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

Asthma Clinical Trial

— SOLANA  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02869438
• Other study ID #: D3250C00038
• Secondary ID: 2016-002094-36U1
• Status: Completed
• Phase: Phase 3
• Start date: November 9, 2016
• Est. completion date: August 1, 2018

Study information

• Verified date: October 2019
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 233
• Est. completion date: August 1, 2018
• Est. primary completion date: August 1, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Asthma
• Inflammation

Intervention

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)

Locations

Country	Name	City	State
Chile	Research Site	Curico
Chile	Research Site	Santiago
Chile	Research Site	Santiago
Chile	Research Site	Santiago
Germany	Research Site	Bamberg
Germany	Research Site	Darmstadt
Germany	Research Site	Frankfurt
Germany	Research Site	Frankfurt am Main
Germany	Research Site	Frankfurt am Main
Germany	Research Site	Hamburg
Germany	Research Site	Hamburg
Germany	Research Site	Hannover
Germany	Research Site	Hannover
Germany	Research Site	Hannover
Germany	Research Site	Mainz
Germany	Research Site	München
Hungary	Research Site	Balassagyarmat
Hungary	Research Site	Edelény
Hungary	Research Site	Farkasgyepü
Hungary	Research Site	Gödöllo
Hungary	Research Site	Hajdúnánás
Hungary	Research Site	Komárom
Hungary	Research Site	Miskolc
Hungary	Research Site	Pécs
Hungary	Research Site	Pécs
Korea, Republic of	Research Site	Cheongju-si
Korea, Republic of	Research Site	Daegu
Korea, Republic of	Research Site	Jeonju-si
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Philippines	Research Site	Iloilo City
Philippines	Research Site	Lipa City
Philippines	Research Site	Manila
Philippines	Research Site	Quezon City
United States	Research Site	Cincinnati	Ohio
United States	Research Site	Denver	Colorado
United States	Research Site	Fort Mitchell	Kentucky
United States	Research Site	Gilbert	Arizona
United States	Research Site	Lampasas	Texas
United States	Research Site	McKinney	Texas
United States	Research Site	Medford	Oregon
United States	Research Site	Miami	Florida
United States	Research Site	New Bern	North Carolina
United States	Research Site	Oklahoma City	Oklahoma
United States	Research Site	Philadelphia	Pennsylvania
United States	Research Site	Rochester	Minnesota
United States	Research Site	Scottsboro	Alabama
United States	Research Site	Tampa	Florida
United States	Research Site	Vero Beach	Florida
United States	Research Site	Winter Park	Florida

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

United States,  Chile,  Germany,  Hungary,  Korea, Republic of,  Philippines, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Serum Concentration of Benralizumab	PK sample was collected pre-dose at each visit	From first dose to end of treatment period (Day 84)
Other	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)
Other	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)
Other	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
Other	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
Other	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
Other	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
Other	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Duration of IP Administration	Duration of IP administration is last IP dose date - first IP dose +1.	From first IP to last IP

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