AstraZeneca Launches Phase 3 THARROS Trial of Breztri to Reduce Cardiopulmonary Events in COPD

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AstraZeneca announced on March 13 that Breztri, the inhaled triple therapy (budesonide/glycopyrronium/formoterol fumarate [BGF]) indicated for maintenance treatment of chronic obstructive pulmonary disease (COPD), will be evaluated in the first-ever prospective phase 3 clinical trial to investigate the potential of an inhaled combination therapy to improve cardiopulmonary outcomes in people with COPD.¹

In its announcement of the phase 3 THARROS trial, AstraZeneca described the population to be enrolled in the study as individuals with COPD who also have elevated cardiopulmonary risk, "irrespective of their exacerbation history."¹

THARROS will pursue a novel composite endpoint that combines cardiac and respiratory outcomes, ie, time to first cardiac event, severe COPD exacerbation, or cardiopulmonary death, which also serves as the trial's primary endpoint, according to AstraZeneca.¹ The randomized multicenter double blind parallel group trial will enroll approximately 5000 individuals aged 40 to 80 years with COPD and cardiopulmonary risk. The random treatment assignment will be to either BGF fixed dose triple therapy or a dual bronchodilator comprised ofglycopyrronium/formoterol fumarate.¹

The increased risks of both pulmonary and cardiac events, including severe or fatal COPD exacerbations, are even higher following an initial disease exacerbation and can remain elevated for up to a year;² moreover, a single COPD exacerbation increases the risk of myocardial infarction two-fold.³

The 2024 GOLD (Global Initiative for Chronic Obstructive Lung Disease) report underscores the important effects of inhaled triple combination therapies on mortality, according to Fernando Martinez, MD, MS, chief, division of pulmonary and critical care medicine at Weill Cornell Medicine and New York-Presbyterian Hospital, and international coordinating investigator on the THARROS trial.¹ "If positive, the THARROS trial will provide critical evidence about the potential of single inhaler, triple combination therapy to reduce severe cardiopulmonary events and further advance treatment goals in COPD, including for patients with no history of exacerbations, for whom no evidence currently exists.”1

David Berg MD, MPH, associate physician in cardiovascular and critical care medicine, Brigham and Women’s Hospital, Harvard Medical School, cites the contribution of large cardiovascular disease outcomes trials to understanding the "potentially broad impact" of the investigational therapies, adding that the THARROS trial "is seeking to provide first-of-its-kind evidence to support a strategy of comprehensive cardiopulmonary risk reduction with a triple therapy.”¹

AstraZeneca also announced the first dosing in a second phase 3 trial, ATHLOS, which is investigating triple therapy BGF against budesonide/formoterol fumarate (BFF) or placebo on cardiopulmonary parameters including hyperinflation and exercise endurance time, in participants with COPD who have exertional breathlessness despite treatment with monotherapy or dual COPD maintenance therapy. This study will include 180 patients aged 40 to 80 years.¹

References

1. AstraZeneca announces initiation of THARROS – a Phase III clinical trial investigating the potential of BREZTRI to improve cardiopulmonary outcomes in people with COPD. News release. AstraZeneca. March 13, 2024. Accessed March 14, 2024. https://www.astrazeneca-us.com/media/press-releases/2024/astrazeneca-announces-initiation-of-tharros-a-phase-iii-clinical-trial-investigating-the-potential-of-breztri-to-improve-cardiopulmonary-outcomes-in-people-with-copd.html

2. Kunisaki KM, Dransfield MT, Anderson JA, et al. Exacerbations of Chronic Obstructive Pulmonary Disease and Cardiac Events. A Post Hoc Cohort Analysis from the SUMMIT Randomized Clinical Trial. Am J Respir Crit Care Med.2018;198(1):51-57.

3. Halpin DMG, Decramer M, Celli BR, et al. Effect of a single exacerbation on decline in lung function in COPD. Resp Med. 2017;128: 85-91.

4. ClinicalTrials.gov. A Study to Evaluate the Effect of Budesonide, Glycopyrronium, Formoterol Fumarate (BGF) Metered Dose Inhaler (MDI), Budesonide and Formoterol Fumarate (BFF) MDI and Placebo MDI on Exercise Parameters in Participants with Chronic Obstructive Pulmonary Disease (COPD). (ATHLOS). Accessible at: https://classic.clinicaltrials.gov/ct2/show/NCT06067828