Clinical Trials Register

Summary
EudraCT Number:	2019-004095-19
Sponsor's Protocol Code Number:	TIO-II-19-1
National Competent Authority:	Bulgarian Drug Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2019-12-19
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

Bulgarian Drug Agency

A.2

EudraCT number

2019-004095-19

A.3

Full title of the trial

A pharmacodynamic, randomised, single dose, cross-over study to compare the bronchodilator effect of a new formulation of Tiotropium DPI versus Spiriva® 18 μg Handihaler®

A.3.1

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

A single dose study to compare the effect of bronchodilatation of two formulations of SMB tiotropium products versus the marketed product Spiriva® 18 μg Handihaler®

A.4.1

Sponsor's protocol code number

TIO-II-19-1

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	Laboratoires SMB S.A.
B.1.3.4	Country	Belgium
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	Laboratoires SMB S.A.
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Laboratoires SMB S.A.
B.5.2	Functional name of contact point	Clinical Trial Department
B.5.3	Address:
B.5.3.1	Street Address	Rue de la Pastorale 26-28
B.5.3.2	Town/ city	Bruxelles
B.5.3.3	Post code	1080
B.5.3.4	Country	Belgium
B.5.4	Telephone number	+3224114828
B.5.5	Fax number	+3224112828
B.5.6	E-mail	DptClinique@smb.be

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	TIOTROPIUM 8.8 µg DPI
D.3.4	Pharmaceutical form	Capsule, hard
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	TIOTROPIUM BROMIDE ANHYDROUS
D.3.9.3	Other descriptive name	ANHYDROUS TIOTROPIUM BROMIDE
D.3.9.4	EV Substance Code	SUB25692
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	8.8
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	Yes
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	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	TIOTROPIUM 2.2 µg DPI
D.3.4	Pharmaceutical form	Capsule, hard
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	TIOTROPIUM BROMIDE ANHYDROUS
D.3.9.3	Other descriptive name	ANHYDROUS TIOTROPIUM BROMIDE
D.3.9.4	EV Substance Code	SUB25692
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	2.2
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	Yes
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: 3
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	Spiriva(r) Handihaler(r) 18μg inhalation powder
D.2.1.1.2	Name of the Marketing Authorisation holder	Boehringer Ingelheim International GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.4	Pharmaceutical form	Capsule, hard
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	TIOTROPIUM BROMIDE MONOHYDRATE
D.3.9.1	CAS number	411207-31-3
D.3.9.3	Other descriptive name	TIOTROPIUM BROMIDE MONOHYDRATE
D.3.9.4	EV Substance Code	SUB21897
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	18
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	Yes
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

Chronic obstructive pulmonary disease (bronchodilating effect)

E.1.1.1

Medical condition in easily understood language

This is a progressive lung diseases including emphysema, chronic bronchitis, and non-reversible asthma. This disease is characterized by increasing breathlessness.

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

Primary Objective
- To assess the non-inferiority between Tiotropium DPI capsule 8.8μg and Spiriva® 18μg Handihaler® by measurement of the bronchodilating effect

E.2.2

Secondary objectives of the trial

• Secondary Objectives
- To assess and compare the safety of both products.
- To demonstrate a difference between the two dosages of SMB tiotropium

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

nclusion criteria

Patients must satisfy the following criteria before entering the study:
1. Male and non-pregnant female aged over 40 years old
2. Documented history of stable COPD with moderate to severe airflow obstruction diagnosed for more than six months according to the GOLD standard prior to the screening visit
3. FEV1 more than or equal to 30% and inferior to 80% of predicted at screening.
4. FEV1/FVC following 200 µg salbutamol treatment intake < 0.7 at screening.
5. Reversibility of at least 12% and 100 ml in FEV1 30-45 minutes after maximum 400 µg of salbutamol
6. Current smokers or history of ex-smokers (≥10 pack-year smoking history).
7. Able to comply with all study procedures, including the use of study inhalers and spirometer
8. Provide written informed consent to participate in the study, indicated by a personal signature and date on the patient consent form

E.4

Principal exclusion criteria

Exclusion criteria

Patients who meet any of the following criteria will be excluded from participating in the study:
1. Evidence of any unstable or untreated clinically significant immunological, cardiac, cardiovascular, neoplastic, endocrine, haematological, gastrointestinal, neurological or psychiatric abnormality or disease. Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the subject at risk during her/his participation, or which could affect the endpoint analysis if the disease/condition exacerbated during the study
2. Respiratory tract infection or COPD exacerbation not completely resolved within the last 2 weeks prior to the screening visit or between the screening and the randomization
3. Abnormality of inspiratory function (e.g. laryngeal obstruction, neuromuscular disease)
4. Need for daily oxygen therapy
5. Asthma, allergic rhinitis, cystic fibrosis, bronchiolitis obliterans, fibrosis, active or latent tuberculosis, α1-antitrypsin deficiency or any other causes of chronic airflow limitation apart from COPD
6. Use of any of the prohibited medications as detailed in the concomitant medication section
7. Patients with any sensitivity or allergy to any of the products used within this clinical trial
8. Female pregnant, breast-feeding or of childbearing potential age without efficient means of birth control (IUD, OCS, implants, hormonal patch, vaginal ring or spermicide and condom)
9. Patients with human immunodeficiency virus (HIV), Hepatitis B (HBV) or Hepatitis C (HCV)
10. Participation in any investigational medical studies within 2 month prior the screening visit

E.5 End points

E.5.1

Primary end point(s)

Primary endpoint:

-Trough FEV1 response defined as change in FEV1 from baseline to FEV1 24h post-dose measurement

E.5.1.1

Timepoint(s) of evaluation of this end point

Visit 2-Visit 3-Visit 4

E.5.2

Secondary end point(s)

Secondary parameters:

Efficacy endpoint:
- Peak bronchodilatory effect (FEV1 max)
- Tmax of FEV1
- Baseline-adjusted area under the curve (AUC) for FEV1 over 24 hours post dosing
- PEF max
- Baseline adjusted AUC of PEF from 0 to 24 hours post dosing
- Change in PEF at 24 hours post dose from baseline
- FEV1 % max
- Baseline adjusted AUC of FEV1% from 0 to 24 hours post dosing
- Change in FEV1% at 24 hours post dose from baseline
- FVC max
- Baseline adjusted AUC of FVC from 0 to 24 hours post dosing
- Change in FVC at 24 hours post dose from baseline
- Partial baseline adjusted AUC for FEV1 from 0 to 4 hours post dose
- Partial baseline adjusted AUC for FEV1 from 4 to 8 hours post dose
- Partial baseline adjusted AUC for FEV1 from 8 to 12 hours post dose
- Partial baseline adjusted AUC for FEV1 from 12 to 24 hours post dose
Safety endpoints:
- Adverse events
- Physical examination
- Vital signs
- 12-lead ECG data

E.5.2.1

Timepoint(s) of evaluation of this end point

Visit 1-Visit 2-Visit 3-Visit 4

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

Yes

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

Yes

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Partially blinded

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

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

Bulgaria

North Macedonia

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

LVLS

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

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

2020-02-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-01-15

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-10-21

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