Clinical trial NCT04421742: The Effect of Beclomethasone/Formoterol in Extra-fine Formulation on Quality of Life and SAD in COPD Patients.
Official title: The Effect of Beclomethasone/Formoterol in Extra-fine Formulation on Quality of Life and Dyspnea is Associated to the Improvement in Small Airway Dysfunction in COPD Patients. A Pilot Study (IOSCOPD20161102)
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Chronic Obstructive Pulmonary Disease
Lead sponsor: University of Parma
Sponsor class: OTHER
Collaborators: name: University of Parma
First posted: 2020-06-09
Enrollment: 43
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: COPD patients of the outpatient clinic of the Respiratory Disease Unit of the University Hospital in Parma (Italy)

Brief summary: In patients with chronic obstructive pulmonary disease (COPD), small-airway dysfunction (SAD) is considered a key element and a functional consequence of the pathology. However, the exact role of SAD as a specific 'pharmacological target' is not yet fully known.

Objectives In an open-label prospective study, we aimed to ascertain whether an extra-fine formulation of Beclomethasone dipropionate/Formoterol fumarate (BDP/FF) NEXThaler® 100/6 μg b.i.d. can improve the impact of the disease on the quality of daily life of COPD patients, acting on SAD.

Methods We studied COPD patients with severe airflow obstruction and 1 moderate exacerbation in the previous year, being treated with BDP/FF NEXThaler® for 12 weeks. They underwent three visits, at the start of the treatment (V1), at 6th week (V2) and at 12th week (V3). By the impulse oscillometry system and by spirometry and plethysmography we measured at each visit the fall in resistance from 5 to 20 Hz (R5-R20) and the residual volume/total lung capacity (RV/TLC). COPD Assessment Test (CAT) and the modified Medical Research Council (mMRC) questionnaire were also measured at each visit to assess the impact of the disease on the quality of life of the patients.

Detailed description: In recent years, there has been a growing interest in deepening the contribution of small airways (with a diameter \<2mm) to the clinical expression of Chronic Obstructive Pulmonary Disease (COPD).

In patients with stable COPD, SAD severity was found to be progressively increased both with the degree of airflow obstruction and with GOLD risk class. Moreover, a correlation between SAD and COPD impact measured with the CAT (COPD Assessment Test) was found, being the severity of SAD a predictor of the impact of the disease (CAT≥10). A close correlation between SAD and both quality of life (measured with the St. George's Respiratory Questionnaire) and perceived dyspnea (measured with the modified Medical Research Council-mMRC scale) was also found in COPD patients.

The exact role of SAD as a specific 'pharmacological target' is not yet fully known. According to the guidelines, the administration of combination such as Beclomethasone dipropionate/Formoterol fumarate (BDP/FF) in extra-fine formulation produced a clinically relevant improvement in quality of life (\> 4 units in the St. George's Respiratory Questionnaire) and in dyspnea. However, it is not yet defined whether exists a correlation between symptomatic improvement and SAD and whether an improvement of symptoms can be achieved acting pharmacologically on SAD.

The rationale for this study is based on the hypothesis that an extra-fine formulation of BDP/FF, designed to target the entire bronchial three, included the peripheral zone, can improve the impact of the disease on the quality of life of COPD patients, acting on SAD. The functional indices of SAD used in this study are from the impulse oscillometry system (IOS), the standard spirometry and the body plethysmography.

The primary endpoint of the study was, therefore, an improvement of the impact of the disease on quality of daily life (CAT) and of dyspnea (mMRC) after 12th week treatment with an extra-fine formulation of BDP/FF in a cohort of COPD patients with severe airway obstruction and one moderate exacerbation in a previous year; secondary endpoint was an improvement of the SAD at the 12th week in these patients.

Eligibility criteria: Inclusion Criteria:

* a documented diagnosis of COPD defined according to the guidelines of the American Thoracic Society (ATS) / European Respiratory Society (ERS);
* smokers or former smokers with a smoking history of at least 10 pack / years;
* subjects with a post-bronchodilator forced expiratory volume at the 1st second (FEV1)/ forced vital capacity (FVC) ratio of \< 0.7 and a FEV1 \<50% pred;
* subjects with a high impact of the COPD on their health status (CAT≥10);
* clinical history of at least 1 moderate exacerbation / year;
* COPD patients being treated with BDP/FF NEXThaler® 100/6 μg in extra-fine formulation no more than 1 (one) week before enrollment.

Exclusion Criteria:

* an exacerbation in the four weeks prior to enrollment;
* other coexisting lung diseases (bronchial asthma, restrictive diseases or bronchiectasis) and severe co-morbidities associated with COPD, such as uncontrolled cardiovascular disease, pneumonia or cancer;
* pregnant patients;
* subjects unable to meet the criteria of acceptability and repeatability of pulmonary function tests, according to the ATS / ERS document

Primary outcomes:
measure: Change (Improvement) of CAT (Italian version)
timeFrame: Change from Baseline CAT at 12th week
measure: Change (Improvement) of mMRC (Italian version)
timeFrame: Change from Baseline mMRC at 12th week
measure: Change (Improvement) of R5-R20 (kPa x s x L-1)
timeFrame: Change from Baseline R5-R20 at 12th week
Secondary outcomes:
Other outcomes:
Locations:
city: Parma
country: Italy
facility: Department of Medicine and Surgery, Respiratory Disease and Lung Function Unit, University of Parma, Italy
Study officials:
affiliation: Hospital-University of Parma, Italy
name: Alfredo A Chetta, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Burgel PR. The role of small airways in obstructive airway diseases. Eur Respir Rev. 2011 Mar;20(119):23-33. doi: 10.1183/09059180.00010410.
citation: Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, Cherniack RM, Rogers RM, Sciurba FC, Coxson HO, Pare PD. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. 2004 Jun 24;350(26):2645-53. doi: 10.1056/NEJMoa032158.
citation: Crisafulli E, Pisi R, Aiello M, Vigna M, Tzani P, Torres A, Bertorelli G, Chetta A. Prevalence of Small-Airway Dysfunction among COPD Patients with Different GOLD Stages and Its Role in the Impact of Disease. Respiration. 2017;93(1):32-41. doi: 10.1159/000452479. Epub 2016 Nov 17.
citation: Wedzicha JA, Singh D, Vestbo J, Paggiaro PL, Jones PW, Bonnet-Gonod F, Cohuet G, Corradi M, Vezzoli S, Petruzzelli S, Agusti A; FORWARD Investigators. Extrafine beclomethasone/formoterol in severe COPD patients with history of exacerbations. Respir Med. 2014 Aug;108(8):1153-62. doi: 10.1016/j.rmed.2014.05.013. Epub 2014 Jun 6.
citation: Charlson M, Szatrowski TP, Peterson J, Gold J. Validation of a combined comorbidity index. J Clin Epidemiol. 1994 Nov;47(11):1245-51. doi: 10.1016/0895-4356(94)90129-5.
citation: George J, Kong DC, Thoman R, Stewart K. Factors associated with medication nonadherence in patients with COPD. Chest. 2005 Nov;128(5):3198-204. doi: 10.1378/chest.128.5.3198.
citation: Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC. Lung volumes and forced ventilatory flows. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. Eur Respir J Suppl. 1993 Mar;16:5-40. No abstract available.
citation: Oostveen E, MacLeod D, Lorino H, Farre R, Hantos Z, Desager K, Marchal F; ERS Task Force on Respiratory Impedance Measurements. The forced oscillation technique in clinical practice: methodology, recommendations and future developments. Eur Respir J. 2003 Dec;22(6):1026-41. doi: 10.1183/09031936.03.00089403.
citation: Oppenheimer BW, Goldring RM, Herberg ME, Hofer IS, Reyfman PA, Liautaud S, Rom WN, Reibman J, Berger KI. Distal airway function in symptomatic subjects with normal spirometry following World Trade Center dust exposure. Chest. 2007 Oct;132(4):1275-82. doi: 10.1378/chest.07-0913. Epub 2007 Sep 21.
citation: Kon SS, Canavan JL, Jones SE, Nolan CM, Clark AL, Dickson MJ, Haselden BM, Polkey MI, Man WD. Minimum clinically important difference for the COPD Assessment Test: a prospective analysis. Lancet Respir Med. 2014 Mar;2(3):195-203. doi: 10.1016/S2213-2600(14)70001-3. Epub 2014 Feb 4.
citation: Han MK, Quibrera PM, Carretta EE, Barr RG, Bleecker ER, Bowler RP, Cooper CB, Comellas A, Couper DJ, Curtis JL, Criner G, Dransfield MT, Hansel NN, Hoffman EA, Kanner RE, Krishnan JA, Martinez CH, Pirozzi CB, O'Neal WK, Rennard S, Tashkin DP, Wedzicha JA, Woodruff P, Paine R 3rd, Martinez FJ; SPIROMICS investigators. Frequency of exacerbations in patients with chronic obstructive pulmonary disease: an analysis of the SPIROMICS cohort. Lancet Respir Med. 2017 Aug;5(8):619-626. doi: 10.1016/S2213-2600(17)30207-2. Epub 2017 Jun 28.
citation: Hogg JC, Chu FS, Tan WC, Sin DD, Patel SA, Pare PD, Martinez FJ, Rogers RM, Make BJ, Criner GJ, Cherniack RM, Sharafkhaneh A, Luketich JD, Coxson HO, Elliott WM, Sciurba FC. Survival after lung volume reduction in chronic obstructive pulmonary disease: insights from small airway pathology. Am J Respir Crit Care Med. 2007 Sep 1;176(5):454-9. doi: 10.1164/rccm.200612-1772OC. Epub 2007 Jun 7.
citation: Basile M, Baiamonte P, Mazzuca E, Principe S, Pennavaria F, Benfante A, Scichilone N. Sleep Disturbances in COPD are Associated with Heterogeneity of Airway Obstruction. COPD. 2018 Jun-Aug;15(4):350-354. doi: 10.1080/15412555.2018.1504015. Epub 2018 Sep 6.
citation: De Backer W, Devolder A, Poli G, Acerbi D, Monno R, Herpich C, Sommerer K, Meyer T, Mariotti F. Lung deposition of BDP/formoterol HFA pMDI in healthy volunteers, asthmatic, and COPD patients. J Aerosol Med Pulm Drug Deliv. 2010 Jun;23(3):137-48. doi: 10.1089/jamp.2009.0772.
citation: de Boer AH, Gjaltema D, Hagedoorn P, Frijlink HW. Can 'extrafine' dry powder aerosols improve lung deposition? Eur J Pharm Biopharm. 2015 Oct;96:143-51. doi: 10.1016/j.ejpb.2015.07.016. Epub 2015 Jul 26.
citation: Virchow JC, Poli G, Herpich C, Kietzig C, Ehlich H, Braeutigam D, Sommerer K, Haussermann S, Mariotti F. Lung Deposition of the Dry Powder Fixed Combination Beclometasone Dipropionate Plus Formoterol Fumarate Using NEXThaler(R) Device in Healthy Subjects, Asthmatic Patients, and COPD Patients. J Aerosol Med Pulm Drug Deliv. 2018 Oct;31(5):269-280. doi: 10.1089/jamp.2016.1359. Epub 2018 Jul 10.
citation: Voshaar T, Spinola M, Linnane P, Campanini A, Lock D, Lafratta A, Scuri M, Ronca B, Melani AS. Comparing usability of NEXThaler((R)) with other inhaled corticosteroid/long-acting beta2-agonist fixed combination dry powder inhalers in asthma patients. J Aerosol Med Pulm Drug Deliv. 2014 Oct;27(5):363-70. doi: 10.1089/jamp.2013.1086. Epub 2013 Dec 3.
citation: Pisi R, Aiello M, Piraino A, Paleari D, Frizzelli A, Bertorelli G, Chetta A. Beclomethasone/Formoterol in Extra-Fine Formulation Improves Small Airway Dysfunction in COPD Patients. Pulm Ther. 2021 Jun;7(1):133-143. doi: 10.1007/s41030-021-00144-x. Epub 2021 Feb 4.