The primary objective of this study is to compare the effects of orally inhaled tiotropium + olodaterol fixed dose combination (2.5 / 5 µg ; 5 / 5 µg) with tiotropium (5 µg), olodaterol (5 µg) and placebo on lung-hyperinflation and endurance time…
ID
Source
Brief title
Condition
- Respiratory disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary study parameters are inspiratory capacity at isotime and endurance
time during constant work rate cycle ergometry to symptom limitation at 75%
Wcap (= maximal work capacity) after 6 weeks of treatment.
Secondary outcome
The secondary endpoints will also be assessed during the constant work rate
cycle ergometry:
- Intensity of breathing discomfort at isotime during constant work rate cycle
ergometry to symptom limitation at 75% Wcap after 6 weeks of
treatment
- FEV1, FVC (trough, 1 hr post-dose)
- Inspiratory capacity (IC) during constant work rate cycle ergometry to
symptom limitation at 75% Wcap: pre-exercise, during exercise and at end
exercise
- Intensity of breathing discomfort during constant work rate cycle ergometry
to symptom limitation at 75% Wcap: pre-exercise, during exercise and at
end-exercise
- Intensity of leg discomfort during constant work rate cycle ergometry to
symptom limitation at 75% Wcap: pre-exercise, during exercise and at
end-exercise
- Locus of symptom limitation (breathing discomfort, leg discomfort, breathing
and leg discomfort, other) during constant work rate cycle ergometry to symptom
limitation at 75% Wcap
Background summary
The COPD treatment guidelines advise treatment with bronchodilators with
different mechanisms of action. Short-acting anticholinergics and
beta2-agonists in fixed dose combinations have shown to be effective and safe
and are user-friendly to patients. Once daily fixed dose combinations of
long-acting anticholinergics and beta2-agonists are not yet available.
Tiotropium bromide is a registered once daily long-acting anticholinergic for
the treatment of COPD and will be combined with a once daily long-acting
beta2-agonist, olodaterol, in this study. Olodaterol is being developed for the
treatment of COPD. It is expected that the combination of these two once daily
bronchodilators with different mechanisms of action will provide an optimal
long term bronchdilation and is user-friendly.
Earlier studies established a satisfactory safety and tolerability profile of 4
weeks once daily treatment with tiotropium + olodaterol and also provided
evidence of the additional bronchodilator efficacy of tiotropium + olodaterol
FDC compared with tiotropium monotherapy or olodaterol monotherapy.
Based on the evidence of the efficacy and safety of the fixed dose combination
of tiotropium and olodaterol up to 4 weeks treatment in patients with COPD, it
is considered appropriate to progress into the next phase of clinical
development and conduct long-term, confirmatory trials to provide substantial
evidence of the efficacy and safety of tiotropium + olodaterol FDC in patients
with COPD.
The present study is intended to provide further evidence of the clinical
efficacy of tiotropium + olodaterol FDC at the impairment-disability interface.
Such an assessment is particularly relevant in COPD, since one of the cardinal
features of the disease is the significant disability experienced by patients
as a result of the impaired lung function, manifested as increased exertional
dyspnea and exercise intolerance. The study design is founded on the
hypothesis that tiotropium reduces the degree of airflow limitation in patients
with COPD during tidal breathing, allowing for a reduction in lung
hyperinflation; the reduced lung hyperinflation leads to a reduction in the
intensity of breathing discomfort experienced during exercise, and a consequent
improvement in symptom-limited exercise tolerance.
Study objective
The primary objective of this study is to compare the effects of orally inhaled
tiotropium + olodaterol fixed dose combination (2.5 / 5 µg ; 5 / 5 µg) with
tiotropium (5 µg), olodaterol (5 µg) and placebo on lung-hyperinflation and
endurance time constant work rate exercise tolerance after 6 weeks of treatment
in patients with COPD. Lung hyperinflation will be assessed by measurement of
inspiratory capacity, and exercise tolerance will be assessed by measurement of
symptom-limited endurance time during constant work rate cycle ergometry.
Study design
After signing Informed Consent and completing an initial screening visit (Visit
1), patients will enter a 2-week run-in period to ensure clinical stability
(i.e. no exacerbations). During this screening period, they will conduct an
incremental work rate test (Visit 1), a training constant work rate test and
baseline constant work rate exercise test (Visit 2).
Patients who meet all the inclusion criteria and none of the exclusion criteria
will be randomized at Visit 3 into the 4 x 6-week double blind, cross-over
treatment portion of the study, in which they will receive four of the
following five treatments for 6 weeks (in a randomized sequence):
1) tiotropium + olodaterol ( 5 / 5 *g) fixed dose combination inhalation
solution, delivered once daily via the RESPIMAT
2) tiotropium + olodaterol (2.5 / 5 *g) fixed dose combination inhalation
solution, delivered once daily via the RESPIMAT
3) tiotropium (5 *g) inhalation solution, delivered once daily via the RESPIMAT
4) olodaterol (5 *g) inhalation solution, delivered once daily via the RESPIMAT
5) placebo inhalation solution, delivered once daily via the RESPIMAT
An interactive voice response system (IVRS) will be used for randomization to a
treatment sequence in this trial and for appropriate re-supply of medication to
patients.
Each treatment period will be separated by a 21-day wash-out period. Patients
will be evaluated for an additional 21 days following completion of the last
6-week treatment period, or, in case of early discontinuation, after the final
dose of study medication.
The study has a double-blind, incomplete cross-over design.
Intervention
Once daily inhalation of studymedication with the Respimat® inhaler with one of
the following treatment arms (randomisation 1:1:1:1:1):
- fixed dose combinatie tiotropium-olodaterol 2.5 / 5 *g
- fixed dose combinatie tiotropium-olodaterol 5 / 5 *g
- tiotropium 5 *g
- olodaterol 5 *g, and
- placebo.
During nine visits spirometry will be performed and in total 7 cycle ergometry
tests will be done.
Study burden and risks
During the course of the study each patient performs 9 times spirometry and 7
times cycle egometry. In principle, no serious risks are involved in
spirometry. Nevertheless, risks and discomforts associated with lung function
testing may include shortness of breath, dizziness, or headache during the
breathing tests. Should this occur, you may receive treatment.
Also cycle ergometry could provoke significant symptoms like sudden chest pain,
sudden changes in blood pressure, loss of coordination, mental confusion or
extreme shortness of breath. Changes may also be seen on ECG or in the
finger/ear clip placed on you to monitor the amount of oxygen in your blood.
The exercise test will be stopped if such signs or symptoms occur. Potential
complications and side effects of exercise include disturbances of heart rhythm
(slow heart rates or severe changes in the rhythm of your heart), heart
attacks, heart failure, and decrease in blood pressure. In addition,
musculoskeletal problems, severe fatigue, dizziness, fainting and body aches
have been reported from exercise tests.
During the cycle ergomotry the patients will be continuously monitored by
qualified study staff. The supervising study doctor will be present during the
initial incremental test and readily available to respond as needed during
subsequent testing. Safety monitoring will include measurement of oxygen
levels, heart rate measurement, ECG monitoring, and supervision . The study
doctor will exclude any person who might not tolerate exercise testing.
During the screeningperiod some medication will be washed-out. For this reason,
all patients will receive Ventolin as rescue medication already at start of
screeningperiod and may also be used during the treatmentperiod. Besides that,
Atrovent may be used during screeningperiod and wash-out periods during the
treatmentperiod. Oral and inhaled corticosteroids are also accepted throughout
the study.
Bloodsampling may also cause some inconvenience. There are also some
restrictions for a patient in terms of food and fluid intake as well as in
physical activities performed in the period before each visit. The total time
spent for each patient is 29-37 hours.
Inhalation of studymedication may cause side effects. Normally, these side
effects are mild and they usually disappear with continued treatment.
Comeniusstraat 6
1817 MS Alkmaar
NL
Comeniusstraat 6
1817 MS Alkmaar
NL
Listed location countries
Age
Inclusion criteria
1. All patients must sign an informed consent consistent with ICH-GCP guidelines prior to participation in the trial, which includes medication washout and restrictions.
2. All patients must have a diagnosis of chronic obstructive pulmonarydisease and must meet the following spirometric criteria:
Patients must have relatively stable airway obstruction with a postbronchodilator FEV1 <80% of predicted normal (ECSC) ; GOLD II - IV and a postbronchodilator FEV1/FVC <70% at Visit 1 (ECSC predicted normal equations)
3. Male or female patients, between 40 and 75 years of age (inclusive) on day of signing informed consent.
4. Patients must be current or ex-smokers with a smoking history of more than 10 pack years. Patients who have never smoked cigarettes must be excluded.
5. Patients must be able to perform technically acceptable pulmonary function tests (spirometry), must be able to complete multiple symptom limited cycle ergometry tests during the study period as required in the protocol.
Exclusion criteria
1. Patients with a significant disease other than COPD; a significant disease is defined as a disease which, in the opinion of the investigator, may (i) put the patient at risk because of participation in the study, (ii) influence the results of the study, or (iii) cause concern regarding the patient's ability to participate in the study,
2. Patients with clinically relevant abnormal baseline haematology, blood chemistry, or urinalysis; all patients with an SGOT >x2 ULN, SGPT >x2 ULN, bilirubin >x2 ULN or creatinine >x2 ULN will be excluded regardless of clinical condition (a repeat laboratory evaluation will not be conducted in these patients).
3. Patients with a history of asthma. For patients with allergic rhinitis or atopy, source documentation is required to verify that the patient does not have asthma. If a patient has a total blood eosinophil count greater than or equal to 600/mm3, source documentation is required to verify that the increased eosinophil count is related to a non-asthmatic condition.
Patients with any of the following conditions:
4. A diagnosis of thyrotoxicosis (due to the known class side effect profile of ß2-agonists).
5. A diagnosis of paroxysmal tachycardia (>100 beats per minute) (due to the known class side effect profile of ß2-agonists).
6. A history of myocardial infarction within 1 year of screening visit (Visit 1).
7. Unstable or life-threatening cardiac arrhythmia.
8. Hospitalized for heart failure within the past year.
9. Known active tuberculosis.
10. A malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years (patients with treated basal cell carcinoma are allowed).
11. A history of life-threatening pulmonary obstruction.
12. A history of cystic fibrosis.
13. Clinically evident bronchiectasis.
14. A history of significant alcohol or drug abuse.
15. Any contraindications for exercise testing as outlined in protocol.
16. Patients who have undergone thoracotomy with pulmonary resection (patients with a history of thoracotomy for other reasons should be evaluated as per exclusion criterion No. 1)
17. Patients being treated with any oral *-adrenergics.
18. Patients being treated with oral corticosteroid medication at unstable doses (i.e., less than six weeks on a stable dose) or at doses in excess of the equivalent of 10 mg of prednisone per day or 20 mg every other day.
19. Patients who regularly use daytime oxygen therapy for more than one hour per day and in the investigator's opinion will be unable to abstain from the use of oxygen therapy during clinic visits.
20. Patients who have completed a pulmonary rehabilitation program in the six weeks prior to the screening visit (Visit 1) or patients who are currently in a pulmonary rehabilitation program.
21. Patients who have a limitation of exercise performance as a result of factors other than fatigue or exertional dyspnoea, such as arthritis in the leg, angina pectoris or claudication or morbid obesity.
22. Patients with an endurance time greater than 25 minutes during the training (Visit 1) or baseline constant work rate cycle ergometry at Visit 2.
23. Patients who have taken an investigational drug within one month or six half lives (whichever is greater) prior to screening visit (Visit 1).
24. Patients with known hypersensitivity to *-adrenergics drugs, anticholinergic drugs, BAC, EDTA or any other component of the Respimat® inhalation solution delivery system.
25. Pregnant or nursing women.
26. Women of childbearing potential not using highly effective methods of birth control.*
Female patients will be considered to be of childbearing potential unless surgically sterilised by hysterectomy or bilateral tubal ligation, or post-menopausal for at least two years.
* as per ICH M3(R2): a highly effective method of birth control is defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly.
27. Patients who have previously been randomized in this study or are currently participating in another study.
28. Patients who are unable to comply with pulmonary medication restrictions prior to randomization.
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 | EUCTR2011-004660-30-NL |
| CCMO | NL38354.096.11 |
| Other | Nu nog niet bekend. Zal worden geregistreerd bij www.clinicaltrial.gov. |