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Clinical Trial Results:
Open label, prospective study to evaluate the effect of step-up from non-extrafine ICS/LABA DPI to extra fine triple therapy with CHF5993 DPI on airway geometry and lung ventilation using FRI in subjects with advanced COPD.

Summary
EudraCT number	2020-002356-20
Trial protocol	BE HU
Global end of trial date	03 Jan 2022

Results information
Results version number	v1(current)
This version publication date	25 Feb 2023
First version publication date	25 Feb 2023
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

CLI-05993BA1-08

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Chiesi Farmaceutici S.p.A.

Sponsor organisation address

Via Palermo, 26/A, Parma, Italy, 43122

Public contact

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

Scientific contact

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

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

27 Jan 2023

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

03 Jan 2022

Was the trial ended prematurely?

Main objective of the trial

To assess the effect of stepping-up from fluticasone dipropionate (FP)/salmeterol (SLM) dry-powder inhaler (DPI) (SERETIDE™ DISKUS™) to extrafine beclometasone dipropionate (BDP)/formoterol fumarate (FF)/glycopyrronium bromide (GB) DPI (CHF5993) on airway geometry and lung ventilation. The primary and secondary endpoints are shown in the database.

Protection of trial subjects

The clinical study was performed in accordance with the principles that have their origin in the declaration of Helsinki, and with local regulations. The study was carried out in accordance with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) notes for guidance on Good Clinical Practice (GCP) (ICH/CPMP/135/95). All patients were to be well trained in the inhalation technique with In-Check Dial at screening to familiarise with the inhalation technique, in the attempt to yield repeatable inhalations. During V1 (screening), all patients were to be trained on the proper use of SERETIDE™ DISKUS™ and CHF5993 NEXThaler® by using In-Check Dial. During the training, two different assessments were to be performed: one set for DISKUS™ resistance, and the second set for NEXThaler®. The study consisted of a screening visit (V1), followed by a 6 week run-in period. At the end of the run-in period (V2), patients were switched to the treatment period for 6 weeks (until V3). A follow-up call was planned after 2 weeks ± 2 days from V3 for males and women of non childbearing potential. The total study duration was approximately 14 weeks per patient.

Background therapy

In the run-in period, patients were administered SERETIDE™ DISKUS™ 500/50 μg one inhalation b.i.d. (batch number: V66D), giving a total daily dose of 1 mg FP (Fluticasone dipropionate) and 100 µg SLM (Salmeterol).

Evidence for comparator

Actual start date of recruitment

11 Jun 2021

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 8

Country: Number of subjects enrolled

Hungary: 17

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

In total, 45 patients were screened of whom 20 were screening failures. The other 25 patients were enrolled and received two inhalations b.i.d. of CHF5993 DPI 100/6/12.5 µg. All enrolled and treated patients completed the study, and 23 patients were included in the PP analysis set.

Screening details

Screening visit was performed 6 weeks ± 2 days before Visit 2. The eligibility (inclusion/exclusion criteria) such as BMI, medical and smoking hystory, hystory of alcohol and drug abuse, vital signs, ECG test, pregnancy test, serology test, documented COVID-19 diagnosis, blood analysis, urine test, intake of concomitants medications were assessed.

Number of subjects started

45 ^[1]

Number of subjects completed

Reason: Number of subjects

Adverse event, non-fatal: 1

Reason: Number of subjects

In-/exclusion criteria: 14

Reason: Number of subjects

Consent withdrawn by subject: 5

Notes
[1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: In total, 45 patients were screened of whom 20 were screening failures. The other 25 patients were enrolled and treated.

Period 1 title

CHF5993 DPI 100/6/12.5 μg (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

CHF5993 DPI 100/6/12.5 μg

Arm description

All patients (25 subjects) received CHF5993 as follows: - Treatment period (6 weeks): two inhalations b.i.d. of CHF5993 DPI 100/6/12.5 µg, giving a total daily dose of BDP/FF/GB 400/24/50 µg. After the screening visit (V1) that was to be performed 6 weeks ± 2 days before Visit 2 (V2), eligible patients were to undergo a 6-week run-in period with FP/SLM DPI 500/50 µg (SERETIDE™ DISKUS™). At the end of the run-in period (V2), patients were to be switched to the treatment period with BDP/FF/GB DPI (CHF5993) for 6 weeks until Visit 3 (V3).

Arm type

Experimental

Investigational medicinal product name

CHF5993 DPI 100/6/12.5 μg

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder

Routes of administration

Respiratory use

Dosage and administration details

Carried out treatment included two inhalations b.i.d. of CHF5993 DPI 100/6/12.5 µg, giving a total daily dose of BDP/FF/GB 400/24/50 µg.

Number of subjects in period 1	CHF5993 DPI 100/6/12.5 μg
Started	25
Completed	25

Baseline characteristics

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Reporting group title

CHF5993 DPI 100/6/12.5 μg

Reporting group description

After the screening visit (V1) that was to be performed 6 weeks ± 2 days before Visit 2 (V2), eligible patients were to undergo a 6-week run-in period with FP/SLM DPI 500/50 µg (SERETIDE™ DISKUS™). At the end of the run-in period (V2), patients were to be switched to the treatment period with BDP/FF/GB DPI (CHF5993) for 6 weeks until Visit 3 (V3). During the treatment period all patients, (25 subjects) received two inhalations b.i.d. of CHF5993 DPI 100/6/12.5 µg, giving a total daily dose of BDP/FF/GB 400/24/50 µg. All enrolled and treated patients completed the study.

Reporting group values	CHF5993 DPI 100/6/12.5 μg	Total
Number of subjects	25	25
Age categorical
Units: Subjects
Adults (45-79 years)	25	25
Age continuous
Units: years
arithmetic mean (standard deviation)	65.0 ( 7.7 )	-
Gender categorical
Units: Subjects
Female	9	9
Male	16	16
Race
Units: Subjects
White	25	25
BMI
Units: kg/m²
arithmetic mean (standard deviation)	27.71 ( 5.05 )	-

End points

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Reporting group title

CHF5993 DPI 100/6/12.5 μg

Reporting group description

Subject analysis set title

Baseline / V2 pre-dose, TLC

Subject analysis set type

Per protocol

Subject analysis set description

Subjects evaluated at Baseline / Visit 2 pre-dose; distal lung region at Total Lung Capacity, TLC. The PP analysis set, defined as all patients from the safety set, excluding patients without any valid evaluation of FRI after the baseline or with important protocol deviations impacting the primary study endpoints, included 23 patients.

Subject analysis set title

V2 post-dose, TLC

Subject analysis set type

Per protocol

Subject analysis set description

Subjects evaluated at Visit 2 post-dose; distal lung region at Total Lung Capacity, TLC. The PP analysis set, defined as all patients from the safety set, excluding patients without any valid evaluation of FRI after the baseline or with important protocol deviations impacting the primary study endpoints, included 23 patients.

Subject analysis set title

V3 pre-dose, TLC

Subject analysis set type

Per protocol

Subject analysis set description

Subjects evaluated at Visit 3 pre-dose; distal lung region at Total Lung Capacity, TLC. The PP analysis set, defined as all patients from the safety set, excluding patients without any valid evaluation of FRI after the baseline or with important protocol deviations impacting the primary study endpoints, included 23 patients.

Subject analysis set title

V3 post-dose, TLC

Subject analysis set type

Per protocol

Subject analysis set description

Subjects evaluated at Visit 3 post-dose; distal lung region at Total Lung Capacity, TLC. The PP analysis set, defined as all patients from the safety set, excluding patients without any valid evaluation of FRI after the baseline or with important protocol deviations impacting the primary study endpoints, included 23 patients.

Subject analysis set title

Baseline / V2 pre-dose, FRC

Subject analysis set type

Per protocol

Subject analysis set description

Subjects evaluated at Baseline / Visit 2 pre-dose; distal lung region at Functional Residual Capacity, FRC. The PP analysis set, defined as all patients from the safety set, excluding patients without any valid evaluation of FRI after the baseline or with important protocol deviations impacting the primary study endpoints, included 23 patients.

Subject analysis set title

V2 post-dose, FRC

Subject analysis set type

Per protocol

Subject analysis set description

Subjects evaluated at Visit 2 post-dose; distal lung region at Functional Residual Capacity, FRC. The PP analysis set, defined as all patients from the safety set, excluding patients without any valid evaluation of FRI after the baseline or with important protocol deviations impacting the primary study endpoints, included 23 patients.

Subject analysis set title

V3 pre-dose, FRC

Subject analysis set type

Per protocol

Subject analysis set description

Subjects evaluated at Visit 3 pre-dose; distal lung region at Functional Residual Capacity, FRC. The PP analysis set, defined as all patients from the safety set, excluding patients without any valid evaluation of FRI after the baseline or with important protocol deviations impacting the primary study endpoints, included 23 patients.

Subject analysis set title

V3 post-dose, FRC

Subject analysis set type

Per protocol

Subject analysis set description

Subjects evaluated at Visit 3 post-dose; distal lung region at Functional Residual Capacity, FRC. The PP analysis set, defined as all patients from the safety set, excluding patients without any valid evaluation of FRI after the baseline or with important protocol deviations impacting the primary study endpoints, included 23 patients.

Primary: Untrimmed siVaw for distal region at TLC – actual value for V2 pre-dose and V3 pre-dose

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End point title

Untrimmed siVaw for distal region at TLC – actual value for V2 pre-dose and V3 pre-dose

End point description

siVaw is Specific Image-Based Airway Volume (at Total Lung Capacity, TLC). Primary efficacy endpoints were presented as the arithmetic mean and the standard deviation (SD). The data were summarized by the descriptive statistics for actual values at each timepoint.

End point type

Primary

End point timeframe

Multi-slice with multidetector computed tomography (MDCT) (inspiratory at TLC and expiratory at FRC) was to be performed pre-dose and within 60-120 min post-dose at V2 and V3. At V2, the upper airway (UA) was also to be be scanned at TLC, pre-dose.

End point values	Baseline / V2 pre-dose, TLC	V3 pre-dose, TLC
Number of subjects analysed	23	23
Units: percentage
arithmetic mean (standard deviation)	1.4088 ( 0.6647 )	1.3550 ( 0.6014 )

Percent change from Baseline to V3 pre-dose; TLC

Statistical analysis description

Overall, distal region value for primary endpoints was log-transformed and analysed using a Mixed Model for Repeated Measures (MMRM). The adjusted % change from baseline to pre-dose at V3 was back transformed and presented with its 95% confidence interval (CI) and related p-value. The value N=46, shown below, is generated automatically and is due to innate error of the EudraCT database system and to the cross-over nature of the study. The correct value for subjects in the analysis is N=23.

Comparison groups

V3 pre-dose, TLC v Baseline / V2 pre-dose, TLC

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[1]

P-value

= 0.4521

Method

Mixed models analysis

Parameter type

Adjusted Mean Change

Point estimate

-3.81

Confidence interval

level

95%

sides

2-sided

lower limit

-13.44

upper limit

6.89

Notes
[1] - The model included the logarithm of baseline (V2 pre-dose, but not for trimmed parameters) at TLC and visit (V2 post-dose, V3 pre-dose, V3 post-dose) as covariates, and the interaction between visit and logarithm of baseline (for untrimmed parameters). The model parameters were estimated using the restricted maximum likelihood method with unstructured variance-covariance matrix and Kenward-Roger approximation to estimate denominator degrees of freedom.

Primary: Trimmed siRaw for distal region at TLC – actual value for V2 pre-dose and V3 pre-dose

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End point title

Trimmed siRaw for distal region at TLC – actual value for V2 pre-dose and V3 pre-dose

End point description

siRaw is the Specific Image-Based Airway Resistance (at Total Lung Capacity, TLC). Primary efficacy endpoints were presented as the arithmetic mean and the standard deviation (SD). The data were summarized by the descriptive statistics for actual values at each timepoint.

End point type

Primary

End point timeframe

End point values	Baseline / V2 pre-dose, TLC	V3 pre-dose, TLC
Number of subjects analysed	22 ^[2]	22 ^[3]
Units: percentage
arithmetic mean (standard deviation)
TLC	0.7160 ( 0.4034 )	0.8492 ( 0.5947 )

Notes
[2] - PP population number of patients/number of patients with data: 23/22
[3] - PP population number of patients/number of patients with data: 23/22

Percent change from Baseline to V3 pre-dose; TLC

Statistical analysis description

Overall, distal region value for primary endpoints was log-transformed and analysed using a Mixed Model for Repeated Measures (MMRM). The adjusted % change from baseline to pre-dose at V3 was back transformed and presented with its 95% confidence interval (CI) and related p-value. The value N=44, shown below, is generated automatically and is due to innate error of the EudraCT database system and to the cross-over nature of the study. The correct value for subjects in the analysis is N=22.

Comparison groups

V3 pre-dose, TLC v Baseline / V2 pre-dose, TLC

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[4]

P-value

= 0.4871

Method

Mixed models analysis

Parameter type

Adjusted Mean Change

Point estimate

11.95

Confidence interval

level

95%

sides

2-sided

lower limit

-19.67

upper limit

56.02

Notes
[4] - The model included the logarithm of baseline (V2 pre-dose, but not for trimmed parameters) at TLC and visit (V2 post-dose, V3 pre-dose, V3 post-dose) as covariates, and the interaction between visit and logarithm of baseline (for untrimmed parameters). The model parameters were estimated using the restricted maximum likelihood method with unstructured variance-covariance matrix and Kenward-Roger approximation to estimate denominator degrees of freedom.

Secondary: Untrimmed siVaw for distal region at TLC and FRC – actual value for V2 pre-dose, V2 post-dose, V3 pre-dose and V3 post-dose

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End point title

Untrimmed siVaw for distal region at TLC and FRC – actual value for V2 pre-dose, V2 post-dose, V3 pre-dose and V3 post-dose

End point description

siVaw is Specific Image-Based Airway Volume (at Total Lung Capacity, TLC and Functional Residual Capacity, FRC). Secondary efficacy endpoints were presented as the arithmetic mean and the standard deviation (SD). The data were summarized by the descriptive statistics for actual values at each timepoint.

End point type

Secondary

End point timeframe

End point values	Baseline / V2 pre-dose, TLC	V2 post-dose, TLC	V3 pre-dose, TLC	V3 post-dose, TLC	Baseline / V2 pre-dose, FRC	V2 post-dose, FRC	V3 pre-dose, FRC	V3 post-dose, FRC
Number of subjects analysed	23	23	23	23	23	23	23	23
Units: percentage
arithmetic mean (standard deviation)	1.4088 ( 0.6647 )	1.8706 ( 0.4954 )	1.3550 ( 0.6014 )	1.9805 ( 0.6390 )	0.6321 ( 0.3164 )	1.0204 ( 0.3404 )	0.6982 ( 0.3198 )	1.0442 ( 0.3825 )

Percent change from Baseline to V2 post-dose; TLC

Statistical analysis description

Overall, distal region value for secondary endpoints was log-transformed and analysed using a Mixed Model for Repeated Measures (MMRM). The adjusted % change from baseline to post-dose at V2 was back transformed and presented with its 95% confidence interval (CI) and related p-value. The value N=46, shown below, is generated automatically and is due to innate error of the EudraCT database system and to the cross-over nature of the study. The correct value for subjects in the analysis is N=23.

Comparison groups

V2 post-dose, TLC v Baseline / V2 pre-dose, TLC

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted Mean Change

Point estimate

39.76

Confidence interval

level

95%

sides

2-sided

lower limit

28.9

upper limit

51.53

Percent change from V3 post to V3 pre-dose; TLC

Statistical analysis description

Overall, distal region value for secondary endpoints was log-transformed and analysed using a Mixed Model for Repeated Measures (MMRM). The adjusted % change from V3 post-dose to V3 pre-dose was back transformed and presented with its 95% confidence interval (CI) and related p-value. The value N=46, shown below, is generated automatically and is due to innate error of the EudraCT database system and to the cross-over nature of the study. The correct value for subjects in the analysis is N=23.

Comparison groups

V3 post-dose, TLC v V3 pre-dose, TLC

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted Mean Change

Point estimate

62.63

Confidence interval

level

95%

sides

2-sided

lower limit

41.78

upper limit

86.56

Percent change from Baseline to V3 pre-dose; FRC

Statistical analysis description

Overall, distal region value for secondary endpoints was log-transformed and analysed using a Mixed Model for Repeated Measures (MMRM). The adjusted % change from baseline to pre-dose at V3 was back transformed and presented with its 95% confidence interval (CI) and related p-value. The value N=46, shown below, is generated automatically and is due to innate error of the EudraCT database system and to the cross-over nature of the study. The correct value for subjects in the analysis is N=23.

Comparison groups

V3 pre-dose, FRC v Baseline / V2 pre-dose, FRC

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0636

Method

Mixed models analysis

Parameter type

Adjusted Mean Change

Point estimate

16.26

Confidence interval

level

95%

sides

2-sided

lower limit

-0.93

upper limit

36.44

Percent change from Baseline to V2 post-dose; FRC

Statistical analysis description

Comparison groups

V2 post-dose, FRC v Baseline / V2 pre-dose, FRC

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Adjusted Mean Change

Point estimate

77.87

Confidence interval

level

95%

sides

2-sided

lower limit

60.28

upper limit

97.39

Percent change from V3 post to V3 pre-dose; FRC

Statistical analysis description

Comparison groups

V3 post-dose, FRC v V3 pre-dose, FRC

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0011

Method

Mixed models analysis

Parameter type

Adjusted Mean Change

Point estimate

39.49

Confidence interval

level

95%

sides

2-sided

lower limit

16.21

upper limit

67.43

Secondary: Trimmed siRaw for distal region at TLC and FRC – actual value for V2 pre-dose, V2 post-dose, V3 pre-dose and V3 post-dose

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End point title

Trimmed siRaw for distal region at TLC and FRC – actual value for V2 pre-dose, V2 post-dose, V3 pre-dose and V3 post-dose

End point description

siRaw is the Specific Image-Based Airway Resistance (at Total Lung Capacity, TLC and Functional Residual Capacity, FRC). Secondary efficacy endpoints were presented as the arithmetic mean and the standard deviation (SD). The data were summarized by the descriptive statistics for actual values at each timepoint.

End point type

Secondary

End point timeframe

End point values	Baseline / V2 pre-dose, TLC	V2 post-dose, TLC	V3 pre-dose, TLC	V3 post-dose, TLC	Baseline / V2 pre-dose, FRC	V2 post-dose, FRC	V3 pre-dose, FRC	V3 post-dose, FRC
Number of subjects analysed	22 ^[5]	23	22 ^[6]	23	22 ^[7]	22 ^[8]	22 ^[9]	22 ^[10]
Units: percentage
arithmetic mean (standard deviation)	0.7160 ( 0.4034 )	0.3685 ( 0.1594 )	0.8492 ( 0.5947 )	0.3121 ( 0.1416 )	0.4981 ( 0.3383 )	0.2200 ( 0.1664 )	0.3625 ( 0.4733 )	0.1889 ( 0.1453 )

Notes
[5] - PP population number of patients/number of patients with data: 23/22.
[6] - PP population number of patients/number of patients with data: 23/22.
[7] - PP population number of patients/number of patients with data: 23/22.
[8] - PP population number of patients/number of patients with data: 23/22.
[9] - PP population number of patients/number of patients with data: 23/22.
[10] - PP population number of patients/number of patients with data: 23/22.

Percent change from Baseline to V2 post-dose; TLC

Statistical analysis description

Overall, distal region value for secondary endpoints was log-transformed and analysed using a Mixed Model for Repeated Measures (MMRM). The adjusted % change from baseline to post-dose at V2 was back transformed and presented with its 95% confidence interval (CI) and related p-value. The value N=45, shown below, is generated automatically and is due to innate error of the EudraCT database system and to the cross-over nature of the study. The correct value for subjects in the analysis is N=22.

Comparison groups

V2 post-dose, TLC v Baseline / V2 pre-dose, TLC

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0002

Method

Mixed models analysis

Parameter type

Adjusted Mean Change

Point estimate

-51.07

Confidence interval

level

95%

sides

2-sided

lower limit

-64.56

upper limit

-32.44

Percent change from V3 post to V3 pre-dose; TLC

Statistical analysis description

Overall, distal region value for secondary endpoints was log-transformed and analysed using a Mixed Model for Repeated Measures (MMRM). The adjusted % change from V3 post-dose to V3 pre-dose was back transformed and presented with its 95% confidence interval (CI) and related p-value. The value N=45, shown below, is generated automatically and is due to innate error of the EudraCT database system and to the cross-over nature of the study. The correct value for subjects in the analysis is N=22.

Comparison groups

V3 post-dose, TLC v V3 pre-dose, TLC

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0009

Method

Mixed models analysis

Parameter type

Adjusted Mean Change

Point estimate

-57.22

Confidence interval

level

95%

sides

2-sided

lower limit

-72.88

upper limit

-32.52

Percent change from Baseline to V3 pre-dose; FRC

Statistical analysis description

Overall, distal region value for secondary endpoints was log-transformed and analysed using a Mixed Model for Repeated Measures (MMRM). The adjusted % change from baseline to pre-dose at V3 was back transformed and presented with its 95% confidence interval (CI) and related p-value. The value N=44, shown below, is generated automatically and is due to innate error of the EudraCT database system and to the cross-over nature of the study. The correct value for subjects in the analysis is N=22.

Comparison groups

Baseline / V2 pre-dose, FRC v V3 pre-dose, FRC

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0261

Method

Mixed models analysis

Parameter type

Adjusted Mean Change

Point estimate

-63.57

Confidence interval

level

95%

sides

2-sided

lower limit

-84.85

upper limit

-12.42

Percent change from Baseline to V2 post-dose; FRC

Statistical analysis description

Overall, distal region value for secondary endpoints was log-transformed and analysed using a Mixed Model for Repeated Measures (MMRM). The adjusted % change from baseline to post-dose at V2 was back transformed and presented with its 95% confidence interval (CI) and related p-value. The value N=44, shown below, is generated automatically and is due to innate error of the EudraCT database system and to the cross-over nature of the study. The correct value for subjects in the analysis is N=22.

Comparison groups

V2 post-dose, FRC v Baseline / V2 pre-dose, FRC

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0006

Method

Mixed models analysis

Parameter type

Adjusted Mean Change

Point estimate

-66.95

Confidence interval

level

95%

sides

2-sided

lower limit

-81.4

upper limit

-41.27

Percent change from V3 post to V3 pre-dose; FRC

Statistical analysis description

Overall, distal region value for secondary endpoints was log-transformed and analysed using a Mixed Model for Repeated Measures (MMRM). The adjusted % change from V3 post-dose to V3 pre-dose was back transformed and presented with its 95% confidence interval (CI) and related p-value. The value N=45, shown below, is generated automatically and is due to innate error of the EudraCT database system and to the cross-over nature of the study. The correct value for subjects in the analysis is N=22.

Comparison groups

V3 pre-dose, FRC v V3 post-dose, FRC

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.3855

Method

Mixed models analysis

Parameter type

Adjusted Mean Change

Point estimate

-29.28

Confidence interval

level

95%

sides

2-sided

lower limit

-68.62

upper limit

59.42

Adverse events

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Timeframe for reporting adverse events

All AEs starting on or after first administration of study drug (CHF5993 DPI) were classified as Treatment-Emergent AEs (TEAEs).

Adverse event reporting additional description

The safety data were summarised in 3 phases: 1)Screening: starting from date signing the ICF until first FP/SLM DPI administration date-1 min/day, 2)Run-in: starting from first FP/SLM DPI administration date until first CHF5993 DPI administration date–1 min/day, 3)Treatment: from first CHF5993 DPI administration date until date of last contact.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.0

Reporting group title

CHF5993 DPI 100/6/12.5 μg - Safety set

Reporting group description

The safety set, defined as all patients who received at least one dose of study drug (CHF5993 DPI), included 25 patients.

Serious adverse events	CHF5993 DPI 100/6/12.5 μg - Safety set
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 25 (0.00%)
number of deaths (all causes)	0
number of deaths resulting from adverse events	0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	CHF5993 DPI 100/6/12.5 μg - Safety set
Total subjects affected by non serious adverse events
subjects affected / exposed	11 / 25 (44.00%)
Nervous system disorders
Headache
subjects affected / exposed	3 / 25 (12.00%)
occurrences all number	3
Sciatica
subjects affected / exposed	1 / 25 (4.00%)
occurrences all number	1
Gastrointestinal disorders
Hiatus hernia
subjects affected / exposed	1 / 25 (4.00%)
occurrences all number	1
Respiratory, thoracic and mediastinal disorders
Pleural calcification
subjects affected / exposed	2 / 25 (8.00%)
occurrences all number	2
Bronchiectasis
subjects affected / exposed	1 / 25 (4.00%)
occurrences all number	1
Pulmonary fibrosis
subjects affected / exposed	1 / 25 (4.00%)
occurrences all number	1
Hepatobiliary disorders
Hepatic steatosis
subjects affected / exposed	1 / 25 (4.00%)
occurrences all number	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 25 (4.00%)
occurrences all number	1

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Were there any global substantial amendments to the protocol? Yes

22 Mar 2021

The following changes have been implemented: -IMP storage conditions updated accordingly to EMA requirements; -Typo corrections.

09 Aug 2021

The following substantial changes have been implemented: -Blood chemistry updated considering the creatinine test replacing BUN analysis; -RSI is now referred to Summary of; -Product Characteristics instead of IB; -Sponsor medical expert contacts updated; -Typo corrections.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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IMP with orphan designation in the indication
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Clinical trials

Clinical Trial Results:
Open label, prospective study to evaluate the effect of step-up from non-extrafine ICS/LABA DPI to extra fine triple therapy with CHF5993 DPI on airway geometry and lung ventilation using FRI in subjects with advanced COPD.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Untrimmed siVaw for distal region at TLC – actual value for V2 pre-dose and V3 pre-dose

Primary: Untrimmed siVaw for distal region at TLC – actual value for V2 pre-dose and V3 pre-dose

Primary: Trimmed siRaw for distal region at TLC – actual value for V2 pre-dose and V3 pre-dose

Primary: Trimmed siRaw for distal region at TLC – actual value for V2 pre-dose and V3 pre-dose

Secondary: Untrimmed siVaw for distal region at TLC and FRC – actual value for V2 pre-dose, V2 post-dose, V3 pre-dose and V3 post-dose

Secondary: Untrimmed siVaw for distal region at TLC and FRC – actual value for V2 pre-dose, V2 post-dose, V3 pre-dose and V3 post-dose

Secondary: Trimmed siRaw for distal region at TLC and FRC – actual value for V2 pre-dose, V2 post-dose, V3 pre-dose and V3 post-dose

Secondary: Trimmed siRaw for distal region at TLC and FRC – actual value for V2 pre-dose, V2 post-dose, V3 pre-dose and V3 post-dose

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: Open label, prospective study to evaluate the effect of step-up from non-extrafine ICS/LABA DPI to extra fine triple therapy with CHF5993 DPI on airway geometry and lung ventilation using FRI in subjects with advanced COPD.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Untrimmed siVaw for distal region at TLC – actual value for V2 pre-dose and V3 pre-dose

Primary: Untrimmed siVaw for distal region at TLC – actual value for V2 pre-dose and V3 pre-dose

Primary: Trimmed siRaw for distal region at TLC – actual value for V2 pre-dose and V3 pre-dose

Primary: Trimmed siRaw for distal region at TLC – actual value for V2 pre-dose and V3 pre-dose

Secondary: Untrimmed siVaw for distal region at TLC and FRC – actual value for V2 pre-dose, V2 post-dose, V3 pre-dose and V3 post-dose

Secondary: Untrimmed siVaw for distal region at TLC and FRC – actual value for V2 pre-dose, V2 post-dose, V3 pre-dose and V3 post-dose

Secondary: Trimmed siRaw for distal region at TLC and FRC – actual value for V2 pre-dose, V2 post-dose, V3 pre-dose and V3 post-dose

Secondary: Trimmed siRaw for distal region at TLC and FRC – actual value for V2 pre-dose, V2 post-dose, V3 pre-dose and V3 post-dose

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Open label, prospective study to evaluate the effect of step-up from non-extrafine ICS/LABA DPI to extra fine triple therapy with CHF5993 DPI on airway geometry and lung ventilation using FRI in subjects with advanced COPD.