Clinical Trials Register

Summary
EudraCT Number:	2007-000010-36
Sponsor's Protocol Code Number:	M/34273/25
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2007-08-20
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

UK - MHRA

A.2

EudraCT number

2007-000010-36

A.3

Full title of the trial

A multiple dose, double-blind, double-dummy, 3 period cross-over, placebo controlled clinical trial to assess the efficacy and safety of once daily inhaled aclidinium bromide 200 µg given either in the morning or in the evening in patients with stable moderate to severe chronic obstructive pulmonary disease (COPD).

A.4.1

Sponsor's protocol code number

M/34273/25

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Laboratorios Almirall, S.A.
B.1.3.4	Country	Spain
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	Aclidinium Bromide
D.3.2	Product code	LAS34273
D.3.4	Pharmaceutical form	Inhalation powder
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	Aclidinium Bromide
D.3.9.1	CAS number	320345-99-1
D.3.9.2	Current sponsor code	LAS34273
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	200
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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 powder
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

Stable moderate to severe Chronic Obstructive Pulmonary Disease (COPD)

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.1
E.1.2	Level	LLT
E.1.2	Classification code	10009033
E.1.2	Term	Chronic obstructive pulmonary disease

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 assess whether the time of dosing (a.m. or p.m.) at steady state influences the bronchodilator response of aclidinium bromide compared to placebo in patients with moderate to severe COPD.

E.2.2

Secondary objectives of the trial

To further evaluate the safety and tolerability of multiple doses of aclidinium bromide in moderate to severe COPD patients.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

For inclusion and randomisation in the trial, patients must meet each of the following criteria:

1. Males and non-pregnant, non-lactating females aged ≥ 40. Women of childbearing potential are allowed to enter the trial ONLY if they use one medically approved (i.e., mechanical or pharmacological) contraceptive measure. A female is considered to be of childbearing potential unless she has had a hysterectomy, is at least one year post-menopausal or has undergone tubal ligation. All women of childbearing potential must have a negative pregnancy test at the screening visit.

2. Patients with a clinical diagnosis of COPD, according to the GOLD guidelines: (http://www.goldcopd.com) and stable airway obstruction.

3. Patients with a post salbutamol FEV1 equal to or greater than 30% of the predicted value and less than 80% of the predicted value (i.e., 30% ≤ 100xobserved post-salbutamol FEV1/ predicted FEV1 <80%)

4. Post-salbutamol FEV1/FVC < 70% at screening visit (i.e,. 100xpost-salbutamol FEV1/FVC < 70%).

5. Current, or ex-cigarette smokers with a smoking history of at least 10 pack-years.
Pack-years are calculated by dividing the number of cigarettes smoked per day by 20 (the number of cigarettes in a pack) and multiplying this figure by the number of years a person has smoked. For example, a person who smokes 40 cigarettes a day and has smoked for 10 years would have a 20 pack-year smoking history (40 cigarettes per day ¸ 20 cigarettes per pack = 2; 2 x 10 years of smoking = 20 pack-years history). Patients smoking other tobacco types will not be allowed, unless they meet the cigarette criterion as well.

6. Patients who are eligible and able to participate in the trial and who consent to do so in writing after the purpose and nature of the investigation have been explained to them.

E.4

Principal exclusion criteria

Patients randomised into the trial must not present any of the following conditions:

1. History or current diagnosis of asthma, allergic rhinitis or atopy.

2. Eosinophil count ≥ 600 cells/mm3.

3. A respiratory tract infection (including the upper respiratory tract) or COPD exacerbation in the six weeks prior to the screening visit. Patients who develop a respiratory tract infection or exacerbation during the screening period will be discontinued from the trial prior to randomisation.

4. Patients who have been hospitalised for an acute COPD exacerbation in the 3 months prior to screening visit.

5. Use of long-term oxygen therapy (≥ 15 hours/day).

6. Clinically significant respiratory conditions defined as:
· Known active tuberculosis.
· History of interstitial lung or pulmonary thromboembolic disease.
· Pulmonary resection during the past 12 months.
· History of life-threatening COPD.
· History of any bronchiectasis secondary to respiratory diseases others than COPD (e.g., cystic fibrosis, Kartagener’s syndrome, etc).
· Patients who in the investigator’s opinion may need pulmonary rehabilitation or a thoracotomy during the trial. Patients on a stable pulmonary rehabilitation program prior to entry and anticipated to be stable throughout the study can be enrolled.
· Lung cancer

7. Clinically significant cardiovascular conditions defined as:
·Myocardial infarction during the last 6 months.
·Unstable arrhythmia which has required changes in the pharmacological therapy or other intervention during the last 12 months, or newly diagnosed arrhythmia within the previous 3 months.
· Hospitalisation within the previous 12 months for heart failure functional classes III (marked limitation of activity and only comfortable at rest) and IV (need of complete rest, confinement to bed or chair, discomfort at any physical activity and presence of symptoms at rest) as per the New York Heart Association.

8. Patients for whom the use of anticholinergic drugs is contraindicated: those with a known symptomatic prostatic hypertrophy, bladder neck obstruction or narrow-angle glaucoma.

9. Patients with any other serious or uncontrolled physical or mental dysfunction which at the discretion of the investigator could place the patient at higher risk derived from his/her participation in the study, could confound the results of the trial, or is likely to prevent the patient from complying with the requirements of the trial or completing the trial period.

10. QTc [calculated according to Bazett’s formula (QTc=QT/RR1/2) above 470 milliseconds in any of the ECGs performed at screening visit or at visit 1 (Day -1).

11. Patients who can not perform repeatable spirometry attempts at the screening visit.

12. History of untoward reactions to inhaled anticholinergics, sympathomimetic amines or inhaled medication or any component thereof (including report of paradoxical bronchospasm).

13. Patients unable to properly use a dry powder or pMDI inhaler device or unable to perform acceptable spirometry.

14. Clinically relevant abnormalities laboratory, ECG parameters (other than QTc), or physical examination results at the screening evaluation that in the investigator’s opinion, preclude study participation.

15. Patients who intend to use any concomitant medication not permitted by this protocol or who have not undergone the required washout period for a particular prohibited medication (see section 10.3.2).

16. Patients with a history of drug and/or alcohol abuse that may prevent compliance with trial activities.

17. Treatment with any Investigational Medicinal Product (IMP) within 1 month prior to the screening visit or the equivalent time of 6 half-lives of the IMP, whichever is longer.

18. Patients who do not maintain regular day/night, waking/sleeping cycles (e.g., history of sleep apnoea syndrome, any disease related with sleep disturbances such as restless-legs syndrome or somnambulism…). Moreover, night shift workers will be excluded.

19. Patients who are unlikely to be co-operative, take their medication, complete their patient diary or attend the clinic at the required times.

E.5 End points

E.5.1

Primary end point(s)

Efficacy variables:

Primary efficacy variable:
• Change from baseline in the trough FEV1 after 6 days of treatment.

Secondary efficacy variables:
• Change from baseline in the trough FVC after 6 days of treatment.
• Change from baseline in the trough IC after 6 days of treatment.
• Change from baseline in the FEV1 and FVC at all time-points after 7 days of treatment in the a.m. regimen and after 6-7 days of treatment in the p.m. regimen.
• Change from baseline in the IC at all time-points after 7 days of treatment in the a.m. regimen and after 6-7 days of treatment in the p.m. regimen.
• Change from baseline in the peak FEV1 and FVC after 7 days of treatment.
• Change from baseline in normalised FEV1 and FVC AUC0-24 after 7 days of treatment in the a.m. regimen and after 6-7 days of treatment in the p.m. regimen.
• Change from baseline in normalised FEV1 and FVC AUC0-12 after 7 days of treatment.
• Change from baseline in normalised FEV1 and FVC AUC12-24 after 7 days of treatment in the a.m. regimen and after 6 days of treatment in the p.m. regimen.
• Use of “as needed” daily rescue medication (number of salbutamol puffs, as recorded by the patient during the treatment period).

Safety variables:
• Adverse Events (AEs).
• Serious Adverse Events (SAEs).
• 12-lead ECG parameters.
• Blood pressure parameters.
• Laboratory parameters (standard haematology, biochemistry and urinalysis).
• Physical examination.

Other variables:
• Use of concomitant medication.
• Number (%) of withdrawals and reasons for withdrawal.

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

Information not present in EudraCT

E.7.1.2

Bioequivalence study

Information not present in EudraCT

E.7.1.3

Other

Information not present in EudraCT

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

Yes

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

Double-Dummy

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.8.3

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

Information not present in EudraCT

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 Patient Last Visit

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

Information not present in EudraCT

F.1.1.2

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

Information not present in EudraCT

F.1.1.3

Newborns (0-27 days)

Information not present in EudraCT

F.1.1.4

Infants and toddlers (28 days-23 months)

Information not present in EudraCT

F.1.1.5

Children (2-11years)

Information not present in EudraCT

F.1.1.6

Adolescents (12-17 years)

Information not present in EudraCT

F.1.2

Adults (18-64 years)

Yes

F.1.3

Elderly (>=65 years)

Yes

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)

At the end of the clinical trial, subjects should continue to take their usual medications, also allowed during the end of the trial and may resume other medications interrupted prior to trial enrolment (with investigator's agreement)

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

2008-02-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2008-02-05

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2008-03-13

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