Section 7 of the protocol:7. TRIAL OBJECTIVES AND PURPOSE* To assess the long term bronchodilator efficacy of Aclidinium bromide/Formoterol fumarate, administered twice a day, compared to Salmeterol/Fluticasone propionate (SeretideTM AccuhalerTM) in…
ID
Source
Brief title
Condition
- Bronchial disorders (excl neoplasms)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Peak-FEV1 (Forced Expiratory Volume in one second) in week 24
Secondary outcome
TDI-focal (Transition Dyspnoea Index) score in week 24
Background summary
Section 8.2 of the protocol
The proposed trial duration of 24 weeks has been chosen in accordance with
CPMP/EWP/562/98 [ref 14 in protocol], considering the intended indication for
Aclidinium bromide/Formoterol fumarate inhalation powder for the maintenance
bronchodilator treatment of airflow obstruction and to relief symptoms of
patients with COPD.
This study will compare a fixed dose combination of a LAMA+LABA (Aclidinium
bromide and Formoterol Fumarate) and a combined LABA+ICS (SeretideTM
AccuhalerTM Salmeterol/Fluticasone proprionate) in order to evaluate the
potential benefits in efficacy and safety of an dual bronchodilator maintenance
treatment (with two long-acting bronchodilators) when compared with the use a
combined LABA+ICS in a symptomatic population of COPD patients.
The study drug dose and dose regimen in this trial have been selected based on
Aclidinium bromide/Formoterol fumarate available data.
Relief medication (salbutamol pMDI 100 *g/puff) will be permitted as needed
throughout the study duration for all participants. In addition, other
medications for the treatment of COPD will be permitted during the study (see
section 10.10 for concomitant medication).
Inhalers and medication kits containing study drug will present the same
external appearance to ensure the double-blind nature of the trial. The
blinding and randomisation of study drug will avoid the chance of bias in
patient treatment assignation as well as patient management during the study
and data interpretation. Additionally, by randomly assigning patients to any of
the possible treatment arms, differences in baseline characteristics of the
treatment groups will be minimised.
The target study population of this study has been defined according to the
classification of the 2013 GOLD guidelines [ref 1 in protocol], considering the
airflow limitation and the patient*s symptomatology. The use of ICS should be
reserved for those patients at high risk (group C and D), defined by a history
of frequent exacerbations or severe airflow limitations (however and despite
these recommendations, there is evidence of inappropriate use of ICS in COPD
patients (Decramer et al, 2013 [ref 15 in protocol], Suissa and Barnes, 2009
[ref 16 in protocol] and Jochmann et al, 2010 [ref 17 in protocol]).
There is no gender-specific distribution in this trial because COPD is not a
gender-specific disease and previous trials data did not shown qualitatively or
quantitatively different efficacy profile when treating males or females. In
view of this, randomisation stratification by gender will not be performed.
The study will assess FEV1 (as a measure of lung function) and other lung
functions, as well as symptomatic benefits, BDI/TDI and SGRQ-C, COPD
exacerbation and use of relief medication, all previously used in similar
studies (Donohue el al, 2010 [ref 18 in protocol], Vincken et al, 2002 [ref 19
in protocol], Tashkin et al, 2008 [ref 6 in protocol]). Similarly, AEs and
commonly used tolerability assessments (e.g., ECG, blood pressure and clinical
laboratory test) will be performed to monitor study drug safety profile and
patient*s wellbeing throughout the trial.
The study will be stratified by prior ICS use and history of exacerbations.
Each patient would be randomised based on their previous history of
exacerbations (0 or *1), and based on whether they were prior ICS user or not.
Therefore, the overall number of randomised subgroups (strata) will be 4 (2
exacerbation history x 2 ICS user levels). Though randomisation is expected to
balance treatment groups among covariate levels, stratification was used to
make sure imbalances were not observed post-hoc for prior ICS use and history
of exacerbations.
Study objective
Section 7 of the protocol:
7. TRIAL OBJECTIVES AND PURPOSE
* To assess the long term bronchodilator efficacy of Aclidinium
bromide/Formoterol fumarate, administered twice a day, compared to
Salmeterol/Fluticasone propionate (SeretideTM AccuhalerTM) in symptomatic COPD
patients.
* To compare the benefits of Aclidinium bromide/Formoterol fumarate,
administered twice a day, versus twice-daily regimen of SeretideTM AccuhalerTM
in disease-related health status and COPD symptoms.
* To evaluate the long term safety and tolerability of Aclidinium
bromide/Formoterol fumarate, administered twice a day, compared to twice daily
SeretideTM AccuhalerTM in the same target population.
Study design
See paragraphs *Trial Design* and *Methodology* beginning at page 5 of the
protocol dated 13 May 2013. Summarising:
Trial is a multiple dose, randomised, double-blind, double-dummy, active
comparator controlled, parallel, multicentre and multinational clinical trial.
The two treatment arms take puffs from 2 inhalers: one with placebo, and one
with study medication. Medication could be Aclidinium bromide/Formoterol
fumarate or Salmeterol/Fluticasone propionate, depending on the randomization.
Intervention
Treatment with study medication instead of the patient's usual treatment.
Study burden and risks
Section 6.1.3 of protocol dated 13 May 2013
6.1.3. Summary of the known potential risks and benefits
The Aclidinium/Formoterol FDC have been investigated in trials involving around
3000 patients.
Preliminary safety results from phase III pivotal trials (M/40464/30 and
LAC-MD-31) are being assessed. The incidence of TEAEs recorded with the
Aclidinium bromide 400 *g/Formoterol fumarate 12 *g dose was similar to the
incidence found with both monotherapies alone.
The most frequently reported treatment emergent adverse events (TEAEs) with the
Aclidinium bromide 400 *g/Formoterol fumarate 12 *g dose compared to placebo
were: headache, nasopharyngitis, back pain, cough, urinary tract infection,
oropharyngeal pain, upper respiratory tract infection, muscle spasm, dry mouth
and tooth abscess.
No clinically relevant changes from baseline in vital signs, ECGs (including
24-hour Holter monitoring) or clinical laboratory parameters attributable to
administration of Aclidinium 400 *g/Formoterol 12 *g were observed.
For more details on the safety and tolerability profile of the aforementioned
compounds, please see the IB11.
AEs which have been associated with Salmeterol/Fluticasone propionate
(SeretideTM) are headache, nasopharyngitis, candidiasis of the mouth and
throat, pneumonia, bronchitis, hypokalaemia, tremor, palpitations, throat
irritation, hoarseness/dysphonia, sinusitis, muscle cramps and traumatic
fractures. In addition, Seretide may cause cardiac arrhythmias e.g.
supraventricular tachycardia, extrasystoles and atrial fibrillation, and a mild
transient reduction in serum potassium at high therapeutic doses. For more
information, please refer to the SmPC (UK), 201213.
Based on the study drug safety profile, no specific risk is anticipated with
the doses and the dose regimen proposed in this trial. Still, investigators
will ensure adequate medical care of the trial participants at all times
throughout the course of the study.
Laureà Miró 408-410
Sant Feliu de Llobregat 08980
ES
Laureà Miró 408-410
Sant Feliu de Llobregat 08980
ES
Listed location countries
Age
Inclusion criteria
For inclusion and randomisation in the trial, patients must meet each of the following criteria at Screening Visit (Visit 1) and at Visit 2 prior to randomisation.

1. Adult male or non-pregnant, non-lactating female aged * 40. Women of childbearing potential will follow specific study requirements.

Explanatory note: 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. Women of childbearing potential are allowed to enter the trial if they show to have a negative serum pregnancy test at the Screening Visit (Visit 1) and are using, during the last two months before the Screening Visit, at least one medically approved and highly effective method of birth control defined as those which result in a low failure rate (i.e less than 1% per year) when used consistently and correctly such as implants, injectables, oral contraceptives combined with at least one barrier method, hormonal intra uterine devices (IUDs), sexual abstinence or vasectomy of the partner.

2. Current or ex-cigarette smoker, with a smoking history of at least 10 pack-years.

Explanatory note: Ex-smoker definition includes those patients who quit smoking more than 6 months prior to the Screening Visit. 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-year history). When the patient has been smoker during several periods of time separated by inactivity periods, the total pack years resulting from several periods of smoking will be added up.

Patients smoking other tobacco types will not be allowed, unless they meet the cigarette criterion as well.

3. Patients with a clinical diagnosis of COPD according to GOLD guidelines 2013, with a post bronchodilator FEV1 <80%, and FEV1/FVC < 70% at Screening Visit (Visit 1).

Explanatory note: Predicted normal values to be used for calculation purposes are to be based on European Community for Steel and Coal predicted values (Quanjer et al. 199320). (i.e., 100xpost-salbutamol FEV1/FVC <70%).

4. Symptomatic patients with a CAT*10 at Screening and Randomisation Visit (Visit 1 and 2)
Explanatory note: CAT questionnaire cannot be repeated.

5. Patient must be able to perform repeatable pulmonary function testing for FEV1 according to ATS/ERS 2005 criteria at Screening Visit.

6. Patient who is 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.
Exclusion criteria
For inclusion and randomisation in the trial, patients must NOT meet any of the following criteria at Screening Visit (Visit 1) and at Visit 2 prior to randomisation.

1. History or current diagnosis of asthma.

2. Patients who develop a respiratory tract infection or COPD exacerbation within 6 weeks (or 3 months if hospitalisation was required) before the Screening Visit (Visit 1) or during the run-in period.

3. Clinically significant respiratory conditions

Explanatory note: Clinically significant respiratory conditions, some examples are:

-Known active tuberculosis or pulmonary hypertension.

-History of interstitial lung disorder: Exposure related interstitial lung disease; isease associated interstitial lung disease; Interstitial lung disease of distinct or unknown cause/pathology.

-History of massive pulmonary thromboembolic disease.

-History of lung lobectomy, lung volume reduction or lung transplantation

-Patients who in the investigator*s opinion may need thoracotomy or other lung surgery during the trial.

-History of bronchiectasis secondary to respiratory diseases others than COPD (e.g., cystic fibrosis, Kartagener*s syndrome, etc).

-Known a1-antitrypsin deficiency

4. Patients with Type I or uncontrolled Type II diabetes, uncontrolled hypo-or hyperthyroidism, hypokalaemia, or hyperadrenergic state, uncontrolled or untreated hypertension.

5. Patient who in the investigator*s opinion may need to start a pulmonary rehabilitation program during the study and/or patients who started/finished it within 3 months prior to Screening Visit.

6. Use of long-term oxygen therapy (* 15 hours/day).

7. Patients treated on daily basis with triple therapy (LABA+LAMA+ICS) within 4 weeks prior to the Screening Visit.

8. Patient who does not maintain regular day/night, waking/sleeping cycles including night shift workers.

Explanatory note: Patients with symptomatic sleep apnoea syndrome, any disease related with sleep disturbances such as restless-legs syndrome or somnambulism are to be excluded. However the use of continuous positive airway pressure (CPAP) is not an exclusion criteria.

9. Clinically significant cardiovascular conditions.

Explanatory note: Clinically significant cardiovascular conditions, some examples are:

-Myocardial infarction within the 6 months prior to Screening Visit (Visit 1)

-Unstable angina or unstable arrhythmia meaning which has required changes in the pharmacological therapy or other intervention within 12 months prior to Screening Visit (Visit 1), or newly diagnosed arrhythmia within the previous 3 months prior to Screening Visit (Visit 1).

-Hospitalisation within 12 months prior to Screening Visit (Visit 1) 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 NYHA.

10. Patient with clinically relevant abnormalities in the results of the clinical laboratory tests, ECG parameters or in the physical examination at the Screening Visit (Visit 1)

11. Patient with a history of hypersensitivity reaction to inhaled anticholinergics, sympathomimetic amines, or inhaled medication or any component thereof (including report of paradoxical bronchospasm).

12. Patient with known narrow-angle glaucoma, symptomatic bladder neck obstruction, acute urinary retention, or patients with symptomatic non-stable prostatic hypertrophy.
Explanatory note: Patients with well-controlled, stable, asymptomatic benign prostatic hypertrophy are not excluded.

13. Patient with known non-controlled history of infection with human immunodeficiency virus (HIV) and/or active hepatitis.

14. History of malignancy of any organ system (including lung cancer), treated or untreated, within the past 5 years other than basal or squamous cell skin cancer.

Explanatory note: Patients are excluded whether or not there is evidence of local recurrence or metastases

15. Patient with any other serious or uncontrolled physical or mental dysfunction.

16. Patient with a history (within 2 years prior to Screening Visit) of drug and/or alcohol abuse that may prevent study compliance based on investigator judgment.

17. Patient unlikely to be cooperative or that can*t comply with the study procedures.

18. Patient treated with any investigational drug within 30 days (or 6 half-lives, whichever is longer) prior to Screening Visit.

19. Patient who intend to use any concomitant medication not permitted by this protocol or who have not undergone the required stabilization periods for prohibited medication.

20. Any other conditions that, in the investigator*s opinion, might indicate the patient to be unsuitable for the study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-000116-14-NL |
| CCMO | NL45272.060.13 |