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

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

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

Conditions
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Chronic Obstructive Pulmonary Disease (COPD)

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


Participation Criteria
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Eligibility Criteria
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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 optimized inhaled dual or triple therapy at a stable dose 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. 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 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. 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. Active vaping of any products or using smoked marijuana within the 6 months prior to randomization and during the study.

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tozorakimab Dose 1<br>Dosing subcutaneously tozorakimab Dose 1 and placebo | Drug: Tozorakimab<br>* Administered subcutaneously tozorakimab Dose 1 and placebo through Week 52.<br>|
| Experimental: Tozorakimab Dose 2<br>Dosing subcutaneously tozorakimab Dose 2 | Drug: Tozorakimab<br>* Administered subcutaneously tozorakimab Dose 2 through Week 52.<br>|
| Placebo Comparator: Placebo<br>Dosing subcutaneously with equivalent volume to tozorakimab | Drug: Placebo<br>* Placebo administered subcutaneously, equivalent volume to tozorakimab through week 52.<br>|

What is the study measuring?
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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]) and then assessed in the overall population of participants. | 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 | 
| Time to first moderate to severe COPD exacerbation in former smokers. | To explore the extent to which treatment with each dose of tozorakimab delays the time to first exacerbation compared with placebo in former smokers. | over 52 weeks | 
| Mean change from baseline in pre-BD, pre-dose trough FEV1 (mL) in former smokers. | Change from baseline in pre-bronchodilator, pre dose trough FEV1 (mL) in former smokers. | Week 52, or over 52 weeks | 
| Mean change from baseline in pre-BD, pre-dose trough FEV1 (mL) in the overall population of current and former smokers. | Change from baseline in pre-bronchodilator, pre dose trough FEV1 (mL) in the overall population of current and former smokers. | Week 52, or over 52 weeks | 
| Percentage of responders achieving MCID in E-RS:COPD total score in former smokers | Responder analyses for E-RS:COPD total score at Week 52 based upon a ≥ 2 point improvement (decrease) from baseline in former smokers. | Week 52 | 
| Percentage of responders achieving MCID in E-RS:COPD total score in the overall population of current and former smokers. | Responder analyses for E-RS:COPD total score at Week 52 based upon a ≥ 2 point improvement (decrease) from baseline in the overall population of current and former smokers. | Week 52 | 
| Mean 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 | 
| Mean change from baseline in E-RS:COPD total score in the overall population of current and former 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 | 
| Percentage of responders achieving MCID in SGRQ total score in former smokers. | Percentage of participants with a decrease in SGRQ total score of ≥ 4 points from baseline in former smokers. | Week 52 | 
| Percentage of responders achieving MCID in SGRQ total score in the overall population of current and former smokers. | Percentage of participants with a decrease in SGRQ total score of ≥ 4 points from baseline in the overall population of current and former smokers. | Week 52 | 
| Mean 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 | 
| Mean 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 | 
| Time to first severe COPD exacerbation in former smokers. | To evaluate hazard ratio of first severe COPD exacerbation in 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. | over 52 weeks | 
| Change from baseline in CAT total score. | Analyses of change from baseline in CAT total score in former smokers. | Week 52 | 
| Percentage of participants with a decrease in CAT total score in former smokers. | Proportion of participants achieving MCID in CAT total score, a decrease in CAT total score of ≥ 2 points from baseline in former smokers. | Week 52 | 
| Proportion of participants having ≥ 1 healthcare resource utilization type in former smokers. | Proportion of participants having ≥ 1 healthcare resource utilization type in former smokers. | over 52 weeks | 
| Annualized rate of healthcare resource utilization in former smokers. | Annualized rate of healthcare resource utilization in former smokers. | over 52 weeks | 
| The change from baseline in mean number of puffs per day in rescue use in former smokers. | Difference in mean number of puffs per day from baseline. | 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 60 weeks | 

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