results First Posted : June 13, 2019
Last Update Posted : June 13, 2019
Sponsor:
Collaborator:
MedImmune LLC
Information provided by (Responsible Party):
AstraZeneca

Study Description
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Brief Summary:
The purpose of the study is to determine if benralizumab reduces COPD exacerbation rate in symptomatic patients with moderate to very severe COPD who are receiving standard of care therapies

Condition or disease Intervention/treatment Phase
Moderate to Very Severe Chronic Obstructive Pulmonary Disease Drug: Benralizumab Arm A Drug: Benralizumab Arm B Drug: Placebo Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1656 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Randomised, Double-blind, 56 Week Placebo-controlled, Parallel Group, Multicentre, Phase 3 Study to Evaluate the Efficacy and Safety of 2 Doses of Benralizumab in Patients With Moderate to Very Severe COPD With a History of Exacerbations
Actual Study Start Date : June 13, 2014
Actual Primary Completion Date : April 10, 2018
Actual Study Completion Date : April 10, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: COPD Lung Diseases

Arms and Interventions
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Arm Intervention/treatment
Experimental: Benralizumab Arm A
Benralizumab administered subcutaneously
 Drug: Benralizumab Arm A
Benralizumab subcutaneously on study week 0 until study week 48 inclusive
Experimental: Benralizumab Arm B
Benralizumab administered subcutaneously
 Drug: Benralizumab Arm B
Benralizumab subcutaneously on study week 0 until study week 48 inclusive
Placebo Comparator: Placebo
Placebo administered subcutaneously
 Drug: Placebo
Placebo subcutaneously on study week 0 until study week 48 inclusive


Outcome Measures
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Primary Outcome Measures :
  1. Annual COPD Exacerbation Rate Over 56 Weeks Treatment Comparison for Patients With Baseline EOS>=220/uL [ Time Frame: From first IP to week 56 ]

    A COPD exacerbation is defined by symptomatic worsening of COPD requiring:

    • Use of systemic corticosteroids for at least 3 days; a single depot injectable dose of corticosteroids will be considered equivalent to a 3-day course of systemic corticosteroids; and/or
    • Use of antibiotics; and/or
    • An inpatient hospitalization or death due to COPD Annual COPD exacerbation rate is the number of exacerbations per year. Its raw rate is calculated by number of exacerbations divided by the treatment period and then normalized to an annual rate, and is estimated by negative binomial model. Rate ratio between two treatment groups is also estimated through this model.


Secondary Outcome Measures :
  1. Annual COPD Exacerbation Rate Over 56 Weeks Treatment Comparison for Patients With Baseline EOS<220/uL [ Time Frame: From first IP to week 56 ]

    A COPD exacerbation is defined by symptomatic worsening of COPD requiring:

    • Use of systemic corticosteroids for at least 3 days; a single depot injectable dose of corticosteroids will be considered equivalent to a 3-day course of systemic corticosteroids; and/or
    • Use of antibiotics; and/or
    • An inpatient hospitalization or death due to COPD Annual COPD exacerbation rate is the number of exacerbations per year. Its raw rate is calculated by number of exacerbations divided by the treatment period and then normalized to an annual rate, and is estimated by negative binomial model. Rate ratio between two treatment groups is also estimated through this model.

  2. Mean Change From Baseline to Week 56 in Pre-bronchodilator FEV1 (L) Value for Patients With Baseline EOS>=220/uL [ Time Frame: First IP up to end of treatment Week 56 ]
    Pre-bronchodilator FEV1 (L) is collected at Weeks 0, 4, 8, 16, 24, 32, 40, 48, and 56. Baseline is the last non-missing value with quality (acceptable or borderline quality grade) prior to the first dose of study treatment.

  3. Mean Change From Baseline in SGRQ Total Score for Patients With Baseline EOS>=220/uL [ Time Frame: First IP up to Week 56 ]
    SGRQ is from 50-item PRO instrument. The SGRQ total score is expressed as a percentage of overall impairment, in which 100% means the worst possible health status and 0 indicates the best possible health status.

  4. Mean Change From Baseline in CAT Total Score for Patients With Baseline EOS>=220/uL [ Time Frame: First IP up to Week 56 ]
    CAT is an 8-item PRO developed to measure the impact of COPD on health status. The instrument uses semantic differential six-point response scales. A CAT total score is the sum of item responses. Score ranges from 0 to 40 with higher scores indicative of greater COPD impact on health status.

  5. Mean Change From Baseline in E-RS: COPD Total Score for Patients With Baseline EOS>=220/uL [ Time Frame: First IP up to Week 56 ]
    The E-RS: COPD is an 11-item PRO developed to evaluate the severity of respiratory symptoms of COPD. Summation of E-RS: COPD item responses produces a total score ranging from 0 to 40, with higher scores indicating greater severity.

  6. Mean Change From Baseline in Total Rescue Medication Use (Number of Puffs Per Day) for Patients With Baseline EOS>=220/uL [ Time Frame: First IP up to Week 56 ]
    The number of rescue medication inhalations and nebulizer treatments taken are recorded by the patient in the eDiary twice daily. Total rescue medication use is the sum of daytime and night-time use.

  7. Mean Change From Baseline in Proportion of Nights Awakenings Due to Respiratory Symptoms for Patients With Baseline EOS>=220/uL [ Time Frame: First IP up to Week 56 ]
    Change from baseline to week 56 in proportion of nights awakenings due to respiratory symptoms.

  8. Number of Participants by Number of COPD Exacerbations Based on EXACT-PRO for Patients With Baseline EOS>=220/uL [ Time Frame: Immediately following first IP up to week 56 ]
    The EXACT-PRO is a 14-item PRO instrument developed to assess the frequency, severity and duration of COPD exacerbations. Respondents are instructed to complete the electronic diary (eDiary) each evening just prior to bedtime and to answer the questions while onsidering their experiences "today". The daily EXACT-PRO total score has a range of 0-100 with higher scores indicative of greater severity. Exacerbation event frequency is calculated by comparing the baseline with daily total scores. An increase in EXACT-PRO total score ≥9 for 3 days or ≥12 for 2 days indicate an exacerbation event has occurred.

  9. Severity of EXACT-PRO for Patients With Baseline EOS>=220/uL [ Time Frame: Immediately following first IP up to week 56 ]
    The EXACT-PRO is a 14-item PRO instrument developed to assess the frequency, severity and duration of COPD exacerbations. Respondents are instructed to complete the electronic diary (eDiary) each evening just prior to bedtime and to answer the questions while onsidering their experiences "today". The daily EXACT-PRO total score has a range of 0-100 with higher scores indicative of greater severity. Severity for the study is the highest score of EXACT-PRO.

  10. Duration of EXACT-PRO for Patients With Baseline EOS>=220/uL [ Time Frame: Immediately following first IP up to week 56 ]
    The EXACT-PRO is a 14-item PRO instrument developed to assess the frequency, severity and duration of COPD exacerbations. Respondents are instructed to complete the electronic diary (eDiary) each evening just prior to bedtime and to answer the questions while onsidering their experiences "today". The daily EXACT-PRO total score has a range of 0-100 with higher scores indicative of greater severity. Event frequency is calculated by comparing the baseline with daily total scores. An increase in EXACT-PRO total score ≥9 for 3 days or ≥12 for 2 days indicate an event has occurred. Calculation of event duration after identification of the following five parameters: 1) onset; 2) three-day rolling average; 3) maximum observed value; 4) threshold for improvement; and 5) recovery. That is, duration of the exacerbation is the time elapse between onset and recovery of the event.

  11. Annual EXACT-PRO Exacerbation Rate Over 56 Weeks Treatment Comparison for Patients With Baseline EOS>=220/uL [ Time Frame: Immediately following first IP up to week 56 ]
    The EXACT-PRO is a 14-item PRO instrument developed to assess the frequency, severity and duration of COPD exacerbations. Respondents are instructed to complete the electronic diary (eDiary) each evening just prior to bedtime and to answer the questions while onsidering their experiences "today". The daily EXACT-PRO total score has a range of 0-100 with higher scores indicative of greater severity. Event frequency is calculated by comparing the baseline with daily total scores. An increase in EXACT-PRO total score ≥9 for 3 days or ≥12 for 2 days indicate an event has occurred. Annual EXACT-PRO exacerbation rate is the number of exacerbations per year. Its raw rate is calculated by number of exacerbations divided by the treatment period and then normalized to an annual rate, and is estimated by negative binomial model. Rate ratio between two treatment groups is also estimated through this model.

  12. Number of Participants Having at Least 1 COPD Exacerbation for Patients With Baseline EOS>=220/uL [ Time Frame: Immediately following first IP up to week 56 ]
    A COPD exacerbation is defined by symptomatic worsening COPD requiring systemic corticosteroids, antibiotics, or an inpatient hospitalization/death due to COPD.

  13. Time to First COPD Exacerbation [ Time Frame: Immediately following first IP up to week 56 ]
    Time to first COPD exacerbation is from the randomization date to the first occurrence of COPD exacerbation

  14. Annual COPD Exacerbation Rate Associated With ER or Hospitalization Over 56 Weeks Treatment Comparison for Patients With Baseline EOS>=220/uL [ Time Frame: Immediately following first IP up to week 56 ]
    Annual COPD exacerbations rate that result in ER or hospitalization is calculated by number of exacerbations resulting ER or hospitalization divided by the treatment period and then normalized to an annual rate, and is estimated by negative binomial model. Rate ratio between two treatment groups is also estimated through this model.

  15. Number of Participants Had COPD-related Healthcare Encounter for Patient With Baseline EOS>=220/uL [ Time Frame: Immediately following first IP up to week 56 ]
    Types of healthcare encounter: Hospitalisations (inc. intensive care and/or general care), Emergency department visits, Unscheduled outpatients visits, Home visits, Telephone calls, and ambulance transports.

  16. Duration of Study Treatment Administration [ Time Frame: From first dose date to last dose date, 48 weeks per protocol. ]
    Duration of study treatment is calculated from first dose date to last dose date + 1 day.

  17. Serum Concentration of Benralizumab [ Time Frame: Pre-first dose and pre-dose at end of treatment (week 56) ]
    PK serum samples were collected pre-dose at each visit.

  18. Immunogenicity of Benralizumab [ Time Frame: Pre-treatment until end of follow-up, week 60 per protocol. ]
    Antidrug antibody (ADA) responses such as ADA prevalence, ADA incidence, ADA persistently positive counts, etc. were presented


Eligibility Criteria
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Ages Eligible for Study:   40 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:1.Informed consent. 2.Subjects 40-85 y.o. 3.Moderate to very severe COPD with Post Bronchodilator (BD) FEV1>20% and ≤65%. 4.≥2 moderate or ≥1 severe COPD exacerbation(s) required treatment or hospitalization within 2-52 weeks prior to Visit1. 5. Modified Medical Research Council (mMRC) score ≥1 at Visit 1. 6.Treatment with double or triple therapy throughout the year prior to Visit 1, constant 2 weeks prior to Visit 1. 7.Tobacco history of ≥10 pack-years. 8.Women of childbearing potential must use a highly effective form of birth control from Visit 1 until 16 weeks after their last dose, and negative serum pregnancy test result at Visit 1. 9.Male subjects who are sexually active must be surgically sterile one year prior to Visit 1 or use an adequate method of contraception from the first Investigational Product (IP) dose until 16 weeks after their last dose. 10.Compliance with maintenance therapy during run-in ≥70%. 11. Blood eosinophils due to subject's stratification and cap for blood eosinophil levels.When any eosinophil cohort is full, subjects in the completed cohort will not be randomised and will be withdrawn from the study. Exclusion criteria: 1. Clinically important pulmonary disease other than COPD or another diagnosed pulmonary or systemic disease associated with elevated peripheral eosinophil counts.

2. Any disorder or major physical impairment that is not stable by Investigator opinion and/or could affect: - subject safety-study findings or their interpretation or subject's ability to complete the entire study duration.

3. Unstable ischemic heart disease, arrhythmia, cardiomyopathy, or other relevant cardiovascular disorder that in Investigator's judgment may put the patient at risk or negatively affect the study outcome.

4. Treatment with systemic corticosteroids and/or antibiotics, and/or hospitalization for a COPD exacerbation within 2 weeks prior to Visit1 or during the enrolment and run-in period.

5. Acute upper or lower respiratory infection requiring antibiotics or antiviral medication within 2 weeks prior to Visit1or during the enrolment and run-in period.

6. Pneumonia within 8 weeks prior to Visit1 or during the enrolment and run-in period.

7. Pregnant, breastfeeding, or lactating women. 8. Risk factors for pneumonia 9. History of anaphylaxis to any other biologic therapy. 10. Long term oxygen therapy with signs and/or symptoms of cor pulmonale, right ventricular failure.

11. Use of immunosuppressive medication within 2 weeks prior to Visit1 and/or during the enrolment and run-in period.

12. Receipt of any investigational non-biologic product within 30 days or 5 half-lives prior to Visit 1.

13. Evidence of active tuberculosis (TB) without an appropriate course of treatment.

14. Lung volume reduction surgery within the 6 months prior to Visit 1. History of partial or total lung resection (single lobe or segmentectomy is acceptable).

15. Asthma as a primary or main diagnosis according to the Global Initiative for Asthma (GINA) guidelines or other accepted guidelines.

16. Previous treatment with benralizumab. 17. Helminth parasitic infection diagnosed within 24 weeks prior to Visit 1.

Contacts and Locations
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Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02138916


Locations
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Sponsors and Collaborators
AstraZeneca
MedImmune LLC
Investigators
Layout table for investigator information
Principal Investigator: Gerard Criner, MD Temple University School of Medicine, 3401 North Broad Street, Suite 745 PP, Philadelphia, PA 19140
  Study Documents (Full-Text)

Documents provided by AstraZeneca:
Statistical Analysis Plan  [PDF] April 23, 2018
Study Protocol  [PDF] July 6, 2015

More Information
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Additional Information:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT02138916    
Other Study ID Numbers: D3251C00003
First Posted: May 15, 2014    Key Record Dates
Results First Posted: June 13, 2019
Last Update Posted: June 13, 2019
Last Verified: June 2019
Keywords provided by AstraZeneca:
Obstructive Lung Diseases
Chronic Obstructive Pulmonary Disease
Lung Disease
 Bronchial Diseases
COPD Exacerbation
Respiratory Tract Diseases
Additional relevant MeSH terms:
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Lung Diseases
Lung Diseases, Obstructive
Pulmonary Disease, Chronic Obstructive
Respiratory Tract Diseases
Chronic Disease
 Disease Attributes
Pathologic Processes
Benralizumab
Anti-Asthmatic Agents
Respiratory System Agents