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

Tracking Information

• First Submitted Date: September 26, 2018
• First Posted Date: September 28, 2018
• Last Update Posted Date: December 16, 2020
• Actual Study Start Date: November 2, 2018
• Actual Primary Completion Date: November 16, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 21, 2020)

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.

Original Primary Outcome Measures (submitted: September 26, 2018)

The change from baseline in number of airway submucosal inflammatory cells/mm2 of bronchoscopic biopsies. [ Time Frame: Week 28 ]

The change from baseline in number of airway submucosal inflammatory cells/mm2 of bronchoscopic biopsies.

Current Secondary Outcome Measures (submitted: May 21, 2020)

• 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
• 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
• 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

Original Secondary Outcome Measures (submitted: September 26, 2018)

• The change in reticular basement membrane (RBM) thickness from baseline, determined by microscopic evaluation of bronchoscopic biopsies [ Time Frame: Week 28 ]
  The change in reticular basement membrane (RBM) thickness from baseline, determined by microscopic evaluation of bronchoscopic biopsies
• The change in % airway epithelial integrity from baseline determined by microscopic evaluation of bronchoscopic biopsies [ Time Frame: Week 28 ]
  The change in % airway epithelial integrity from baseline determined by microscopic evaluation of bronchoscopic biopsies
• 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: Week 28 ]
  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

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study to Evaluate Tezepelumab on Airway Inflammation in Adults With Uncontrolled Asthma (CASCADE)
• 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)
• 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.
• 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 Type: Interventional
• Study Phase: Phase 2

Study Design

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

Condition

• Asthma
• Bronchial Diseases
• Respiratory Tract Diseases
• Lung Diseases, Obstructive
• Lung Diseases
• Respiratory Hypersensitivity
• Hypersensitivity, Immediate
• Hypersensitivity
• Immune System Diseases

Intervention

• Biological: Tezepelumab
  Tezepelumab subcutaneous injection
• Other: Placebo
  Placebo subcutaneous injection

Study Arms

• Experimental: Tezepelumab
  Tezepelumab subcutaneous injection
  Intervention: Biological: Tezepelumab
• Placebo Comparator: Placebo
  Placebo subcutaneous injection
  Intervention: Other: Placebo

• Publications *: 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 16, 2020): 116
• Original Estimated Enrollment (submitted: September 26, 2018): 110
• Actual Study Completion Date: November 16, 2020
• Actual Primary Completion Date: November 16, 2020 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, Denmark, Germany, United Kingdom, United States

Administrative Information

• NCT Number: NCT03688074
• Other Study ID Numbers: D5180C00013
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• 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

• IPD Sharing Statement: Not Provided
• Responsible Party: AstraZeneca
• Study Sponsor: AstraZeneca
• Collaborators: Amgen

Investigators

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

• PRS Account: AstraZeneca
• Verification Date: December 2020