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NCT Number: NCT00662792

Efficacy and Safety Comparison of Tiotropium Daily + Salmeterol Daily or Twice Daily Versus Tiotropium Daily in Patients With COPD

The primary objective of this trial is to establish superiority of the once-daily Tiotropium plus Salmeterol Inhalation Powder in daytime lung function response and non-inferiority in night-time lung function response over the comparator treatments inhaled in their established dose regimens when administered for 6-week periods to patients with chronic obstructive pulmonary disease (COPD). The main secondary objective is to evaluate the safety of the Tiotropium plus Salmeterol Inhalation Powder versus the comparator treatments.

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Key information

Conditions

Pulmonary Disease, Chronic Obstructive Chronic Disease Disease Attributes Lung Diseases Lung Diseases, Obstructive Pathologic Processes Pathological Conditions, Signs and Symptoms Respiratory Tract Diseases

Age range

40 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

1184.13.1302 Boehringer Ingelheim Investigational Site, Berlin, Germany

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • All patients must sign an informed consent consistent with ICH-GCP guidelines and local legislations prior to any study-related procedures, which includes medication washout and restrictions.
  • All patients must have a diagnosis of COPD and must meet the following criteria:

relatively stable* airway obstruction with a post-bronchodilator FEV1 < 80% of predicted normal and post-bronchodilator FEV1 < 70% of post-bronchodilator FVC at Visit 1 (according to GOLD criteria).

  • The randomisation of patients with any respiratory infection or COPD exacerbation in the 6 weeks prior to the Screening Visit (Visit 1) or during the baseline period should be postponed. Patients may be randomised 6 weeks following recovery from the infection or exacerbation. Predicted normal values will be calculated according to ECSC.
  • Male or female patients 40 years of age or older.
  • Patients must be current or ex-smokers with a smoking history of 10 pack-years.
  • Patients must be able to perform technically acceptable pulmonary function tests
  • Patients must be able to inhale medication in a competent manner.
  • Patients must be able to perform all necessary recordings in the diary.

Exclusion criteria

  • Significant diseases other than COPD
  • Patients with clinically significant abnormal baseline haematology, blood chemistry or urinalysis, if the abnormality defines a significant disease as defined in exclusion criterion No. 1.
  • Patients with a recent history of myocardial infarction.
  • Patients with any unstable or life-threatening cardiac arrhythmia requiring intervention or change in drug therapy during the past year.
  • Hospitalisation for cardiac failure during the past year.
  • Malignancy within the last five years excluded basal cell carcinoma.
  • Patients with a history of asthma or who have a total blood eosinophil count 600/mm3.
  • Patients with a history of life threatening pulmonary obstruction, or a history of cystic fibrosis or clinically evident bronchiectasis.
  • Known active tuberculosis.
  • Patients with a history of alcohol or drug abuse.
  • Thoracotomy with pulmonary resection.
  • Rehabilitation program within the last six weeks
  • Patients who regularly use daytime oxygen therapy
  • Patients who have taken an investigational drug within 30 days
  • Use of not allowed medications
  • Known hypersensitivity to used drugs or other components of the study medication.
  • Pregnant or nursing women
  • Women of childbearing potential not using a highly effective method of birth control. Highly effective methods of birth control are 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, combined oral contraceptives, some IUDs, sexual abstinence or vasectomised partner. 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.
  • Patients who are currently participating in another study.

Treatment and study plan

Tiotropium (Tio18GEL)

Drug

18 µg Tiotropium (Tio18GEL) inhalation powder

Salmeterol MDPI (Salm50DPI)

Drug

50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID)

Tiotropium (T18GEL) + Salmeterol MDPI (S_DPI)

Drug

18 µg Tiotropium (T18GEL) inhalation powder plus 50 µg Salmeterol MDPI (S_DPI) twice daily (BID)

Tiotropium/Salmeterol (T+S_PE)

Drug

Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S_PE) inhalation powder

Primary outcomes

  1. Response in Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve From 0 - 12 Hours (AUC0-12)

    Time frame: At baseline and 10 minutes (min) prior to inhalation and 30 min, 60 min, 2, 3, 4, 6, 8, 10 and 12 hours after inhalation of the morning dose after 6 weeks of treatment.

    FEV1 AUC was defined as the area under the FEV1 curve normalized for time. It was calculated from time 0 to 12 h (FEV1 AUC0-12), using the trapezoidal rule divided by the corresponding duration (12 h) to give the results in liter (L). FEV1 AUC0-12h response is defined as the change from baseline:

    FEV1 AUC0-12h response = FEV1 AUC0-12h - FEV1 (Baseline). The FEV1 baseline value is defined as the pre-dose FEV1 measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.

  2. Response in Forced Expiratory Volume in Second (FEV1) Area Under the Curve From 12 - 24 Hours (AUC12 -24)

    Time frame: At baseline and 10 minutes (min) prior to inhalation and 30 min, 60 min, 2, 10, 11, and 12 hours after inhalation of the evening dose after 6 weeks of treatment.

    The FEV1 AUC was defined as the area under the FEV1 curve (AUC) normalised for time. It was calculated from time 12 to 24 h (FEV1 AUC12-24), using the trapezoidal rule divided by the corresponding duration (i.e. 12 h) to give the results in L.

    AUC12-24h response is defined as the change from baseline:

    FEV1 AUC12-24h response = FEV1 AUC12-24h - FEV1 (Baseline). The FEV1 baseline value is defined as the pre-dose FEV1 measurement in the morning at the randomization visit (Visit 2) just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.

  3. Response in Peak Forced Expiratory Volume in 1 Second (FEV1)

    Time frame: At baseline and within 3 hours post-morning dose after 6 weeks of treatment.

    Peak FEV1 was defined as the highest FEV1 reading observed within 3 hours after inhalation of the last morning dose of each randomized treatment. Peak FEV1 response is defined as change from baseline:

    Peak FEV1 response = Peak FEV1 - FEV1 (Baseline). The FEV1 baseline value is defined as the pre-dose FEV1 measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.

  4. Response in Trough Forced Expiratory Volume in 1 Second (FEV1)

    Time frame: At baseline and 5 minutes prior to the last administration of the morning dose after 6 weeks of treatment.

    Trough FEV1 is determined at the end of each treatment period and is defined as the pre-dose FEV1 measured just prior to the last administration of the morning dose of randomized treatment.

    Trough FEV1 response is defined as the change from baseline:

    Trough FEV1 response = Trough FEV1 - FEV1 (Baseline) The FEV1 baseline value is defined as the pre-dose FEV1 measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.

Secondary outcomes

  1. Response in Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve From 0-24 Hours (AUC0-24)

    Time frame: At baseline and 10 minutes (min) prior and 60 min, 2, 3, 4, 6, 8, 10 and 12 hours after inhalation of the morning dose and 30 min, 60 min, 2, 10, 11, and 12 hours after inhalation of the evening dose after 6 weeks of treatment.

    FEV1 AUC was defined as the area under the FEV1 curve normalized for time. It was calculated from time 0 to 24 h (FEV1 AUC0-24), using the trapezoidal rule divided by the corresponding duration (24 h) to give the results in liter (L). FEV1 AUC0-24h response is defined as the change from baseline:

    FEV1 AUC0-24h response = FEV1 AUC0-24h - FEV1 (Baseline). The FEV1 baseline value is defined as the pre-dose FEV1 measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.

  2. Response in Forced Vital Capacity (FVC) Area Under the Curve From 0 to 12 Hours (AUC0-12)

    Time frame: At baseline and 10 minutes (min) prior to inhalation and 30 min, 60 min, 2, 3, 4, 6, 8, 10 and 12 hours after inhalation of the morning dose after 6 weeks of treatment.

    FVC AUC was defined as the area under the FVC curve normalized for time. It was calculated from time 0 to 12 h (FVC AUC0-12), using the trapezoidal rule divided by the corresponding duration (12 h) to give the results in liter (L). FVC AUC0-12h response is defined as the change from baseline:

    FVC AUC0-12h response = FVC AUC0-12h - FVC (Baseline). The baseline value for FVC based parameters is defined as the pre-dose FVC measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.

  3. Response in Forced Vital Capacity (FVC) Area Under the Curve From 12 to 24 Hours (AUC12-24)

    Time frame: At baseline and 10 minutes (min) prior to inhalation and 30 min, 60 min, 2, 10, 11 and 12 hours after inhalation of the evening dose after 6 weeks of treatment.

    The FVC AUC was defined as the area under the FVC curve (AUC) normalised for time. It was calculated from time 12 to 24 h (FVC AUC12-24), using the trapezoidal rule divided by the corresponding duration (i.e. 12 h) to give the results in L.

    AUC12-24h response is defined as the change from baseline:

    FVC AUC12-24h response = FVC AUC12-24h - FVC (Baseline). The FVC baseline value is defined as the pre-dose FVC measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.

  4. Response in Forced Vital Capacity (FVC) Area Under the Curve From 0 - 24 Hours (AUC0-24)

    Time frame: At baseline and 10 minutes (min) prior and 60 min, 2, 3, 4, 6, 8, 10 and 12 hour after inhalation the morning dose and 30 min, 60 min, 2, 10, 11, and 12 hours after inhalation of the evening dose after 6 weeks of treatment.

    The FVC AUC was defined as the area under the FVC curve (AUC) normalised for time. It was calculated from time 0 to 24 h (FVC AUC0-24), using the trapezoidal rule divided by the corresponding duration (i.e. 24 h) to give the results in L. AUC response was defined as the change from the baseline FVC; baseline was defined as the FVC measured on randomisation visit. Mean is adjusted mean.

  5. Response in Peak Forced Vital Capacity (FVC)

    Time frame: At baseline and within 3 hours post-morning dose after 6 weeks of treatment.

    Peak FEV1 was defined as the highest FEV1 reading observed within 3 hours after inhalation of the last morning dose of each randomized treatment.

    Peak FEV1 response is defined as change from baseline:

    Peak FEV1 response = Peak FEV1 - FEV1 (Baseline). The FEV1 baseline value is defined as the pre-dose FEV1 measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.

  6. Response in Trough Forced Vital Capacity (FVC)

    Time frame: At baseline and 5 minutes prior to the last administration of the morning dose after 6 weeks of treatment.

    Trough FVC1 is determined at the end of each 6-week treatment period and is defined as the pre-dose FVC1 measured just prior to the last administration of the morning dose of randomized treatment.

    Trough FVC1 response is defined as the change from baseline:

    Trough FVC1 response = Trough FVC1 - FVC1 (Baseline) The FVC1 baseline value is defined as the pre-dose FVC1 measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.

  7. Response in Peak Expiratory Flow Rate (PEF) Area Under the Curve Form 0 to 12 Hours (AUC0-12)

    Time frame: At baseline and 10 minutes (min) prior and 30 min, 60 min, 2, 3, 4, 6, 8, 10 and 12 hours after inhalation of the morning dose after 6 weeks of treatment.

    PEF(L/min) AUC0-12(h) response is defined as the change from baseline. AUC0-12(h) was calculated as the area under the curve from 0 to 12 hours using the trapezoidal rule, divided by the full duration (12 hours) to report in liter/minutes.

    PEF AUC0-12h response = PEF AUC0-12h - PEF (Baseline). The PEF baseline value is defined as the pre-dose PEF measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.

  8. Response in Peak Expiratory Flow Rate (PEF) Area Under the Curve From 12 to 24 Hours (AUC12-24)

    Time frame: At baseline and 10 minutes (min) prior and 30 min, 60 min, 2, 10, 11 and 12 hours after inhalation of the evening dose after 6 weeks of treatment.

    PEF(L/min) AUC12-24(h) response is defined as the change from baseline. AUC12-24(h) was calculated as the area under the curve from 12 to 24 hours using the trapezoidal rule, divided by the full duration (12 hours) to report in liter/minutes.

    PEF AUC12-24h response = PEF AUC12-24h - PEF (Baseline). The PEF baseline value is defined as the pre-dose PEF measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.

  9. Response in Peak Expiratory Flow Rate (PEF) Area Under the Curve From 0 to 24 Hours (AUC0-24)

    Time frame: At baseline and 10 minutes (min) prior and 60 min, 2, 3, 4, 6, 8, 10 and 12 hours after inhalation of the morning dose and 30 min, 60 min, 2, 10, 11, and 12 hours after inhalation of the evening dose after 6 weeks of treatment.

    PEF(L/min) AUC0-24(h) response is defined as the change from baseline. AUC0-24(h) was calculated as the area under the curve from 0 to 24 hours using the trapezoidal rule, divided by the full duration (24 hours) to report in liter/minutes.

    PEF AUC0-24h response = PEF AUC0-24h - PEF (Baseline). The PEF baseline value is defined as the pre-dose PEF measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.

  10. Response in Peak PEF (Peak Expiratory Flow Rate)

    Time frame: At baseline and within 3 hours post-morning dose after 6 weeks of treatment.

    Peak PEF was defined as the highest PEF reading observed within 3 hours after inhalation of the last morning dose of randomized treatment.

    Peak PEF response is defined as change from baseline:

    Peak PEF response = Peak PEF - PEF (Baseline). The PEF baseline value is defined as the pre-dose PEF measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.

  11. Response in Trough Peak Expiratory Flow Rate (PEF)

    Time frame: At baseline and 5 minutes prior to the last administration of the morning dose after 6 weeks of treatment.

    Trough PEF is determined at the end of each treatment period and is defined as the pre-dose PEF measured just prior to the last administration of the morning dose of randomized treatment. Trough PEF response is defined as the change from baseline:

    Trough PEF response = Trough PEF - PEF (Baseline) The PEF baseline value is defined as the pre-dose PEF measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.

  12. Response in Individual Forced Expiratory Volume in 1 Second (FEV1) Over a 24 Hour Observation Period

    Time frame: At baseline, pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 12.5, 13, 14, 22, 23, and 24 hours post morning dose after 6 weeks of treatment.

    Response in individual forced expiratory volume in 1 second (FEV1) over a 24 hour observation period. Response is defined as change from baseline.

    Means are adjusted for treatment, centre, treatment period and patient within centre.

  13. Response in Individual Forced Vital Capacity (FVC) Over a 24 Hour Observation Period

    Time frame: At baseline, pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 12.5, 13, 14, 22, 23 and 24 hours post morning dose after 6 weeks of treatment.

    Response in forced vital capacity (FVC) over a 24 hour observation period. Response is defined as change from baseline.

  14. Response in Individual Peak Expiratory Flow (PEF) Over a 24 Hour Observation Period

    Time frame: At baseline, pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 12.5, 13, 14, 22, 23, and 24 hours post morning dose after 6 weeks of treatment.

    Response in individual peak expiratory flow (PEF) over a 24 hour observation period. Response is defined as change from baseline.

    Means are adjusted for treatment, centre, treatment period and patient within centre.

  15. Response in Morning and Evening Peak Expiratory Flow Rate (PEF), Recorded by Patients at Home

    Time frame: At baseline and last 3 weeks of 6-week treatment period.

    The mean PEF is defined as the mean of the values obtained during the weeks after the first three weeks of treatment. Morning and evening mean PEF were calculated and analyzed separately. PEF was measured twice daily (in the morning prior to inhalation of study medication and in the evening prior to inhalation of study medication).

    Morning and evening mean PEF response are defined as the change from morning and evening baseline, respectively.

    Morning and evening mean PEF baseline are defined as the mean of the morning and evening values, respectively obtained from the last week preceding the randomization visit.

    Mean is adjusted for treatment, center, treatment period and patient within center.

  16. Response in Morning and Evening Forced Expiratory Volume in 1 Second (FEV1) Recorded by Participants at Home

    Time frame: At baseline and last 3 weeks of 6-week treatment period.

    Per treatment period, the morning mean FEV1 (mean of the pre-dose morning FEV1 measurements) and evening mean FEV1 (mean of the pre-dose evening FEV1 measurement) were calculated. Per treatment period the data obtained after the first 3 weeks were used for calculating these means.

    Morning and evening mean FEV1 responses are defined as the change from morning and evening baseline, respectively. The baseline values, morning and evening mean FEV1(Baseline), are defined as the mean of the morning and evening values, respectively obtained from the last week preceding the randomization visit .

    Mean is adjusted for treatment, centre, treatment period and patient within centre.

  17. Response in Mean Number of Days With Rescue Medication Use

    Time frame: At baseline and last 3 weeks of 6-week treatment period.

    Response (change from baseline) in mean number of days with rescue medication use in day-time, night-time and 24-hours. Per treatment period, the response in mean number of days using rescue medication was calculated for day-time (from inhalation of morning dose until 12 hours thereafter), night-time (from inhalation of evening dose until 12 hours thereafter) and 24h-total (from inhalation of morning dose until 24 hours thereafter) separately.

    Per 6-week treatment period the data obtained after the first 3 weeks was used for calculating means. Mean is adjusted mean.

  18. Response in Mean Number of Puffs of Rescue Medication

    Time frame: At baseline and last 3 weeks of 6-week treatment period.

    Response in mean number of puffs of rescue medication. Per treatment period, the response in mean number of puffs rescue medication used was calculated, for day-time (from inhalation of morning dose until 12 hours thereafter), night-time (from inhalation of evening dose until 12 hours thereafter) and 24h-total (from inhalation of morning dose until 24 hours thereafter) separately. Per 6-week treatment period the data obtained after the first 3 weeks was used for calculating means. Night-time, day-time and 24h-total mean number of puffs rescue medication used responses are defined as the change from night-time, day-time and 24h-total baseline, respectively.

    The baseline values, night-time, day-time and 24h-total mean mean number of puffs rescue medication used (Baseline), are defined as the mean of the night-time, day-time and 24h-total values, respectively obtained from the last week preceding the randomisation visit.

  19. Response in Mean Number of Days With Night-time Awakenings

    Time frame: At baseline and last 3 weeks of 6-week treatment period.

    Response in mean number of days with night-time awakenings. Per treatment period, the mean number days with awakening during the night was calculated. Per 6-week treatment period the data obtained after the first 3 weeks was used for calculating this mean. Mean number of days with night-time awakenings response is defined as the change from baseline. The baseline value, mean number of days with night-time awakenings (Baseline), is defined as the mean of the number of days with night-time awakenings obtained from the last week preceding the randomization visit.

  20. Response in Mean Number of Days With Night-time Awakenings Due to Shortness of Breath (SOB)

    Time frame: At baseline and last 3 weeks of 6-week treatment period.

    Per treatment period, the mean number days with awakening (only chronic obstructive pulmonary disease (COPD) related awakenings) during the night was calculated. Per 6-week treatment period the data obtained after the first 3 weeks was used for calculating the mean.

    Mean number of days with COPD related awakenings response is defined as the change from baseline.

    The baseline value, mean number of days with COPD related awakenings (Baseline), is defined as the mean of the number of days with COPD related awakenings obtained from the last week preceding the randomization visit.

  21. Response in Means Number of Awakenings Due to Shortness of Breath (SOB)

    Time frame: At baseline and last 3 weeks of 6-week treatment period.

    Per treatment period, the mean number of awakening (only chronic obstructive pulmonary disease (COPD) related awakenings) during the night was calculated. Per 6-week treatment period the data obtained after the first 3 weeks was used for calculating this mean. Mean number of COPD related awakenings response is defined as the change from baseline. The baseline value, mean number of COPD related awakenings (Baseline), is defined as the mean of the number of days with COPD related awakenings obtained from the last week preceding the randomization visit.

  22. Response in Average Shortness of Breath (SOB) Score at Night

    Time frame: At baseline and last 3 weeks of 6-week treatment period.

    Response in average shortness of breath (SOB) score at night. The SOB measured the shortness of breath, ranging from 1 to 5, where 1 = not at all, 2 = a little bit, 3 = somewhat, 4 = quite a bit and 5 = very much. A higher score indicates a worse outcome.

    Per 6-week treatment period the data obtained after the first 3 weeks was used for calculating the mean.

  23. Number of Participants With Drug Related Adverse Events

    Time frame: From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.

    Number of participants with drug related adverse events.

  24. Number of Patients With Marked Changes in Vital Signs

    Time frame: At baseline and 6 hours following the morning dose of study medication after 6 weeks of treatment.

    Marked changes from baseline in vital signs were defined as followed:

    Systolic blood pressure

    • Increase of ≥25 millimetre of mercury (mmHg) above baseline
    • Decrease below 100 mmHg if not at that level at baseline and a decrease of >10 mmHg below baseline

    Diastolic blood pressure

    • Increase above 90 mmHg and an increase of >10 mmHg above baseline
    • Decrease below 60 mmHg if not at that level at baseline and a decrease of >10 mmHg below baseline

    Pulse

    • Increase above 100 bpm if not at that level at baseline and an increase of >10 bpm above baseline
    • Decrease below 60 bpm if not at that level at baseline and a decrease of >10 bpm below baseline

    Baseline is defined as the pre-dose measurement at randomisation visit.

Sponsors and collaborators

Lead sponsor

Boehringer Ingelheim

Industry

Registry information

Official study title

A Randomised, Double-blind Clinical Efficacy and Safety Comparison of Tiotropium/Salmeterol 7.5/25 Inhalation Powder in the Morning Via Tiotropium/Salmeterol HandiHaler, Tiotropium 18 Mcg Inhalation Powder in the Morning Via Spiriva HandiHaler, Salmeterol 50 Mcg MDPI in the Morning and Evening and the Free Combination Tiotropium 18 Mcg Inhalation Powder in the Morning Via Spiriva HandiHaler Plus Salmeterol 50 Mcg MDPI in the Morning and Evening Following Chronic Administration (6-week Treatment Periods) in Patients With COPD

Important dates

Study start
2008
Primary completion
2009
Study completion
2009
First posted
Apr 21, 2008
Registry last updated
Jun 28, 2022

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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