The purpose of this study is to determine whether the efficacy and safetyof QVA149 (110/50 *g o.d.) and triple treatment with tiotropium (18 *go.d.) + salmeterol/fluticasone propionate FDC (50/500 *g b.i.d.) arecomparable in patients with moderate…
ID
Source
Brief title
Condition
- Respiratory tract infections
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Patients who have signed Informed Consent Form prior to
initiation of any study-related procedure.
* Male and female adults aged * 40 years.
* Patients with moderate to severe airflow obstruction with stable
COPD according to the 2014 GOLD Guidelines.
* Patients with a post-bronchodilator FEV1 *40 and < 80% of the
predicted normal value, and post-bronchodilator FEV1/FVC <
0.70 at run-in Visit 101.
(Post refers to 15 min after inhalation of 400 *g of salbutamol).
* Current or ex-smokers who have a smoking history of at least 10
pack years (e.g. 10 pack years = 1 pack /day x 10 years, or *
pack/day x 20 years). An ex-smoker is defined as a patient who
has not smoked for * 6 months at screening.
* Patients who are on triple treatment at least for the last 6 months
(LAMA +LABA/ICS).
Secondary outcome
* Key exclusion criteria. Full criteria are within the protocol:
* Patients 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:
* long and short acting anticholinergic agents
* long and short acting beta-2 agonists
* sympathomimetic amines
* lactose or any of the other excipients of trial medication
* History or current diagnosis of ECG abnormalities indicating
significant risk of safety for patients participating in the study
such as:
* Concomitant clinically significant cardiac arrhythmias, e.g.,
sustained ventricular tachycardia, and clinically significant
second or third degree AV block without a pacemaker
* History of familial long QT syndrome or known family history of
Torsades de Pointes
* Resting QTc (Fridericia method) *450 msec for males and
females at Visit 101.
* Concomitant use of agents known to significantly prolong the QT
interval unless they can be permanently discontinued for the
duration of study.
* Patients who have clinically significant renal, cardiovascular
(such as but not limited to unstable ischemic heart disease,
NYHA Class III/IV left ventricular failure, myocardial infarction),
arrhythmia (see below for patients with atrial fibrillation),
neurological, endocrine, immunological, psychiatric,
gastrointestinal, hepatic, or hematological abnormalities which
could interfere with the assessment of the efficacy and safety of
the study treatment.
* Patients who have had more than one COPD exacerbation that
required treatment with antibiotics and/or oral corticosteroids
and/or hospitalization in the 12 months prior to Visit 1.
* Patients who developed a COPD exacerbation of any severity
either 6 weeks before the screening (Visit 1) or between
screening (Visit 1) and treatment (Visit 201) will not be eligible
but will be permitted to be re-screened after a minimum of 6
weeks after the resolution of the COPD exacerbation.
* Patients with any history of asthma.
* Patients with a blood eosinophil count > 600/mm3 during
screening (Visit 101).
* Patients unable to use an electronic patient diary.
* Patients unable to use a dry powder inhaler device or a
pressurized MDI (rescue medication) or unable to comply with
the study regimen. Spacer devices are not permitted.
* 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.
Background summary
Chronic Obstructive Pulmonary Disease (COPD), a common preventable and treatable
disease, is characterized by persistent airflow limitation that is usually
progressive and
associated with an enhanced chronic inflammatory response in the airways and
the lung to
noxious particles or gases. Current treatment guidelines for COPD recommend the
use of
bronchodilators for all severities, either on an as-required basis, or regular
basis (GOLD 2014).
Inhaled long-acting bronchodilator therapy such as *2 agonists (LABAs, such as
formoterol,
salmeterol and indacaterol) and muscarinic antagonists (LAMAs, such as
tiotropium and
glycopyrronium bromide) are established and widely used treatment options for
COPD
(GOLD 2014).
Published studies (Mak et al 1990; Carstairs et al 1985; Ikeda et al 2012) have
shown that the
mechanisms of action of long-acting bronchodilator therapy such as LABAs and
LAMAs are
complementary due to the differential density of *2-adrenoceptors and
M3-receptors in
central versus smaller airways. Thus, LABAs should be more effective in
relaxing small
airways and LAMAs in large airways. There is also clinical evidence that
suggests that
combining bronchodilators from these two pharmacological classes results in
significantly
greater improvements in lung function (FEV1) compared with the individual
components
alone (Cazzola and Molimard 2010, Wang et al 2011). Studies to date have also
shown other
meaningful outcomes such as improvement in inspiratory capacity, reduction in
dyspnea,
improved symptom scores, and less rescue medication use, as compared with
individual drugs
used alone (Van der Molen and Cazzola 2012).
QVA149 is a fixed combination of a long acting *2-agonist (Indacaterol maleate
* QAB149)
and a long acting muscarinic antagonist (Glycopyrronium bromide * NVA237). This
combination product will be delivered by the Novartis Single Dose Dry Powder
Inhaler
(SDDPI).
QVA149 was investigated in a comprehensive phase III program development
comprising
more than 11,000 COPD patients across more than 40 countries. Data from this
QVA149
Phase III Development Program have demonstrated improvement in lung function,
quality of
life, decrease in COPD symptoms and decrease in short-acting *2 agonist (SABA)
use with a
safety profile similar to placebo (Vogelmeier et al 2013, Bateman et al 2013).
When compared to current standard of care treatments like
fluticasone/salmeterol or OL
tiotropium, QVA149 phase III studies demonstrated significant improvements in
terms of
lung function, dyspnea, symptoms, quality of life and short-acting *2 agonist
)- free days
(Vogelmeier et al 2013, Bateman et al 2013). Additional information can be
found in the
QVA149 Investigator*s Brochure.
These comparative studies have been performed in COPD populations with
comparable stage
and clinical characteristics between the treatments arms.
Building on the strength and value of combination therapies, the clinical
practice of using
*triple therapy* for COPD treatment has become popular in recent years. This
approach
generally consists of combining a LABA and an ICS fixed-dose combination such as
salmeterol/fluticasone propionate (SFC) with an anticholinergic/muscarinic
antagonist (i.e.,
long-acting tiotropium bromide or short-acting ipratropium bromide). The
rationale for using
these compounds together lies in the fact that they have different molecular
mechanisms of
action and, consequently, their combined use could maximize their clinical
benefits for
patients suffering from this debilitating disease (Salama et al 2011).
According to GOLD 2014 COPD guidelines long term treatment with inhaled
corticosteroids
is recommended for patients with severe and very severe COPD and frequent
exacerbations
that are not adequately controlled by long-acting bronchodilators (Evidence A).
These
guidelines also emphasize that long-term treatment containing inhaled
corticosteroids should
not be prescribed outside their indications, due to the risk of pneumonia and
the possibility of
an increased risk of fractures following long-term exposure. QVA149 once daily
provided
clinically relevant improvements in lung function compared with SFC twice daily
with
significant symptomatic benefits in patients with moderate-to-severe COPD and
no history of
exacerbation in the last year. (Vogelmeier et al 2013). This study confirmed
the superiority of
dual bronchodilator treatment to a Fixed Dose Combination (FDC) of ICS/LABA in
this
population.
Current GOLD guidelines (GOLD 2014) recommend the use of triple therapy as an
alternative first-line choice for the maintenance treatment of only group D
patients. While
current guidelines suggest using LABAs and/or muscarinic antagonists and ICSs
in only a
small number of patients, the use of this triple therapy (in which a
combination inhaler is
prescribed in combination with another single drug inhaler) is more widely used
in clinical
practice than recommended (Jones 2009, Salama et al 2011). In research
conducted at US
primary care sites, it has been found that 20% of Stage 1 and 39% of Stage 2
COPD patients
are currently using ICS (Small et al 2012) In fact, there is evidence of
widespread use of triple
therapy for COPD even in primary care where patients have predominantly mild
disease and
occasional bronchitis (Gaebel et al 2011).
There is insufficient evidence to determine if triple therapy is superior to
dual bronchodilator
therapy in patients without a history of frequent exacerbations (Gaebel et al
2011). It is also
unclear whether these patients could be managed just as effectively with dual
bronchodilator
therapy as triple, with less cost and improved patient convenience.
The effect of QVA149 vs. triple treatment with LABA/ICS FDC+LAMA has not been
studied.
Study objective
The purpose of this study is to determine whether the efficacy and safety
of QVA149 (110/50 *g o.d.) and triple treatment with tiotropium (18 *g
o.d.) + salmeterol/fluticasone propionate FDC (50/500 *g b.i.d.) are
comparable in patients with moderate to severe COPD without a history
of frequent exacerbations.
Study design
The study is a multicenter, randomized, parallel-group, double-blind,
triple-dummy study to assess the efficacy of the two active treatment
arms of QVA149 (110/50 *g o.d.) and tiotropium (18 *g o.d) +
salmeterol/fluticasone propionate FDC (50/500 b.i.d) in patients with
moderate-to-severe COPD.
Intervention
QVA149 110/50 *g capsules o.d. for inhalation, supplied in blisters
delivered via Novartis single dose dry powder inhaler Novartis single
dose dry powder inhalerNovartis single dose dry powder inhaler.
Salmeterol/fluticasone propionate FDC 50/500 *g dry inhalation powder
delivered via Accuhaler*.
Tiotropium 18 *g capsules o.d. for inhalation, supplied as commercially
available blisters, delivered via HandiHaler®.
Study burden and risks
The risk to patients in this trial will be minimized by compliance with all of
the eligibility
criteria and by close clinical monitoring. Altering the current COPD medication
regimen
during the run-in period and switching from one triple treatment to another one
(if the current
triple combination is different than study triple combination) or randomizing
the patients
during the study treatment either to the same triple treatment as in run-in or
QVA149 is not
likely to pose any risk of *under-treatment*. Although ICS is withdrawn in the
QVA149 arm
ICS is not recommended in these patients according to the current GOLD COPD
strategy
document (GOLD 2014). Therefore all patients are receiving sufficient COPD
treatment in
both arms, along with appropriate rescue medication.
Providing the patients with rescue medication (short acting beta agonist; SABA)
and active
treatment during the screening, run-in period and throughout the study
mitigates any
deterioration risk. Repetitive lung function measurement maneuvers during the
study can lead
to cough, shortness of breath, dizziness, or exhaustion. Since the patient only
carries out
forced maneuvers during clinic visits (not at home), these are performed under
medical
supervision to ensure availability of immediate aid if required. The
assessments are infrequent
and part of the regular medical assessments of this patient population.
The risk of side effects from the study medication are known for compounds
QVA149,
QAB149 and NVA237. The most frequently reported side effects seen for QVA149 to
date
are; nasopharyngitis, upper respiratory tract infection, cough, and headache.
See QVA149
Investigator*s Brochure and for QAB149 and NVA237 see QAB149 and NVA237
sections of
the QVA149 Investigator*s Brochure.
The risk of side effects for the active comparator salmeterol/fluticasone
50/500 *g b.i.d) are
those known for salmeterol and fluticasone, such as tremor, headache,
palpitations,
pneumonia, bronchitis, hypokalemia, nasopharyngitis, throat irritation,
sinusitis, muscle
cramps, traumatic fractures, hoarseness and candidiasis in the mouth and
throat. (Seretide
Accuhaler® 50/500 *g SmPC).
The most common adverse reactions for the other active comparator, Tiotropium
(>5%
incidence in the 1-year placebo-controlled trials) are upper respiratory tract
infection, dry
mouth, sinusitis, pharyngitis, non-specific chest pain, urinary tract
infection, dyspepsia, and
rhinitis (Spiriva Handihaler* 18 *g SmPC).
The United States Food and Drug Administration (FDA) issued a warning
concerning long
acting beta-2 agonists (LABA). The warning states that LABAs may increase the
chance of
severe asthma episodes and asthma related death in patients with asthma. The
warning was
based on a study that evaluated the safety of salmeterol, which showed an
increase in asthma
related deaths in patients with asthma receiving salmeterol and their usual
asthma medication.
This increased risk has not been demonstrated in patients with COPD.
Hogeweg 35-h
Zaltbommel 5301 LJ
NL
Hogeweg 35-h
Zaltbommel 5301 LJ
NL
Listed location countries
Age
Inclusion criteria
Patients eligible for inclusion in this study have to fulfill all of the following criteria:
1. Patients who have signed Informed Consent Form prior to initiation of any study-related
procedure.
2. Male and female adults aged * 40 years.
3. Patients with moderate to severe airflow obstruction with stable COPD (Stage 2 or Stage 3)
according to the 2014 GOLD Guidelines.
4. Patients with a post-bronchodilator FEV1 *40 and < 80% of the predicted normal value,
and post-bronchodilator FEV1/FVC < 0.70 at run-in Visit 101.
(Post refers to 15 min after inhalation of 400 *g of salbutamol) (Readings assessed by site
and checked centrally).
5. Current or ex-smokers who have a smoking history of at least 10 pack years (e.g. 10 pack
years <= 1 pack /day x 10 years, or * pack/day x 20 years). An ex-smoker is defined as a
patient who has not smoked for * 6 months at screening.
6. Patients who are on triple treatment at least for the last 6 months (LAMA +LABA/ICS).
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No
additional exclusions may be applied by the investigator, in order to ensure that the study
population will be representative of all eligible patients.
1. Use of other investigational drugs/devices (approved or unapproved) at the time of
enrollment, or within 30 days or 5 half-lives of Visit 1, whichever is longer.
2. Patients 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:
* long and short anticholinergic agents
* long and short acting beta-2 agonists
* sympathomimetic amines
* lactose or any of the other excipients of trial medication
3. History or current diagnosis of ECG abnormalities indicating significant risk of safety for
patients participating in the study such as:
* Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular
tachycardia, and clinically significant second or third degree AV block without a
pacemaker
* History of familial long QT syndrome or known family history of Torsades de Pointes
4. Resting QTc (Fridericia method) *450 msec for males and females at Visit 101.
5. Concomitant use of agents known to significantly prolong the QT interval unless it can be
permanently discontinued for the duration of study.
6. Patients who have a clinically significant laboratory abnormality at Visit 101 and would
be at potential risk if enrolled into the study.
7. Patients who have clinically significant renal, cardiovascular (such as but not limited to
unstable ischemic heart disease, NYHA Class III/IV left ventricular failure, myocardial
infarction), arrhythmia (see below for patients with atrial fibrillation), neurological,
endocrine, immunological, psychiatric, gastrointestinal, hepatic, or hematological
abnormalities which could interfere with the assessment of the efficacy and safety of the
study treatment.
8. Patients with paroxysmal (e.g. intermittent) atrial fibrillation are excluded. Patients with
persistent atrial fibrillation as defined by continuous atrial fibrillation for at least 6 months
and controlled with a rate control strategy (i.e., beta blocker, calcium channel blocker,
pacemaker placement, digoxin or ablation therapy) for at least 6 months may be
considered for inclusion. In such patients, atrial fibrillation must be present at Visit 101
and Visit 102) visits, with a resting ventricular rate < 100/min. At visit 101, atrial
fibrillation must be confirmed by central reading.
9. Patients with narrow-angle glaucoma, symptomatic benign prostatic hyperplasia or
bladder-neck obstruction or moderate to severe renal impairment or urinary retention
(BPH patients who are stable on treatment can be considered).
10. Patients who have not achieved acceptable spirometry results at Visit 101 in accordance
with ATS (American Thoracic Society)/ERS (European Respiratory Society) criteria for
acceptability (one retest may be performed for patients that don*t meet the acceptability
criteria).
11. Patients who have had more than one COPD exacerbation that required treatment with
antibiotics and/or oral corticosteroids and/or hospitalization in the last year prior to Visit 1.
12. Patients who developed a COPD exacerbation of any severity either 6 weeks before the
screening (Visit 1) or between screening (Visit 1) and treatment (Visit 201) will not be
eligible but will be permitted to be re-screened after a minimum of 6 weeks after the
resolution of the COPD exacerbation.
13. Patients who have had a respiratory tract infection within 4 weeks prior to screening Visit
1.
14. Patients who develop a respiratory tract infection between screening and treatment will
not be eligible, but will be permitted to be re-screened 4 weeks after the resolution of the
respiratory tract infection.
15. Patients requiring long term oxygen therapy prescribed for >12 hours per day.
16. Patients with any history of asthma.
17. Patients with a blood eosinophil count > 600/mm3 during screening (Visit 101).
18. Patients with allergic rhinitis who use a H1 antagonist or intra-nasal corticosteroids
intermittently (treatment with a stable dose or regimen is permitted).
19. Patients with concomitant pulmonary disease (e.g. lung fibrosis, sarcoidosis, interstitial
lung disease, pulmonary hypertension, clinically significant bronchiectasis).
20. Patients with a diagnosis of *-1 anti-trypsin deficiency.
21. Patients with active pulmonary tuberculosis.
22. Patients with pulmonary lobectomy or lung volume reduction surgery or lung
transplantation.
23. Patients participating in or planning to participate in the active phase of a supervised
pulmonary rehabilitation program during the study (Maintenance program is permitted).
24. Patients receiving any medications in the classes listed in Table 5-1.
25. Patients receiving any COPD related medications in the classes specified in Table 5-2
must undergo the required washout period prior to Visit 101 and follow the adjustment to
treatment program.
26. Patients receiving medications in the classes listed in Table 5-3 should be excluded unless
the medication has been stable for the specified period and the stated conditions have been
met.
27. Patients unable to use an electronic patient diary.
28. Patients unable to use a dry powder inhaler device or a pressurized MDI (rescue
medication) or unable to comply with the study regimen. Spacer devices are not permitted.
29. 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.
30. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female
after conception and until the termination of gestation, confirmed by a positive hCG
laboratory test.
31. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using effective methods of contraception during
dosing of study treatment. Effective contraception methods include:
* Total abstinence (when this is in line with the preferred and usual lifestyle of the
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation
methods) and withdrawal are not acceptable methods of contraception
* Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In
case of oophorectomy alone, only when the reproductive status of the woman has
been confirmed by follow up hormone level assessment
* Male sterilization (at least 6 m prior to screening). For female patients on the study,
the vasectomized male partner should be the sole partner for that patient
* Barrier methods of contraception: Condom or Occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository
* Use of oral, injected or implanted hormonal methods of contraception or other forms
of hormonal contraception that have comparable efficacy (failure rate <1%), for
example hormone vaginal ring or transdermal hormone contraception
* Placement of an intrauterine device (IUD) or intrauterine system (IUS)
In case of use of oral contraception women should have been stable on the same pill for a
minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have had 12
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy
(with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of
oophorectomy alone, only when the reproductive status of the woman has been confirmed by
follow up hormone level assessment is she considered not of child bearing potential.
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 | EUCTR201500011422-NL |
| CCMO | NL54207.100.15 |