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

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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

Tracking Information
First Submitted Date  ICMJE March 26, 2014
First Posted Date  ICMJE May 15, 2014
Results First Submitted Date  ICMJE March 19, 2019
Results First Posted Date  ICMJE June 13, 2019
Last Update Posted Date June 13, 2019
Actual Study Start Date  ICMJE June 13, 2014
Actual Primary Completion Date April 10, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 12, 2019)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: May 13, 2014)
Evaluation of the effect of benralizumab on COPD exacerbations in subjects with moderate to very severe COPD [ Time Frame: Immediately following administration of study drug up to 56 weeks ]
Annual COPD (Chronic Obstructive Pulmonary Disease) exacerbation rate.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 12, 2019)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
Original Secondary Outcome Measures  ICMJE
 (submitted: May 13, 2014)
  • Evaluation of the effect of benralizumab on health status/health-related quality of life [ Time Frame: up to 56 weeks ]
    SGRQ (St. George's Respiratory Questionnaire), CAT (Chronic Obstructive Pulmonary Disease assessment tool)
  • Evaluation of the effect of benralizumab on pulmonary function [ Time Frame: up to 56 weeks ]
    Pre-dose/pre-bronchodilator FEV1 at the study center
  • Evaluation of the effect of benralizumab on respiratory symptoms [ Time Frame: up to 56 weeks ]
    BDI/TDI (Baseline/Transitional Dyspnea Index)
  • Evaluation of the effect of benralizumab on rescue medication use [ Time Frame: up to 56 weeks ]
    Total rescue medication use (average puffs/day), recorded by patient using electronic diary
  • Evaluation of the effect of benralizumab on nocturnal awakenings [ Time Frame: Up to 56 weeks ]
    Number of nights with awakening due to COPD, recorded by patient using electronic diary.
  • Evaluation of the effect of benralizumab on the severity, frequency and duration of EXACT-PRO defined events [ Time Frame: Up to 56 weeks. ]
    EXACT-PRO (Exacerbations of Chronic Pulmonary Disease Tool - Patient-reported Outcome) questionnaire
  • Evaluation of the effect of benralizumab on healthcare resource utilization due to COPD [ Time Frame: up to 56 weeks ]
    Annual rate of hospitalizations, combined hospitalizations and emergency department visits, unscheduled visits and healthcare encounters due to COPD
  • Evaluation of the pharmacokinetics parameters of benralizumab. [ Time Frame: up to 60 weeks ]
    PK (pharmacokinetics) - steady-state serum pre-dose concentration
  • Assessment of the safety and tolerability of benralizumab [ Time Frame: From baseline visit up to 56 weeks. ]
    Adverse Events/ Serious Adverse Events (AE/SAE) - Laboratory variables - 12 lead ECG (Electrocardiogram) - Physical Examination - Vital Signs
  • Evaluation of the immunogenicity of benralizumab [ Time Frame: up to 60 weeks ]
    Determination of Anti-drug antibodies (ADA)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures
 (submitted: May 13, 2014)
  • Evaluation of the effect of benralizumab on general health status [ Time Frame: up to 56 weeks ]
    EQ-5D-5L (European Quality of Life-5 Dimensions) questionnaire
  • Evaluation of the impact of benralizumab on blood eosinophil levels [ Time Frame: Up to 60 weeks ]
    Blood eosinophils levels
 
Descriptive Information
Brief Title  ICMJE Benralizumab Efficacy in Moderate to Very Severe Chronic Obstructive Pulmonary Disease (COPD) With Exacerbation History
Official Title  ICMJE 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
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
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Moderate to Very Severe Chronic Obstructive Pulmonary Disease
Intervention  ICMJE
  • Drug: Benralizumab Arm A
    Benralizumab subcutaneously on study week 0 until study week 48 inclusive
  • Drug: Benralizumab Arm B
    Benralizumab subcutaneously on study week 0 until study week 48 inclusive
  • Drug: Placebo
    Placebo subcutaneously on study week 0 until study week 48 inclusive
Study Arms  ICMJE
  • Experimental: Benralizumab Arm A
    Benralizumab administered subcutaneously
    Intervention: Drug: Benralizumab Arm A
  • Experimental: Benralizumab Arm B
    Benralizumab administered subcutaneously
    Intervention: Drug: Benralizumab Arm B
  • Placebo Comparator: Placebo
    Placebo administered subcutaneously
    Intervention: Drug: Placebo
Publications *

*   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: May 31, 2017)
1656
Original Estimated Enrollment  ICMJE
 (submitted: May 13, 2014)
3486
Actual Study Completion Date  ICMJE April 10, 2018
Actual Primary Completion Date April 10, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 40 Years to 85 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 Austria,   Canada,   Czechia,   Germany,   Hungary,   Italy,   Japan,   Korea, Republic of,   Netherlands,   Poland,   Romania,   Russian Federation,   South Africa,   Spain,   Switzerland,   United Kingdom,   United States
Removed Location Countries Czech Republic
 
Administrative Information
NCT Number  ICMJE NCT02138916
Other Study ID Numbers  ICMJE D3251C00003
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party AstraZeneca
Study Sponsor  ICMJE AstraZeneca
Collaborators  ICMJE MedImmune LLC
Investigators  ICMJE
Principal Investigator: Gerard Criner, MD Temple University School of Medicine, 3401 North Broad Street, Suite 745 PP, Philadelphia, PA 19140
PRS Account AstraZeneca
Verification Date June 2019

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