Clinical trial NCT01914757: Efficacy and Safety Study of Benralizumab in Adults and Adolescents Inadequately Controlled on Inhaled Corticosteroid Plus Long-acting β2 Agonist
Official title: A Multicentre, Randomized, Double-blind, Parallel Group, Placebocontrolled, Phase 3 Study to Evaluate the Efficacy and Safety of Benralizumab in Asthmatic Adults and Adolescents Inadequately Controlled on Inhaled Corticosteroid Plus Long-acting β2 Agonist (CALIMA)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Asthma
Keywords: Asthma, Bronchial Diseases, Respiratory Tract Diseases, Lung Diseases, Obstructive Lung Diseases
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2013-08-02
Enrollment: 2508
Sex: ALL
Minimum age (years): 12
Maximum age (years): 75
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine whether Benralizumab reduces the exacerbation rate in patients with a history of asthma exacerbations and uncontrolled asthma receiving ICS-LABA with or without oral corticosteroids and additional asthma controllers.


Eligibility criteria: Inclusion Criteria:

1. Provision of informed consent prior to any study specific procedures
2. Female and male aged 12 to 75 years, inclusively, at the time of Visit 1
3. History of physician-diagnosed asthma requiring treatment with medium-to-high dose ICS (\>250µg fluticasone dry powder formulation equivalents total daily dose) and a LABA, for at least 12 months prior to Visit 1.
4. Documented treatment with ICS and LABA for at least 3 months prior to Visit 1 with or without oral corticosteroids and additional asthma controllers. 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. For ICS/LABA combination preparations, the mid-strength approved maintenance dose in the local country will meet this ICS criterion.

Exclusion criteria:

1. Clinically important pulmonary disease other than asthma (e.g. 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 (e.g. allergic bronchopulmonary aspergillosis/mycosis, Churg- Strauss syndrome, hypereosinophilic syndrome)
2. 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
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. Any clinically significant abnormal findings in physical examination, vital signs, haematology, clinical chemistry, or urinalysis during screening/run-in 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

Primary outcomes:
measure: Annual Asthma Exacerbation Rate in Adult and Adolescent Patients With Uncontrolled Asthma for Patients With Baseline Eosinophils >=300/uL
timeFrame: Immediately following the first administration of study drug through Study Week 56.
Secondary outcomes:
measure: Annual Asthma Exacerbation Rate in Adult and Adolescent Patients With Uncontrolled Asthma for Patients With Baseline Eosinophils <300/uL
timeFrame: Immediately following the first administration of study drug through Study Week 56.
measure: Mean Change From Baseline to Week 56 in Pre-bronchodilator FEV1 (L) Value for Patients With Baseline Eosinophils >=300/uL
timeFrame: Immediately following the first administration of study drug through Study Week 56.
measure: Mean Change From Baseline to Week 56 in Pre-bronchodilator FEV1 (L) Value for Patients With Baseline Eosinophils <300/uL
timeFrame: Immediately following the first administration of study drug through Study Week 56.
measure: Mean Change From Baseline to Week 56 Asthma Symptoms Score for Patients With Baseline Eosinophils >=300/uL
timeFrame: Immediately following the first administration of study drug through Study Week 56.
measure: Mean Change From Baseline to Week 56 Asthma Symptoms Score for Patients With Baseline Eosinophils <300/uL
timeFrame: Immediately following the first administration of study drug through Study Week 56.
measure: Change in Asthma Rescue Medication Use
timeFrame: Immediately following the first administration of study drug through Study Week 56.
measure: Home Lung Function Assessments Based on PEF
timeFrame: Immediately following the first administration of study drug through Study Week 56.
measure: Proportion of Nights With Awakening Due to Asthma
timeFrame: Immediately following the first administration of study drug through Study Week 56.
measure: Mean Change From Baseline to Week 56 in ACQ-6 for Patients With Baseline Eosinophils >=300/uL
timeFrame: Immediately following the first administration of study drug through Study Week 56.
measure: Mean Change From Baseline to Week 56 in ACQ-6 for Patients With Baseline Eosinophils <300/uL
timeFrame: Immediately following the first administration of study drug through Study Week 56.
measure: Number of Patients With >=1 Asthma Exacerbation
timeFrame: Immediately following the first administration of study drug through Study Week 56
measure: Time to First Asthma Exacerbation
timeFrame: Immediately following the first administration of study drug through Study Week 56
measure: Annual Rate of Asthma Exacerbation Resulting Emergency Room Visits and Hospitalizations
timeFrame: Immediately following the first administration of study drug through Study Week 56.
measure: Pharmacokinetics of Benralizumab
timeFrame: Baseline, Week 4, Week 8, Week 16, Week 24, Week 32, Week 40, Week 48, Week 56, Week 60
measure: Immunogenicity of Benralizumab
timeFrame: Pre-treatment until end of follow-up
measure: Extent of Exposure
timeFrame: Immediately following the first administration of study drug through Study Week 56
measure: Mean Change From Baseline to Week 56 in AQLQ(S)+12
timeFrame: Immediately following the first administration of study drug through Study Week 56
measure: Change From Baseline to Week 56 in EQ-5D-5L VAS
timeFrame: Immediately following the first administration of study drug through Study Week 56
measure: Mean Work Productivity Loss Due to Asthma
timeFrame: Immediately following the first administration of study drug through Study Week 56
measure: Mean Productivity Loss Due to Asthma in Classroom
timeFrame: Immediately following the first administration of study drug through Study Week 56
measure: Number of Participants That Utilized Health Care Resources
timeFrame: Immediately following the first administration of study drug through Study Week 56
measure: Patient and Clinician Assessment of Response to Treatment
timeFrame: Immediately following the first administration of study drug through Study Week 56
Other outcomes:
Locations:
city: Andalusia
country: United States
facility: Research Site
state: Alabama
city: Birmingham
country: United States
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state: Alabama
city: Flagstaff
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state: Arizona
city: Glendale
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state: Arizona
city: Phoenix
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state: Arizona
city: Tucson
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state: Arizona
city: Alhambra
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state: California
city: Anaheim
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facility: Research Site
state: California
city: Beverly Hills
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state: California
city: Garden Grove
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state: California
city: Lakewood
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state: California
city: North Hollywood
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state: California
city: Northridge
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state: California
city: Palmdale
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state: California
city: Rancho Mirage
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state: California
city: Redondo Beach
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state: California
city: Rolling Hills Estate
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state: California
city: Sacramento
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state: California
city: Stockton
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state: California
city: Thousand Oaks
country: United States
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state: California
city: Upland
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state: California
city: Ventura
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state: California
city: Walnut Creek
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city: Westminister
country: United States
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state: California
city: Woodland
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city: Centennial
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state: Colorado
city: Colorado Springs
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state: Colorado
city: Wheat Ridge
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state: Colorado
city: Celebration
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state: Florida
city: Fort Lauderdale
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state: Florida
city: Hialeah
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city: Homestead
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state: Florida
city: Jacksonville
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city: Lehigh Acres
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city: Miami
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city: Ocala
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city: Orlando
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city: Ormond Beach
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city: Virginia Gardens
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city: Gainesville
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state: Georgia
city: Smyrna
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state: Georgia
city: Eagle
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state: Idaho
city: Shiloh
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state: Illinois
city: Lenexa
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city: Fort Mitchell
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state: Kentucky
city: Covington
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city: Bangor
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city: Farmington Hills
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state: Michigan
city: Flint
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city: Traverse City
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city: Minneapolis
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city: St Louis
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city: Las Vagas
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state: Nevada
city: Union
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state: New Jersey
city: Bronx
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state: New York
city: Durham
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state: North Carolina
city: Wilmington
country: United States
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state: North Carolina
city: Cincinnati
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state: Ohio
city: Columbus
country: United States
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city: Dayton
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city: Middleburg Heights
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city: Oklahoma City
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state: Oklahoma
city: Corvallis
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state: Oregon
city: Portland
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city: Jefferson Hills
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state: Pennsylvania
city: Pittsburgh
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city: Indian Land
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state: South Carolina
city: Rapid City
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state: South Dakota
city: Knoxville
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state: Tennessee
city: Arlington
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city: Austin
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state: Texas
city: Boerne
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state: Texas
city: Dallas
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state: Texas
city: Houston
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state: Texas
city: San Antonio
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state: Texas
city: Midvale
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state: Utah
city: Murray
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state: Utah
city: Fairfax
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state: Virginia
city: Falls Church
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state: Virginia
city: Madison
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state: Wisconsin
city: Milwaukee
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state: Wisconsin
city: Buenos Aires
country: Argentina
facility: Research Site
city: Caba
country: Argentina
facility: Research Site
city: Ciudad Autónoma de Bs. As.
country: Argentina
facility: Research Site
city: Ciudad de Buenos Aires
country: Argentina
facility: Research Site
city: Concepción del Uruguay
country: Argentina
facility: Research Site
city: Corrientes
country: Argentina
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city: Córdoba
country: Argentina
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city: Florida
country: Argentina
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city: Godoy Cruz
country: Argentina
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city: La Plata
country: Argentina
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city: Mar del Plata
country: Argentina
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city: Mendoza
country: Argentina
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city: Ranelagh
country: Argentina
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city: Rosario
country: Argentina
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city: San Miguel de Tucuman
country: Argentina
facility: Research Site
city: Calgary
country: Canada
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state: Alberta
city: Sherwood Park
country: Canada
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state: Alberta
city: Vancouver
country: Canada
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state: British Columbia
city: Moncton
country: Canada
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state: New Brunswick
city: Burlington
country: Canada
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state: Ontario
city: Hamilton
country: Canada
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state: Ontario
city: Ottawa
country: Canada
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state: Ontario
city: Toronto
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state: Ontario
city: Montreal
country: Canada
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state: Quebec
city: St Charles Borromee
country: Canada
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state: Quebec
city: Quebec
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city: Concepcion
country: Chile
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city: Quillota
country: Chile
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city: Santiago
country: Chile
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country: Chile
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city: Valparaiso
country: Chile
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city: Viña del Mar
country: Chile
facility: Research Site
city: Aschaffenburg
country: Germany
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city: Bamberg
country: Germany
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city: Berlin
country: Germany
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city: Bonn
country: Germany
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city: Frankfurt/Main
country: Germany
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city: Frankfurt
country: Germany
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country: Germany
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city: Gelsenkirchen
country: Germany
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country: Germany
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city: Hannover
country: Germany
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city: Herford
country: Germany
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city: Leipzig
country: Germany
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country: Germany
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city: München
country: Germany
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city: Neu-Isenburg
country: Germany
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city: Rostock
country: Germany
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country: Germany
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city: Witten
country: Germany
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city: Asahi-shi
country: Japan
facility: Research Site
city: Chiyoda-ku
country: Japan
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city: Chuo-ku
country: Japan
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city: Fukuoka-shi
country: Japan
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city: Himeji-shi
country: Japan
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city: Hiroshima-shi
country: Japan
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city: Itabashi-ku
country: Japan
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city: Kagoshima-shi
country: Japan
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city: Kishiwada-shi
country: Japan
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city: Kobe-shi
country: Japan
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city: Kokubunji-shi
country: Japan
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city: Matsue-shi
country: Japan
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city: Minato-ku
country: Japan
facility: Research Site
city: Mizunami-shi
country: Japan
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city: Niigata-shi
country: Japan
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city: Obihiro-shi
country: Japan
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city: Oita-shi
country: Japan
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city: Ota-shi
country: Japan
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city: Sagamihara-shi
country: Japan
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city: Sakai-shi
country: Japan
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city: Sakaide-shi
country: Japan
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city: Sapporo-shi
country: Japan
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city: Sendai-shi
country: Japan
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city: Setagaya-ku
country: Japan
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city: Shibuya-ku
country: Japan
facility: Research Site
city: Shinagawa-ku
country: Japan
facility: Research Site
city: Sumida-ku
country: Japan
facility: Research Site
city: Takamatsu-shi
country: Japan
facility: Research Site
city: Toshima-ku
country: Japan
facility: Research Site
city: Tsukubo-gun
country: Japan
facility: Research Site
city: Yokohama-shi
country: Japan
facility: Research Site
city: Iloilo City
country: Philippines
facility: Research Site
city: Lipa City
country: Philippines
facility: Research Site
city: Quezon City
country: Philippines
facility: Research Site
city: Aleksandrów Łódzki
country: Poland
facility: Research Site
city: Białystok
country: Poland
facility: Research Site
city: Bielsko Biala
country: Poland
facility: Research Site
city: Bydgoszcz
country: Poland
facility: Research Site
city: Bystra Śląska
country: Poland
facility: Research Site
city: Gdańsk
country: Poland
facility: Research Site
city: Gorzów Wlkp
country: Poland
facility: Research Site
city: Karczew
country: Poland
facility: Research Site
city: Katowice
country: Poland
facility: Research Site
city: Koszalin
country: Poland
facility: Research Site
city: Kraków
country: Poland
facility: Research Site
city: Lubin
country: Poland
facility: Research Site
city: Lublin
country: Poland
facility: Research Site
city: Ostrów Wielkopolski
country: Poland
facility: Research Site
city: Poznań
country: Poland
facility: Research Site
city: Ruda Slaska
country: Poland
facility: Research Site
city: Rzeszów
country: Poland
facility: Research Site
city: Skierniewice
country: Poland
facility: Research Site
city: Szczecin
country: Poland
facility: Research Site
city: Tarnów
country: Poland
facility: Research Site
city: Toruń
country: Poland
facility: Research Site
city: Trzebnica
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Wieluń
country: Poland
facility: Research Site
city: Wroclaw
country: Poland
facility: Research Site
city: Wrocław
country: Poland
facility: Research Site
city: Zabrze
country: Poland
facility: Research Site
city: Łódź
country: Poland
facility: Research Site
city: Łęczna
country: Poland
facility: Research Site
city: Żnin
country: Poland
facility: Research Site
city: Bragadiru
country: Romania
facility: Research Site
city: Brasov
country: Romania
facility: Research Site
city: Bucharest
country: Romania
facility: Research Site
city: Constanta
country: Romania
facility: Research Site
city: Deva
country: Romania
facility: Research Site
city: Iasi
country: Romania
facility: Research Site
city: Timisoara
country: Romania
facility: Research Site
city: Goteborg
country: Sweden
facility: Research Site
city: Luleå
country: Sweden
facility: Research Site
city: Lund
country: Sweden
facility: Research Site
city: Chernivtsi
country: Ukraine
facility: Research Site
city: Dnipropetrovsk
country: Ukraine
facility: Research Site
city: Ivano-Frankivsk
country: Ukraine
facility: Research Site
city: Kharkiv
country: Ukraine
facility: Research Site
city: Kyiv
country: Ukraine
facility: Research Site
city: Lutsk
country: Ukraine
facility: Research Site
city: Mykolayiv
country: Ukraine
facility: Research Site
city: Uzhgorod
country: Ukraine
facility: Research Site
city: Vinnytsia
country: Ukraine
facility: Research Site
city: Vinnytsya
country: Ukraine
facility: Research Site
city: Zaporizhzhia
country: Ukraine
facility: Research Site
city: Zaporozhye
country: Ukraine
facility: Research Site
Study officials:
affiliation: The Lung Centre, Gordon and Leslie Diamond Health Care Centre, Vancouver Canada
name: Mark Fitzgerald, MD, PhD, Professor of Medicine
role: PRINCIPAL_INVESTIGATOR
References:
citation: Menzies-Gow A, Hoyte FL, Price DB, Cohen D, Barker P, Kreindler J, Jison M, Brooks CL, Papeleu P, Katial R. Clinical Remission in Severe Asthma: A Pooled Post Hoc Analysis of the Patient Journey with Benralizumab. Adv Ther. 2022 May;39(5):2065-2084. doi: 10.1007/s12325-022-02098-1. Epub 2022 Mar 14.
citation: Lugogo NL, Kreindler JL, Martin UJ, Cook B, Hirsch I, Trudo FJ. Blood eosinophil count group shifts and kinetics in severe eosinophilic asthma. Ann Allergy Asthma Immunol. 2020 Aug;125(2):171-176. doi: 10.1016/j.anai.2020.04.011. Epub 2020 Apr 22.
citation: Jackson DJ, Humbert M, Hirsch I, Newbold P, Garcia Gil E. Ability of Serum IgE Concentration to Predict Exacerbation Risk and Benralizumab Efficacy for Patients with Severe Eosinophilic Asthma. Adv Ther. 2020 Feb;37(2):718-729. doi: 10.1007/s12325-019-01191-2. Epub 2019 Dec 14.
citation: Chipps BE, Hirsch I, Trudo F, Alacqua M, Zangrilli JG. Benralizumab efficacy for patients with fixed airflow obstruction and severe, uncontrolled eosinophilic asthma. Ann Allergy Asthma Immunol. 2020 Jan;124(1):79-86. doi: 10.1016/j.anai.2019.10.006. Epub 2019 Oct 15.
citation: Chupp G, Lugogo NL, Kline JN, Ferguson GT, Hirsch I, Goldman M, Zangrilli JG, Trudo F. Rapid onset of effect of benralizumab on morning peak expiratory flow in severe, uncontrolled asthma. Ann Allergy Asthma Immunol. 2019 May;122(5):478-485. doi: 10.1016/j.anai.2019.02.016. Epub 2019 Feb 23.
citation: Bleecker ER, Wechsler ME, FitzGerald JM, Menzies-Gow A, Wu Y, Hirsch I, Goldman M, Newbold P, Zangrilli JG. Baseline patient factors impact on the clinical efficacy of benralizumab for severe asthma. Eur Respir J. 2018 Oct 18;52(4):1800936. doi: 10.1183/13993003.00936-2018. Print 2018 Oct.
citation: DuBuske L, Newbold P, Wu Y, Trudo F. Seasonal variability of exacerbations of severe, uncontrolled eosinophilic asthma and clinical benefits of benralizumab. Allergy Asthma Proc. 2018 Sep 4;39(5):345-349. doi: 10.2500/aap.2018.39.4162. Epub 2018 Aug 4.
citation: Chipps BE, Newbold P, Hirsch I, Trudo F, Goldman M. Benralizumab efficacy by atopy status and serum immunoglobulin E for patients with severe, uncontrolled asthma. Ann Allergy Asthma Immunol. 2018 May;120(5):504-511.e4. doi: 10.1016/j.anai.2018.01.030. Epub 2018 Feb 1.
citation: Ohta K, Adachi M, Tohda Y, Kamei T, Kato M, Mark Fitzgerald J, Takanuma M, Kakuno T, Imai N, Wu Y, Aurivillius M, Goldman M. Efficacy and safety of benralizumab in Japanese patients with severe, uncontrolled eosinophilic asthma. Allergol Int. 2018 Apr;67(2):266-272. doi: 10.1016/j.alit.2017.10.004. Epub 2017 Nov 8.
citation: FitzGerald JM, Bleecker ER, Nair P, Korn S, Ohta K, Lommatzsch M, Ferguson GT, Busse WW, Barker P, Sproule S, Gilmartin G, Werkstrom V, Aurivillius M, Goldman M; CALIMA study investigators. Benralizumab, an anti-interleukin-5 receptor alpha monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016 Oct 29;388(10056):2128-2141. doi: 10.1016/S0140-6736(16)31322-8. Epub 2016 Sep 5.