Clinical Trials Register

Summary
EudraCT Number:	2020-002389-16
Sponsor's Protocol Code Number:	CLI-05993AA3-06
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-12-09
Trial 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

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2020-002389-16

A.3

Full title of the trial

A phase III, 52-week, multinational, multicenter, randomized, double-blind, 2-arm parallel group study comparing efficacy, safety and tolerability of the fixed dose triple combination of beclomethasone dipropionate plus formoterol fumarate plus glycopyrronium bromide (CHF 5993) with the fixed dose dual combination of beclomethasone dipropionate plus formoterol fumarate (CHF 1535), both administered via pMDI 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 to evaluate efficacy, safety and tolerability of a drug CHF 5993 with a drug CHF 1535, both administered via Pressurised Metered Dose Inhaler in subjects with chronic obstructive pulmonary disease

A.3.2

Name or abbreviated title of the trial where available

Triton

A.4.1

Sponsor's protocol code number

CLI-05993AA3-06

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT04320342

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
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.5.6	E-mail	clinicaltrials_info@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	No
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	CHF 5993 pMDI US 100/6/12.5 μg per actuation
D.3.2	Product code	CHF5993
D.3.4	Pharmaceutical form	Pressurised 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	BECLOMETHASONE DIPROPIONATE
D.3.9.1	CAS number	5534-09-8
D.3.9.2	Current sponsor code	CHF718
D.3.9.3	Other descriptive name	BDP
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 dihydrate
D.3.9.1	CAS number	43229-80-7
D.3.9.2	Current sponsor code	CHF1531.02
D.3.9.3	Other descriptive name	FF
D.3.9.4	EV Substance Code	SUB25660
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 BROMIDE
D.3.9.1	CAS number	596-51-0
D.3.9.2	Current sponsor code	CHF5259.02
D.3.9.3	Other descriptive name	GB
D.3.9.4	EV Substance Code	SUB07951MIG
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	12.5
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	Comparator
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	INNOVAIR® Beclometasone/Formoterol Aerosol (Solution) 100 μg/6 μg 120 doses
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	Mexico
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	INNOVAIR®
D.3.2	Product code	CHF1535 pMDI
D.3.4	Pharmaceutical form	Pressurised 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	Formoterol fumarate dihydrate
D.3.9.1	CAS number	43229-80-7
D.3.9.3	Other descriptive name	FF
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	BECLOMETASONE DIPROPIONATE
D.3.9.1	CAS number	5534-09-8
D.3.9.2	Current sponsor code	CHF718
D.3.9.3	Other descriptive name	BDP
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.3.11 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	Pressurised 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 (COPD)

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	10010952
E.1.2	Term	COPD
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 demonstrate the efficacy of CHF 5993 to improve lung function (pre-dose morning FEV1) compared with CHF 1535

E.2.2

Secondary objectives of the trial

To demonstrate the efficacy of CHF 5993 to improve post-dose lung function (2-hour post dose FEV1) compared with CHF 1535
To demonstrate the efficacy of CHF 5993 in reducing the annual rate of moderate and severe COPD exacerbations compared with CHF 1535
To assess the long-term safety and tolerability of CHF 5993 compared with CHF 1535
To evaluate the effect of CHF 5993 on other lung function parameters, subject’s health status and clinical outcome measures compared with CHF 1535

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Population Pharmacokinetic parameters for Beclomethasone 17-Monopropionate (B17MP), Glycopyrronium bromide (GB) and formoterol, as applicable, from subset of subjects undergoing blood collection at Week 0 (V2), Week 28 (V7) and Week 52(V11).

E.3

Principal inclusion criteria

1. A signed and dated written informed consent must be obtained prior to initiating any study related procedures
2. Outpatient population
3. Male or female subjects aged >40 years
4. A female is eligible to participate in the study if she is of non-childbearing potential OR childbearing potential with negative serum and urine pregnancy tests at screening, and is willing to use highly effective birth control methods for the full duration of the study (for more details for criteria 4. see study protocol)
5. COPD diagnosis for at least 12 months before the screening visit in accordance with the definition by the GOLD 2020 Report
6. Current or ex-smokers who quit smoking at least 6 months prior to screening with a smoking history of at least 10 pack-years
7. Symptomatic subjects based on COPD Assessment Test (CAT) score ≥10
8. A pre- and post-bronchodilator FEV1/FVC ratio <0.70 at screening
9. A post-bronchodilator FEV1 <50% predicted normal at screening and a documented history of ≥1 moderate or severe COPD exacerbation in the previous 12 months
OR
a post-bronchodilator FEV1 ≥50% and <80% of predicted normal at screening and a documented history of ≥2 moderate COPD exacerbations or ≥1 severe COPD exacerbation in the previous 12 months Global Lung Function Initiative reference equations will be used to calculate percent predicted values (for COPD exacerbation details see study protocol).
10. Subjects receiving daily inhaled maintenance therapy for their COPD, at a stable dose for at
least 3 months prior to the screening and randomization visits
11. Documentation (including imagery and report) of chest x-ray (CXR) or CT scan performed within 6 months prior to the screening visit, without evidence of significant abnormalities (other than those related to the presence of COPD).
12. A cooperative attitude and ability to demonstrate correct use of the pMDI inhalers and eDiary.

E.4

Principal exclusion criteria

1. Female subjects who are pregnant (as evident by a positive urine hCG or serum β-hCG test) or lactating
2. Subjects using the following medications prior to the screening visit and during the run-in period:
a. Systemic/oral/parenteral corticosteroids in the prior 4 weeks
b. Use of antibiotics for a lower respiratory tract infection (e.g. pneumonia) or COPD exacerbation in the prior 4 weeks
c. Any long-term chronic maintenance use of antibiotic treatment in the prior 4 weeks
d. Oral xanthine derivatives (e.g. theophylline) in the prior 7 days
3. A moderate or severe COPD exacerbation or a respiratory tract infection (e.g., pneumonia) that has not resolved ≤14 days prior to the screening visit or during the run-in period
4. Subjects being treated with non-cardioselective β-blockers
5. Subjects requiring long term (> 15 hours daily) oxygen therapy
6. Known respiratory disorders other than COPD which may impact the efficacy of the study drug according to investigator’s judgement.
7. Lung transplant surgery or lung volume reduction surgery
8. 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
9. History of hypersensitivity to M3 receptor antagonists, β2 agonists, corticosteroids or any of the excipients contained in any of the study drugs used in the trial which may raise contraindications or impact the efficacy of the study drug according to the investigator’s judgement
10. Subject has severe, acute or uncontrolled cardiovascular condition (such as but not limited to unstable ischemic heart disease, NYHA Class IV, left ventricular failure, acute myocardial infarction or unstable angina) in the last 6 months
11. An abnormal and clinically significant 12-lead ECG at either the screening or randomization visit.
12. 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
13. Unstable or uncontrolled concurrent disease which may impact the efficacy or safety of the study drug or the subject’s participation in the study according to investigator’s judgment
14. Malignancy that has not been in complete remission for at least 1 year or any untreated (e.g. resected for cure) localized carcinomas
For complete list of exclusion criteria see protocol.

E.5 End points

E.5.1

Primary end point(s)

Change from baseline in pre-dose morning FEV1 at week 28 (V7)

E.5.1.1

Timepoint(s) of evaluation of this end point

From randomization (V2) till week 28 (V7)

E.5.2

Secondary end point(s)

Efficacy:
1.Change from baseline in 2-hour post-dose morning FEV1 at week 28 (V7)
2.Rate of moderate and severe COPD exacerbations over 52 weeks of treatment
Safety:
1.Incidence of treatment-emergent adverse events (TEAEs), adverse drug reactions (ADRs), serious ADRs, serious AEs (SAEs), severe AEs, TEAEs leading to discontinuation from study drug, and TEAEs leading to death
2.Incidence of treatment-emergent pneumonia
3. Incidence of treatment-emergent major adverse cardiovascular events (MACE).

E.5.2.1

Timepoint(s) of evaluation of this end point

Efficacy
1.From randomization (V2) till week 28 (V7)
2.From randomization (V2) till week 52 (V11)
Safety:
1-3.From randomization (V2) till week 53 (V12)

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

Yes

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

Yes

E.6.13.1

Other scope of the trial description

Tolerability

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)

Yes

E.7.4

Therapeutic use (Phase IV)

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

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

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

779

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Argentina

Bulgaria

Czechia

Hungary

Mexico

Poland

Russian Federation

Ukraine

United States

E.8.7

Trial has a data monitoring committee

Yes

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

The last visit 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:

1934

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

1000

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

169

F.4.2

For a multinational trial

F.4.2.1

In the EEA

716

F.4.2.2

In the whole clinical trial

2934

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)

At completion of subject’s participation / Early Termination or discontinuation of study drug, it is the investigator’s responsibility to prescribe appropriate COPD treatment or to restore their initial therapy or to refer them to their primary care physician. The sponsor will not provide the study drug after subject completes randomized treatment period.

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

2021-02-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-01-29

P. End of Trial
P.	End of Trial Status	Ongoing

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