Comparison of Two Daily Dose Regimens of Tiotropium 5 µg... | NCT01696071

ID	Type	Description	Link
2012-001873-10	EudraCT Number	EudraCT

Name	Class
Pfizer	INDUSTRY

Label	Type	Description	Intervention Names
Treatment A	Experimental	2 puffs of daily dose (5 mcg) in the evening and 2 puffs of matching placebo in the morning via Respimat inhaler	Drug: Tiotropium 5 mcg qd
Treatment B	Experimental	2 puffs of half daily dose (2.5 mcg) twice daily, in the evening and in the morning via Respimat inhaler	Drug: Tiotropium 2.5 mcg bid

Name	Type	Description	Arm Group Labels	Other Names
Tiotropium 5 mcg qd	Drug	2 puffs (2.5 mcg each) in the evening 5 mcg in total and 2 puffs of matching placebo in the morning	Treatment A

Measure	Description	Time Frame
Forced Expiratory Volume in One Second (FEV1) Area Under the Curve From 0 - 24h (AUC 0-24) Response.	Mixed Model Repeated Measure (MMRM) results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. AUC0-24h calculated using the trapezoidal rule divided by the observation time (24 hours) to report in litres. The values recorded at 11 hours 50 minutes and at 23 hours 50 minutes post dosing were assigned to 12 and 24 hours, respectively.	Baseline FEV1 taken at visit 2 prior to the first evening dose of randomised study medication. Then, 10 minutes (min) prior to dose to 30 min,1 hour (h),2h,3h,4h,11h50min,12h30min,13h,14h,15h,16h,18h,20h,22h and 23h,23h50min relative to dose after 4 weeks

Measure	Description	Time Frame
FEV1 AUC0-12h Response	MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. AUC0-12h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres.	Baseline FEV1 taken at visit 2 prior to the first evening dose of randomised study medication. Then, 10 minutes(min) prior to dose to 30min,1hour(h),2h,3h,4h,11h50min,12h30min,13h,14h,15h,16h,18h,20h,22h and 23h,23h50min relative to dose after 4 weeks

Eligibility Module

Eligibility Criteria

Inclusion criteria:

All patients must sign and date an Informed Consent Form consistent with ICH-GCP guidelines and local legislation prior to participation in the trial.
Male or female patients aged at least 18 years at Visit 0 but not more than 75 years at Visit 0.
All patients must have at least a 3 months history of asthma at the time of enrolment (signing ICF) into the trial. The initial diagnosis of asthma must have been made before the patient's age of 40.
All patients must have a pre-bronchodilator FEV1 = 60% predicted and = 90% of predicted normal at Visit 1.Variation of absolute pre-bronchodilator FEV1 values at Visit 1 and Visit 2 must be within ± 30%.
Patient's diagnosis of asthma has to be confirmed at Visit 1 with bronchodilator reversibility (ie 10 minutes prior to and 15-30 minutes after inhalation of 400 µg salbutamol) defined as an FEV1 increase of = 12% and = 200 mL.
All patients must have a diagnosis of moderate persistent asthma and must be symptomatic despite their current maintenance treatment with medium doses of ICS.
All patients must be symptomatic at Visit 1and Visit 2 as defined by an ACQ mean score of = 1.5.
All patients must have maintenance treatment with stable medium daily dose of ICS for at least 4 weeks prior to Visit 1.
Patients must be never-smokers or ex-smokers who stopped smoking at least one year prior to enrolment (Visit 0) and who have a smoking history of less than 10 pack-years at Visit 0.
Patients must be able to use the Respimat inhaler correctly.
Patients must be able to perform all trial related procedures including technically acceptable pulmonary function tests and use of the AM3 (e-diary) compliance of at least 80% is required.
Patients taking a chronic pulmonary medication allowed by the study protocol must be willing to continue this therapy for the entire duration of the study (exception: times of acute disease deterioration).

Exclusion criteria:

Patients with a significant disease other than asthma. 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 trial, or (ii) influence the results of the trial, or (iii) cause concern regarding the patient's ability to participate in the trial.
Patients with a clinically relevant abnormal screening hematology or blood chemistry at Visit 1 if the abnormality defines a significant disease as defined in exclusion criterion no. 1.
Patients requiring more than 12 puffs of rescue medication (salbutamol MDI) per 24 hours for more than 2 consecutive days between Visit 1 and Visit 2 (screening period).
Patients with a recent history (ie six months or less) of Acute Coronary Syndrome (STEMI, non-STEMI, Unstable Angina Pectoris) prior to Visit 1 (screening).
Patients who have been hospitalised for cardiac failure during the past year prior to Visit 1 (screening).
Patients with any unstable or life-threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year prior to Visit 1 (screening).
Patients with lung diseases other than asthma (eg COPD).
Patients with known active tuberculosis.
Patients with malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years prior to Visit 1 (screening). Patients with treated basal cell carcinoma are allowed.
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.
Patients with significant alcohol or drug abuse on Investigator's assessment within the past two years prior to Visit 1 (screening).
Patients who are currently in a pulmonary rehabilitation program or have completed a pulmonary rehabilitation program in the 6 weeks prior to Visit 1 (screening).
Patients with known hypersensitivity to anticholinergic drugs, BAC, EDTA or any other components of the study medication delivery systems.
Pregnant or nursing women, including female patients with positive ß-HCG test at Visit 1.
Female patients of child-bearing potential not using highly effective method of birth control. As defined in ICH (M3) [R09-1400], note 3, highly effective methods of birth control are defined as those, alone or in combination, that result in a low failure rate (ie less than 1% per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence or vasectomised partner. Barrier contraceptives (eg male condom or diaphragm) are acceptable if used in combination with spermicides (eg foam, gel).

Female patients will be considered to be of childbearing potential unless surgically sterilised by hysterectomy or bilateral tubal ligation/salpingectomy, or post-menopausal for at least two years.
Patients who have been treated with restricted medication prior to Visit 1 and/or during the screening period.
Patients with any asthma exacerbation or any respiratory tract infection in the four weeks prior to Visit 1 or during the screening period.

Visit 1 and/or Visit 2 should be postponed in case of an asthma exacerbation or respiratory tract infection. Refer to Section 6.1 for information on re-scheduling of visits.
Patients who are currently participating in another trial or who have been participating in another trial within one month prior to Visit 0, and patients who have previously been randomised in this trial.

Name	Affiliation	Role
Boehringer Ingelheim	Boehringer Ingelheim	Study Chair

Facility	Status	City	State	ZIP	Country	Contacts
205.441.43004 Boehringer Ingelheim Investigational Site		Grieskirchen			Austria
205.441.43003 Boehringer Ingelheim Investigational Site

ID	Title	Description
FG000	Tio R2.5 Twice Daily (BID) / Tio R5 Once Daily (QD)	Subjects were randomised to receive treatment with 2.5 μg tiotropium inhalation solution twice daily (i.e. in the morning and in the evening) and 5 μg tiotropium inhalation solution once daily in the evening via Respimat inhaler in a crossover manner using a predefined randomisation sequence. Treatment 1: Tio 2.5 µg BID (twice daily):Oral inhalation via the( Tiotropium-Respimat) inhaler of 2.5 µg twice daily i.e 2 actuations of 1.25 µg tiotropium in the morning and in the evening (total daily dose of 5 μg) Treatment 2: Tio 5 µg QD (once daily):Oral inhalation via the( Tiotropium-Respimat) inhaler of 5 µg once daily i.e 2 actuations of 2.5 µg tiotropium in the evening and 2 actuations of placebo in the morning (total daily dose of 5 μg)

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Forced Expiratory Volume in One Second (FEV1) Area Under the Curve From 0 - 24h (AUC 0-24) Response.

Mixed Model Repeated Measure (MMRM) results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. AUC0-24h calculated using the trapezoidal rule divided by the observation time (24 hours) to report in litres.

The values recorded at 11 hours 50 minutes and at 23 hours 50 minutes post dosing were assigned to 12 and 24 hours, respectively.

Full Analysis Set (FAS): The full analysis set (FAS) includes all patients in the treated set who had baseline data and at least one on-treatment efficacy value after 4 weeks on treatment within a period.

Posted

Least Squares Mean

Standard Error

Liters

Baseline FEV1 taken at visit 2 prior to the first evening dose of randomised study medication. Then, 10 minutes (min) prior to dose to 30 min,1 hour (h),2h,3h,4h,11h50min,12h30min,13h,14h,15h,16h,18h,20h,22h and 23h,23h50min relative to dose after 4 weeks

ID	Title	Description
OG000	Tio R2.5 BID	Tiotropium 2.5 mcg BID morning and evening delivered by the Respimat inhaler, on top of maintenance therapy with inhaled corticosteroid (iCS).
OG001	Tio R5 QD	Tiotropium 5 mcg QD in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top of maintenance therapy with iCS.

Units	Counts
Participants	OG00098 OG00197

Title

Denominators

Categories

Title	Measurements
	OG0000.219± 0.031 OG0010.217± 0.031

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	No p-values are presented as no formal statistical hypothesis was tested.	Mixed Models Analysis	MMRM, adjusted for treatment, period, patient and study baseline			Mean Difference (Final Values)	-0.002	Standard Error of the Mean	0.018		95	-0.038	0.034			Tio R5 QD - Tio R2.5 BID	No	Superiority or Other

Secondary

FEV1 AUC0-12h Response

MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. AUC0-12h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres.

Posted

Least Squares Mean

Standard Error

Litres

Baseline FEV1 taken at visit 2 prior to the first evening dose of randomised study medication. Then, 10 minutes(min) prior to dose to 30min,1hour(h),2h,3h,4h,11h50min,12h30min,13h,14h,15h,16h,18h,20h,22h and 23h,23h50min relative to dose after 4 weeks

ID	Title	Description
OG000	Tio R2.5 BID	Tiotropium 2.5 mcg BID morning and evening delivered by the Respimat inhaler, on top of maintenance therapy with iCS.
OG001	Tio R5 QD	Tiotropium 5 mcg QD in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top of maintenance therapy with iCS.

Secondary

FEV1 AUC12-24h Response

MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. AUC12 -24h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres.

Posted

Least Squares Mean

Standard Error

Litres

Baseline FEV1 taken at visit 2 prior to the first evening dose of randomised study medication. Then, 10 minutes(min) prior to dose to 30min,1hour(h),2h,3h,4h,11h50min,12h30min,13h,14h,15h,16h,18h,20h,22h and 23h,23h50min relative to dose after 4 weeks

ID	Title	Description
OG000	Tio R2.5 BID	Tiotropium 2.5 mcg BID morning and evening delivered by the Respimat inhaler, on top of maintenance therapy with iCS.
OG001	Tio R5 QD	Tiotropium 5 mcg QD in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top of maintenance therapy with iCS.

Secondary

Peak FEV1 Response.

MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. Peak FEV1 was defined as the highest FEV1 reading observed within the 24 hour period following inhalation of the last evening dose of study medication (FEV1 Peak0-24h). The values recorded at 11 hours 50 minutes and at 23 hours 50 minutes post dosing were assigned to 12 and 24 hours, respectively.

Posted

Least Squares Mean

Standard Error

Litres

10 minutes (min) prior to dose to 30 min,1 hour (h),2h,3h,4h,11h50min,12h30min,13h,14h,15h,16h,18h,20h,22h and 23h,23h50min relative to dose after 4 weeks.

ID	Title	Description
OG000	Tio R2.5 BID	Tiotropium 2.5 mcg BID morning and evening delivered by the Respimat inhaler, on top of maintenance therapy with iCS.
OG001	Tio R5 QD	Tiotropium 5 mcg QD in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top of maintenance therapy with iCS.

Secondary

Trough FEV1 (L) Response.

Posted

Least Squares Mean

Standard Error

Litres

10 minutes (min) prior to dose after 4 weeks

ID	Title	Description
OG000	Tio R2.5 BID	Tiotropium 2.5 mcg BID morning and evening delivered by the Respimat inhaler, on top of maintenance therapy with iCS.
OG001	Tio R5 QD	Tiotropium 5 mcg QD in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top of maintenance therapy with iCS.

Units	Counts
Participants

Secondary

Forced Vital Capacity (FVC) AUC0-24h Response

The values recorded at 11 hours 50 minutes and at 23 hours 50 minutes post dosing were assigned to 12 and 24 hours, respectively.

Posted

Least Squares Mean

Standard Error

Litres

Baseline taken at visit 2 prior to the first evening dose of randomised study medication. Then, 10 minutes(min) prior to dose to 30min,1hour(h),2h,3h,4h,11h50min,12h30min,13h,14h,15h,16h,18h,20h,22h and 23h,23h50min relative to dose after 4 weeks

ID	Title	Description
OG000	Tio R2.5 BID	Tiotropium 2.5 mcg BID morning and evening delivered by the Respimat inhaler, on top of maintenance therapy with iCS.
OG001	Tio R5 QD	Tiotropium 5 mcg QD in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top of maintenance therapy with iCS.

Secondary

FVC AUC0-12h Response

MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. AUC0-12h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres.

Posted

Least Squares Mean

Standard Error

Litres

ID	Title	Description
OG000	Tio R2.5 BID	Tiotropium 2.5 mcg BID morning and evening delivered by the Respimat inhaler, on top of maintenance therapy with iCS.
OG001	Tio R5 QD	Tiotropium 5 mcg QD in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top of maintenance therapy with iCS.

Secondary

FVC AUC12-24h Response

MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. AUC12 -24h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres.

Posted

Least Squares Mean

Standard Error

Litres

ID	Title	Description
OG000	Tio R2.5 BID	Tiotropium 2.5 mcg BID morning and evening delivered by the Respimat inhaler, on top of maintenance therapy with iCS.
OG001	Tio R5 QD	Tiotropium 5 mcg QD in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top of maintenance therapy with iCS.

Secondary

Peak FVC Response

MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. Peak FVC was defined as the highest FVC reading observed within the 24 hour period following inhalation of the last evening dose of study medication (FVC Peak0-24h).

Posted

Least Squares Mean

Standard Error

Litres

ID	Title	Description
OG000	Tio R2.5 BID	Tiotropium 2.5 mcg BID morning and evening delivered by the Respimat inhaler, on top of maintenance therapy with iCS.
OG001	Tio R5 QD	Tiotropium 5 mcg QD in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top of maintenance therapy with iCS.

Secondary

Trough FVC Responses

Posted

Least Squares Mean

Standard Error

Litres

Baseline taken at visit 2 prior to the first evening dose of randomised study medication. Then, 10 minutes(min) prior to dose after 4 weeks

ID	Title	Description
OG000	Tio R2.5 BID	Tiotropium 2.5 mcg BID morning and evening delivered by the Respimat inhaler, on top of maintenance therapy with iCS.
OG001	Tio R5 QD	Tiotropium 5 mcg QD in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top of maintenance therapy with iCS.

Units	Counts
Participants

Secondary

Peak Expiratory Flow (PEF) AUC0-24h Response

MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. AUC0-24h calculated using the trapezoidal rule divided by the observation time (24 hours) to report in litres per minute.

Posted

Least Squares Mean

Standard Error

Litres/min

ID	Title	Description
OG000	Tio R2.5 BID	Tiotropium 2.5 mcg BID morning and evening delivered by the Respimat inhaler, on top of maintenance therapy with iCS.
OG001	Tio R5 QD	Tiotropium 5 mcg QD in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top of maintenance therapy with iCS.

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Tio R2.5 Bid	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top of maintenance therapy with iCS.			1	98	0	98
EG001	Tio R5 qd	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top of maintenance therapy with iCS.			0	98	0	98

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Cervix carcinoma stage 0	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MEDDRA 16.0	Systematic Assessment		EG0001 affected98 at risk EG0010 affected98 at risk
Cervical dysplasia	Reproductive system and breast disorders	MEDDRA 16.0	Systematic Assessment		EG0001 affected98 at risk EG0010 affected98 at risk

ID	Term
D001982	Bronchial Diseases
D012140	Respiratory Tract Diseases
D008173	Lung Diseases, Obstructive
D008171	Lung Diseases
D012130	Respiratory Hypersensitivity
D006969	Hypersensitivity, Immediate
D006967	Hypersensitivity
D007154	Immune System Diseases

ID	Term
D000069447	Tiotropium Bromide
C494814	BID protein, human

ID	Term
D012602	Scopolamine Derivatives
D014326	Tropanes
D053961	Azabicyclo Compounds
D001372	Aza Compounds
D009930	Organic Chemicals
D000470	Alkaloids
D006571	Heterocyclic Compounds
D019086	Bridged Bicyclo Compounds, Heterocyclic
D006572	Heterocyclic Compounds, Bridged-Ring