A Phase IIb, Multicentre, Double-blind, Placebo-controlled Dose Range Finding Study to Assess Efficacy and Safety of Tozorakimab in Adult Participants With Uncontrolled Asthma on Medium-to-High Dose Inhaled Corticosteroids (UMBRIEL)
Overview
- Phase
- Phase 2
- Status
- Recruiting
- Sponsor
- AstraZeneca AB
- Enrollment
- 540
- Locations
- 12
- Primary Endpoint
- To evaluate the effect of two dose levels of tozorakimab compared with placebo on annualised rate of severe asthma exacerbations
Overview
Brief Summary
This Phase IIb study is designed to demonstrate the efficacy and safety and determine the dose of tozorakimab in adult participants with uncontrolled moderate-to-severe asthma (receiving medium-to-high dose inhaled corticosteroid / long-acting beta-2 agonist). The study population was identified based on tozorakimab mechanism of action and unmet need in adult asthma patients who remain uncontrolled on standard of care. Based on the findings of the asthma Phase II study (Study D181C00001), participants are included from across the spectrum of baseline eosinophil levels. Asthma is a chronic inflammatory disease of the airways characterised by bronchial hyperreactivity and reversible airflow limitation. India has a high and growing burden of asthma: according to the Global Burden of Disease Report 2019, India ranks number one in the world in terms of burden, disability-adjusted life years and deaths related to asthma. Over 34 million people in India have asthma, and although this reflects only 13 percent of the world’s population with asthma, 42 percent of global asthma deaths occur in India. People with asthma in India also suffer a disproportionately high burden of day-to-day symptoms, effects on quality of life, and absence from school and work. In low-income households, even minor levels of healthcare utilization can be financially catastrophic. For patients who are symptomatic on inhaled corticosteroid monotherapy, the addition of long-acting beta-2 agonist is the recommended treatment. However, there are many patients with asthma who are still symptomatic despite treatment with inhaled corticosteroid and long-acting beta-2 agonist combinations (Rabe et al 2004). Biologic therapies that inhibit specific molecular targets, including Immunoglobulin E and T-helper 2 cytokines and their respective receptors are increasingly available, but are currently mainly indicated for subsets of patients with uncontrolled, moderate-to-severe asthma, despite medium to high dose inhaled corticosteroid. Omalizumab is indicated for patients with moderate-to-severe persistent asthma with proven reactivity to an aeroallergen. Benralizumab and Mepolizumab are indicated for add-on maintenance treatment of patients with severe or moderate-to-severe asthma with an eosinophilic phenotype. There remains significant unmet need in asthma patients with blood eosinophil counts less than 300 cells per microliter at baseline and on improving aspects of asthma other than exacerbations including lung function and patient related outcomes (Doroudchi et al 2020). There are several recommended step-up therapy options available. However, despite the introduction of approved biologics, a proportion of patients continue to experience exacerbations, indicating that there remains an unmet medical need in the severe asthma space. Various asthma phenotypes have been described to have an increased and modifiable risk of exacerbations, identified by key prognostic and theragnostic biomarker, such as blood eosinophils and Fractional exhaled Nitric Oxide (FeNO), as well as clinical risk factors (Couillard et al 2022). In recent years, treatment goals in asthma have also shifted towards achieving clinical remission, though a universally accepted definition has yet to be established. Hence, substantial unmet need remains
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Masking
- Participant and Investigator Blinded
Eligibility Criteria
- Ages
- 18.00 Year(s) to 75.00 Year(s) (—)
- Sex
- All
Inclusion Criteria
- •Participants are eligible to be included in the study only if all of the following criteria apply: Informed Consent Provision of signed and dated written informed consent prior to any study-specific procedures.
- •Optional: Provision of signed and dated written Optional Genetic Research Information informed consent before the sample collection for optional genetic research that supports the Genomic Initiative.
- •Age Adults aged 18 to 75, inclusive when signing the informed consent at V
- •For Republic of Korea only, participants must be greater than or equal to 19 to 75 years old, inclusive.
- •Type of Participant and Disease Characteristics Documented physician-diagnosis of asthma for at least 12 months prior to V1, according to GINA guidelines (GINA 2024), and as evidenced by any of the following: Post-BD reversibility of FEV1 greater than or equal to 12percentage and greater than or equal to 200mL within 5 years prior to V1 or at V1 Treated with medium- or high-dose ICS (as per GINA 2024 report) in combination with LABA (GINA step 4 or 5 therapy); the dose of ICS must be stable for at least 30 days prior to V
- •The ICS can be contained within an ICS-LABA or ICS-LABA-LAMA fixed- dose combination product.
- •Treatment with additional asthma controller therapies (eg, LAMA, OCS) at a stable dose greater than or equal to 3 months prior to V1, with the intent to continue with the controller on a stable dose throughout the study, is allowed.
- •Individual component changes or switches between devices are allowed as long as the participant remains on the same class therapies in equivalent doses.
- •Demonstration of uncontrolled asthma through ACQ-6 score greater than or equal to 1.5 at screening and randomisation.
- •Pre-bronchodilator FEV1 greater than or equal to 40percentage to less than or equal to 90percentage of predicted normal at both screening and randomisation.
Exclusion Criteria
- •Participants are excluded from the study if any of the following criteria apply: 1 BMI greater than 40 kg m2 at V1 2 Participants who are unable to demonstrate ability to perform acceptable inhaler and spirometry techniques. Medical Conditions 3 Major surgery within 8 weeks prior to V1, or planned major inpatient surgery, major procedure or hospitalisation during the screening, intervention, or follow-up periods. 4 Any other clinically relevant abnormal findings on vital signs, physical examination or laboratory testing, including haematology, coagulation, serum chemistry, urinalysis or ECG during the screening period that, in the opinion of the investigator or medical monitor might compromise the safety of the participant in the study or interfere with evaluation of the study intervention. Abnormal findings include, but are not limited to: (a) ALT or AST greater than 2 × ULN (b) TBL greater than 1.5 × ULN (unless due to Gilbert s disease) 5 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. 6 Unstable cardiovascular disorders, including but not limited to ischaemic heart disease, arrhythmia, cardiomyopathy, heart failure (NYHA class IV), uncontrolled hypertension as defined by the Investigator, or any other relevant cardiovascular disorder as judged by the Investigator; or any ECG abnormality obtained during the screening/run-in period that in Investigator s judgement may put the participant at risk or negatively affect the outcome of the study. 7 Completed treatment for respiratory infection and/or asthma exacerbation with systemic corticosteroids and/or antibiotics/antivirals in the 4 weeks prior to V
- •8 Clinically significant pulmonary disease other than asthma, including but not limited to those with co-existent COPD. 9 History of severe episodes of colitis within one year before enrolment, active inflammatory bowel disease, high risk of having severe flare-ups during the study, or unexplained diarrhoea within the 4 weeks before randomisation. 10 History of clinically significant aortic stenosis or pulmonary arterial hypertension 11 Participants who, in the opinion of the Investigator, have evidence of active tuberculosis (TB) or are currently on treatment for active or latent TB. Investigation for active or latent TB, with interferon-gamma release assay (IGRA) and/or chest X-ray, should only be considered if deemed clinically indicated by the Principal Investigator. 12 Medical history of or treatment for hepatitis B or hepatitis C, except for cured hepatitis C, as defined by: (a) Positive test for HBsAg (b) Positive test for anti-HBc: Participants who test positive for anti-HBc antibody but negative for HBsAg may be enrolled if their hepatitis virus DNA test result is negative. (c) Positive test for anti-hepatitis C antibody: Participants who test positive for anti- hepatitis C antibody may be enrolled if their hepatitis C viral RNA test result is negative in the absence of cirrhosis. 13 History of known immunodeficiency disorder, including a positive test for HIV-1 or HIV-
- •14 Current smokers, former smokers with greater than 10 pack-years history, or former smokers who stopped smoking less than 6 months before V1 (including all forms of tobacco, e-cigarettes (vaping), and other recreational drugs, including marijuana). 15 History of current or previous alcohol or drug misuse in the last 12 months prior to V
- •16 Malignancy, current or within the past 5 years, except for adequately treated non-invasive basal cell and squamous cell carcinoma of the skin and cervical carcinoma-in-situ treated with apparent success more than one year prior to enrolment. Suspected malignancy or undefined neoplasms. 17 Known history of anaphylaxis that required the use of epinephrine/adrenaline or hospitalisation. 18 Known history of immune complex disease (Type III hypersensitivity reactions) to monoclonal or polyclonal antibody administration. 19 A helminth parasitic infection diagnosed within 24 weeks of V1 that has not been treated or has not responded to standard of care therapy 20 Use of as-required anti-inflammatory ICS therapy for asthma (including anti- inflammatory reliever/maintenance and reliever therapy) within 30 days of V
- •Note: Participants can be converted to an equivalent twice daily dose of ICS/LABA and considered for screening after greater than or equal to 30 days. 21 Treatment with marketed or investigational systemic biologics within 4 months, or inhaled biologics for asthma within 4 weeks, or a minimum of 5 half-lives, whichever is longer, prior to V
- •Exceptions include:.
- •Participants on stable therapy for at least 3 months before randomisation, who intend to stay on treatment throughout the study with marketed biologics that are not likely to interfere with the safety assessment and/or efficacy of tozorakimab for the treatment of osteoporosis, migraine pain, T2DM, obesity, ocular, cardiovascular, or metabolic diseases are allowed to participate in the study. Examples of approved marketed biologics include: denosumab, romosozumab, CGRP-antagonists, GLP-1 agonists, GIP/GLP-1 agonists, PCSK9 inhibitors, recombinant botulinum neurotoxin, mAbs targeting SARS-COV-2 viral components (marketed or authorised), recombinant erythropoietin, VEGF inhibitors for ocular diseases.
- •Medications not listed here should be discussed with the study team. 22 Use of the following therapeutic interventions within the specified time before screening: (a) Participants who have previously received tozorakimab. (b) Increased or new systemic steroid use within 4 weeks prior to the Screening Visit. (c) Live, attenuated vaccine in the 4 weeks prior to randomisation (Note: Vaccines with adenoviral vectors that are unable to replicate, eg, ChAdOx1, are not considered live or attenuated). (d) Any systemic immunosuppressive therapy within 3 months of randomisation. (e) Allergen immunotherapy within 3 months of randomisation, except for stable maintenance dose allergen-specific immunotherapy started 4 weeks prior to V
- •(f) Bronchial thermoplasty in the last 12 months prior to V
- •N.B. Intranasal / topical steroid use is permitted, provided that there has been a stable treatment regimen for at least 4 weeks. Other exclusions 23 Donation of blood (greater than or equal to 450 mL) within 3 months or donation of plasma within 14 days before V1 24 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca and/or vendor and/or site staff). 25 Receipt of any investigational non-biologic product within 30 days or 5 half-lives prior to randomisation, whichever is longer. Lifestyle Considerations Meals and Dietary Restrictions.
Outcomes
Primary Outcomes
To evaluate the effect of two dose levels of tozorakimab compared with placebo on annualised rate of severe asthma exacerbations
Time Frame: Population: Participants with uncontrolled moderate to severe asthma and greater than or equal to 1 severe exacerbation a within 12 months prior to screening. | Endpoint: Annualised rate of severe asthma exacerbations Summary measure: Rate ratio tozorakimab versus placeb Intercurrent event strategy - Treatment policy Supportive analysis: While-on-treatment
Secondary Outcomes
- To evaluate the effect of two dose levels of tozorakimab as compared to placebo on annualised rate of severe asthma exacerbations in participants with uncontrolled moderate to severe asthma and baseline eosinophils less than 300 cells per microliter and history of greater than or equal to 2 severe exacerbations within 12 months prior to screening.(Population: Participants with uncontrolled moderate to severe asthma and baseline eosinophils less than 300 cells per microliter and history of greater than or equal 2 severe exacerbations within 12 months prior to screening.)
- To evaluate the effect of two dose levels of tozorakimab compared to placebo on time to first severe asthma exacerbations.(Population: Participants with uncontrolled moderate-to-severe asthma and greater than or equal to 1 severe exacerbation within 12 months prior to screening Endpoint: Time-to-first severe asthma exacerbation)
- To evaluate the effect of two dose levels of tozorakimab as compared to placebo on lung function.(Population: Participants with uncontrolled moderate to severe asthma and greater than or equal to 1 severe exacerbation within 12 months prior to screening Endpoints:)
- To evaluate the effect of two dose levels of tozorakimab as compared to placebo on asthma symptoms and control.(Population: Participants with uncontrolled moderate-to-severe asthma and greater than or equal to 1 severe exacerbation within 12 months prior to screening.)
- To evaluate the PK and immunogenicity of tozorakimab.(Population: Participants with uncontrolled moderate-to-severe asthma)
Investigators
Dr Randeep Guleria
Medanta- The Medicity