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A Study to Evaluate the Onset of Effect and Time Course of Change in Lung Function With Benralizumab in Severe, Uncontrolled Asthma Patients With Eosinophilic Inflammation (SOLANA)

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ClinicalTrials.gov Identifier: NCT02869438
Recruitment Status : Completed
First Posted : August 17, 2016
Results First Posted : October 7, 2019
Last Update Posted : October 7, 2019
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Tracking Information
First Submitted Date  ICMJE August 16, 2016
First Posted Date  ICMJE August 17, 2016
Results First Submitted Date  ICMJE July 23, 2019
Results First Posted Date  ICMJE October 7, 2019
Last Update Posted Date October 7, 2019
Actual Study Start Date  ICMJE November 9, 2016
Actual Primary Completion Date August 1, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 15, 2019)
  • Change From Baseline (Visit 4) to Day 28 (Visit 8), Day 56 (Visit 9), and Day 84 (Visit 10) in Pre-BD FEV1 [ Time Frame: From first IP dose to Day 84 ]
    The average over the mean differences between benralizumab and placebo for change from baseline in pre-BD FEV1 is used to determine if the study is positive and to determine maintenance of effect. The first post baseline time point where the p-value for the mean difference between benralizumab and placebo is less than or equal to 0.05 is used to determine time to onset of effect.
  • Change From Baseline (Visit 4) to End of Treatment Day 84 (Visit 10) in Residual Volume (RV) [ Time Frame: From first IP dose to Day 84 ]
    Body plethysmography was performed for sub-study patients. Lung volume subdivisions measures were performed by the investigator or qualified designee according to ATS/ERS guidelines.
Original Primary Outcome Measures  ICMJE
 (submitted: August 16, 2016)
  • Effect of benralizumab on the time course of change on lung function [ Time Frame: Day 84 (Visit 10) ]
    Change from baseline to end of treatment between benralizumab and placebo in pre-BD FEV1
  • Effect of benralizumab on the time course of change in lung function as assessed through body plethysmography [ Time Frame: Day 84 (Visit 10) ]
    Change from baseline to end of treatment in the following measures compared to placebo: Residual volume (RV)
Change History Complete list of historical versions of study NCT02869438 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: September 15, 2019)
  • Percent Change From Baseline to End of Treatment in Eosinophils Counts [ Time Frame: From first IP dose to Day 84 ]
    Percent change from baseline to Day 84
  • Change From Baseline (Visit 4) to Post Baseline Visits in Pre-BD FEV1 [ Time Frame: From first IP dose to Day 84 ]
    Post baseline visits include Day 3, Day 7, Day 14, Day 28, Day 56, Day 84. [Note: Day 28, 56, 84 are presented in the Primary measure.]
  • Change From Baseline to Post Baseline for Pre-BD FVC [ Time Frame: From first IP dose to Day 84 ]
    Post baseline visits include Day 3, Day 7, Day 14, Day 28, Day 56, and Day 84.
  • Percentage of Pre-BD FEV1 Responder [ Time Frame: From first IP dose to Day 84 ]
    Pre-BD FEV1 responder is defined as change from baseline in FEV1 >=100 ml
  • Change From Baseline in ACQ-6 [ Time Frame: From first IP dose to Day 84 ]
    ACQ-6 contains one bronchodilator question and 5 symptom questions. Questions are rated from 0 (totally controlled) to 6 (severely uncontrolled). Mean ACQ-6 score is the average of the responses. Mean scores of <=0.75 indicates well-controlled asthma, scores between 0.75 to <=1.5 indicate partly controlled asthma, and >1.5 indicates not well controlled asthma.
  • Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) [ Time Frame: From first IP dose to Day 84 ]
    The SGRQ is designed to measure health impairment in patients with asthma and COPD. It contains two parts: Part 1 (Questions 1 to 8) covers the patients' recollection of their symptoms over a preceding 4 weeks; Part 2, 42 items, relates to the daily activity and psychosocial impacts of the individual's respiratory condition. Total score is presented as a percentage of overall impairment, in which 100 represents the worst possible health status, while 0 indicates the best.
  • Change From Baseline to End of Treatment in FeNO [ Time Frame: From first IP dose to Day 84 ]
    Airway inflammation was evaluated via fractional exhaled nitric oxide (FeNO) measurement.
  • Change From Baseline to End of Treatment in Total Lung Capacity (TLC) for Sub-study Patients [ Time Frame: From first IP dose to Day 84 ]
    Lung volume subdivisions include total lung capacity (TLC), residual volume (RV), vital capacity (VC), functional residual capacity (FRC), and inspiratory capacity (IC), as well as airway resistance (Raw and SGaw) measurements.
  • Change From Baseline to End of Treatment in Ratio of Residual Volume (RV) and Total Lung Capacity (TLC) for Sub-study Patients [ Time Frame: From first IP dose to Day 84 ]
    Lung volume subdivisions include total lung capacity (TLC), residual volume (RV), vital capacity (VC), functional residual capacity (FRC), and inspiratory capacity (IC), as well as airway resistance (Raw and SGaw) measurements.
  • Change From Baseline to End of Treatment in Inspiratory Capacity (IC) for Sub-study Patients [ Time Frame: From first IP dose to Day 84 ]
    Lung volume subdivisions include total lung capacity (TLC), residual volume (RV), vital capacity (VC), functional residual capacity (FRC), and inspiratory capacity (IC), as well as airway resistance (Raw and SGaw) measurements.
  • Change From Baseline to End of Treatment in Functional Residual Capacity (FRC) for Sub-study Patients [ Time Frame: From first IP dose to Day 84 ]
    Lung volume subdivisions include total lung capacity (TLC), residual volume (RV), vital capacity (VC), functional residual capacity (FRC), and inspiratory capacity (IC), as well as airway resistance (Raw and SGaw) measurements.
  • Change From Baseline to End of Treatment in Vital Capacity (VC) for Sub-study Patients [ Time Frame: From first IP dose to Day 84 ]
    Lung volume subdivisions include total lung capacity (TLC), residual volume (RV), vital capacity (VC), functional residual capacity (FRC), and inspiratory capacity (IC), as well as airway resistance (Raw and SGaw) measurements.
  • Duration of IP Administration [ Time Frame: From first IP to last IP ]
    Duration of IP administration is last IP dose date - first IP dose +1.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 16, 2016)
  • Effect of benralizumab on the time course of change and maintenance on lung function [ Time Frame: Day 84 (Visit 10) ]
    Change from baseline in pre-BD FEV1 and pre-BD FVC at all clinic visits compared to placebo
  • Time course of effect of benralizumab on blood eosinophils and correlate changes in eosinophil depletion with lung function [ Time Frame: Day 84 (Visit 10) ]
    Change from baseline in blood eosinophils (from hematology) to end of treatment together with the correlation with lung function
  • Time course of the effect of benralizumab on asthma control metrics [ Time Frame: Day 84 (Visit 10) ]
    Change from baseline in Asthma Control Quesitonnaire-6 (ACQ-6) score at all post-baseline timepoints
  • Time course of effect of benralizumab on health related quality of life [ Time Frame: Day 84 (Visit 10) ]
    Change from baseline in St. George's Respiratory Questionnaire (SGRQ) score at all postbaseline assessment timepoints
  • Effect of benralizumab on the time course of change in exhaled nitric oxide (FeNO) [ Time Frame: Day 84 (Visit 10) ]
    Change from baseline in FeNO (ppb) compared to placebo to end of treatment
  • Effect of benralizumab on the time course of change in lung function as assessed through body plethysmography [ Time Frame: Day 84 (Visit 10) ]
    Change from baseline (Visit 4) to end of treatment (Visit 10) in the following measures compared to placebo :
    • Total lung capacity (TLC)
    • RV/TLC ratio
    • Inspiratory capacity (IC)
    • Functional residual capacity (FRC)
    • Vital capacity (VC)
Current Other Pre-specified Outcome Measures
 (submitted: September 15, 2019)
  • Serum Concentration of Benralizumab [ Time Frame: From first dose to end of treatment period (Day 84) ]
    PK sample was collected pre-dose at each visit
  • PK Parameter of Benralizumab (Cmax) [ Time Frame: First IP dose cycle (ie, data collected on Days 3, 7, 14 and 28) ]
    PK parameters are derived in patients with at least three qualifiable serum PK concentrations post first dose (collected on Day 3, 7, and either 14, or 28)
  • Anti-drug Antibody Responses [ Time Frame: From first IP dose to end of treatment period (Day 84) ]
    Anti-drug antibody responses at baseline and post baseline, including nAb responses
  • Change From Baseline to End of Treatment in PGI-S [ Time Frame: From first IP dose to Day 84 ]
    The patient global impression of severity (PGI-S) is a single item designed to capture the patient's perception of overall symptom severity at the time of the completion using a 6-point categorical response scale (no symptom [0] to very severe symptom [5])
  • Change From Baseline to End of Treatment in CGI-C [ Time Frame: From first IP dose to Day 84 ]
    Clinician global impression of change (CGI-C) is used for an overall evaluation of response to treatment. The investigator is asked to rate the degree of change in overall asthma status compare to the start of treatment. A 7-point rating scale is used from 1=very much improved to 7=very much worse.
  • Change From Baseline to End of Treatment in PGI-C [ Time Frame: From first IP dose to Day 84 ]
    Patient global impression of change (PGI-C) is used for an overall evaluation of response to treatment. The patient is asked to rate the degree of change in overall asthma status compare to the start of treatment. A 7-point rating scale is used from 1=very much improved to 7=very much worse.
  • Change From Baseline to End of Treatment in Specific Airway Resistance (SGaw) for Sub-study Patients [ Time Frame: From first IP dose to Day 84 ]
    Lung volume subdivisions include total lung capacity (TLC), residual volume (RV), vital capacity (VC), functional residual capacity (FRC), and inspiratory capacity (IC), as well as airway resistance (Raw and SGaw) measurements.
  • Change From Baseline to End of Treatment in Airway Resistance (Raw) for Sub-study Patients [ Time Frame: From first IP dose to Day 84 ]
    Lung volume subdivisions include total lung capacity (TLC), residual volume (RV), vital capacity (VC), functional residual capacity (FRC), and inspiratory capacity (IC), as well as airway resistance (Raw and SGaw) measurements.
Original Other Pre-specified Outcome Measures
 (submitted: August 16, 2016)
  • Evaluation of the pharmacokinetics (PK) and immunogenicity of benralizumab [ Time Frame: Day 84 (Visit 10) ]
    • Serum PK
    • Anti-drug antibodies
  • Assessment the safety and tolerability of benralizumab [ Time Frame: Day 84 (Visit 10) ]
    • Adverse events (AEs) and serious adverse events (SAEs)
    • Laboratory variables
    • Physical Examination
  • Evaluation of patient impression of overall asthma severity (PGI-S) and overall change from baseline as reported by the patient (PGIC) and clinician (CGI-C) [ Time Frame: Day 84 (Visit 10) ]
    • Change from baseline in PGI-S at all post-baseline assessment timepoints
    • Clinician-reported global change in asthma from baseline as measured by CGI-C
    • Patient-reported global change in asthma from baseline as measured by PGI-C
  • Effect of benralizumab on the time course of change in lung function as assessed through body plethysmography [ Time Frame: Day 84 (Visit 10) ]
    Change from baseline to end of treatment in the following measures compared to placebo:
    • Specific airway resistance (SGaw)
    • Airway resistance (Raw)
 
Descriptive Information
Brief Title  ICMJE A Study to Evaluate the Onset of Effect and Time Course of Change in Lung Function With Benralizumab in Severe, Uncontrolled Asthma Patients With Eosinophilic Inflammation
Official Title  ICMJE A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled, Phase 3b Study to Evaluate the Onset of Effect and Time Course of Change in Lung Function With Benralizumab in Severe, Uncontrolled Asthma Patients With Eosinophilic Inflammation
Brief Summary The purpose of this study is to investigate the onset and maintenance of effect of benralizumab on lung function, blood eosinophils, asthma control metrics and quality of life during 12-week treatment in patients with uncontrolled, severe asthma with eosinophilic inflammation. A subset of patients will take part in body plethysmography substudy to further investigate the effect on lung function.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Other
Condition  ICMJE Asthma
Intervention  ICMJE
  • Drug: Benralizumab
    Benralizumab administered subcutaneously at Visit 1 (Day 0), Visit 8 (Day28 +/- 3 days) and Visit 9 (Day 56 +/- 3 days)
  • Other: Placebo
    Placebo administered subcutaneously at Visit 1 (Day 0), Visit 8 (Day28 +/- 3 days) and Visit 9 (Day 56 +/- 3 days)
Study Arms  ICMJE
  • Experimental: Benralizumab arm
    Benralizumab administered subcutaneously
    Intervention: Drug: Benralizumab
  • Placebo Comparator: Placebo arm
    Placebo administered subcutaneously
    Intervention: Other: Placebo
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: September 15, 2019)
233
Original Estimated Enrollment  ICMJE
 (submitted: August 16, 2016)
230
Actual Study Completion Date  ICMJE August 1, 2018
Actual Primary Completion Date August 1, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion criteria

  1. Written informed consent for study participation must be obtained prior to any study related procedures being performed and according to international guidelines and/or applicable European Union (EU) guidelines.
  2. Female and male aged 18 to 75 years inclusively at the time of Visit 1
  3. Documented current treatment with ICS and LABA for at least 30 days prior to Visit 1. The ICS and LABA can be parts of a combination product or given by separate inhalers. The ICS dose must be greater than or equal to 500 μg/day fluticasone propionate dry powder formulation or equivalent daily. Additional asthma controller medications, eg, oral corticosteroids, long-acting antimuscarinics (LAMAs), LTRAs, theophylline etc. are allowed if they have been used for at least 30 days prior to Visit 1
  4. History of at least 2 asthma exacerbations that required treatment with systemic corticosteroids (intramuscular (IM), intravenous (IV), or oral) in the 12 months prior to Visit 1. For patients receiving corticosteroids as a maintenance therapy, the corticosteroid treatment for the exacerbation is defined as a temporary increase of their maintenance dose.
  5. Pre-bronchodilator (pre-BD) FEV1 of < 80% predicted at Visit 2 or Visit 3
  6. ACQ-6 score ≥1.5 at Visit 1
  7. Evidence of asthma as documented by airway reversibility (FEV1 ≥12% and 200 ml) demonstrated at Visit 1, Visit 2 or Visit 3. For patients entering the body plethysmography sub-study, reversibility must be demonstrated at Visit 1 or at Visit 2 only
  8. Peripheral blood eosinophil count of ≥300 cells/μL assessed by central lab at Visit 1
  9. Women of childbearing potential (WOCBP) must use an effective form of birth control confirmed by the Investigator. WOCBP must also have negative serum pregnancy test result on Visit 1.

    Women not of childbearing potential are defined as women who are either permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are postmenopausal. Women will be considered postmenopausal if they have been amenorrheic for 12 months prior to the planned date of randomization without an alternative medical cause. The following agespecific requirements apply:

    • Women <50 years old are considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatment and follicle stimulating hormone (FSH) levels in the postmenopausal range.
    • Women ≥50 years old are considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatment.
  10. All male patients who are sexually active must agree to use a double barrier method of contraception (condom with spermicide) from the first dose of IP until 16 weeks after their last dose
  11. Weight of ≥40 kg

Additional inclusion criteria applicable for the Body Plethysmography substudy 1.Residual volume ≥125% of predicted at Visit 3.

Inclusion criteria at randomization visit

  1. At least 1 of the following within 7 days prior to randomization:

    • Daytime or nighttime asthma symptoms for 2 or more days;
    • Rescue SABA use for 2 or more days;
    • Nighttime awakenings due to asthma at least 1 night during the 7-day period
  2. ACQ >0.75 at Visit 4 prior to randomization.
  3. A negative urine pregnancy test in WOCBP prior to administration of IP

Exclusion criteria

  1. Clinically important pulmonary disease other than asthma (eg, active lung infection, COPD, bronchiectasis, pulmonary fibrosis, cystic fibrosis, hypoventilation syndrome associated with obesity, lung cancer, alpha 1 anti-trypsin deficiency, and primary ciliary dyskinesia) or ever been diagnosed with pulmonary or systemic disease, other than asthma, that are associated with elevated peripheral eosinophil counts (eg, allergic bronchopulmonary aspergillosis/mycosis, Churg-Strauss syndrome, hypereosinophilic syndrome)
  2. Life-threatening asthma defined as episodes requiring intubation associated with hypercapnia, respiratory arrest, hypoxic seizures, or asthma related syncopal episodes within the 12 months prior to Visit 1.
  3. Acute upper or lower respiratory infections requiring antibiotics or antiviral medication within 30 days prior to the date informed consent is obtained or during the screening/run-in period
  4. An upper respiratory tract infection or an asthma exacerbation that required treatment with systemic corticosteroids or an increase in regular maintenance dose of OCS during the screening/run-in period prior to randomization Visit 4
  5. Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, haematological, psychiatric, or major physical impairment that is not stable in the opinion of the Investigator and could:

    • Affect the safety of the patient throughout the study
    • Influence the findings of the studies or their interpretations
    • Impede the patient's ability to complete the entire duration of study
  6. Known history of allergy or reaction to any component of the investigational product formulation
  7. History of anaphylaxis to any biologic therapy
  8. History of Guillain-Barré syndrome
  9. A helminth parasitic infection diagnosed within 24 weeks prior to the date informed consent is obtained that has not been treated with, or has failed to respond to standard of care therapy
  10. Any clinically significant abnormal findings in physical examination, vital signs, hematology, clinical chemistry, or urinalysis during screening period, which in the opinion of the Investigator, may put the patient at risk because of his/her participation in the study, or may influence the results of the study, or the patient's ability to complete entire duration of the study
  11. Any clinically significant cardiac disease or any electrocardiogram (ECG) abnormality obtained during the screening/run-in period, which in the opinion of the Investigator may put the patient at risk or interfere with study assessments
  12. History of alcohol or drug abuse within 12 months prior to the date informed consent is obtained
  13. Positive hepatitis B surface antigen, or hepatitis C virus antibody serology, or a positive medical history for hepatitis B or C. Patients with a history of hepatitis B vaccination without history of hepatitis B are allowed to enroll
  14. A history of known immunodeficiency disorder including a positive human immunodeficiency virus (HIV) test
  15. Current smokers or former smokers with a smoking history of ≥10 pack years. A former smoker is defined as a patient who quit smoking at least 6 months prior to Visit 1
  16. Current malignancy, or history of malignancy, except for:

    • Patients who have had basal cell carcinoma, localized squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible provided that the patient is in remission and curative therapy was completed at least 12 months prior to the date informed consent was obtained.
    • Patients who have had other malignancies are eligible provided that the patient is in remission and curative therapy was completed at least 5 years prior to the date informed consent was obtained.
  17. Use of immunosuppressive medication (including but not limited to: oral corticosteroids [for reasons other than asthma], methotrexate, troleandomycin, cyclosporine, azathioprine, intramuscular long-acting depot corticosteroids or any experimental anti-inflammatory therapy) within 3 months prior to the date informed consent
  18. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥1.5 times the upper limit of normal (ULN) confirmed during screening period
  19. Receipt of immunoglobulin or blood products within 30 days prior to the date informed consent is obtained
  20. Receipt of any marketed (eg, omalizumab, mepolizumab etc.) or investigational biologic within 4 months or 5 half-lives prior to the date informed consent is obtained, whichever is longer
  21. Receipt of live attenuated vaccines 30 days prior to the date of randomization
  22. Receipt of any investigational medication within 30 days or 5 half-lives prior to randomization, whichever is longer
  23. Previously received benralizumab (MEDI-563)
  24. Planned surgical procedures during the conduct of the study
  25. Currently breastfeeding or lactating women
  26. Previous randomization in the present study
  27. Concurrent enrolment in another interventional or post-authorization safety study (PASS).
  28. AstraZeneca staff involved in the planning and/or conduct of the study
  29. Employees of the study center or any other individuals involved with the conduct of the study or immediate family members of such individuals

Exclusion criteria at randomization Visit 4

1. Greater than/equal to 20% change in mean Pre BD FEV1 value at randomization Visit 4 from the mean pre BD FEV1 calculated from the pre BD FEV1 recorded at Visit 2 and Visit 3

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 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 Chile,   Germany,   Hungary,   Korea, Republic of,   Philippines,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02869438
Other Study ID Numbers  ICMJE D3250C00038
2016-002094-36 ( EudraCT Number )
U1111-1185-6625 ( Other Identifier: WHO (UTN number) )
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: Reynold A Panettieri, Doctor of Medicine Child Health Institute of NJ, 89 French Street, Suite 4210, New Brunswick, NJ, 08901, USA
PRS Account AstraZeneca
Verification Date September 2019

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