Clinical trial NCT03170271: A Study of the Safety and Effectiveness of Benralizumab to Treat Patients With Severe Uncontrolled Asthma.
Official title: A Multicenter, Randomized, Double-blind, Parallel Group, Placebo Controlled, Phase 3b Study to Evaluate the Safety and Efficacy of Benralizumab 30 mg sc in Patients With Severe Asthma Uncontrolled on Standard of Care Treatment
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Asthma
Keywords: Asthma, Bronchial Diseases, Respiratory Tract Diseases, Lung Diseases, Obstructive Lung Diseases
Additional relevant MeSH terms:
Asthma
Inflammation
Bronchial Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases Respiratory Hypersensitivity
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases
Pathologic Processes
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2017-05-31
Enrollment: 660
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to investigate the effect of benralizumab on the rate of asthma exacerbations, patient reported quality of life and lung function during the 24-week treatment in patients with uncontrolled, severe asthma with an eosinophilic phenotype. A subset of patients will be assessed for their ongoing chronic rhinosinusitis with nasal polyps. The study design has been updated to include a 56-week open label ANDHI in Practice (ANDHI IP) sub study upon the completion of the 24-week double-blind period of the ANDHI study.

Detailed description: This is a Phase IIIb, randomized, double-blind, placebo controlled, parallel group study designed to evaluate the efficacy and the safety of repeat dosing of benralizumab 30 mg subcutaneous (sc) versus placebo on top of standard of care asthma therapy in patients with severe uncontrolled asthma. Approximately 630 patients with peripheral blood eosinophil counts ≥150 cells/μL will be randomized 2:1 to receive benralizumab 30 mg sc or matched placebo for 24 weeks.

After enrolment, eligible patients will enter an up to 42-day screening/run-in period. Patients who meet eligibility criteria will be randomized 2:1 on Day 0 to receive either benralizumab or placebo every 56 days (every 8 weeks) through Week 16, with end of treatment (EOT) at Day 168 (Week 24). At the completion of the 24-week doubleblind period of the ANDHI study, eligible patients in benralizumab and placebo arm may enter a 56-week open label period (ANDHI in Practice \[ANDHI IP\] substudy), in which concomitant asthma therapies will be tapered as directed by the protocol in those patients who achieve and maintain asthma control (defined as ACQ6 score \<1.5 and no clinically significant asthma exacerbations that required a burst of systemic corticosteroid or a hospitalization due to asthma between reduction visits) with add-on benralizumab.

Eligibility criteria: Inclusion Criteria:

1. Female and male patients aged 18 to 75 years inclusively at the time of Visit 1 with a history of physician-diagnosed asthma requiring treatment with medium-to-high dose Inhaled Corticosteroids (ICS) plus asthma controller, for at least 12 months prior to Visit 1.
2. Documented current treatment with high daily doses of ICS plus at least one other asthma controller for at least 3 months prior to Visit 1.
3. History of at least 2 asthma exacerbations while on ICS plus another asthma controller that required treatment with systemic corticosteroids (IM, IV, or oral) in the 12 months prior to Visit 1.
4. ACQ6 score ≥1.5 at Visit 1.
5. Screening pre-bronchodilator (pre-BD) FEV1 of \<80% predicted at Visit 2.
6. Excessive variability in lung function by satisfying ≥ 1 of the following criteria:

   1. Airway reversibility (FEV1 ≥12%) using a short-acting bronchodilator demonstrated at Visit 2 or Visit 3.
   2. Airway reversibility to short-acting bronchodilator (FEV1 ≥12%) documented during the 12 months prior to enrolment Visit 1.
   3. Daily diurnal peak flow variability of \>10% when averaged over 7 continuous days during the study run-in period
   4. An increase in FEV1 of ≥12% and 200 mL after a therapeutic trial of systemic corticosteroid (eg, OCS), given outside of an asthma exacerbation, documented in the 12 months prior enrolment Visit 1.
   5. Airway hyper-responsiveness (methacholine: PC20 of \<8 mg/mL, histamine: PD20 of \<7.8 μmol, mannitol: decrease in FEV1 as per the labelled product instructions) documented in the 24 months prior to randomization Visit 4.
7. Peripheral blood eosinophil count either:

   * 300 cells/μL assessed by central laboratory at either Visit 1 or Visit 2

OR

≥150 to \<300 cells/μL assessed by central laboratory at either Visit 1 or Visit 2, IF ≥1 of the following 5 clinical criteria (a to e) is met:

1. Using maintenance OCS (daily or every other day OCS requirement in order to maintain asthma control; maximum total daily dose 20 mg prednisone or equivalent) at screening
2. History of nasal polyposis
3. Age of asthma onset ≥18 years
4. Three or more documented exacerbations requiring systemic corticosteroid treatment during the 12 months prior to screening
5. Pre-bronchodilator forced vital capacity \<65% of predicted, as assessed at Visit 2 (note that screening pre-BD FEV1 Inclusion Criterion #6 must still be satisfied)

For inclusion in the open label ANDHI IP sub study patients should meet the following criteria:

1. Patients study must have completed ANDHI EOT Visit 11.
2. Written informed consent must also be obtained prior to any study related procedures being performed in the open label ANDHI IP sub study.
3. Patients who have received any approved or investigational targeted biologic for the treatment of asthma (e.g. commercial mepolizumab, reslizumab, benralizumab) may be included if the last dose is ≥ 2 months of Visit 13.

Exclusion Criteria:

1. Clinically important pulmonary disease other than asthma
2. Acute upper or lower respiratory infections within 30 days prior to the date informed consent.
3. 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.
4. History of alcohol or drug abuse within 12 months prior to the date informed consent is obtained.
5. A history of known immunodeficiency disorder.
6. Current smokers or former smokers with a smoking history of ≥10 pack years.
7. Previously received benralizumab (MEDI-563).
8. Receipt of any investigational medication as part of a research study within approximately 5 half-lives prior to randomization.
9. Receipt of immunoglobulin or blood products within 30 days prior to the date informed consent is obtained.
10. Receipt of live attenuated vaccines 30 days prior to the date of randomization; other types of vaccines are allowed.
11. Concurrent enrolment in another interventional or post-authorization safety study

Exclusion criteria for the open label ANDHI IP sub study:

Patients should not enter the open label ANDHI IP sub study if any of the following exclusion criteria are fulfilled. Each exclusion criterion should be reviewed in all potential participants, including those who transition directly from the double-blind period and those with a delay between completing the EOT Visit 11 and the first open label visit (Visit 13).

1. Patients who participated in the double-blind period but failed to complete the ANDHI EOT Visit 11. Patients who completed the ANDHI FU Visit 12 are not excluded from participation in the ANDHI IP sub study.
2. Unable to commit to the monthly visits as required by the protocol, or unable to commit to undergoing protocol guided reductions in asthma therapy, as directed by the Investigator.
3. Patients who experienced a severe or serious treatment-related AE during the double-blind period and, and those whom Investigator judges it is not in the patient's best interest to extend possible treatment with benralizumab.
4. Approved or off-label use of systemic immunosuppressive medications within 3 months prior to the first open label visit (Visit 13). These include but are not limited to small molecules such as methotrexate, cyclosporine, azathioprine, and immunosuppressive/immunomodulating biologics such as tumour necrosis factor (TNF) blockers. Regular use of systemic OCS is also excluded except for the indication of asthma.
5. Receipt of live attenuated vaccines 30 days prior to the first visit in the open label ANDHI IP sub study (Visit 13); other types of vaccines are allowed.
6. Planned surgical procedures during the conduct of the study.
7. Positive urine pregnancy test at Visit 13, or currently breastfeeding or lactating women.

Primary outcomes:
measure: Annualized Rate of Asthma Exacerbations Over the Treatment Period (up to Week 24)
timeFrame: Baseline (Week 0) up to Week 24
Secondary outcomes:
measure: Change From Baseline in Saint George Respiratory Questionnaire (SGRQ) Total Score to the EOT (Week 24)
timeFrame: Baseline (Week 0) and Week 24
measure: Change From Baseline in Pre-Bronchodilator (BD) Forced Expiratory Volume in First Second (FEV1) to the EOT (Week 24)
timeFrame: Baseline (Week 0) and Week 24
measure: Change From Baseline in Asthma Control Questionnaire 6 (ACQ-6) Score to the EOT (Week 24)
timeFrame: Baseline (Week 0) and Week 24
measure: Time to First Asthma Exacerbation (up to Week 24)
timeFrame: Baseline (Week 0) up to Week 24
measure: Change From Run-in Baseline Home Peak Expiratory Flow (PEF) (Morning and Evening) to the EOT (Week 24)
timeFrame: Run-in baseline (from Day -28 to Day 0) and Week 24
measure: Change From Baseline in Short Form 36-item Health Survey, Version 2 (SF-36v2) to the EOT (Week 24)
timeFrame: Baseline (Week 0) and Week 24
measure: Patient Global Impression of Severity (PGI-S): Responder Status at the EOT (Week 24)
timeFrame: Baseline (Week 0) and Week 24
measure: Clinician Global Impression of Change (CGI-C) and Patient Global Impression of Change (PGI-C): Responder Status at the EOT (Week 24)
timeFrame: Baseline (Week 0) and Week 24
measure: Change From Baseline in Predominant Symptom and Impairment Assessment (PSIA) Severity Score for Average of Top 3 Ranked Symptoms/Impairments and for Top Ranked Symptom/Impairment at the EOT (Week 24)
timeFrame: Baseline (Week 0) and Week 24
measure: Change From Baseline in the Sino-Nasal Outcome Test Item 22 (SNOT-22) Total Score to the EOT (Week 24)
timeFrame: Baseline (Week 0) and Week 24
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Research Site
state: Alabama
city: Tucson
country: United States
facility: Research Site
state: Arizona
city: Little Rock
country: United States
facility: Research Site
state: Arkansas
city: Bakersfield
country: United States
facility: Research Site
state: California
city: Encinitas
country: United States
facility: Research Site
state: California
city: Long Beach
country: United States
facility: Research Site
state: California
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Mission Viejo
country: United States
facility: Research Site
state: California
city: Newport Beach
country: United States
facility: Research Site
state: California
city: Riverside
country: United States
facility: Research Site
state: California
city: San Diego
country: United States
facility: Research Site
state: California
city: Stockton
country: United States
facility: Research Site
state: California
city: Walnut Creek
country: United States
facility: Research Site
state: California
city: Aurora
country: United States
facility: Research Site
state: Colorado
city: New Haven
country: United States
facility: Research Site
state: Connecticut
city: Waterbury
country: United States
facility: Research Site
state: Connecticut
city: Clearwater
country: United States
facility: Research Site
state: Florida
city: Jacksonville
country: United States
facility: Research Site
state: Florida
city: Kissimmee
country: United States
facility: Research Site
state: Florida
city: Miami
country: United States
facility: Research Site
state: Florida
city: Miami
country: United States
facility: Research Site
state: Florida
city: Winter Park
country: United States
facility: Research Site
state: Florida
city: Albany
country: United States
facility: Research Site
state: Georgia
city: Savannah
country: United States
facility: Research Site
state: Georgia
city: Peoria
country: United States
facility: Research Site
state: Illinois
city: South Bend
country: United States
facility: Research Site
state: Indiana
city: Iowa City
country: United States
facility: Research Site
state: Iowa
city: West Des Moines
country: United States
facility: Research Site
state: Iowa
city: Lakeside Park
country: United States
facility: Research Site
state: Kentucky
city: Owensboro
country: United States
facility: Research Site
state: Kentucky
city: Shreveport
country: United States
facility: Research Site
state: Louisiana
city: Chevy Chase
country: United States
facility: Research Site
state: Maryland
city: White Marsh
country: United States
facility: Research Site
state: Maryland
city: North Dartmouth
country: United States
facility: Research Site
state: Massachusetts
city: Ann Arbor
country: United States
facility: Research Site
state: Michigan
city: Ypsilanti
country: United States
facility: Research Site
state: Michigan
city: Minneapolis
country: United States
facility: Research Site
state: Minnesota
city: Saint Louis
country: United States
facility: Research Site
state: Missouri
city: Missoula
country: United States
facility: Research Site
state: Montana
city: Lincoln
country: United States
facility: Research Site
state: Nebraska
city: Highland Park
country: United States
facility: Research Site
state: New Jersey
city: Marlton
country: United States
facility: Research Site
state: New Jersey
city: Northfield
country: United States
facility: Research Site
state: New Jersey
city: Piscataway
country: United States
facility: Research Site
state: New Jersey
city: Toms River
country: United States
facility: Research Site
state: New Jersey
city: Verona
country: United States
facility: Research Site
state: New Jersey
city: Albuquerque
country: United States
facility: Research Site
state: New Mexico
city: Bronx
country: United States
facility: Research Site
state: New York
city: New Hyde Park
country: United States
facility: Research Site
state: New York
city: New York
country: United States
facility: Research Site
state: New York
city: Rochester
country: United States
facility: Research Site
state: New York
city: Staten Island
country: United States
facility: Research Site
state: New York
city: Staten Island
country: United States
facility: Research Site
state: New York
city: Charlotte
country: United States
facility: Research Site
state: North Carolina
city: Elizabeth City
country: United States
facility: Research Site
state: North Carolina
city: Gastonia
country: United States
facility: Research Site
state: North Carolina
city: Greenville
country: United States
facility: Research Site
state: North Carolina
city: High Point
country: United States
facility: Research Site
state: North Carolina
city: Winston-Salem
country: United States
facility: Research Site
state: North Carolina
city: Winston-Salem
country: United States
facility: Research Site
state: North Carolina
city: Cincinnati
country: United States
facility: Research Site
state: Ohio
city: Cincinnati
country: United States
facility: Research Site
state: Ohio
city: Grove City
country: United States
facility: Research Site
state: Ohio
city: Edmond
country: United States
facility: Research Site
state: Oklahoma
city: Tulsa
country: United States
facility: Research Site
state: Oklahoma
city: Clackamas
country: United States
facility: Research Site
state: Oregon
city: Philadelphia
country: United States
facility: Research Site
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Research Site
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Research Site
state: Pennsylvania
city: Reading
country: United States
facility: Research Site
state: Pennsylvania
city: Anderson
country: United States
facility: Research Site
state: South Carolina
city: Gaffney
country: United States
facility: Research Site
state: South Carolina
city: Greenville
country: United States
facility: Research Site
state: South Carolina
city: Greenville
country: United States
facility: Research Site
state: South Carolina
city: North Charleston
country: United States
facility: Research Site
state: South Carolina
city: Rock Hill
country: United States
facility: Research Site
state: South Carolina
city: Sioux Falls
country: United States
facility: Research Site
state: South Dakota
city: Franklin
country: United States
facility: Research Site
state: Tennessee
city: Cypress
country: United States
facility: Research Site
state: Texas
city: Dallas
country: United States
facility: Research Site
state: Texas
city: Dallas
country: United States
facility: Research Site
state: Texas
city: Fort Worth
country: United States
facility: Research Site
state: Texas
city: Galveston
country: United States
facility: Research Site
state: Texas
city: McKinney
country: United States
facility: Research Site
state: Texas
city: San Antonio
country: United States
facility: Research Site
state: Texas
city: San Antonio
country: United States
facility: Research Site
state: Texas
city: San Antonio
country: United States
facility: Research Site
state: Texas
city: Provo
country: United States
facility: Research Site
state: Utah
city: South Burlington
country: United States
facility: Research Site
state: Vermont
city: Abingdon
country: United States
facility: Research Site
state: Virginia
city: Fairfax
country: United States
facility: Research Site
state: Virginia
city: North Chesterfield
country: United States
facility: Research Site
state: Virginia
city: Williamsburg
country: United States
facility: Research Site
state: Virginia
city: Everett
country: United States
facility: Research Site
state: Washington
city: Spokane
country: United States
facility: Research Site
state: Washington
city: Tacoma
country: United States
facility: Research Site
state: Washington
city: Madison
country: United States
facility: Research Site
state: Wisconsin
city: Milwaukee
country: United States
facility: Research Site
state: Wisconsin
city: Milwaukee
country: United States
facility: Research Site
state: Wisconsin
city: West Allis
country: United States
facility: Research Site
state: Wisconsin
city: Feldbach
country: Austria
facility: Research Site
city: Wien
country: Austria
facility: Research Site
city: Liège
country: Belgium
facility: Research Site
city: Montigny-le-Tilleul
country: Belgium
facility: Research Site
city: Namur
country: Belgium
facility: Research Site
city: Calgary
country: Canada
facility: Research Site
state: Alberta
city: Vancouver
country: Canada
facility: Research Site
state: British Columbia
city: Vancouver
country: Canada
facility: Research Site
state: British Columbia
city: Kelowna
country: Canada
facility: Research Site
state: Columbia Británica
city: Winnipeg
country: Canada
facility: Research Site
state: Manitoba
city: Ajax
country: Canada
facility: Research Site
state: Ontario
city: Burlington
country: Canada
facility: Research Site
state: Ontario
city: Mississauga
country: Canada
facility: Research Site
state: Ontario
city: Toronto
country: Canada
facility: Research Site
state: Ontario
city: Montreal
country: Canada
facility: Research Site
state: Quebec
city: Quebec
country: Canada
facility: Research Site
city: Aarhus N
country: Denmark
facility: Research Site
city: Odense C
country: Denmark
facility: Research Site
city: Vejle
country: Denmark
facility: Research Site
city: Helsinki
country: Finland
facility: Research Site
city: Turku
country: Finland
facility: Research Site
city: Bayonne
country: France
facility: Research Site
city: Besancon Cedex
country: France
facility: Research Site
city: Brest Cedex 2
country: France
facility: Research Site
city: Dijon
country: France
facility: Research Site
city: GRENOBLE Cedex 9
country: France
facility: Research Site
city: La Roche sur Yon
country: France
facility: Research Site
city: Le Kremlin-Bicêtre
country: France
facility: Research Site
city: Lille cedex
country: France
facility: Research Site
city: Lyon Cedex 4
country: France
facility: Research Site
city: Marseille
country: France
facility: Research Site
city: Montpellier
country: France
facility: Research Site
city: Nantes Cedex 1
country: France
facility: Research Site
city: Nice cedex 1
country: France
facility: Research Site
city: Paris Cedex 18
country: France
facility: Research Site
city: Pessac
country: France
facility: Research Site
city: Reims
country: France
facility: Research Site
city: Rouen Cedex
country: France
facility: Research Site
city: Saint-Quentin cedex
country: France
facility: Research Site
city: Strasbourg Cedex
country: France
facility: Research Site
city: Toulouse Cedex 09
country: France
facility: Research Site
city: Vandoeuvre-Les-Nancy
country: France
facility: Research Site
city: Berlin
country: Germany
facility: Research Site
city: Bochum
country: Germany
facility: Research Site
city: Bonn
country: Germany
facility: Research Site
city: Cottbus
country: Germany
facility: Research Site
city: Essen
country: Germany
facility: Research Site
city: Hamburg
country: Germany
facility: Research Site
city: Jena
country: Germany
facility: Research Site
city: Marburg
country: Germany
facility: Research Site
city: Oldenburg
country: Germany
facility: Research Site
city: Regensburg
country: Germany
facility: Research Site
city: Rheine
country: Germany
facility: Research Site
city: Rüdersdorf
country: Germany
facility: Research Site
city: Wangen
country: Germany
facility: Research Site
city: Brescia
country: Italy
facility: Research Site
city: Catania
country: Italy
facility: Research Site
city: Catanzaro
country: Italy
facility: Research Site
city: Cona
country: Italy
facility: Research Site
city: Foggia
country: Italy
facility: Research Site
city: Garbagnate Milanese
country: Italy
facility: Research Site
city: Legnago
country: Italy
facility: Research Site
city: Matera
country: Italy
facility: Research Site
city: Milaan
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Modena
country: Italy
facility: Research Site
city: Napoli
country: Italy
facility: Research Site
city: Padova
country: Italy
facility: Research Site
city: Palermo
country: Italy
facility: Research Site
city: Pavia
country: Italy
facility: Research Site
city: Piacenza
country: Italy
facility: Research Site
city: Pietra Ligure
country: Italy
facility: Research Site
city: Reggio Emilia
country: Italy
facility: Research Site
city: Roma
country: Italy
facility: Research Site
city: Rozzano
country: Italy
facility: Research Site
city: Verona
country: Italy
facility: Research Site
city: Amersfoort
country: Netherlands
facility: Research Site
city: Deventer
country: Netherlands
facility: Research Site
city: Enschede
country: Netherlands
facility: Research Site
city: Harderwijk
country: Netherlands
facility: Research Site
city: Helmond
country: Netherlands
facility: Research Site
city: Nijmegen
country: Netherlands
facility: Research Site
city: Zwolle
country: Netherlands
facility: Research Site
city: Bergen
country: Norway
facility: Research Site
city: Lørenskog
country: Norway
facility: Research Site
city: Badalona(Barcelona)
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Benalmádena
country: Spain
facility: Research Site
city: Jerez de la Frontera
country: Spain
facility: Research Site
city: Laredo
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Malaga
country: Spain
facility: Research Site
city: Palma de Mallorca
country: Spain
facility: Research Site
city: Pozuelo de Alarcon
country: Spain
facility: Research Site
city: Sabadell
country: Spain
facility: Research Site
city: Salamanca
country: Spain
facility: Research Site
city: Santiago de Compostela
country: Spain
facility: Research Site
city: Sevilla
country: Spain
facility: Research Site
city: Taco
country: Spain
facility: Research Site
city: Valdemoro
country: Spain
facility: Research Site
city: Lund
country: Sweden
facility: Research Site
city: Stockholm
country: Sweden
facility: Research Site
city: Östersund
country: Sweden
facility: Research Site
city: Birmingham
country: United Kingdom
facility: Research Site
city: Bradford
country: United Kingdom
facility: Research Site
city: Cambridge
country: United Kingdom
facility: Research Site
city: Chertsey
country: United Kingdom
facility: Research Site
city: Dundee
country: United Kingdom
facility: Research Site
city: Glasgow
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Nottingham
country: United Kingdom
facility: Research Site
Study officials:
affiliation: Aero Allergy Research Lab of Savannah
name: Brad Goodman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Sikand Institute of Pulmonary Research
name: Vinay Sikand, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Riverside Medical Center
name: Willaim Cherry, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Chong LY, Piromchai P, Sharp S, Snidvongs K, Webster KE, Philpott C, Hopkins C, Burton MJ. Biologics for chronic rhinosinusitis. Cochrane Database Syst Rev. 2021 Mar 12;3(3):CD013513. doi: 10.1002/14651858.CD013513.pub3.
citation: Harrison TW, Chanez P, Menzella F, Canonica GW, Louis R, Cosio BG, Lugogo NL, Mohan A, Burden A, McDermott L, Garcia Gil E, Zangrilli JG; ANDHI study investigators. Onset of effect and impact on health-related quality of life, exacerbation rate, lung function, and nasal polyposis symptoms for patients with severe eosinophilic asthma treated with benralizumab (ANDHI): a randomised, controlled, phase 3b trial. Lancet Respir Med. 2021 Mar;9(3):260-274. doi: 10.1016/S2213-2600(20)30414-8. Epub 2020 Dec 22.