CHF5993 and CHF1535 pMDI on Lung Hyperinflation and Exercise Endurance Time in Subjects With COPD (TRIFORCE)

A Double Blind, Multicentre, Randomised, Placebo-Controlled, 3-Way Cross-Over Study To Evaluate The Effect Of A Triple Combination Of Beclometasone Dipropionate And Formoterol Fumarate Plus Glycopyrronium (CHF5993) And A Dual Combination Of Beclometasone Dipropionate Plus Formoterol Fumarate (CHF1535) Both Administered Via pMDI On Lung Hyperinflation And Exercise Endurance Time In Subjects With Chronic Obstructive Pulmonary Disease (COPD)

Double Blind, Multinational, Multicentre, Randomised, Placebo-Controlled, 3-Way Cross-Over Study To Evaluate The Effect Of A Triple Combination Of Beclometasone Dipropionate And Formoterol Fumarate Plus Glycopyrronium (CHF5993) And A Dual Combination Of Beclometasone Dipropionate Plus Formoterol Fumarate (CHF1535) Both Administered Via pMDI On Lung Hyperinflation And Exercise Endurance Time In Subjects With Chronic Obstructive Pulmonary Disease (COPD)

Study Overview

• Status: Completed
• Conditions: Chronic Obstructive Pulmonary Disease
• Intervention / Treatment: Drug: CHF5993; Drug: CHF1535; Other: Matched placebo

• Study Type: Interventional
• Enrollment (Actual): 106
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • Berlin Spandauer Damm
    • Berlin-Spandau, Berlin Spandauer Damm, Germany, 130 D-14050
      • PAREXEL International GmbH Early Phase Clinical Unit Berlin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. A signed and dated written informed consent obtained prior to any study-related procedures.
2. Outpatient population.
3. Male or female subjects.
4. COPD diagnosis for at least 12 months before the Screening visit in accordance with the definition by the GOLD 2020 report.
5. Current or ex-smokers (who quit smoking for at least 6 months prior to Screening Visit) with a smoking history of at least 10 pack-years [pack-years = (number of cigarettes per day x number of years)/20]. E-cigarettes smoking cannot be used to calculate pack-year history.
6. A post-bronchodilator FEV1/FVC < 0.7 within 30 min after 4 puffs (4 x 100 µg) of salbutamol pMDI and a post-bronchodilator FEV1 ≥ 40% and <80% of the predicted normal values. If this is not met at screening, the test can be repeated once before randomisation.
7. Pre-bronchodilator functional residual capacity (FRC) of > 120% of predicted normal FRC values at Screening visit 1. If this criterion is not met at screening, the test can be repeated once before randomisation.
8. A score of >2 on the Modified Medical Research Council Dyspnea Scale (mMRC) at Visit 1.
9. Subjects on mono- or dual inhaled maintenance COPD treatment at a stable dose for at least 3 months prior to screening.
10. A cooperative attitude and ability to correctly use the study inhalers.

11. Female subjects must be women either of non-childbearing potential (WONCBP) defined as physiologically incapable of becoming pregnant (i.e. post-menopausal or permanently sterile) or physiologically capable of becoming pregnant (i.e. women of childbearing potential (WOCBP)).

    Inclusion criteria assessed prior to Randomization:

12. CWRCE at Visit 1b: between 2 min and 11 min at 80% of maximum workload. In case the subject cycles for a shorter (i.e. < 2 min) or longer (i.e. > 11 min) period, the visit can be repeated with an adjusted workload once within a 1-week period.
13. Oxygen saturation (SpO2 measured by pulse oximeter) at least 82% during the incremental exercise test (IET) performed in the run-in period.
14. Subjects must be able to complete CWRCE at Visit 1b and then at Visit 2 without requirement for supplemental oxygen.

Exclusion Criteria:

1. Pregnant or lactating women.
2. Known respiratory disorders other than COPD which may impact the efficacy of the study drug according the investigator's judgment. This can include but is not limited to current diagnosis of asthma, alfa-1 antitrypsin deficiency, active tuberculosis, lung cancer, severe bronchiectasis unrelated to COPD, sarcoidosis, lung fibrosis, pulmonary hypertension and interstitial lung disease.
3. Unstable concurrent disease: e.g. fever, uncontrolled hyperthyroidism, uncontrolled diabetes mellitus or other endocrine disease; significant hepatic impairment; significant renal impairment; uncontrolled gastrointestinal disease (e.g. active peptic ulcer); uncontrolled cardiac disease, uncontrolled neurological disease; uncontrolled haematological disease; uncontrolled autoimmune disorders, or other which may impact the efficacy or the safety of the study drug according to investigator's judgment.
4. Moderate (requiring prescriptions of systemic corticosteroids and/or antibiotics) or severe (leading to hospitalization) COPD exacerbation in the 3 and 12 months, respectively, prior to Screening visit 1 and during the run-in period.

8. Subjects requiring long term (> 15 hours a day) oxygen therapy for chronic hypoxemia.

5. Subjects who have clinically severe cardiovascular condition (such as but not limited to unstable ischemic heart disease, NYHA Class IV, left ventricular failure, myocardial infarction in the prior 6 months, not controlled arrhythmia etc.), which may impact the efficacy or the safety of the study drug according to the investigator's judgement.

6. An abnormal and clinically significant 12-lead electrocardiogram (ECG) which may impact the safety of the subject according to investigator's judgement. Subjects whose 12-lead ECG shows QTcF >450 ms for males or QTcF >470 ms for females at screening visit are not eligible.

7. History of hypersensitivity to M3 receptor antagonists, β2-agonist, corticosteroids or any of the excipients contained in any of the formulations used in the trial which may raise contra-indications or impact the efficacy of the study drug according to the investigator's judgement.

8. Subjects with serum potassium levels ≤ 3.5 mEq/L (or 3.5 mmol/L) 9. Subjects with body mass index less than 15 or greater than 35 kg/m2. 10. History of alcohol abuse and/or substance/drug abuse within 12 months prior to screening visit.

11. Subjects with contraindications to cardiopulmonary exercise testing, including those whose exercise test is limited by non-respiratory or cardiovascular condition, e.g. by neurologic, orthopaedic, or other disorders.

12. Participation in another clinical trial where investigational drug was received less than 30 days or 5 half-lives whichever is longer prior to screening visit.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: CHF5993; pMDI fixed combination product of beclometasone dipropionate (BDP) 100 µg plus 6 µg of formoterol fumarate (FF) and 10 µg of glycopyrronium (G)	Drug: CHF5993; Pressurized metered dose inhaler (pMDI) 2 inhalations bid; Other Names: TRIMBOW®
Active Comparator: CHF1535; pMDI fixed combination product beclometasone dipropionate (BDP) 100 µg plus 6 µg of formoterol fumarate (FF)	Drug: CHF1535; Pressurized metered dose inhaler (pMDI) 2 inhalations bid; Other Names: FOSTER®
Placebo Comparator: Matched placebo; Matched placebo pMDI	Other: Matched placebo; Pressurized metered dose inhaler (pMDI) 2 inhalations bid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Inspiratory capacity (IC) prior to Constant Work Rate Cycle Ergometry (CWRCE) test	Change from baseline in 2-hour post-dose	3 weeks of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
IC at Isotime, defined as the shortest CWRCE test duration among baseline and end of treatment period.	Change from baseline	3 weeks of treatment
Exercise endurance time (EET)	Change from baseline in 2-hour post-dose	3 weeks of treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
EET between CHF5993 and CHF1535	Change from baseline in 2-hour post-dose	3 weeks of treatment
Pre-dose morning Forced Expiratory Volume in 1 second (FEV1)	Change from baseline	3 weeks of treatment
Pre-dose Forced Vital Capacity (FVC)	Change from baseline	3 weeks of treatment
Functional Residual Capacity (FRC)	Change from baseline in 2-hour post-dose	3 weeks of treatment
Pre-dose IC	Change from baseline	3 weeks of treatment
Residual Volume (RV)	Change from baseline in 2-hour post-dose	3 weeks of treatment
RV/Total Lung Capacitity (TLC) ratio	Change from baseline in 2-hour post-dose	3 weeks of treatment
Dyspnoea intensity at isotime (using the modified Borg scale)	Change from baseline	3 weeks of treatment
Physical activity (steps/day)	Change from baseline	3 weeks of treatment

Collaborators and Investigators

• Sponsor: Chiesi Farmaceutici S.p.A.
• Investigators: Study Director: Henrik Watz, MD, Pulmonary Research Institute at LungenClinic Grosshansdorf, German Center for Lung Research

Study record dates

Study Major Dates

• Study Start (Actual): October 28, 2021
• Primary Completion (Actual): February 24, 2023
• Study Completion (Actual): February 24, 2023

Study Registration Dates

• First Submitted: October 12, 2021
• First Submitted That Met QC Criteria: October 25, 2021
• First Posted (Actual): October 27, 2021

Study Record Updates

• Last Update Posted (Actual): March 24, 2023
• Last Update Submitted That Met QC Criteria: March 23, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Lung hyperinflation, exercise endurance time
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
• Other Study ID Numbers: CLI-05993AA1-17; 2020-004718-36 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Chiesi commits to sharing with qualified scientific and medical Researchers, conducting legitimate research, Patient-level Data, Study-level Data, the Clinical Protocol and the full CSR, providing access to clinical trial information consistently with the principle of safeguarding commercially confidential information and patient privacy. Any shared Patient-level Data is anonymized to protect personally identifiable information.

Chiesi access criteria and complete process for clinical data sharing is available on the Chiesi Group website.

• IPD Sharing Access Criteria: Chiesi access criteria and complete process for clinical data sharing is available on the Chiesi Group website.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No