Study to Evaluate Tezepelumab on Airway Inflammation in Adults With Uncontrolled Asthma (CASCADE) (CASCADE)

• ClinicalTrials.gov Identifier: NCT03688074
• Recruitment Status: Completed
• First Posted: September 28, 2018
• Last Update Posted: December 16, 2020
• Sponsor: AstraZeneca
• Collaborator: Amgen
• Information provided by (Responsible Party): AstraZeneca

Study Description

Brief Summary:

A phase 2, multicentre, randomized, double-blind, placebo-controlled, parallel group study to evaluate the effect of tezepelumab on airway inflammation in adults with inadequately controlled asthma.

Condition or disease	Intervention/treatment	Phase
Asthma; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases	Biological: Tezepelumab; Other: Placebo	Phase 2

Detailed Description:

This is a multicentre, randomized, double-blind, placebo-controlled, parallel group study to evaluate the effect of tezepelumab on airway inflammation in adults with inadequately controlled moderate-to-severe asthma, taking inhaled corticosteroids and at least one additional asthma controller. Approximately 110 subjects will be randomized globally. Subjects will receive tezepelumab, or placebo, administered via subcutaneous injection at the study site, over a 28-week treatment period. Although, due to the Covid-19 pandemic this may be an extended time frame for some subject visits. The study also includes a post-treatment follow-up period of 12 weeks.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 116 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Subjects will be randomized in a 1:1 ratio to either tezepelumab or matching placebo both administered subcutaneously.
• Masking: Triple (Participant, Care Provider, Investigator)
• Masking Description: Double-blind
• Primary Purpose: Treatment
• Official Title: A Phase 2, Randomized, Double-blind, Parallel Group, Placebo Controlled Study to Evaluate the Effect of Tezepelumab on Airway Inflammation in Adults With Inadequately Controlled Asthma on Inhaled Corticosteroids and at Least One Additional Asthma Controller (CASCADE)
• Actual Study Start Date: November 2, 2018
• Actual Primary Completion Date: November 16, 2020
• Actual Study Completion Date: November 16, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Tezepelumab; Tezepelumab subcutaneous injection	Biological: Tezepelumab; Tezepelumab subcutaneous injection
Placebo Comparator: Placebo; Placebo subcutaneous injection	Other: Placebo; Placebo subcutaneous injection

Outcome Measures

Primary Outcome Measures :

1. The change from baseline in number of airway submucosal inflammatory cells/mm2 of bronchoscopic biopsies. [ Time Frame: Baseline, End of Treatment (EoT). The EoT will be performed at Week 28 for the majority of subjects but may be performed at later timepoints for some subjects (Week 32, etc.) due to up to 6 additional doses added during the Covid-19 pandemic. ]
   The change from baseline in number of airway submucosal inflammatory cells/mm2 of bronchoscopic biopsies.

Secondary Outcome Measures :

1. The change in reticular basement membrane (RBM) thickness from baseline, determined by microscopic evaluation of bronchoscopic biopsies [ Time Frame: Baseline, End of Treatment (EoT). The EoT will be performed at Week 28 for the majority of subjects but may be performed at later timepoints for some subjects (Week 32, etc.) due to up to 6 additional doses added during the Covid-19 pandemic. ]
   The change in reticular basement membrane (RBM) thickness from baseline, determined by microscopic evaluation of bronchoscopic biopsies
2. The change in % airway epithelial integrity from baseline determined by microscopic evaluation of bronchoscopic biopsies [ Time Frame: Baseline, End of Treatment (EoT). The EoT will be performed at Week 28 for the majority of subjects but may be performed at later timepoints for some subjects (Week 32, etc.) due to up to 6 additional doses added during the Covid-19 pandemic. ]
   The change in % airway epithelial integrity from baseline determined by microscopic evaluation of bronchoscopic biopsies
3. The change in number of airway submucosal inflammatory cells per mm2 from baseline, across the spectrum of T2 status, determined by microscopic evaluation of bronchoscopic biopsies [ Time Frame: Baseline, End of Treatment (EoT). The EoT will be performed at Week 28 for the majority of subjects but may be performed at later timepoints for some subjects (Week 32, etc.) due to up to 6 additional doses added during the Covid-19 pandemic. ]
   The change in number of airway submucosal inflammatory cells per mm2 from baseline, across the spectrum of T2 status, determined by microscopic evaluation of bronchoscopic biopsies

Eligibility Criteria

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

Criteria

Principal Inclusion Criteria:

• Subject must be 18 to 75 years of age.
• Documented physician-diagnosed asthma for at least 12 months.
• Subjects who have received a physician- prescribed asthma controller medication with medium or high dose ICS for at least 12 months; must be stable for at least 3 months prior to screening visit.
• At least one additional maintenance asthma controller medication is required according to standard practice of care and must be documented for at least 3 months.
• At enrolment, the subject must have a predicted normal value for the morning pre-bronchodilator FEV1>50% and more than 1L.
• Evidence of asthma as documented by reversibility of FEV1 ≥12% and ≥200 mL in the previous 12 months prior to screening, or during the screening period prior to randomization.
• ACQ-6 score ≥ 1.5 during the screening period prior to randomization.

Principal Exclusion Criteria:

• Any clinically important pulmonary disease other than asthma.
• History of cancer.
• Hospitalization or required OCS for asthma exacerbation within 6 weeks of enrolment or >3 exacerbations requiring OCS or hospitalization in the year prior to visit 1 or who had been intubated or admitted to ICU for asthma exacerbation in the year prior to enrolment.
• History of a clinically significant infection, including upper (URTI) or lower respiratory tract infection (LRTI), requiring treatment with antibiotics or antiviral medications finalized <2 weeks before visit 1 or during the run-in period.
• Current smokers or subjects with smoking history ≥10 pack-yrs, including e-cigarettes. Former smokers with a smoking history of <10 pack-yrs must have stopped for at least 6 months prior to visit 1, including e-cigarette use.
• History of chronic alcohol or drug abuse within 12 months prior to visit 1.
• Tuberculosis requiring treatment within 12 months prior to visit 1.
• History of known immunodeficiency disorder including a positive HIV test at visit 1, or the subject is taking antiretroviral medications as determined by medical history and/or subject's verbal report.
• History of anaphylaxis or documented immune complex disease (type III hypersensitivity reactions) following any biologic therapy Subject randomized in a previous Tezepelumab study or in a current study with another investigational product.
• Pregnant, breastfeeding or lactating women.

Contacts and Locations

Locations

United States, Colorado

Research Site

Denver, Colorado, United States, 80206

United States, Connecticut

Research Site

New Haven, Connecticut, United States, 06520

United States, Massachusetts

Research Site

Boston, Massachusetts, United States, 02115

United States, Pennsylvania

Research Site

Pittsburgh, Pennsylvania, United States, 15213

United States, Texas

Research Site

Galveston, Texas, United States, 77555

Canada, Alberta

Research Site

Calgary, Alberta, Canada, T2N 4Z6

Canada, British Columbia

Research Site

Vancouver, British Columbia, Canada, V5Z 1M9

Canada, Ontario

Research Site

Hamilton, Ontario, Canada, L8N 3Z5

Research Site

Ottawa, Ontario, Canada, K1H 8L6

Canada, Quebec

Research Site

Montreal, Quebec, Canada, H4A 3J1

Canada

Research Site

Quebec, Canada, G1V 4G5

Denmark

Research Site

Aarhus N, Denmark, 8200

Research Site

Hvidovre, Denmark, 2650

Research Site

København NV, Denmark, 2400

Research Site

Naestved, Denmark, 4700

Research Site

Odense C, Denmark, 5000

Research Site

Vejle, Denmark, 7100

Research Site

Ålborg, Denmark, 9000

Germany

Research Site

Frankfurt/Main, Germany, 60389

Research Site

Frankfurt, Germany, 60596

Research Site

Grosshansdorf, Germany, 22927

Research Site

Landsberg, Germany, 86899

United Kingdom

Research Site

Cambridge, United Kingdom, CB2 0QQ

Research Site

Leicester, United Kingdom, LE3 9QP

Research Site

London, United Kingdom, W1G 8HU

Research Site

Manchester, United Kingdom, M23 9QZ

Research Site

Nottingham, United Kingdom, NG5 1PB

Research Site

Oxford, United Kingdom, OX3 7FZ

Sponsors and Collaborators

AstraZeneca

Amgen

Investigators

• Principal Investigator: Chris Brightling; University of Leicester, United Kingdom

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Emson C, Diver S, Chachi L, Megally A, Small C, Downie J, Parnes JR, Bowen K, Colice G, Brightling CE. CASCADE: a phase 2, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the effect of tezepelumab on airway inflammation in patients with uncontrolled asthma. Respir Res. 2020 Oct 13;21(1):265. doi: 10.1186/s12931-020-01513-x.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT03688074
• Other Study ID Numbers: D5180C00013
• First Posted: September 28, 2018
• Last Update Posted: December 16, 2020
• Last Verified: December 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by AstraZeneca:

Asthma; Uncontrolled asthma; Severe uncontrolled asthma

Additional relevant MeSH terms:

Asthma; Lung Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Bronchial Diseases; Respiratory Hypersensitivity; Hypersensitivity; Immune System Diseases; Hypersensitivity, Immediate; Inflammation; Pathologic Processes