Tiotropium is available in the pharmacy as solution for inhalation (daily dose of 5 mcg) and as inhalation powder (daily dose of 18 mcg). The objective of the present study is to compare three doses of tiotropum solution for inhalation (daily dose…
ID
Source
Brief title
Condition
- Respiratory disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The systemic availability after inhalation of different tiotropium doses will
be assessed by the following primary endpointrs:
- Cmax,ss = maximum tiotropium concentration in plasma in steady state
condition,
- AUC(0-6),ss = area under the tiotropium concentration-time curve in plasma in
steady state condition for the time interval till 6 hours post inhalation.
Secondary outcome
Secundary study parameters (outcome of the study) are:
- pharmacokinetics of tiotropium in steady state condition (refer to page 48 of
the protocol): time interval between inhalation and the maximum tiotropium
concentration in plasma [t (max)], terminal elimination halflife (t 1/2), mean
residence time in the body after inhalation (MRTih), clearance (CL/F), volume
of distribution (Vz/F), fraction eliminated via the urine (fe), renal clearance
(CLr), plasma concentration just before inhalation of the last dose (Cpre),
minimum concentration in plasma (Cmin).
- pulmonary function parameters (refer to page 40 of the protocol): trough FEV1
and trough FVC (= value measured just before inhalation of the last dose), FEV1
AUC(0-6) en FVC AUC(0-6) (= areas under the FEV1 and FVC - time curves
normalized for time), individual FEV1 and FVC values measured at all time
points at the end of each 4-week period.
- safety endpoints: adverse events, continuous ECG recording (Holter during 6
hours) at the end of each period (only in patients participating in the
pharmacokinetic assessments).
Background summary
An existing pharmacokinetic dose-response evaluation of tiotropium solution for
inhalation (1.25 mcg - 20 mcg) in COPD is based on renal excretion; in this
dose-response pulmonary function tests were also performed. The study included
parallel groups and had a small number of patients per dose strenght, meaning
that the statistical power could have been insufficient for a proper comparison
of the different tiotropium doses. In addition, another comparative study
(crossover design) was performed with tiotropium solution for inhalation and
inhalation powder in which plasma samples were taken only 10 min after
inhalation (refer to page 17 of study protocol).
In the present crossover study the systemic availability of tiotropium solution
for inhalation (5 mcg) will be extensively investigated and compared with
tiotropium inhalation powder (18 mcg) by frequent blood sampling, in particular
in the first 40 min after inhalation. The study includes also two lower doses
(1.25 mcg and 2.5 mcg) which could be relevant for future combination therapy
with a long-acting sympathicomimetic agent. In addition to pharmacokinetics,
pulmonary function tests will provide valuable information on the dose-response
relationship in terms of efficacy in COPD.
Study objective
Tiotropium is available in the pharmacy as solution for inhalation (daily dose
of 5 mcg) and as inhalation powder (daily dose of 18 mcg). The objective of the
present study is to compare three doses of tiotropum solution for inhalation
(daily dose of 1.25 mcg, 2.5 mcg and 5 mcg; the latter is the approved daily
dose) with the approved daily dose of 18 mcg (inhalation powder) in terms of
pharmacokinetics (systemic availability), efficacy (improvement of lung
function) and safety. The pharmacokinetics will provide important information
on the systemic availability and renal excretion of tiotropium (following
inhalation of different doses and a different formulation). Data on the
dose-response relationship in terms of lung function improvement (FEV1, FVC)
and systemic availability including the two lower tiotropium doses (as solution
for inhalation) is in particular of importance for future combination therapy
of tiotropium and other bronchodilators for the treatment of COPD.
Study design
The randomised, placebo-controlled crossover study exists of five 4-week
treatment periods: 1 open-label period with inhalation powder (tiotropium 18
µg) and 4 double-blind periods with solution for inhalation ( tiotropium 1.25
µg, 2.5 µg, 5 µg and placebo).
Intervention
4 double-blind and 1 open-label treatment periods (crossover);
- double-blind blind (solution for inhalation):
1. placebo (in the morning),
2. tiotropium 1.25 µg (in the morning),
3. tiotropium 2,5 µg (in the morning),
4. tiotropium 5 µg (in the morning),
- open-label (inhalation powder):
5. tiotropium 18 µg (in the morning).
Study burden and risks
Prior to the 5 treatment periods the patient will have to visit the clinic 2
times during the screening period. At the last visit in this period the first
dose of study medication of the first treatment period will be inhaled. During
the 5 treatment periods of in total 20 weeks the patient will have to visit the
clinic 5 times for pulmonary function tests. In case the patient participates
in the pharmacokinetic assessments, there are 5 additional visits in this
period. Blood sampling (via a catheter) will be performed by an expereinced
stud ynurse in order to avoid any burden . All visits are scheduled at the end
of each 4- week period. After completion of the last treatment period there
will be a final post-study visit.
During each treatment period patients will have active bronchodilator therapy
(salmeterol or formoterol and if necessary salbutamol as rescue medication) in
addition to the study medication (4 periods with tiotropium and 1 period with
placebo). During the washout period of salmeterol and formoterol prior to each
test-day salbutamol is allowed; possibly that during the washout period in the
treatment period with placebo the patient may suffer from more complaints of
symptoms in case salbutamol provides insufficient relief.
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 and local legislations prior to any study-related procedures, including medication washout and restrictions.
2. Male or female patients 40 years of age or older.
3. Patients must be current or ex-smokers with a smoking history of at least 10 pack-years.
4. All patients must have a diagnosis of COPD (refer to page 22 of study protocol).
5. Patients must be able to perform technically acceptable pulmonary function tests.
6. Patients must be able to inhale medication in a competent manner from the Respimat and HandiHaler devices.
Exclusion criteria
1. Significant diseases other than COPD (refer to page 23 of study protocol).
2. Patients with a recent history of myocardial infarction.
3. Patients with any unstable of life-threatening cardiac arrhythmia requiring intervention or change in drug therapy during the past year.
4. Hospitalisation for cardiac failure during the past year.
5. Patients with a history of asthma or who have a total eosinophil count equal to or above 600/mm3.
6. Use of systemic corticosteroid medication at unstable doses (less than 6 weeks on stable dose) or at doses in excess of the equivalent of 10 mg prednisone per day or 20 mg every other day.
7. Pregnant or nursing women.
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 | EUCTR2009-016251-21-NL |
| CCMO | NL33405.096.10 |