A Phase III, Multicentre, Randomised, Double-blind, Chronic-dosing, Parallel-group, Placebo-controlled Extension Study to Evaluate the Long-term Efficacy and Safety of Tozorakimab in Participants with Chronic Obstructive Pulmonary Disease (COPD) with a History of Exacerbations (PROSPERO)

The primary objective of this study is to evaluate the long-term effect of tozorakimab as an add-on to standard of care compared with standard of care plus placebo on the rate of severe chronic obstructive pulmonary disease exacerbations in former smokers. This endpoint is clinically relevant as severe exacerbations represent critical events that significantly impact patient morbidity, mortality, and healthcare resource utilization in COPD populations with a history of exacerbations.

The secondary objectives include:

• To evaluate the long-term effect of tozorakimab as an add-on to standard of care compared with standard of care plus placebo on the rate of severe COPD exacerbations in former or current smokers.

• To evaluate the long-term effect of tozorakimab as an add-on to standard of care compared with standard of care plus placebo on the time to first severe COPD exacerbation.

• To evaluate the long-term effect of tozorakimab as an add-on to standard of care compared with standard of care plus placebo on the time to first moderate to severe COPD exacerbation.

• To evaluate the long-term effect of tozorakimab as an add-on to standard of care compared with standard of care plus placebo on the rate of moderate to severe COPD exacerbations.

• To evaluate the effect of tozorakimab as an add-on to standard of care compared with standard of care plus placebo on time to all-cause death.

• To evaluate the pharmacokinetics and immunogenicity of tozorakimab.

• To evaluate the long-term effect of tozorakimab as an add-on to standard of care compared with standard of care plus placebo on COPD-related healthcare utilization.

The clinical trial enrolled a total of **968 participants** diagnosed with **Chronic Obstructive Pulmonary Disease (COPD)**. The study population included both **male and female subjects** comprising **adults** and **elderly individuals**. Participants were selected based on their completion of the treatment period in predecessor studies without premature discontinuation from investigational product, and having received their last dose of investigational product within the previous 12 weeks without withdrawal from the predecessor study. The trial population consisted of **former smokers**. Female participants of childbearing potential were required to have a negative urine pregnancy test at the initial visit and demonstrate willingness to continue using contraceptive methods as agreed to for the predecessor OBERON or TITANIA studies. All participants were required to be capable of providing signed informed consent. The trial included a **vulnerable population**.

This is a Phase III, multicentre, randomized, double-blind, chronic-dosing, parallel-group, placebo-controlled extension study designed to evaluate the long-term efficacy and safety of tozorakimab in participants with Chronic Obstructive Pulmonary Disease with a history of exacerbations. The study will assess tozorakimab as an add-on to standard of care compared with standard of care plus placebo. The investigational medicinal product, tozorakimab, is administered as a solution for injection via subcutaneous route. A matching placebo will be administered to the control group. Additionally, salbutamol, a short-acting beta2-agonist, will be used as an auxiliary medicinal product administered via inhalation, with a maximum daily dose of 800 µg and a maximum total dose of 1600 µg. The maximum treatment period for all investigational products is 52 weeks. The study commenced recruitment in April 2023 with an estimated completion date in February 2026.

The primary objective is to evaluate the long-term effect of tozorakimab on the rate of severe COPD exacerbations in former smokers. The primary endpoint is the annualized rate of severe COPD exacerbation for tozorakimab versus placebo in former smokers. Secondary endpoints include the annualized rate of severe COPD exacerbations in former or current smokers, time to first severe COPD exacerbations in both former smokers and in former or current smokers combined, time to first moderate to severe COPD exacerbation, annualized rate of moderate-to-severe COPD exacerbations, time to death (all-cause mortality), pharmacokinetics, immunogenicity, assessment of long-term safety and tolerability of tozorakimab, and annualized rate of COPD exacerbations requiring hospitalization and/or emergency room/emergency department visits in both former smokers and in former or current smokers combined.

Eligible participants are those who have completed the treatment period and have not been prematurely discontinued from investigational product in the predecessor studies (OBERON or TITANIA). Participants must have received their last dose of investigational product in the predecessor studies within the previous 12 weeks and must not have been withdrawn from the predecessor study. Female participants of childbearing potential must have a negative urine pregnancy test at Visit 1 and must be willing to continue using contraceptive methods as agreed to for the predecessor studies. All participants must be capable of giving signed informed consent.

Participant involvement in this extension study is expected to last up to 52 weeks of treatment. The study involves a sequence of visits beginning with Visit 1, which serves as the screening and enrollment visit for participants transitioning from predecessor studies. Subsequent follow-up visits will occur at regular intervals throughout the treatment period to monitor efficacy, safety, and tolerability, as well as to collect samples for pharmacokinetic and immunogenicity assessments. The end-of-study visit will be conducted upon completion of the 52-week treatment period. Participants may be subject to early termination from the study under conditions such as withdrawal of consent, safety concerns, loss to follow-up, or investigator decision based on clinical judgment.

The experimental medication under investigation is tozorakimab, a protein-based therapeutic agent administered as a solution for injection via the subcutaneous route. The maximum daily dose is 300 milligrams, with a maximum total dose of 300 milligrams per administration. The treatment period extends up to 52 weeks. Tozorakimab is delivered using a device for injection administration and serves as the primary test product in this clinical trial, added to standard-of-care therapy for participants with chronic obstructive pulmonary disease with a history of exacerbations.

The comparator treatment consists of a placebo matching tozorakimab, administered subcutaneously to maintain blinding in this double-blind study design. The placebo has a maximum daily dose of 300 milligrams and a maximum total dose of 300 milligrams per administration, with an identical treatment period of 52 weeks. The placebo is also administered in addition to standard-of-care therapy to ensure consistency across treatment arms.

An auxiliary medication permitted in the study is salbutamol, also known by the synonym albuterol, a chemical substance classified as a short-acting beta2-agonist. Salbutamol is administered via inhalation with a maximum daily dose of 800 micrograms and a maximum total dose of 1600 micrograms. The treatment period for salbutamol is also 52 weeks. This medication represents standard-of-care therapy for symptom relief in participants with chronic obstructive pulmonary disease and is available to all participants regardless of treatment arm assignment.

Efficacy will be assessed through multiple parameters evaluating chronic obstructive pulmonary disease exacerbations and clinical outcomes. The primary endpoint is the annualized rate of severe COPD exacerbation for tozorakimab versus placebo in former smokers. Secondary efficacy endpoints include the annualized rate of severe COPD exacerbations in former or current smokers, time to first severe COPD exacerbations in former smokers, time to first severe COPD exacerbations in former or current smokers, time to first moderate to severe COPD exacerbation, and annualized rate of moderate-to-severe COPD exacerbations. Additional secondary endpoints encompass time to death (all-cause mortality), annualized rate of COPD exacerbations requiring hospitalization and/or emergency room/emergency department visits in former smokers, and annualized rate of COPD exacerbations requiring hospitalization and/or emergency room/emergency department visits in former or current smokers. Pharmacokinetics and immunogenicity will also be evaluated as part of the secondary efficacy assessments. The maximum treatment period for efficacy evaluation is 52 weeks.