Efficacy and Safety of Tozorakimab in Symptomatic Chronic Obstructive Pulmonary Disease With a History of Exacerbations

Study Overview
=================
Brief Summary
-----------------
The purpose of this Phase III study is to evaluate the efficacy and safety of tozorakimab administered subcutaneously (SC) in adult participants with symptomatic COPD with a history of ≥ 2 moderate or ≥ 1 severe exacerbations of COPD in the 12 months prior to enrolment. Participants should be receiving optimised treatment with inhaled maintenance therapy (ICS/LABA/LAMA triple therapy, or dual therapy if triple is not considered appropriate) throughout at least the last 3 months prior to enrolment.

Official Title
-----------------
A Phase III, Multicentre, Randomised, Double-blind, Chronic-dosing, Parallel-group, Placebo-controlled Study to Evaluate the Efficacy and Safety of Tozorakimab in Participants With Symptomatic Chronic Obstructive Pulmonary Disease (COPD) With a History of COPD Exacerbations (MIRANDA)

Conditions
-----------------
Chronic Obstructive Pulmonary Disease (COPD)

Intervention / Treatment
-----------------
* Drug: Placebo
* Drug: Tozorakimab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participant must be ≥ 40 years of age and capable of giving signed informed consent. Documented diagnosis of COPD for at least one year prior to enrolment. Post BD FEV1/FVC < 0.70 and post-BD FEV1 >20% of predicted normal value Documented history of ≥ 2 moderate or ≥ 1 severe COPD exacerbations within 12 months prior to enrolment. Documented optimised inhaled dual or triple therapy for at least 3 months prior to enrolment. Smoking history of ≥ 10 pack-years. CAT total score ≥ 10, with each of the phlegm (sputum) and cough items with a score ≥ 2 Exclusion Criteria: Clinically important pulmonary disease other than COPD. Radiological findings suggestive of a respiratory disease other than COPD that is significantly contributing to the participant's respiratory symptoms. Radiological findings of pulmonary nodules suspicious for lung cancer, as per applicable guidances, without appropriate follow up prior to randomisation. Radiological findings suggestive of acute infection. Current diagnosis of asthma, prior history of asthma, or asthma-COPD overlap. Childhood history of asthma is allowed and defined as asthma diagnosed and resolved before the age of 18 Any unstable disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, haematological, psychiatric disorder, major physical and/or cognitive impairment that could affect safety, study findings or participants ability to complete the study. COPD exacerbation, within 2 weeks prior to randomization, that was treated with systemic corticosteroids and/or antibiotics, and/or led to hospitalization. Active significant infection within the 4 weeks prior to randomization, pneumonia within 6 weeks prior to randomization, or medical condition that predisposes the participant to infection. Suspicion of, or confirmed, ongoing SARS-CoV-2 infection. Significant COVID-19 illness within the 6 months prior to enrolment. Unstable cardiovascular disorder. Diagnosis of cor pulmonale, pulmonary arterial hypertension and/or right ventricular failure. History of active severe inflammatory bowel disease or colitis within one year prior to enrolment, or unexplained diarrhoea within the 4 weeks prior to randomisation. History of known immunodeficiency disorder, including a positive test for HIV-1 or HIV 2. History of positive test or treatment for hepatitis B or hepatitis C (except for cured hepatitis C) Evidence of active liver disease, including jaundice during screening. 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. Participants who have evidence of active TB. History of partial or total lung resection. Scheduled major surgical procedure during the course of the study. Participants that have previously received tozorakimab. Any clinically significant abnormal findings in physical examination, vital signs, ECG, or laboratory testing during the screening period, which in the opinion of the investigator may put the participant at risk because of their participation in the study, or may influence the results of the study, or the participant's ability to complete the entire duration of the study.

Ages Eligible for Study
-----------------
Minimum Age: 40 Years
Maximum Age: 130 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tozorakimab<br>Dosing subcutaneously tozorakimab | Drug: Tozorakimab<br>* Administered subcutaneously tozorakimab and placebo throughout the study.<br>|
| Placebo Comparator: Placebo<br>Dosing subcutaneously with equivalent volume to tozorakimab | Drug: Placebo<br>* Placebo administered subcutaneously, equivalent volume to tozorakimab throughout the study.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized rate of moderate to severe COPD exacerbations in participants who are former smokers. | The primary endpoint will be assessed first in the primary population (former smokers with symptomatic COPD and a history of exacerbations, on optimised treatment with maintenance inhaled therapy [triple therapy, or dual therapy if triple is not considered appropriate]). | Over 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized rate of moderate to severe COPD exacerbations in former or current smokers. | The annualized rate will be assessed in the overall population of participants including current and former smokers with symptomatic COPD and history of exacerbations, on optimised treatment with maintenance inhaled therapy. | Over 52 weeks | 
| Change from baseline in SGRQ total score from in former smokers | Difference in mean change from baseline in SGRQ total score in former smokers. | Over 52 weeks | 
| Change from baseline in SGRQ total score from in the overall population of current and former smokers. | Difference in mean change from baseline in SGRQ total score in the overall population of current and former smokers. | Over 52 weeks | 
| Annualized rate of severe COPD exacerbations in former smokers | The rate ratio of severe COPD exacerbations will be assessed in former smokers. | Variable duration period up to study completion, maximum of approximately 3 years | 
| Annualized rate of severe COPD exacerbations in former or current smokers | The rate ratio of severe COPD exacerbations will be assessed in the overall population of current and former smokers. | Variable duration period up to study completion, maximum of approximately 3 years | 
| Change from baseline in E-RS:COPD total score in former smokers | Difference in mean change in E-RS:COPD total score from baseline in former smokers. | Over 52 weeks | 
| Change from baseline in E-RS:COPD total score in former or current smokers | Difference in mean change in E-RS:COPD total score from baseline in the overall population of current and former smokers. | Over 52 weeks | 
| Change from baseline in pre-bronchodilator, pre dose trough FEV1 (mL) in former smokers | Change from baseline in pre-bronchodilator, pre dose trough FEV1 (mL) in former smokers. | Week 52, over 52 weeks | 
| Change from baseline in pre-bronchodilator, pre dose trough FEV1 (mL) in former or current smokers | Change from baseline in pre-bronchodilator, pre dose trough FEV1 (mL) in the overall population of current and former smokers. | Week 52, over 52 weeks | 
| Time to first moderate to severe COPD exacerbation | Time to first moderate to severe COPD exacerbation compared with placebo. | Over 52 weeks | 
| Time to first severe COPD exacerbation | Time to first severe COPD exacerbation compared with placebo. | Variable duration period up to study completion, maximum of approximately 3 years | 
| Change from baseline in CAT total score | Change from baseline in CAT total score compared with placebo. | Week 52 | 
| Proportion of participants achieving MCID in CAT score | Proportion of participants achieving MCID in CAT score (percentage of participants with a decrease in CAT total score of ≥ 2 points from baseline). | Week 52 | 
| Proportion of participants achieving MCID in SGRQ total score | Proportion of participants achieving MCID in SGRQ score (percentage of participants with a decrease in SGRQ total score of ≥ 4 points from baseline). | Week 52 | 
| Proportion of participants achieving MCID in E-RS:COPD total score | Proportion of participants achieving MCID in E-RS:COPD total score (percentage of participants with a decrease in E-RS:COPD total score of ≥ 2 points from baseline). | Week 52 | 
| Annualized rate of healthcare resource utilization | Annualized rate of healthcare resource utilization. | Variable duration period up to study completion, maximum of approximately 3 years | 
| Change from baseline in rescue medication | Change from baseline (difference in mean number of puffs/day) in rescue medication use. | Over 52 weeks | 
| Trough serum concentrations of tozorakimab | Pharmacokinetics: concentrations of tozorakimab in trough serum. | Over 52 weeks | 
| Presence of anti-drug antibodies | Immunogenicity: presence of tozorakimab anti-drug antibodies in blood serum. | Over 52 weeks | 
| Time to death | Time to death (all-cause mortality) | Variable duration period up to study completion, maximum of approximately 3 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Chronic Obstructive Pulmonary Disease, COPD, tozorakimab, MEDI3506, exacerbations, LABA/LAMA, ICS