A Study to Evaluate Efficacy and Safety of Tiotropium in... | NCT01383499

NCT01383499

ID	Type	Description	Link
2010-022458-18	EudraCT Number

Status Module

Sponsor/Collaborators Module

Name	Class
Pfizer	INDUSTRY

Oversight Module

No data available

No data is available for this block.

Description Module

Conditions Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Treatment A	Experimental	patients inhale 2 puffs (low dose) once daily in the evening via Respimat inhaler	Drug: Tiotropium bromide
Treatment B	Experimental	patients inhale 2 puffs (medium dose) once daily in the evening via Respimat inhaler	Drug: Tiotropium bromide
Treatment C	Experimental	patients inhale 2 puffs (high dose) once daily in the evening via Respimat inhaler	Drug: Tiotropium bromide
Treatment D	Placebo Comparator	patients inhale 2 puffs of placebo inhalation solution matching tiotropium once daily in the evening via Respimat inhaler	Drug: Tiotropium bromide

Name	Type	Description	Arm Group Labels	Other Names
Tiotropium bromide	Drug	inhalation solution administered via Respimat in 3 different doses	Treatment D

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Forced Expiratory Volume (FEV1) Peak (0-3h) Response	The FEV1 peak (0-3h) response is determined at the end of the 4 week treatment period. This is the difference between the maximum FEV1 measured within the first 3 hours post dosing and the FEV1 baseline measurement. Analysis adjusted for treatment, period, patient and baseline using a mixed model.	Baseline and 4 weeks

Secondary Outcomes

Measure	Description	Time Frame
Trough FEV1 Response	The trough FEV1 is defined as the pre-dose FEV1 measured just prior to the last administration of randomised treatment. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.	Baseline and 4 weeks
Forced Vital Capacity (FVC) Peak (0-3h) Response

Eligibility Module

Eligibility Criteria

Inclusion criteria:

Patients must meet all of the following inclusion criteria to be eligible for enrollment into this study:

All patients' parents (or legally accepted caregivers) must sign and date an informed consent prior to any study procedures including medication washout and restrictions. In addition, an informed assent suitable for this age group has to be obtained from patients.
Male or female patients between 6 and 11 years of age (up to 1 day prior to their 12th birthday at Visit 1).
All patients must have at least a 6-month history of asthma at the time of enrolment into the trial.
All patients must have been on maintenance treatment with inhaled corticosteroids at a stable medium dose - a patient is eligible on =200 µg to =400 µg Budesonide DPI or equivalent.
All patients must be symptomatic (partly controlled) at Visit 1 (screening) and prior to randomisation at Visit 2 as defined by an ACQ mean score of =1.5.
All patients must have a pre-bronchodilator FEV1 =60% and =90% of predicted normal at Visit 1. Variation of absolute FEV1 values of Visit 2 (pre-dose) as compared to values at Visit 2 (pre-bronchodilator) must be within ± 30%.
All patients must demonstrate an increase in FEV1 of =12% 15 to 30 min. after 200 µg salbutamol (albuterol) at Visit 1.
Patients must be able to inhale from the Respimat® inhaler correctly.
Patients must be able to perform all trial related procedures including technically acceptable spirometric manoeuvres according to current ATS/ERS standards and the use of the electronic diary/peak flow meter.

Exclusion criteria:

Patients with any of the following characteristics will not be eligible for entry into this study:

Patients with a significant disease other than asthma.
Patients with clinically relevant abnormal screening haematology or blood chemistry will be excluded if the abnormality defines a significant disease as defined in exclusion criterion 1. For participation in PK sampling, a haemoglobin of less than 11.3 g/dL will be regarded as exclusion criterion.
Patients with a history of congenital or acquired heart disease, or patients who have been hospitalised for cardiac syncope or failure during the past year.
Patients with any unstable or life-threatening cardiac arrhythmia, including cardiac arrhythmia requiring intervention (e.g. pacemaker implantation, catheter ablation etc.) or a change in drug therapy within the past year.
Patients with a malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years.
Patients with clinically significant lung diseases other than asthma, such as CF, or bronchopulmonary dysplasia.
Patients with known active tuberculosis.
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 who are currently in a pulmonary rehabilitation program or have completed a pulmonary rehabilitation program in the 6 weeks prior to the screening visit (Visit 1).
Patients with known hypersensitivity to anticholinergic drugs, BAC, EDTA or any other components of the tiotropium inhalation solution.
Patients with known narrow-angle glaucoma, or any other disease where anticholinergic treatment is contraindicated.
Patients with moderate to severe renal impairment, as defined by a creatinine clearance <50 mL/min./1.73 m2 BSA, as tiotropium is a predominantly renally excreted drug.

Contacts/Locations Module

Name	Affiliation	Role
Boehringer Ingelheim	Boehringer Ingelheim	Study Chair

Facility	Status	City	State	ZIP	Country	Contacts
205.425.49005 Boehringer Ingelheim Investigational Site		Bochum			Germany
205.425.49004 Boehringer Ingelheim Investigational Site

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
25851298	Derived	Vogelberg C, Moroni-Zentgraf P, Leonaviciute-Klimantaviciene M, Sigmund R, Hamelmann E, Engel M, Szefler S. A randomised dose-ranging study of tiotropium Respimat(R) in children with symptomatic asthma despite inhaled corticosteroids. Respir Res. 2015 Feb 7;16(1):20. doi: 10.1186/s12931-015-0175-9.

IPD Sharing Statement Module

No data available

No data is available for this block.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Tio R5/Placebo/Tio R1.25	Patients treated with Tiotropium 5 mcg in Period 1, with Placebo in Period 2 and with Tiotropium 1.25 mcg in Period 3. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off treatment periods) between treatments.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Annotation Section

No data available

No data is available for this block.

Document Section

No data available

No data is available for this block.

Derived Section

Miscellaneous Info Module

Submission Tracking

No data available

No data is available for this block.

Condition Browse Module

Intervention Browse Module

Masking Info

Total number of patients randomised and treated at all in the study.

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	BG0008.8± 1.7

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG00032
Male	BG00069

Forced expiratory volume in 1s (FEV1)

Mean

Standard Deviation

Litre

Title

Denominators

Categories

Title	Measurements
	BG0001.640± 0.386

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 (FEV1) Peak (0-3h) Response

The FEV1 peak (0-3h) response is determined at the end of the 4 week treatment period. This is the difference between the maximum FEV1 measured within the first 3 hours post dosing and the FEV1 baseline measurement. Analysis adjusted for treatment, period, patient and baseline using a mixed model.

The Full analysis set (FAS) is defined as patients randomised, treated, with baseline data and at least one on-treatment efficacy measurement after 4 weeks on treatment within a period.

Posted

Least Squares Mean

Standard Error

Litre

Baseline and 4 weeks

ID	Title	Description
OG000	Placebo	Placebo once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
OG001	Tio R1.25	Tiotropium 1.25 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
OG002	Tio R2.5	Tiotropium 2.5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
OG003	Tio R5	Tiotropium 5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.

Units	Counts
Participants	OG00076 OG00175 OG00274 OG003

Title

Denominators

Categories

Title	Measurements
	OG0000.185± 0.025 OG0010.261± 0.026 OG0020.290± 0.026 OG003

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 OG003	Tio R5 minus Placebo	Mixed model repeated measures (MMRM)	This MMRM model includes treatment, period and baseline as fixed effects, and patient as random effect.	0.0002	First step of closed testing procedure, where the active treatments are compared to placebo. If this statistical test significant at the 0.05 alpha level then proceed to comparison of the next lower dose to placebo.	Mean Difference (Final Values)	0.087	Standard Error of the Mean	0.023	2-Sided	95	0.042	0.132				No	Superiority or Other

Secondary

Trough FEV1 Response

The trough FEV1 is defined as the pre-dose FEV1 measured just prior to the last administration of randomised treatment. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.

FAS with at least one on-treatment value.

Posted

Least Squares Mean

Standard Error

Litre

Baseline and 4 weeks

ID	Title	Description
OG000	Placebo	Placebo once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
OG001	Tio R1.25	Tiotropium 1.25 mcg once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
OG002	Tio R2.5	Tiotropium 2.5 mcg once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
OG003	Tio R5

Secondary

Forced Vital Capacity (FVC) Peak (0-3h) Response

The FVC peak (0-3h) response is determined at the end of the 4 week treatment period. This is the difference between the maximum FVC measured within the first 3 hours post dosing and the FVC baseline measurement. Analysis adjusted for treatment, period, patient and baseline using a mixed model.

FAS with at least one on-treatment value.

Posted

Least Squares Mean

Standard Error

Litre

Baseline and 4 weeks

ID	Title	Description
OG000	Placebo	Placebo once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
OG001	Tio R1.25	Tiotropium 1.25 mcg once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
OG002	Tio R2.5	Tiotropium 2.5 mcg once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
OG003	Tio R5

Secondary

FVC Trough Response

The trough FVC response is defined as the pre-dose FVC measured just prior to the last administration of randomised treatment. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.

FAS with at least one on-treatment value.

Posted

Least Squares Mean

Standard Error

Litre

Baseline and 4 weeks

ID	Title	Description
OG000	Placebo	Placebo once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
OG001	Tio R1.25	Tiotropium 1.25 mcg once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
OG002	Tio R2.5	Tiotropium 2.5 mcg once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
OG003	Tio R5

Secondary

FEV1 Area Under the Curve From 0 to 3 h (AUC0-3h) Response

FEV1 (AUC0-3h) will be calculated as the area under the curve from 0 to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.

FAS with at least one on-treatment value.

Posted

Least Squares Mean

Standard Error

Litre

Baseline and 4 weeks

ID	Title	Description
OG000	Placebo	Placebo once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
OG001	Tio R1.25	Tiotropium 1.25 mcg once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
OG002	Tio R2.5	Tiotropium 2.5 mcg once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
OG003

Secondary

FVC Area Under the Curve From 0 to 3 h (AUC0-3h) Response

FVC (AUC0-3h) will be calculated as the area under the curve from 0 to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.

FAS with at least one on-treatment value.

Posted

Least Squares Mean

Standard Error

Litre

Baseline and 4 weeks

ID	Title	Description
OG000	Placebo	Placebo once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
OG001	Tio R1.25	Tiotropium 1.25 mcg once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
OG002	Tio R2.5	Tiotropium 2.5 mcg once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
OG003

Secondary

Mean Morning Peak Expiratory Flow (PEF) Response

Mean morning PEF assessed by patients at home. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.

FAS with at least one on-treatment value. For outcome measures obtained by AM3 device one patient in the "TioR2.5" group had no on-treatment data.

Posted

Least Squares Mean

Standard Error

Litre/min

Baseline and 4 weeks

ID	Title	Description
OG000	Placebo	Placebo once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
OG001	Tio R1.25	Tiotropium 1.25 mcg once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
OG002	Tio R2.5	Tiotropium 2.5 mcg once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
OG003	Tio R5

Secondary

Mean Evening PEF Response

Mean Evening PEF assessed by patients at home. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.

FAS with at least one on-treatment value. For outcome measures obtained by AM3 device one patient in the "TioR2.5" group had no on-treatment data.

Posted

Least Squares Mean

Standard Error

Litre/min

Baseline and 4 weeks

ID	Title	Description
OG000	Placebo	Placebo once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
OG001	Tio R1.25	Tiotropium 1.25 mcg once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
OG002	Tio R2.5	Tiotropium 2.5 mcg once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
OG003	Tio R5

Secondary

Change From Baseline in the Number of Puffs of Rescue Medication Per Period (24 h, Daytime and Night-time Use)

Mean number of inhalations (puffs) of unscheduled rescue salbutamol therapy during whole day (24 h, daytime and night-time use). Analysis adjusted for treatment, period, patient and baseline using a mixed model.

FAS with at least one on-treatment value. For outcome measures obtained by AM3 device one patient in the "TioR2.5" group had no on-treatment data.

Posted

Least Squares Mean

Standard Error

Puffs

Baseline and 4 weeks

ID	Title	Description
OG000	Placebo	Placebo once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
OG001	Tio R1.25	Tiotropium 1.25 mcg once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
OG002	Tio R2.5	Tiotropium 2.5 mcg once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.

Secondary

Control of Asthma as Assessed by Asthma Control Questionnaire (ACQ)

ACQ is a questionnaire consisting of seven point Likert scale ranging from 0 to 6, whereby 0 represents good control and 6 represents poor control of asthma. The scale describes the frequency and severity of asthma symptoms. Analysis adjusted for treatment, period, patient and baseline using a mixed model.

FAS with at least one on-treatment value.

Posted

Least Squares Mean

Standard Error

Score

4 weeks

ID	Title	Description
OG000	Placebo	Placebo once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
OG001	Tio R1.25	Tiotropium 1.25 mcg once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
OG002	Tio R2.5	Tiotropium 2.5 mcg once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
OG003

Secondary

Change From Baseline in Mean Number of Nighttime Awakenings

Mean number of nighttime awakenings due to asthma symptoms as assessed by patients eDiary incorporated in the AM3® device. Analysis adjusted for treatment, period, patient and baseline using a mixed model. The scores for this question used the following scale where: 1='Did not wake up', 2='Woke up once', 3='Woke up 2-5 times', 4='Woke up more than 5 times' and 5='Was awake all night'.

FAS with at least one on-treatment value. For outcome measures obtained by AM3 device one patient in the "TioR2.5" group had no on-treatment data.

Posted

Least Squares Mean

Standard Error

scores on a scale

Baseline and last week of treatment (week 4)

ID	Title	Description
OG000	Placebo	Placebo once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
OG001	Tio R1.25	Tiotropium 1.25 mcg once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
OG002	Tio R2.5	Tiotropium 2.5 mcg once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.

Arm/Groups

ID	Title	Description	Serious Events (At Risk)	Other Events (At Risk)
EG000	Placebo	Placebo once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	76	76
EG001	Tio R1.25	Tiotropium 1.25 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	75	75
EG002	Tio R2.5	Tiotropium 2.5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	74	74
EG003	Tio R5	Tiotropium 5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	76	76

ID	Term
D001249	Asthma

Ancestor Terms

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

Ancestor Terms

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

Tiotropium 5 mcg once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.