Clinical Trials Register

Summary
EudraCT Number:	2020-004718-36
Sponsor's Protocol Code Number:	CLI-05993AA1-17
National Competent Authority:	Poland - Office for Medicinal Products
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2021-04-07
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Poland - Office for Medicinal Products

A.2

EudraCT number

2020-004718-36

A.3

Full title of the trial

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)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A clinical study in which two different study drugs (CHF5993 and CHF1535) and placebo are administered with the same aerosol spray inhaler to evaluate the effect of study drugs on lung function parameters, exercise tolerance and physical activity in subjects with Chronic Obstructive Pulmonary Disease

A.4.1

Sponsor's protocol code number

CLI-05993AA1-17

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Chiesi Farmaceutici S.p.A
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Chiesi Farmaceutici S.p.A
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Chiesi Farmaceutici S.p.A
B.5.2	Functional name of contact point	Clinical Project Manager-Varoli G.
B.5.3	Address:
B.5.3.1	Street Address	Via Palermo 26/A
B.5.3.2	Town/ city	Parma
B.5.3.3	Post code	43122
B.5.3.4	Country	Italy
B.5.4	Telephone number	+390521 279718
B.5.5	Fax number	+390521279333
B.5.6	E-mail	g.varoli@chiesi.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	TRIMBOW®
D.2.1.1.2	Name of the Marketing Authorisation holder	Chiesi Farmaceutici S.p.A
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	TRIMBOW®
D.3.2	Product code	CHF5993
D.3.4	Pharmaceutical form	Inhalation solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Inhalation use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BECLOMETASONE DIPROPIONATE
D.3.9.1	CAS number	5534-09-8
D.3.9.2	Current sponsor code	CHF 718
D.3.9.4	EV Substance Code	SUB00681MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	FORMOTEROL FUMARATE
D.3.9.1	CAS number	43229-80-7
D.3.9.3	Other descriptive name	FORMOTEROL FUMARATE
D.3.9.4	EV Substance Code	SUB02257MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	6
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	GLYCOPYRRONIUM
D.3.9.3	Other descriptive name	GLYCOPYRRONIUM
D.3.9.4	EV Substance Code	SUB02381MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	FOSTER®
D.2.1.1.2	Name of the Marketing Authorisation holder	Chiesi Farmaceutici S.p.A.
D.2.1.2	Country which granted the Marketing Authorisation	Poland
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	FOSTER®
D.3.2	Product code	CHF1535
D.3.4	Pharmaceutical form	Inhalation solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Inhalation use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BECLOMETASONE DIPROPIONATE
D.3.9.1	CAS number	5534-09-8
D.3.9.2	Current sponsor code	CHF 718
D.3.9.4	EV Substance Code	SUB00681MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	FORMOTEROL FUMARATE
D.3.9.1	CAS number	43229-80-7
D.3.9.3	Other descriptive name	FORMOTEROL FUMARATE
D.3.9.4	EV Substance Code	SUB02257MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	6
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Inhalation solution
D.8.4	Route of administration of the placebo	Inhalation use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Chronic Obstructive Pulmonary Disease (COPD)

E.1.1.1

Medical condition in easily understood language

Chronic Obstructive Pulmonary Disease

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10009032
E.1.2	Term	Chronic obstructive lung disease
E.1.2	System Organ Class	100000004855

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

• To evaluate the effect of CHF5993 and CHF1535 compared with placebo in terms of change from baseline in 2-hour post-dose inspiratory capacity (IC) prior to constant work-rate cycle ergometry (CWRCE) test at Week 3 (of treatment)

E.2.2

Secondary objectives of the trial

• To evaluate the effect of CHF5993 and CHF1535 compared with placebo in terms of change from baseline in IC at isotime at Week 3.
• To evaluate the effect of CHF5993 and CHF1535 compared with placebo in terms of change from baseline in 2-hour post-dose exercise endurance time (EET) at Week 3.
• To evaluate the safety profile of the study treatments in terms of occurrence of treatment-emergent adverse events (TEAEs), adverse drug reactions (ADRs), severe ADRs, serious AEs (SAEs), severe AEs, AEs leading to discontinuation from study treatment and AEs leading to death.
• To evaluate the safety profile of the study treatments in terms of change from baseline in systolic blood pressure, diastolic blood pressure and heart rate.

E.2.3

Trial contains a sub-study

E.3

Principal 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 > 40 years at Screening visit
4.COPD diagnosis for at least 12 months before the Screening visit according to 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
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.
7.Pre-bronchodilator functional residual capacity (FRC) of > 120% of predicted normal FRC values at Screening visit 1.
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)) fulfilling one of the following criteria:
•WOCBP with fertile male partners: they and/or their partner must be willing to use a highly effective birth control method from the signature of the informed consent and until the follow-up contact or
•WOCBP with non-fertile male partners (contraception is not required in this case)
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

E.4

Principal 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.
3.Unstable concurrent disease which may impact the efficacy or the safety of the study drug according to investigator’s judgment.
4.Any other disease/condition which in the opinion of investigator is likely to impact subject’s cardiopulmonary status or the ability to perform functional (exercise) testing during the study.
5.Evidence of symptomatic advanced peripheral artery disease.
6.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
7.Lung transplant or lung volume reduction surgery (subjects with lung volume reduction surgery are excluded if the procedure was performed within 1 year before the Screening visit)
8.Subjects requiring long term (> 15 hours a day) oxygen therapy for chronic hypoxemia
9.Subjects who have clinically severe cardiovascular condition which may impact the efficacy or the safety of the study drug according to the investigator’s judgement
10.An abnormal and clinical.ly significant 12-lead ECG which may impact the safety of the subject according to investigator’s judgement. Subjects whose electrocardiogram (ECG) (12 lead) shows QTcF >450 ms for males or QTcF >470 ms for females at screening or at randomisation visits are not eligible.
11.Medical diagnosis of narrow-angle glaucoma, prostatic hypertrophy or bladder neck obstruction that in the opinion of the investigator would prevent use of anticholinergic agents
12.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
13.Clinically significant laboratory abnormalities indicating a significant or unstable concomitant disease which may impact the efficacy or the safety of the study drug according to investigator’s judgement
14.Subjects with body mass index less than 15 or greater than 35 kg/m2
15.Malignancy that has not been in complete remission for at least 1 year or any untreated (e.g. resected for cure) localized carcinomas
16.History of alcohol abuse and/or substance/drug abuse within 12 months prior to screening visit
17.Subjects who are mentally or legally incapacitated, or subjects incarcerated as a result of an official or judicial order
18.Subjects who are in the acute phase of pulmonary rehabilitation program within 1 month before the Screening visit or planning to enrol in the acute phase of such program during the study. Subjects who are in the maintenance phase of a pulmonary rehabilitation program are not excluded
19.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
20.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

E.5 End points

E.5.1

Primary end point(s)

•Change from baseline in 2-hour post-dose IC prior to CWRCE test after 3 weeks of treatment

E.5.1.1

Timepoint(s) of evaluation of this end point

At the end of each 3-week treatment period

E.5.2

Secondary end point(s)

• Change from baseline in IC at isotime after 3 weeks of treatment.
• Change from baseline in 2-hour post-dose EET after 3 weeks of treatment.
• Occurrence of TEAEs, adverse drug reactions (ADRs), severe ADRs, serious TEAEs (SAEs), severe TEAEs, TEAEs leading to discontinuation from study treatment and TEAEs leading to death.
• Change from baseline in SBP, DBP and HR after 3 weeks of treatment.

E.5.2.1

Timepoint(s) of evaluation of this end point

• At the end of each 3-week treatment period
• Safety endpoints will be monitored throughout all the study period

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

Yes

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

Last follow-up contact of the last subject in the trial

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

102

F.4.2.2

In the whole clinical trial

102

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

The investigator will prescribe the most appropriate treatment or restore the initial therapy or refer to General Practitioner

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-06-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-03-24

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-02-24

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