CCD-05993AA1-16

Chiesi Farmaceutici S.p.A.

Via Palermo 26/A, Parma, Italy, 43122

Clinical Trial Transparency, Chiesi Farmaceutici S.p.A, clinicaltrials_info@chiesi.com

Clinical Trial Transparency, Chiesi Farmaceutici S.p.A, clinicaltrials_info@chiesi.com

No

No

No

Final

24 Sep 2019

No

Yes

31 Jan 2019

No

Evaluate the effect of inhaled extrafine CHF5993 pMDI on airway volumes and resistance, by using functional respiratory imaging (FRI) in patients with chronic obstructive pulmonary disease (COPD), treated with a non extrafine extemporary triple combination for three months before entering the study. The IMP has both bronchodilatory and anti-inflammatory properties and is used for the treatment of patients with severe COPD or with asthma. Each subject inhaled CHF5993 two times daily; total daily dose: 400 μg BDP, 24 μg FF, and 50 μg GB, for 24 weeks. Functional Respiratory Imaging (FRI) with computational fluid dynamics (CFD) analysis was used to demonstrate the effect of the IMP on airway parameters in the distal and central regions of the lung and to image the deposition of the extrafine formulation into the deep lung. Lung imaging was obtained from computed tomography (CT) scans, taken upon inspiration and expiration.

The clinical study was performed in accordance with the principles that have their origin in the declaration of Helsinki, and with local regulations. Furthermore, the study was performed in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) notes for guidance on Good Clinical Practice (GCP) (ICH/CPMP/135/95). Before the start of the study, all subjects gave their written informed consent to participate in the study after having been informed of the nature and implications of the study. At completion of subject's participation in the study, it was the Investigator’s responsibility to prescribe the most appropriate treatment for the subject or to restore the initial therapy or to refer to the general practitioner. Low-dose multislice CT scans were performed at pre-dose, at Visit 2 (Week 0), Visit 5 (Week 12), and Visit 8 (Week 24). At Visit 2, a scan of the upper airway was also performed. Adverse events (AEs) and vital signs were recorded at all visits (from screening onward, during the treatment phase of 24 weeks). If the investigator deemed it necessary, a visit was scheduled at 7 days after the last drug administration. A follow-up call was scheduled for all subjects and it was performed 7 days after the last study drug administration.

20 Nov 2017

No

No

Belgium: 14

Hungary: 7

21

21

0

0

0

0

0

0

8

13

0

Treatment (overall period)

Not applicable

Open-label study; not blinded.

CHF 5993 (100/6/12.5 μg), pMDI

BDP/FF/GB, Fixed combination of beclomethasone dipropionate, formoterol fumarate, glycopyrronium bromide

Pressurised inhalation, solution

Inhalation use

CHF 5993 is a fixed combination of BDP, FF, and GB. Single actuation of the CHF 5993 pMDI contains: 100μg BDP/6μg FF/12.5μg GB. Each subject inhaled CHF 5993 100/6/12.5 μg pMDI as two inhalations twice a day (two inhalations in the morning and two inhalations in the evening), giving a total daily dose of 400 μg BDP, 24 μg FF, and 50 μg GB.

Subjects with COPD

Subjects with COPD

Baseline, FRC

Subjects evaluated at baseline; lung level FRC

Week 12, FRC

Subjects evaluated at week 12; lung level FRC

Week 24, FRC

Subjects evaluated at week 24; lung level FRC

Baseline, TLC

Subjects evaluated at baseline; lung level TLC

Week 12, TLC

Subjects evaluated at week 12; lung level TLC

Week 24, TLC

Subjects evaluated at week 24; lung level TLC

Baseline

Subjects evaluated at baseline.

Week 24

Subjects evaluated at week 24.

Specific image-based airway volumes (siVaw): Computerised tomography-based (CT-based) airway volumes, normalised by the lung volume. Percent change from baseline to week 12 and 24 of treatment. Lung level: FRC and TLC. The primary region evaluated was the distal lung region. Percent change from baseline is presented using descriptive statistics (geometric mean and coefficient of variation). Specific image-based airway volumes are the CT-based airway volumes normalised by the lung volume. The siVaw as an FRI parameter is derived from the airway volume (iVaw). Because the airway volume is dependent on the lung volume, the airway volumes had to be made specific to facilitate the comparison between the study visits. The lung volume could be determined from the CT scans for both FRC and TLC, by identifying and grouping the voxels (a value in three-dimensional space) that represent the air in the lungs. The specificity was calculated by dividing the airway volume by the lung volume.

Primary

Baseline, week 12, week 24.

Percent change from baseline at week 12; within group comparison. Lung level: FRC The value N=35 (Subjects in this analysis) shown below, is generated automatically and is due to an innate error of the EudraCT database system. The correct value for subjects in the analysis is N=17.

Week 12, FRC v Baseline, FRC

35

Pre-specified

5.01

2-sided

Percent change from baseline at week 24; within group comparison. The value N=34 (Subjects in this analysis) shown below, is generated automatically and is due to an innate error of the EudraCT database system. The correct value for subjects in the analysis is N=17.

Week 24, FRC v Baseline, FRC

34

Pre-specified

3.47

2-sided

Percent change from baseline at week 12; within group comparison. The value N=39 (Subjects in this analysis) shown below, is generated automatically and is due to an innate error of the EudraCT database system. The correct value for subjects in the analysis is N=20.

Baseline, TLC v Week 12, TLC

39

Pre-specified

7.91

2-sided

Percent change from baseline at week 24; within group comparison. The value N=39 (Subjects in this analysis) shown below, is generated automatically and is due to an innate error of the EudraCT database system. The correct value for subjects in the analysis is N=20.

Week 24, TLC v Baseline, TLC

39

Pre-specified

15.96

2-sided

Specific image-based airway resistance (siRaw). Percent change from baseline to week 12 and 24 of treatment. Lung level: FRC and TLC. The primary region evaluated was the distal lung region. Analysis was done for the Functional Residual Capacity (FRC) and for the Total Lung Capacity (TLC). Results represent the actual values per time point for siRaw at baseline, week 12, and week 24. Percent change from baseline is presented using descriptive statistics (geometric mean and coefficient of variation). Specific image-based airway resistance is the CFD-based airway resistance normalised by the lung volume and was determined using CFD. The specific airway resistance (siRaw) as an FRI parameter is derived from the airway resistance (iRaw). Because the airway resistance is dependent on the lung volume, the airway resistance had to be made specific to facilitate the comparison between the visits.

Primary

Baseline, week 12, week 24.

Percent change from baseline at week 12; within group comparison. Lung level: FRC The value N=35 (Subjects in this analysis) shown below, is generated automatically and is due to an innate error of the EudraCT database system. The correct value for subjects in the analysis is N=17.

Week 12, FRC v Baseline, FRC

35

Pre-specified

65.87

2-sided

Percent change from baseline at week 24; within group comparison. Lung level: FRC The value N=34 (Subjects in this analysis) shown below, is generated automatically and is due to an innate error of the EudraCT database system. The correct value for subjects in the analysis is N=17.

Week 24, FRC v Baseline, FRC

34

Pre-specified

62.84

2-sided

Percent change from baseline at week 24; within group comparison. Lung level: TLC The value N=39 (Subjects in this analysis) shown below, is generated automatically and is due to an innate error of the EudraCT database system. The correct value for subjects in the analysis is N=20.

Week 12, TLC v Baseline, TLC

39

Pre-specified

-27.35

2-sided

Percent change from baseline at week 24; within group comparison. Lung level: TLC The value N=39 (Subjects in this analysis) shown below, is generated automatically and is due to an innate error of the EudraCT database system. The correct value for subjects in the analysis is N=20.

Week 24, TLC v Baseline, TLC

39

Pre-specified

-30.81

2-sided

Internal airflow distribution (Internal lobar airflow distribution). Percent change from baseline to week 24 of treatment. Percent change from baseline is presented using descriptive statistics (geometric mean and coefficient of variation). Lobar volume (iVlobe) is an FRI-based ventilation parameter, obtained by identifying and grouping voxels that represent the air in the lungs. The lung volume could be determined from the scans at both FRC and TLC. The subject-specific airflow distribution could be established by assessing lobar volume expansion. Results represent the actual values per time point, at baseline and week 24. Lung level: Not applicable Lung region: Upper lobes

Secondary

Baseline, week 24.

Percent change from baseline at week 24; within group comparison. The value N=37 (Subjects in this analysis) shown below, is generated automatically and is due to an innate error of the EudraCT database system. The correct value for subjects in the analysis is N=19.

Week 24 v Baseline

37

Pre-specified

-0.62

2-sided

Air trapping. Percent change from baseline to week 24 of treatment. Percent change from baseline is presented using descriptive statistics (geometric mean and coefficient of variation). Air trapping, also called gas trapping, is an abnormal retention of air in the lungs. It is observed in obstructive lung diseases such as asthma and bronchiolitis obliterans syndrome, and in chronic obstructive pulmonary diseases such as emphysema and chronic bronchitis. FRI-based air trapping was defined as all the intrapulmonary voxels with Hounsfield Units (HU) between -1024 and -850, using the expiratory scans at FRC. Results represent the actual values per time point, at baseline and week 24. Lung level: FRC Lung region: Total lung region

Secondary

Baseline, week 24.

Percent change from baseline at week 24; within group comparison. The value N=37 (Subjects in this analysis) shown below, is generated automatically and is due to an innate error of the EudraCT database system. The correct value for subjects in the analysis is N=19.

Week 24 v Baseline

37

Pre-specified

1.79

2-sided

Emphysema (Low Attenuation Score) Percent change from baseline to week 24 of treatment. Percent change from baseline is presented using descriptive statistics (geometric mean and coefficient of variation). The low attenuation areas on CT scans have been reported to represent emphysematous changes of the lung. Emphysema is a long-term, progressive disease of the lungs that primarily causes shortness of breath due to over-inflation of the alveoli. FRI-based emphysema calculations were defined as all the intrapulmonary voxels with HU between -1024 and -950, using the inspiratory scans at TLC. Results represent the actual values per time point, at baseline and week 24. Lung level: TLC Lung region: Total lung region

Secondary

Baseline, week 24.

Percent change from baseline at week 24; within group comparison. The value N=39 (Subjects in this analysis) shown below, is generated automatically and is due to an innate error of the EudraCT database system. The correct value for subjects in the analysis is N=20.

Week 24 v Baseline

39

Pre-specified

-5.47

2-sided

Airway wall volume. Percent change from baseline to week 24 of treatment. Percent change from baseline is presented using descriptive statistics (geometric mean and coefficient of variation). The airway wall volume (iVaww) consisted of all visible tissue in the CT scan that encompassed the airway wall. The airway wall volume can typically be described to the same generation level as the volume description of the airway lumen. This is where the airway diameter is around 1 2 mm. Results represent the actual values per time point, at baseline and week 24. Lung level: TLC Lung region: Distal lung region

Secondary

Baseline, week 24.

Percent change from baseline at week 24; within group comparison. The value N=39 (Subjects in this analysis) shown below, is generated automatically and is due to an innate error of the EudraCT database system. The correct value for subjects in the analysis is N=20.

Baseline v Week 24

39

Pre-specified

6.02

2-sided

Blood vessel density. Percent change from baseline to week 24 of treatment. Percent change from baseline is presented using descriptive statistics (geometric mean and coefficient of variation). Blood vessel density (iVbv) was determined through segmentation and 3D reconstruction of the blood vessels. The segmentation was based on a HU threshold between -600 and 600 and was performed on the TLC scan. The blood vessel density can be considered a surrogate for perfusion. If a contrast agent was used, the HU threshold changed to capture voxels between 200 and 1873. The use of a contrast agent was not strictly required but recommended for patients with significant fibrosis or opaque (high attenuation) regions. Results represent the actual values per time point, at baseline and week 24. Lung level: TLC Lung region: Distal lung region

Secondary

Baseline, week 24.

Percent change from baseline at week 24; within group comparison. The value N=39 (Subjects in this analysis) shown below, is generated automatically and is due to an innate error of the EudraCT database system. The correct value for subjects in the analysis is N=20.

Week 24 v Baseline

39

Pre-specified

-0.53

2-sided

Ventilation/Perfusion matching. Percent change from baseline to week 24 of treatment. Percent change from baseline is presented using descriptive statistics (geometric mean and coefficient of variation). By relating the regional ventilation to the regional perfusion, an assessment of the ventilation perfusion mismatch and potential reduction in the mismatch could be made. Results represent the actual values per time point, at baseline and week 24. Lung level: Not applicable Lung region: Total lung region

Secondary

Baseline, week 24.

Percent change from baseline at week 24; within group comparison. The value N=37 (Subjects in this analysis) shown below, is generated automatically and is due to an innate error of the EudraCT database system. The correct value for subjects in the analysis is N=19.

Week 24 v Baseline

37

Pre-specified

-2.99

2-sided

Aerosol deposition for BDP, FF, and GB. Percent change from baseline to week 24 of treatment. Percent change from baseline is presented using descriptive statistics (geometric mean and coefficient of variation). Regional aerosol deposition was determined by simulating the flow in the patient-specific geometries using patient-specific boundary conditions by means of CFD. While solving the flow equations, simultaneously particles were released in the flow and the force mass balance of the individual particles was determined through additional discrete phase computations. When a calculated particle trajectory intersected with the airway wall, the particle was trapped in that location. This allowed determining the regional concentration of inhaled aerosols and consequently the effective lung dose of inhaled medication. Results represent the actual values per time point, at baseline and week 24. Lung level: TLC Lung region: Peripheral lung region

Secondary

Baseline, week 24.

Aerosol deposition, BDP Percent change from baseline at week 24; within group comparison. The value N=39 (Subjects in this analysis) shown below, is generated automatically and is due to an innate error of the EudraCT database system. The correct value for subjects in the analysis is N=20.

Week 24 v Baseline

39

Pre-specified

0.29

2-sided

Aerosol deposition, FF Percent change from baseline at week 24; within group comparison. The value N=39 (Subjects in this analysis) shown below, is generated automatically and is due to an innate error of the EudraCT database system. The correct value for subjects in the analysis is N=19.

Week 24 v Baseline

39

Pre-specified

0.29

2-sided

Aerosol deposition, GB Percent change from baseline at week 24; within group comparison. The value N=39 (Subjects in this analysis) shown below, is generated automatically and is due to an innate error of the EudraCT database system. The correct value for subjects in the analysis is N=19.

Week 24 v Baseline

39

Pre-specified

0.3

2-sided

Dynamic lung volumes calculated by spirometry: Forced Expiratory Volume in one second (FEV1) FEV1 is one of the lung function tests, obtained by spirometry. The volume of air that can be forced out in one second after taking a deep breath is an important measure of pulmonary function.For FEV1, the highest value (L) from three technically satisfactory attempts (1 minute apart) were recorded. Descriptive statistics were used to calculate the results shown below, which represent the actual values per time point, at baseline and at pre-dose week 24.

Secondary

Baseline, pre dose at week 24.

Change from baseline at week 24, FEV1. Within group comparison. Change from baseline is presented using descriptive statistics. The value N=40 (Subjects in this analysis) shown below, is generated automatically and is due to an innate error of the EudraCT database system. The correct value for subjects in the analysis is N=20.

Week 24 v Baseline

40

Pre-specified

0.056

2-sided

Dynamic lung volumes, spirometry: Peak Expiratory Flow (PEF) PEF is one of the lung function tests, obtained by spirometry. PEF is a person's maximum speed of expiration, as measured with a peak flow meter Descriptive statistics were used to calculate the results shown below, which represent the actual values per time point, at baseline and at pre-dose week 24.

Secondary

Baseline, pre dose at week 24.

Change from baseline at week 24, PEF. Within group comparison. Change from baseline is presented using descriptive statistics. The value N=40 (Subjects in this analysis) shown below, is generated automatically and is due to an innate error of the EudraCT database system. The correct value for subjects in the analysis is N=20.

Week 24 v Baseline

40

Pre-specified

0.033

2-sided

Static lung volumes calculated by body plethysmography: Inspiratory capacity (IC), Total lung capacity (TLC), Residual volume (RV) Body plethysmography is a well-established technique of lung function determination, providing measures of the lung that reflect a multitude of functional and structural aspects. It is an alternative method of measuring lung volume that takes advantage of the principle of Boyle’s law i.e. the volume of gas at a constant temperature varies inversely with the pressure applied to it. The primary advantage of body plethysmography is that it can measure the total volume of air in the chest, including gas trapped in bullae. Another advantage is that this test can be performed quickly while patient is breathing at tidal volume. Descriptive statistics were used to calculate the results shown below, which represent the actual values per time point. The number of patients contributing to the end points is also shown.

Secondary

Baseline, pre dose at week 24.

Change from baseline at pre dose on week 24, IC. Within group comparison. Change from baseline is presented using descriptive statistics. The value N=39 (Subjects in this analysis) shown below, is generated automatically and is due to an innate error of the EudraCT database system. The correct value for subjects in the analysis is N=19.

Week 24 v Baseline

39

Pre-specified

0.173

2-sided

Standard deviation

0.388

Change from baseline at pre dose at week 24, TLC Within group comparison. Change from baseline is presented using descriptive statistics. The value N=39 (Subjects in this analysis) shown below, is generated automatically and is due to an innate error of the EudraCT database system. The correct value for subjects in the analysis is N=20.

Week 24 v Baseline

39

Pre-specified

0.118

2-sided

Standard deviation

0.739

Change from baseline at pre dose at week 24, RV Within group comparison. Change from baseline is presented using descriptive statistics. The value N=39 (Subjects in this analysis) shown below, is generated automatically and is due to an innate error of the EudraCT database system. The correct value for subjects in the analysis is N=20.

Week 24 v Baseline

39

Pre-specified

0.034

2-sided

Standard deviation

0.747

Saint George Respiratory Questionnaire (SGRQ) The SGRQ is an index designed to measure and quantify health-related health status in patients with chronic airflow limitation. Results obtained as a score from SGRQ have been shown to correlate well with established measures of symptom level, disease activity, and disability. Three component are used to calculate the SGRQ score: Symptom level, Impacts, and Activity. A Total score is also calculated and this summarises the impact of the disease on overall health status. Scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status. Results show the SGRQ score at baseline and at week 24 of treatment. The number of subjects (N) contributing to the data is also indicated.

Secondary

Baseline, week 24.

Change from baseline at week 24; SGRQ Total score. Within group comparison, using descriptive statistics. The value N=38 (Subjects in this analysis) shown below, is generated automatically and is due to an innate error of the EudraCT database system. The correct value for subjects in the analysis is N=19.

Baseline v Week 24

38

Pre-specified

-2.81

2-sided

Standard deviation

11.23

Change from baseline at week 24; SGRQ Symptoms score. Within group comparison, using descriptive statistics. The value N=38 (Subjects in this analysis) shown below, is generated automatically and is due to an innate error of the EudraCT database system. The correct value for subjects in the analysis is N=19.

Week 24 v Baseline

38

Pre-specified

-3.59

2-sided

Standard deviation

18.27

Change from baseline at week 24; SGRQ Impacts. Within group comparison, using descriptive statistics. The value N=38 (Subjects in this analysis) shown below, is generated automatically and is due to an innate error of the EudraCT database system. The correct value for subjects in the analysis is N=19.

Week 24 v Baseline

38

Pre-specified

0.98

2-sided

Standard deviation

12.71

Change from baseline at week 24; SGRQ Activity. Within group comparison, using descriptive statistics. The value N=38 (Subjects in this analysis) shown below, is generated automatically and is due to an innate error of the EudraCT database system. The correct value for subjects in the analysis is N=19.

Week 24 v Baseline

38

Pre-specified

-8.31

2-sided

Standard deviation

22.91

Treatment period: from first treatment inhalation of IMP until study completion (24 weeks) or study discontinuation.

Analyses of adverse events were based on the safety population, defined as all randomised subjects who received at least one dose of IMP. Adverse events were analysed according to the treatment-emergent principle.

20.0

Subjects with COPD