Clinical Trials Register

Summary
EudraCT Number:	2019-002256-16
Sponsor's Protocol Code Number:	19-01SPIOMI
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2019-09-30
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

Germany - BfArM

A.2

EudraCT number

2019-002256-16

A.3

Full title of the trial

Acute and two-week effects of Spiolto® Respimat® (Tiotropium/Olodaterol) on cardiac function, the autonomic nervous system and small airway function in hyperinflated COPD subjects

Akute und zweiwöchige Effekte von Spiolto® Respimat® (Tiotropium/Olodaterol) auf die Herzfunktion, das autonome Nervensystem und die kleinen Atemwege bei überblähten COPD-Patienten

A.3.1

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

Acute and two-week effects of Spiolto® Respimat® (Tiotropium/Olodaterol) on cardiac function, the autonomic nervous system and small airway function in hyperinflated COPD subjects

Akute und zweiwöchige Effekte von Spiolto® Respimat® (Tiotropium/Olodaterol) auf die Herzfunktion, das autonome Nervensystem und die kleinen Atemwege bei überblähten COPD-Patienten

A.4.1

Sponsor's protocol code number

19-01SPIOMI

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	Fraunhofer Society
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Boehringer Ingelheim Pharma GmbH & Co. KG
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Fraunhofer-Institute for Toxicology and Experimental Medicine ITEM
B.5.2	Functional name of contact point	Jens Hohlfeld
B.5.3	Address:
B.5.3.1	Street Address	Feodor-Lynen-Straße 15
B.5.3.2	Town/ city	Hannover
B.5.3.3	Post code	30625
B.5.3.4	Country	Germany
B.5.6	E-mail	jens.hohlfeld@item.fraunhofer.de

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	Spiolto® Respimat®
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	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	Spiolto® Respimat®
D.3.4	Pharmaceutical form	Inhalation solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Respiratory use (Noncurrent) Inhalation use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Tiotropiumbromid
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	2.5
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Olodaterol Hydrochloride
D.3.9.1	CAS number	868049-49-4
D.3.9.3	Other descriptive name	OLODATEROL HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB131075
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	2.5
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
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

Chronisch obstruktive Lungenerkrankung

E.1.1.1

Medical condition in easily understood language

Chronic Obstructive Pulmonary Disease

Chronisch obstruktive Lungenerkrankung

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	PT
E.1.2	Classification code	10009033
E.1.2	Term	Chronic obstructive pulmonary disease
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 determine the change from baseline in left ventricular end-diastolic volume (LVEDV) index evaluated by MRI in mL/m2 after single dose administration of Spiolto® Respimat® versus nebulized saline in hyperinflated COPD patients.

E.2.2

Secondary objectives of the trial

To determine the change from baseline in
• LVEDV evaluated by MRI in mL/m2 after multiple dose administration of Spiolto® Respimat® compared with single dose administration.
• muscle sympathetic nerve activity evaluated by microneurography as bursts/ 100 heart beats after single dose administration of Spiolto® Respimat® versus nebulized saline.
• residual volume and other lung function parameters such as FEV1, FVC, IC, TLC, specific airway resistance, FRC and forced expiratory flows after single dose of Spiolto® Respimat® versus nebulized saline and after multiple dose administration of Spiolto® Respimat® compared with single dose administration
• exhaled particle numbers per volume after single dose of Spiolto® Respimat® versus nebulized saline.
• exhaled particle numbers per volume after multiple dose administration of Spiolto® Respimat® compared with single dose administration.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Able and willing to give written informed consent.
2. Male and female subjects, aged ≥ 40 years. Women will be considered for inclusion if they are:
Not pregnant, as confirmed by pregnancy test (see flow chart), and not nursing.
Of non-child bearing potential (i.e. physiologically incapable of becoming pregnant, including any female who is post-menopausal, with documented proof of hysterectomy or tubal ligation, or meets clinical criteria for menopause and has been amenorrhoeic for more than 1 year prior to the screening visit).
Of childbearing potential and using a highly effective method of contraception during the entire study (vasectomised partner, sexual abstinence - the lifestyle of the female should be such that there is complete abstinence from intercourse from two weeks prior to the first dose of study medication until at least 72 hours after treatment -, implants, injectables, combined oral contraceptives, hormonal IUDs or double-barrier methods, i.e. any double combination of IUD, condom with spermicidal gel, diaphragm, sponge, and cervical cap).
3. Subjects with stable COPD according to the current GOLD guidelines (GOLD 2018).
4. Subjects with airflow limitation indicated by a post-bronchodilator FEV1 <80% of the predicted normal value and a post-bronchodilator FEV1/FC<0.7 at Visit 1. Post-bronchodilator refers to within 10-15 min after inhalation of 400 µg (4x100 µg) of salbutamol.
5. Current or ex-smokers who have a smoking history of at least 10 pack years. (Ten pack-years are defined as 20 cigarettes a day for 10 years, or 10 cigarettes a day for 20 years etc.)
6. Hyperinflated subjects with RVol>135% predicted as measured at Visit 1, before intake of salbutamol.

E.4

Principal exclusion criteria

1.Any clinically relevant abnormal findings in physical examination, clinical chemistry, haematology, urinalysis, vital signs, lung function or ECG at screening visit, which, in the opinion of the investigator, may either put the subject at risk because of participation in the study or may influence the results of the study, or the subject’s ability to participate in the study.
2.Past or present disease, which as judged by the investigator, may affect the outcome of this study. These diseases include, but are not limited to, cardiovascular disease (including but not confined to aneurysm, hypokalemia, decompensated heart failure or hypertrophic obstructive cardiomyopathy), malignancy, hepatic disease, renal disease, haematological disease, neurological disease, endocrine disease (including but not confined to thyrotoxicosis) or pulmonary disease other than COPD (including but not confined to tuberculosis, bronchiectasis, cystic fibrosis, pulmonary hypertension, sarcoidosis, interstitial lung disease or lung fibrosis).
3.Use of other investigational drug (approved or unapproved) at the time of enrolment, or within 30 days or 5 half-lives prior to Visit 1, whichever is longer.
4.History of drug or alcohol abuse.
5.Risk of non-compliance with study procedures.
6.Suspected inability to understand the protocol requirements, instructions and study-related restrictions, the nature, scope, and possible consequences of the study.
7.History of an acute respiratory infection four weeks prior to Visit 1 and between Visit 1 and 3. These patients will not be eligible, but will be permitted to rescreened 4 weeks after the resolution of the respiratory tract infection.
8.Subjects with conditions contraindicated for treatment with, or having a history of reactions/hypersensitivity to any of the following inhaled drugs, drugs of a similar class or any component thereof:
•anticholinergics
•long and short acting beta-2 agonists
•sympathomimetic amines
9.Subjects with a history of long QT syndrome or whose QTcF (Fridericia method) measured at Visit 1 is prolonged (>450 ms for males and >470 ms for females). These subjects should not be re-screened.
10.Subjects who have clinically significant cardiovascular abnormalities, which could interfere with the assessment of the study treatment (such as but not limited to cardiac arrhythmias, heart failure with left ventricular ejection fraction < 40 % as determined by MRI scan at Visit 2, unstable ischemic heart disease, NYHA Class III/IV left ventricular failure, history of myocardial infarction 6 months prior to Visit 1 or uncontrolled hypertension)
11.Subjects with a known history or current atrial fibrillation to be confirmed by ECG at Visit 1.
12.Subjects with pacemaker or bypass.
13.Subjects with extensive tattoos.
14.Subjects with a mean sitting systolic blood pressure >160 mmHg and/or mean sitting diastolic blood pressure > 90 mmHg at Visit 1. These subjects will be permitted to be re-screened after initiation or intensification of an antihypertensive therapy and achieving a controlled disease status.
15.History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.
16.Subjects with narrow-angle glaucoma, symptomatic benign prostatic hyperplasia or bladder-neck obstruction or severe renal impairment (GFR ≤ 50 mL/min/1.73 m2) including those with end-stage renal disease requiring dialysis or urinary retention. Benign Prostatic Hyperplasia (BPH) subjects who are stable on treatment can be considered.
17.Subjects with insulin-dependent diabetes mellitus.
18.Clinically evident polyneuropathy.
19.Subjects with active/ clinical history of asthma.
20.Subjects unable to undergo MRI scans, including claustrophobia or presence of any metal objects within the patient, preventing from MRI scan (e.g. pacemaker, aneurysm clips).
21.History of one COPD exacerbation that required treatment with antibiotics, systemic steroids (oral or intravenous) or hospitalization within 3 months prior to Visit 1, to 3. Subjects may be re-screened after a minimum of 3 months after the resolution of the COPD exacerbation.
22.More than one COPD exacerbation that required treatment with antibiotics, systemic steroids (oral or intravenous) or hospitalization within one year before Visit 1.
23.Subjects requiring long term oxygen therapy on a daily basis for chronic hypoxemia.
24.Subjects with pulmonary lobectomy or lung volume reduction surgery or lung transplantation.
25.Subjects with a pre-existing diagnosis of alpha-1 antitrypsin deficiency or an alpha-1 antitrypsin blood level below the normal range on Visit 1
26.Subjects with a body mass index (BMI) of more than 35 kg/m2.
27.Subjects participating in or planning to participate in the active phase of a supervised pulmonary rehabilitation program during the study.

E.5 End points

E.5.1

Primary end point(s)

To determine the change from baseline in left ventricular end-diastolic volume index evaluated by MRI in mL/m2 after single dose administration of Spiolto® Respimat® versus nebulized saline in hyperinflated COPD patients.

E.5.1.1

Timepoint(s) of evaluation of this end point

Visit number 2, 3, 4

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

Visit number 2, 3, 4, 5

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

Yes

E.6.4

Safety

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

Yes

E.8.1.4

Double blind

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

Yes

E.8.4

The trial involves multiple sites in the 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

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

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.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
G.4 Investigator Network to be involved in the Trial: 1

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2019-12-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-01-28

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2023-04-18

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