CTRI/2024/12/078263 [Registered on: 17/12/2024] Trial Registered Prospectively
Last Modified On:
17/09/2025
Post Graduate Thesis
No
Type of Trial
Interventional
Type of Study
Drug
Study Design
Randomized, Parallel Group Trial
Public Title of Study
A Study Evaluating the Efficacy of Breztri/Trixeo on Cardiopulmonary Outcomes
in Chronic Obstructive Pulmonary Disease
Scientific Title of Study
A Randomized, Double-blind, Parallel Group, Multi-center, Phase III Study to Assess the Efficacy of Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhaler Relative to Glycopyrronium and Formoterol Fumarate MDI on Cardiopulmonary Outcomes in Chronic Obstructive Pulmonary Disease (THARROS)
Trial Acronym
THARROS
Secondary IDs if Any
Secondary ID
Identifier
D5989C00001 CSP Version 2.0 dated 28-Jan-2024
Protocol Number
NCT06283966
ClinicalTrials.gov
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Name
Tapankumar M Shah
Designation
Senior Director Asia Area Cluster Head SMM Country Head R and D Biopharmaceuticals
Affiliation
AstraZeneca Pharma India Ltd.
Address
Block N1, 12th Floor, Manyata Embassy Business Park,
Rachenahalli, Outer Ring Road,
India
Bangalore KARNATAKA 560045 India
Phone
9535104975
Fax
Email
tapankumar.shah@astrazeneca.com
Details of Contact Person Scientific Query
Name
Tapankumar M Shah
Designation
Senior Director Asia Area Cluster Head SMM Country Head R and D Biopharmaceuticals
Affiliation
AstraZeneca Pharma India Ltd.
Address
Block N1, 12th Floor, Manyata Embassy Business Park,
Rachenahalli, Outer Ring Road,
India
KARNATAKA 560045 India
Phone
9535104975
Fax
Email
tapankumar.shah@astrazeneca.com
Details of Contact Person Public Query
Name
Tapankumar M Shah
Designation
Senior Director Asia Area Cluster Head SMM Country Head R and D Biopharmaceuticals
Affiliation
AstraZeneca Pharma India Ltd.
Address
Block N1, 12th Floor, Manyata Embassy Business Park,
Rachenahalli, Outer Ring Road,
India
KARNATAKA 560045 India
Phone
9535104975
Fax
Email
tapankumar.shah@astrazeneca.com
Source of Monetary or Material Support
AstraZeneca AB, 151 85 Södertälje, Sweden
AstraZeneca K.K., 3-1, Ofuka-cho, Kita-ku, Osaka 530-0011, Japan
Primary Sponsor
Name
AstraZeneca AB
Address
151 85 Södertälje, Sweden
Type of Sponsor
Pharmaceutical industry-Global
Details of Secondary Sponsor
Name
Address
AstraZeneca KK
3-1, Ofuka-cho, Kita-ku, Osaka 530-0011, Japan
AstraZeneca Pharma India Ltd
Block N1, 12th Floor, Manyata Embassy Business Park,
Rachenahalli, Outer Ring Road, Bangalore - 560045,
Karnataka, India
Countries of Recruitment
Argentina Australia Austria Brazil Bulgaria Canada Chile China Colombia Czech Republic Denmark Finland France Germany Greece Hungary India Italy Japan Malaysia Mexico Norway Peru Philippines Poland Republic of Korea Romania Serbia Slovakia Spain Sweden Taiwan Thailand Turkey Ukraine United Kingdom United States of America
Albuterol sulfate/salbutamol Sulfate
Dose: Inhaler (90 μg (US)/100 μg (EU/RoW) per actuation
Route: Oral Inhalation; Frequency: 2 inhalations as needed for 36 weeks
Intervention
Blinded Budesonide, glycopyrronium, and formoterol fumarate MDI 320/14.4/9.6 μg
Budesonide, glycopyrronium, and formoterol fumarate pressurized inhalation suspension; Dose: Inhaler (160/7.2/4.8 μg per actuation) ; Route: Oral Inhalation; Frequency: 2 inhalations BID, for 36 months
Comparator Agent
Placebo
Placebo MDI to match BGF and GFF MDI for training; Dose: Inhaler (No active ingredient); Route: Oral Inhalation; Frequency: 2 inhalations BID for 36 weeks
Intervention
Run-in Glycopyrronium and formoterol fumarate
Glycopyrronium and formoterol fumarate pressurized inhalation suspension; Dose: Inhaler (7.2/4.8 μg per actuation) ; Route: Oral Inhalation; Frequency: 2 inhalations BID, for 2 Weeks and then for 36 weeks
Inclusion Criteria
Age From
40.00 Year(s)
Age To
80.00 Year(s)
Gender
Male
Details
1.Male or female participants must be 40 to 80 years of age inclusive, at the time of signing the ICF.
Type of Participant and Disease Characteristics
2.Demonstrate acceptable MDI administration technique at Visit 1 and Visit 2 (randomization).
NOTE:Historical use of a spacer device within the 8 weeks prior to and/or during the Screening and Randomized Treatment Periods is not permitted
3.A diagnosis of COPD confirmed by a post-bronchodilator FEV1/FVC ratio less than 70% at Visit 1.
4.Current or former smokers with a history of at least 10 pack-years of cigarette smoking; defined as (number of cigarettes per day/20) x number of years smoked. Previous smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1.
NOTE: Pipe, cigar, and/or electronic cigarette use cannot be used to calculate pack-year history.
5.A baseline peripheral blood eosinophil count of greater than or equal 100 cells/mm3 assessed at Visit 1 by the central laboratory
6.A CAT score of greater than or equal to 10 at V1.
-Each of the phlegm (sputum) and cough item sub-scores must be greater than or equal 2.
7.Participant must fulfill at least 1 of the 4 CV disease/risk factor criteria below [(a), (b), (c), or (d)]. A minimum of 50% of participants must meet criterion (a):
(a)Established CV disease defined as documented evidence of any of the following:
-angina pectoris with objective evidence of myocardial ischemia
-myocardial infarction
-percutaneous coronary intervention
-coronary artery bypass grafting
-objective findings of coronary stenosis (greater than or equal 50%) in at least 2 coronary artery territories (ie, left anterior descending, ramus intermedius, left circumflex, right coronary artery) involving the main vessel, a major branch, or a bypass graft
-chronic heart failure with NYHA Class II-III functional limitation at V1.
NOTE:No more than 10% of participants should enter through only the heart failure criterion.
-NYHA Class II is defined as patients comfortable at rest; ordinary physical activity results in fatigue, palpitations, breathlessness, or angina pectoris
-NYHA Class III is defined as patients comfortable at rest, but with less than ordinary physical activity causing fatigue, dyspnea, palpitations, or angina
NOTE:NYHA Class IV is not inclusionary and is defined as patients experiencing symptoms even while at rest.
-peripheral arterial disease (any of the following):
-peripheral arterial intervention, stenting surgical revascularization
-lower extremity amputation as a result of peripheral arterial obstructive disease
-current symptoms of intermittent claudication AND ankle/brachial index less than 90 documented within the last 12 months
-angiographic evidence of peripheral artery disease
(b)Combination of any 3 of the following 5 CV risk factors:
-Hypertension (at least one of the following):
- A documented history (in the previous 6 months) of BP greater than 140/90 mm/Hg confirmed at Visit 1 with both an elevated systolic BP (greater than 140 mmHg) and an elevated diastolic BP (greater than 90 mmHg) on the last 2 of 3 measurements
-Receiving at least one anti-hypertensive therapy prescribed by a physician for BP lowering.
-Documented history of diabetes mellitus
-Documented history of chronic kidney disease, with eGFR greater than or equal 20 mL/min/1.73 m2 and less than 60 mL/min/1.73 m2 measured at Visit 1.
-Documented history of dyslipidemia in previous 12 months defined as at least one of the following:
-An LDL-C greater than 130 mg/dL (3.36 mmol/L) measured at Visit 1.
-An HDL-C less than 40 mg/dL (1.03 mmol/L) for men or less than 50 mg/dL (1.29 mmol/L) for women measured at V 1.
-On lipid lowering therapy prescribed by a physician for hypercholesterolemia (LDL-C greater than 130 mg/dL [3.36 mmol/L]) for greater than 12 months. This should be verified by documentation of a laboratory value LDL-C of greater than 130 mg/dL (3.36 mmol/L).
-Documented history of obesity with confirmation of BMI greater than or equal 30 kg/m2 at Visit 1
(c)High risk of CV disease determined using an established CV risk assessment tool for participants without established CV disease
(d)NOTE: The CV risk scoring should be done on a validated scoring system, particularly Q-RISK-3 (score greater than 20%), ASCVD risk equation (score greater than 20%), Framingham risk score (score greater than 20%) or SCORE2/SCORE2-OP. AstraZeneca will also accept other CV risk assessment tools used in the country/region with equivalent risk (high on the scale), provided this is confirmed with the AstraZeneca study team prior to V2.
Documented CV risk assessment done within 6 months of Visit 1 is acceptable.
(e)Documented historical CT coronary artery calcification scoring in the setting of either of the following:
-greater than or equal to moderate coronary artery calcification score/assessment plus any one other CV risk listed in (b) above
-severe/heavy coronary artery calcification score/assessment
NOTE:Documented reports of coronary artery calcification scoring based on visual assessment by a radiologist or other individual with appropriate expertise who is qualified to report on such imaging per local practice//guidelines is acceptable and eligibility should be confirmed with AstraZeneca prior to Visit 2.
In addition, in cases where the Agatston score is available, the following thresholds can be used: moderate greater than 100 (101 – 1000) and severe/heavy greater than 1000.
8.Willing and, in the opinion of the investigator, able to adjust current COPD therapy, as required by the protocol.
9.Willing to visit at the study site or participate in virtual visits as required per the protocol to complete all study assessments.
Sex and Contraceptive/Barrier Requirements
10.A female is eligible to enter and participate in the study if the female is of:
-Non-childbearing potential: either permanently sterilized (hysterectomy, bilateral oophorectomy, bilateral salpingectomy) or who are post-menopausal. A female will be considered post-menopausal if they have been amenorrheic for 12 months prior to the planned date of randomization without an alternative medical cause. The following age- specific requirements apply:
-Female less than 50 years old would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatment and follicle-stimulating hormone levels in the post-menopausal range.
-Female greater than or equal 50 years old would be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatment.
-Childbearing potential: has a negative serum pregnancy test at Visit 1 and must use one highly effective form of birth control. A highly effective method of contraception is defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly. At enrollment, women of childbearing potential who are sexually active with a non-sterilized male partner should be stable on their chosen method of highly effective birth control, as defined below, and willing to remain on birth control until at least 14 days after last dose of study intervention. Cessation of contraception after this point should be discussed with a responsible physician.
-Highly effective birth control methods include:
-sexual abstinence as defined as complete abstinence from intercourse when it is the preferred and usual lifestyle of the participant
- contraceptive subdermal implant
- intrauterine device or intrauterine system
- oral contraceptive (combined or progesterone only)
- injectable progestogen
- contraceptive vaginal ring
- percutaneous contraceptive patches
- Male partner sterilization
- bilateral tubal ligation
11.Capable of giving signed informed consent
ExclusionCriteria
Details
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1 Active diagnosis of asthma within the past 5 years (previous diagnosis as a child or adolescent are eligible), asthma-COPD overlap, or any other chronic respiratory disease other than COPD such as alpha-1 antitrypsin deficiency, active tuberculosis, lung fibrosis, sarcoidosis, interstitial lung disease, and pulmonary hypertension.
2 End-stage renal disease requiring renal replacement therapy or eGFR
less than 20 mL/min/1.73 m2.
3 History of heart or lung transplant or actively listed for heart or lung transplant.
4 Implanted left ventricular assist device or implant anticipated in less than 3 months.
5 History of lung cancer and/or treatment for lung cancer within the 5 years prior to Visit 1.
6 Unstable or life-threatening cardiac disease – participants with any of the following at Visit 1 would be excluded:
(a) An MI or unstable angina in the last 8 weeks
(b) Unstable or life-threatening cardiac arrhythmia requiring intervention in the last 8 weeks.
NOTE: Any participant who experiences unstable or life-threatening cardiac disease during the run-in period will be excluded but can be rescreened 8 weeks after the resolution of the event.
7 Pneumonia and/or moderate or severe COPD exacerbation that has not resolved at least
8 weeks prior to Visit 1 Any life-threatening condition, including malignancy, with a life expectancy less than 5 years, other than CV disease or COPD, that might prevent the participant from
completing the study.
Prior/Concomitant Therapy
9 Use of maintenance ICS treatment within the past 12 months.
10 Unable to abstain from protocol-defined prohibited medications
Prior/Concurrent Clinical Study Experience
11 Participation in another clinical study with a study intervention administered in the last 30 days or 5 half-lives, whichever is longer prior to Visit 1 (any other investigational product that is not identified in this protocol is prohibited for use during the duration of the study).
12 Participants with a known hypersensitivity to LAMA, LABA or ICS or any component of the MDI.
Other Exclusions
13 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
14 Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
15 Previous randomization in the present study.
16 For females only - currently pregnant (confirmed with positive pregnancy test) or breast- feeding.
Lifestyle Considerations
1.1.1 Meals and Dietary Restrictions
Participants must be fasting for 9 to 12 hours prior to the blood draw at Visit 1. Participants who have not fasted prior to Visit 1 should return to the clinic to have the blood draw performed within 3 business days.
1.1.2 Caffeine, Alcohol, and Tobacco
Participants must abstain from ingesting caffeine- or xanthine-containing products (eg, coffee, tea, cola drinks, and chocolate) for 6 hours prior to spirometry testing (assessed at Visit 1).
Participants are required to refrain from smoking (including electronic cigarettes) for at least 4 hours prior to spirometry testing.
Participants must abstain from consuming any intoxicants within 24 hours before spirometry testing.
1.1.3 Activity
Participants should avoid engaging in strenuous exertion for at least 30 minutes prior to spirometry.
1.1.4 Illicit Drugs or Drugs of Abuse
Illicit drugs or drugs of abuse will not be allowed from Visit 1 to the end of the follow-up visit or whenever the participant withdraws from the study. If any illicit drugs or drugs of abuse are used by the participant during the study, the dates of use and the amount will be documented, and the participant will be discontinued from randomized study intervention and withdrawn from the study at the discretion of the investigator.
Method of Generating Random Sequence
Stratified randomization
Method of Concealment
Centralized
Blinding/Masking
Participant and Investigator Blinded
Primary Outcome
Outcome
TimePoints
Evaluate the effect of BGF MDI 320/14.4/9.6μg compared with GFF MDI 14.4/9.6μg On cardiopulmonary outcomes
Time to first severe cardiac or COPD event
The composite primary endpoint comprises time to:
- The first HF acute healthcare visit/hospitalization
- MI hospitalization
- Severe COPD exacerbation
- Cardiopulmonary death
Secondary Outcome
Outcome
TimePoints
Evaluate the effect of combination triple therapy (BGF MDI 320/14.4/9.6 μg)
compared with dual bronchodilator therapy (GFF MDI
14.4/9.6 μg) on severe COPD exacerbations in a population with COPD not receiving ICS.
Endpoint: Time to first severe COPD exacerbation event (hospitalization for COPD or death due to COPD)
Supportive Estimand:
Endpoint: Severe COPD exacerbation (hospitalization for COPD or death due to COPD) rate
Evaluate the effect of combination triple therapy (BGF MDI 320/14.4/9.6 μg)
compared with dual bronchodilator therapy (GFF MDI
14.4/9.6 μg) on severe cardiac events in a population with COPD not receiving ICS.
Endpoint: Time to first severe cardiac event (cardiac death, non-fatal HF acute healthcare visit/hospitalization or non-fatal MI hospitalization)
Supportive Estimand:
Endpoint: Severe cardiac event rate
Evaluate the effect of combination triple therapy (BGF MDI 320/14.4/9.6 μg)
compared with dual bronchodilator therapy (GFF MDI
14.4/9.6 μg) on cardiopulmonary deaths in a population with COPD not receiving ICS.
Endpoint: Time to cardiopulmonary death
Evaluate the effect of combination triple therapy (BGF MDI 320/14.4/9.6 μg) compared with dual bronchodilator therapy (GFF MDI 14.4/9.6 μg) on moderate/severe COPD exacerbations in a population with COPD not receiving ICS
Endpoint: Moderate/severe COPD exacerbation rate
Supportive Estimand:
Endpoint: Time to first moderate or severe COPD exacerbation event
Evaluate the effect of combination triple therapy (BGF MDI 320/14.4/9.6 μg) compared with dual bronchodilator therapy (GFF MDI 14.4/9.6 μg) on the time to MI hospitalization (or cardiac death) in a population with COPD not receiving ICS.
Endpoint: Time to MI hospitalization or cardiac death
Evaluate the effect of combination triple therapy (BGF MDI 320/14.4/9.6 μg) compared with dual bronchodilator therapy (GFF MDI 14.4/9.6 μg) on the time to HF acute healthcare visit/ hospitalization (or cardiac death) in a population with COPD not receiving ICS
Endpoint: Time to HF acute healthcare visit/hospitalization or cardiac death
Target Sample Size
Total Sample Size="5000" Sample Size from India="65" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
Phase of Trial
Phase 3
Date of First Enrollment (India)
27/12/2024
Date of Study Completion (India)
Applicable only for Completed/Terminated trials
Date of First Enrollment (Global)
21/02/2024
Date of Study Completion (Global)
Applicable only for Completed/Terminated trials
Estimated Duration of Trial
Years="4" Months="0" Days="0"
Recruitment Status of Trial (Global)
Open to Recruitment
Recruitment Status of Trial (India)
Not Yet Recruiting
Publication Details
N/A
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
Brief Summary
This study seeks
to confirm previous findings and aims to demonstrate that triple ICS/LAMA/LABA
therapy with BGF MDI 320/14.4/9.6 µg (Breztri/Trixeo) will improve
cardiopulmonary outcomes relative to LAMA/LABA therapy with GFF MDI 14.4/9.6 µg
(Bevespi) in a population with COPD and high cardiopulmonary risk. The study’s
primary composite endpoint is time to first severe cardiac or COPD event. The
composite primary endpoint comprises time to the first HF acute healthcare visit/hospitalization,
MI hospitalization, severe COPD exacerbation, or cardiopulmonary death.
Evaluating a combined cardiopulmonary outcome assessing key clinical
deteriorations that captures mortality and hospitalization (ie, cardiac/COPD hospitalization
and cardiopulmonary death) is important in patients with COPD and elevated
cardiac risk given cardiopulmonary outcomes are fundamental features of the
disease. AstraZeneca considers this of key importance to prescribers treating
both pulmonary and cardiac diseases. The data from the clinical question at
hand, whether BGF MDI reduces severe cardiopulmonary outcomes in a population
not on ICS therapy, will be novel with the potential to change clinical
practice