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)

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

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.

Study Overview

• Status: Completed
• Conditions: Asthma
• Intervention / Treatment: Drug: Benralizumab; Other: Placebo

• Study Type: Interventional
• Enrollment (Actual): 233
• Phase: Phase 3

Contacts and Locations

Study Locations

• Chile
  • Curico, Chile, 3341643
    • Research Site
  • Santiago, Chile, 404366
    • Research Site
  • Santiago, Chile, 7750495
    • Research Site
  • Santiago, Chile, 7500692
    • Research Site
• Germany
  • Bamberg, Germany, 96049
    • Research Site
  • Darmstadt, Germany, 64283
    • Research Site
  • Frankfurt, Germany, 60596
    • Research Site
  • Frankfurt am Main, Germany, 60596
    • Research Site
  • Frankfurt am Main, Germany, 60389
    • Research Site
  • Hamburg, Germany, 20354
    • Research Site
  • Hamburg, Germany, 22299
    • Research Site
  • Hannover, Germany, 30625
    • Research Site
  • Hannover, Germany, D-30173
    • Research Site
  • Hannover, Germany, 30167
    • Research Site
  • Mainz, Germany, 55131
    • Research Site
  • München, Germany, 81377
    • Research Site
• Hungary
  • Balassagyarmat, Hungary, 2660
    • Research Site
  • Edelény, Hungary, 3780
    • Research Site
  • Farkasgyepü, Hungary, 8582
    • Research Site
  • Gödöllő, Hungary, 2100
    • Research Site
  • Hajdúnánás, Hungary, 4080
    • Research Site
  • Komárom, Hungary, 2900
    • Research Site
  • Miskolc, Hungary, 3529
    • Research Site
  • Pécs, Hungary, 7626
    • Research Site
  • Pécs, Hungary, 7635
    • Research Site
• Korea, Republic of
  • Cheongju-si, Korea, Republic of, 28644
    • Research Site
  • Daegu, Korea, Republic of, 42415
    • Research Site
  • Jeonju-si, Korea, Republic of, 54907
    • Research Site
  • Seoul, Korea, Republic of, 03722
    • Research Site
  • Seoul, Korea, Republic of, 05505
    • Research Site
  • Seoul, Korea, Republic of, 03080
    • Research Site
  • Seoul, Korea, Republic of, 06351
    • Research Site
  • Seoul, Korea, Republic of, 06591
    • Research Site
  • Seoul, Korea, Republic of, 03312
    • Research Site
• Philippines
  • Iloilo City, Philippines, 5000
    • Research Site
  • Lipa City, Philippines
    • Research Site
  • Manila, Philippines, 1000
    • Research Site
  • Quezon City, Philippines, 0870
    • Research Site
• United States
  • Alabama
    • Scottsboro, Alabama, United States, 35768
      • Research Site
  • Arizona
    • Gilbert, Arizona, United States, 85234
      • Research Site
  • Colorado
    • Denver, Colorado, United States, 80206
      • Research Site
  • Florida
    • Miami, Florida, United States, 33174
      • Research Site
    • Tampa, Florida, United States, 33607
      • Research Site
    • Vero Beach, Florida, United States, 32960
      • Research Site
    • Winter Park, Florida, United States, 32789
      • Research Site
  • Kentucky
    • Fort Mitchell, Kentucky, United States, 41017
      • Research Site
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Research Site
  • North Carolina
    • New Bern, North Carolina, United States, 28562
      • Research Site
  • Ohio
    • Cincinnati, Ohio, United States, 45231
      • Research Site
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73103
      • Research Site
  • Oregon
    • Medford, Oregon, United States, 97504
      • Research Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
      • Research Site
  • Texas
    • Lampasas, Texas, United States, 76550
      • Research Site
    • McKinney, Texas, United States, 75069
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Benralizumab arm; Benralizumab administered subcutaneously	Drug: Benralizumab; Benralizumab administered subcutaneously at Visit 1 (Day 0), Visit 8 (Day28 +/- 3 days) and Visit 9 (Day 56 +/- 3 days)
Placebo Comparator: Placebo arm; Placebo administered subcutaneously	Other: Placebo; Placebo administered subcutaneously at Visit 1 (Day 0), Visit 8 (Day28 +/- 3 days) and Visit 9 (Day 56 +/- 3 days)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline (Visit 4) to Day 28 (Visit 8), Day 56 (Visit 9), and Day 84 (Visit 10) in Pre-BD FEV1	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.	From first IP dose to Day 84
Change From Baseline (Visit 4) to End of Treatment Day 84 (Visit 10) in Residual Volume (RV)	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.	From first IP dose to Day 84

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline to End of Treatment in Eosinophils Counts	Percent change from baseline to Day 84	From first IP dose to Day 84
Change From Baseline (Visit 4) to Post Baseline Visits in Pre-BD FEV1	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.]	From first IP dose to Day 84
Change From Baseline to Post Baseline for Pre-BD FVC	Post baseline visits include Day 3, Day 7, Day 14, Day 28, Day 56, and Day 84.	From first IP dose to Day 84
Percentage of Pre-BD FEV1 Responder	Pre-BD FEV1 responder is defined as change from baseline in FEV1 >=100 ml	From first IP dose to Day 84
Change From Baseline in ACQ-6	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.	From first IP dose to Day 84
Change From Baseline in St. George's Respiratory Questionnaire (SGRQ)	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.	From first IP dose to Day 84
Change From Baseline to End of Treatment in FeNO	Airway inflammation was evaluated via fractional exhaled nitric oxide (FeNO) measurement.	From first IP dose to Day 84
Change From Baseline to End of Treatment in Total Lung Capacity (TLC) for Sub-study Patients	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.	From first IP dose to Day 84
Change From Baseline to End of Treatment in Ratio of Residual Volume (RV) and Total Lung Capacity (TLC) for Sub-study Patients	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.	From first IP dose to Day 84
Change From Baseline to End of Treatment in Inspiratory Capacity (IC) for Sub-study Patients	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.	From first IP dose to Day 84
Change From Baseline to End of Treatment in Functional Residual Capacity (FRC) for Sub-study Patients	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.	From first IP dose to Day 84
Change From Baseline to End of Treatment in Vital Capacity (VC) for Sub-study Patients	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.	From first IP dose to Day 84
Duration of IP Administration	Duration of IP administration is last IP dose date - first IP dose +1.	From first IP to last IP

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum Concentration of Benralizumab	PK sample was collected pre-dose at each visit	From first dose to end of treatment period (Day 84)
PK Parameter of Benralizumab (Cmax)	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)	First IP dose cycle (ie, data collected on Days 3, 7, 14 and 28)
Anti-drug Antibody Responses	Anti-drug antibody responses at baseline and post baseline, including nAb responses	From first IP dose to end of treatment period (Day 84)
Change From Baseline to End of Treatment in PGI-S	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])	From first IP dose to Day 84
Change From Baseline to End of Treatment in CGI-C	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.	From first IP dose to Day 84
Change From Baseline to End of Treatment in PGI-C	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.	From first IP dose to Day 84
Change From Baseline to End of Treatment in Specific Airway Resistance (SGaw) for Sub-study Patients	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.	From first IP dose to Day 84
Change From Baseline to End of Treatment in Airway Resistance (Raw) for Sub-study Patients	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.	From first IP dose to Day 84

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Principal Investigator: Reynold A Panettieri, Doctor of Medicine, Child Health Institute of NJ, 89 French Street, Suite 4210, New Brunswick, NJ, 08901, USA

Publications and helpful links

Helpful Links

• Protocol
• SAP

Study record dates

Study Major Dates

• Study Start (Actual): November 9, 2016
• Primary Completion (Actual): August 1, 2018
• Study Completion (Actual): August 1, 2018

Study Registration Dates

• First Submitted: August 16, 2016
• First Submitted That Met QC Criteria: August 16, 2016
• First Posted (Estimate): August 17, 2016

Study Record Updates

• Last Update Posted (Actual): October 29, 2019
• Last Update Submitted That Met QC Criteria: October 15, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: Asthma, Bronchial Diseases, Respiratory Tract Diseases, Lung Diseases, Obstructive Lung Diseases
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Inflammation; Asthma; Anti-Asthmatic Agents; Respiratory System Agents; Benralizumab
• Other Study ID Numbers: D3250C00038; 2016-002094-36 (EudraCT Number); U1111-1185-6625 (Other Identifier: WHO (UTN number))