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CASCADE: a phase 2, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the effect of
Claire Emson1, Sarah Diver2, Latifa Chachi2
1Translational Science and Experimental Medicine, Research & Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA. Claire.emson@astrazeneca.com.
Background:
Patients with severe, uncontrolled asthma, particularly those with a non-eosinophilic phenotype, have a great unmet need for new treatments that act on a broad range of inflammatory pathways in the airway. Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin, an epithelial cytokine. In the PATHWAY phase 2b study (NCT02054130), tezepelumab reduced exacerbations by up to 71% in adults with severe, uncontrolled asthma, irrespective of baseline eosinophilic inflammatory status. This article reports the design and objectives of the phase 2 CASCADE study.
Methods:
CASCADE is an ongoing exploratory, phase 2, randomized, double-blind, placebo-controlled, parallel-group study aiming to assess the anti-inflammatory effects of tezepelumab 210 mg administered subcutaneously every 4 weeks for 28 weeks in adults aged 18-75 years with uncontrolled, moderate-to-severe asthma. The primary endpoint is the change from baseline to week 28 in airway submucosal inflammatory cells (eosinophils, neutrophils, T cells and mast cells) from bronchoscopic biopsies. Epithelial molecular phenotyping, comprising the three-gene-mean technique, will be used to assess participants' type 2 (T2) status to enable evaluation of the anti-inflammatory effect of tezepelumab across the continuum of T2 activation. Other exploratory analyses include assessments of the impact of tezepelumab on airway remodelling, including reticular basement membrane thickening and airway epithelial integrity. At the onset of the COVID-19 pandemic, the protocol was amended to address the possibility that site visits would be limited. The amendment allowed for: at-home dosing of study drug by a healthcare professional, extension of the treatment period by up to 6 months so patients are able to attend an onsite visit to undergo the end-of-treatment bronchoscopy, and replacement of final follow-up visits with a virtual or telephone visit.
Discussion:
CASCADE aims to determine the mechanisms by which tezepelumab improves clinical asthma outcomes by evaluating the effect of tezepelumab on airway inflammatory cells and remodelling in patients with moderate-to-severe, uncontrolled asthma. An important aspect of this study is the evaluation of the anti-inflammatory effect of tezepelumab across patients with differing levels of eosinophilic and T2 inflammation.
Trial Registration:
NCT03688074 (ClinicalTrials.gov). Registered 28 September 2018.
Insights
Tezepelumab, a new asthma treatment, targets airway inflammation by blocking thymic stromal lymphopoietin. The CASCADE study evaluates its anti-inflammatory effects across different asthma phenotypes.
Area of Science:
- Pulmonology
- Immunology
- Clinical Trials
Background:
- Severe, uncontrolled asthma lacks effective treatments, especially for non-eosinophilic phenotypes.
- Thymic stromal lymphopoietin (TSLP) is a key epithelial cytokine in airway inflammation.
- Previous studies (e.g., PATHWAY) showed tezepelumab reduced exacerbations in severe asthma.
Purpose of the Study:
- To assess the anti-inflammatory effects of tezepelumab in moderate-to-severe uncontrolled asthma.
- To evaluate tezepelumab's impact on airway inflammatory cells and remodelling.
- To understand tezepelumab's efficacy across a spectrum of type 2 (T2) inflammation.
Main Methods:
- Phase 2, randomized, double-blind, placebo-controlled study (CASCADE).
- Tezepelumab 210 mg administered subcutaneously every 4 weeks for 28 weeks.
- Primary endpoint: change in airway submucosal inflammatory cells (eosinophils, neutrophils, T cells, mast cells) via bronchoscopic biopsies.
- Epithelial molecular phenotyping to assess T2 status.
- Protocol amendments due to COVID-19 included at-home dosing and extended treatment periods.
Main Results:
- Study is ongoing; results not yet available.
Conclusions:
- CASCADE aims to elucidate the mechanisms of tezepelumab's clinical benefits in asthma.
- The study will evaluate tezepelumab's effects on airway inflammation and remodelling.
- Key focus on understanding tezepelumab's anti-inflammatory action across varying T2 and eosinophilic inflammation levels.
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