Clinical Trials Register

Summary
EudraCT Number:	2019-002238-35
Sponsor's Protocol Code Number:	CLI-05993CB1-01
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:	2019-10-31
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

2019-002238-35

A.3

Full title of the trial

A SINGLE-DOSE, UNCONTROLLED, OPEN LABEL, NON-RANDOMIZED,
CLINICAL PHARMACOLOGY STUDY OF CHF 5993 100/6/12.5 μg PMDI (FIXED COMBINATION
OF BECLOMETASONE DIPROPIONATE PLUS FORMOTEROL FUMARATE PLUS GLYCOPYRRONIUM BROMIDE) IN ASTHMATIC ADOLESCENT PATIENTS AND ADULT PATIENTS

A.3.1

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

Open label, non-randomized, single dose PK/PD study in adolescent asthmatic patients and adult asthmatic patients

A.4.1

Sponsor's protocol code number

CLI-05993CB1-01

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/179/2019

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 Farmaeutici 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.5.4	Telephone number	+390521279093
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	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	Italy
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
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	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.3.8 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.3.9.2	Current sponsor code	CHF1531.02
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	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.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

asthma

E.1.1.1

Medical condition in easily understood language

asthma

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10003553
E.1.2	Term	Asthma
E.1.2	System Organ Class	10038738 - Respiratory, thoracic and mediastinal disorders

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 systemic exposure to B17MP (active metabolite of BDP), formoterol and Glycopyrronium Bromide (GB) as AUC0-t, (index of total systemic exposure) after inhalation of CHF 5993 pMDI in adolescent asthmatic patients in comparison to adult
asthmatic patients.

E.2.2

Secondary objectives of the trial

 To evaluate the pharmacokinetic profile of BDP and additional PK parameters of B17MP, formoterol and GB after inhalation of CHF 5993 pMDI in adolescent asthmatic patients in comparison to adult asthmatic patients.
 To evaluate the systemic effects in terms of heart rate and circulating potassium and glucose levels and also the general safety and tolerability profile of BDP/B17MP, formoterol and GB after inhalation of CHF 5993 pMDI in adolescent asthmatics.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patient’s and / or patient legal representative’s/parents’ (where applicable) written informed consent obtained prior to any study related procedure.
2. Ability to understand the study procedures, the risks involved, and ability to be trained to use the pMDI device correctly with AIM™ (Aerosol Inhalation Monitor) Vitalograph®.
3. Male and female adolescents, aged ≥ 12 and < 18 years or male and female adults, aged ≥ 18 and < 65 years.
4. Body mass index (BMI) within the range of 18.0 to 30.0 kg/m2 inclusive and body weight ≥ 39 kg.
5. A diagnosis of asthma as defined in the GINA guidelines (updated 2019) at least 6 months before the screening visit.
6. Male/female adolescent and adult patients with controlled asthma according to GINA guidelines (updated 2019) to allow a wash out period from inhaled BDP of 2 days before study treatment visit.
7. Male/female adolescents and adults with controlled asthma on regular treatment with medium doses of ICS according to GINA guideline alone or in fixed dose combinations with LABA and using short-acting inhaled β2-agonists as a reliever. Inhaled Corticosteroid Adults and adolescents
8. Adolescents and adults with a forced expiratory volume in one second (FEV1)> 70% of predicted values (% pred) after withholding short acting β2-agonist treatment for a minimum of 6h prior to screening or 24 hours in case of long acting β2-agonist.
9. Non-smokers or ex-smokers who smoked < 5 pack years (packyears= the number of cigarette packs per day, times the number of years) and stopped smoking > 1 year prior to screening.
10. Good physical and mental status, determined on the basis of the medical history and a general clinical examination, at screening and at Visit 1 before dosing.
11. Female patients of non-childbearing potential (WONCBP) defined as physiologically incapable of becoming pregnant (i.e. post-menopausal or permanently sterile) and female patients of childbearing potential (WOCBP) fulfilling one of the following
criteria:
a. 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 visit or
b. WOCBP with non-fertile male partners (contraception is not required in this case).

E.4

Principal exclusion criteria

1. Blood donation (equal or more than 450 ml) or blood loss, less than 2 months prior to screening or prior to Visit 1.
2. Abnormal haemoglobin level defined as < 12.0 g/dl in adolescent male and < 12.0 g/dl in adolescent female; < 13.0 g/dl in adult male and < 12.0 g/dl in adult female;
3. For females only: pregnant and lactating female patients, confirmed by a positive urine pregnancy test at screening or urine pregnancy test at Visit 1 before dosing.
4. Diagnosis of COPD, in adult patients, as defined by the current GOLD guidelines (2019 Report).
5. Positive to HIV1 or HIV2 or positive results for Hepatitis which
indicates acute or chronic Hepatitis B (i.e. positive HB surface antigen HBsAg, positive HB core antibody anti-HBc) or Hepatitis C (positive HCV antibody).
6. Unsuitable veins for repeated venepuncture.
7. Documented history of alcohol abuse within 12 months prior to screening.
8. Documented history of drug abuse within 12 months prior to screening, or positive urine drug test performed at screening or before dosing.
9. Patients who have a positive urine test for cotinine at screening or before dosing.
10. Clinically relevant abnormal laboratory values, suggesting an unknown disease and requiring further clinical investigation.
11. Clinically relevant and uncontrolled cardiac, hepatic, renal, gastrointestinal, endocrine, metabolic, neurologic, or psychiatric disorder that may interfere with successful completion of this protocol.
12. Known intolerance/hypersensitivity to any of the excipients/components contained in any of the formulations used in the trial.
13. Patients with medical diagnosis of narrow-angle glaucoma, prostatic hypertrophy or bladder neck obstruction that in the opinion of the investigator would prevent use of an anticholinergic.
14. Abnormal 12-lead digitized Electrocardiogram (12-lead ECG) parameter (i.e.: QRS > 120 msec and/or PR > 210 msec and/or HR < 40 bpm and/or HR > 110 bpm and/or QTcF > 450 ms for males or QTcF > 470 ms for females, considering the average from triplicate) or 12-lead ECG evaluated as abnormal clinically significant by the investigator, at screening.
15. Abnormal Blood Pressure (i.e.: Diastolic Blood Pressure > 90 mmHg and/or Systolic Blood Pressure > 140 mmHg, considering the average from triplicate) at screening.
16. Participation in another clinical trial with an investigational drug in the 30 days or 5 half-lives of that investigational drug (whichever is longer) preceding the administration of the study drug; a longer and more appropriate time could be considered by the principal investigator based on the elimination half-life and/or
long-term toxicity of the previous investigational drug.
17. Patients taking enzyme-inducing drugs, enzyme-inhibiting drugs, biologic drugs or any drug known to have a well-defined potential for hepatotoxicity (e.g. isoniazide, nimesulide, ketoconazole) in the 3 months before screening or Visit 1.
18. Patients who have a high caffeine intake (> 5 caffeinated beverages e.g., coffee, tea, cola per day).
19. Patients who have had a lower respiratory tract infection (LRTI) within 4 weeks prior to screening or Visit 1.
20. Patients who are night shift workers with night shifts within 8 weeks prior to screening or Visit 1 and during the study.

E.5 End points

E.5.1

Primary end point(s)

The efficacy and safety endpoints are standard for evaluation of this drug class in Asthma and will allow to determine the effect of the IMP. Please refer to the protocol.

E.5.1.1

Timepoint(s) of evaluation of this end point

Determination of Glycopyrronium Bromide levels in human plasma &
Determination of potassium and glucose in human serum:

Blood collection will occur prior to dosing and in the 0-10h interval after
dosing, at following time points: pre-dose (within 75 min before dosing), 5, 15 and 30 min, 1, 2, 4, 8 and 10 hours post-dose.

E.5.2

Secondary end point(s)

The efficacy and safety endpoints are standard for evaluation of this drug class in Asthma and will allow to determine the effect of the IMP. Please refer to the protocol.

E.5.2.1

Timepoint(s) of evaluation of this end point

The efficacy and safety endpoints are standard for evaluation of this drug class in Asthma and will allow to determine the effect of the IMP. Please refer to the protocol.

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

E.6.5

Efficacy

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

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

A single-dose, uncontrolled, open label, non-randomized

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

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

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

LPLV

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

Yes

F.1.1

Number of subjects for this age range:

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)

Yes

F.1.1.6.1

Number of subjects for this age range:

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)

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

F.4.2.2

In the whole clinical trial

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)

None

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

2020-01-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-11-12

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-02-04

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