Bronchial Obstruction, Premature Birth
Conditions
Keywords
Tiotropium, LAMA, Preterm Infants, Spirometry
Brief summary
The purpose of this clinical trial is to evaluate the efficacy and safety of inhaled tiotropium bromide (Spiriva Respimat) in preterm-born children and adolescents suffering from chronic bronchial obstruction. Preterm infants often experience persistent narrowing of the airways, which leads to shortness of breath, chronic respiratory symptoms, and reduced exercise tolerance. Tiotropium is a long-acting muscarinic antagonist (LAMA) that helps dilate the airways and facilitate breathing. While this medication is already approved for pediatric patients aged 6 years and older with severe asthma, its efficacy and safety have not yet been validated in the specific population of preterm infants with bronchial obstruction. This study aims to fill this clinical knowledge gap. This is a non-commercial, monocentric, prospective, randomized, open-label, phase IV study utilizing a 2x2 crossover design. The trial will enroll 50 participants aged 6 to 18 years. Each participant will undergo two distinct 3-month phases: a treatment period with daily inhaled tiotropium (5 µg once daily) and a control observation period without long-term anticholinergic therapy. The sequence of these periods will be randomly assigned to each participant. The primary objective is to demonstrate lung function improvement by evaluating the change in forced expiratory volume in 1 second (FEV1) expressed in liters and Forced Vital Capacity (FVC) expressed in liters between the treatment and control periods. No blood samples or invasive procedures are required for this study.
Detailed description
This clinical trial is designed as an investigator-initiated, academic, phase IV, randomized, open-label, 2x2 crossover study to evaluate the response to inhaled tiotropium bromide in children and adolescents born prematurely who suffer from chronic bronchial obstruction. The study consists of two different sequences: * Sequence A (Treatment first): Participants receive inhaled tiotropium (5 µg once daily via Spiriva Respimat) for 3 months, followed by a 4-week washout period, and subsequently undergo a 3-month control observation period under standard treatment. * Sequence B (Control first): Participants start with a 3-month control observation period under standard treatment, followed immediately (without a washout period) by a 3-month treatment period with daily inhaled tiotropium. Clinical and spirometric assessments (including Forced Expiratory Volume in 1 second in liters - FEV₁, Forced Vital Capacity in liters - FVC, Peak Expiratory Flow in liters per second - PEF, Forced Expiratory Flow between 25% and 75% of FVC in liters per second - FEF₂₅-₇₅ parameters) will be performed at baseline, at the crossover point (end of the first period), and at the end of the study (end of the second period). Participants or their parents will maintain daily diaries to log respiratory symptoms, rescue medication - short-acting beta₂-agonist (SABA) use, and potential acute exacerbations throughout the trial.
Interventions
Inhaled tiotropium bromide administered via Spiriva Respimat inhaler. Dose: 5 µg (2 actuations of 2.5 µg) once daily for a total duration of 12 weeks.
Sponsors
General University Hospital, Prague
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Masking description
The clinical trial is conducted as an open-label study for participants, care providers, and investigators during the daily treatment and observation phases. However, to mitigate potential evaluation bias, the primary outcome parameter (spirometry FEV1 data) will be assessed centrally by a blinded independent expert.
Intervention model description
This is a prospective, randomized, 2x2 crossover study consisting of two treatment sequences. Sequence A involves a 3-month period of inhaled tiotropium treatment, followed by a 4-week washout period, and then a 3-month control observation period. Sequence B involves a 3-month control observation period, followed directly by a 3-month period of inhaled tiotropium treatment without an intermediate washout period.
Eligibility
Sex/Gender
ALL
Age
6 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
* Age between 6 and 18 years. * History of preterm birth (defined as delivery at \< 37 gestational weeks). * Spirometrically proven bronchial obstruction, defined as a z-score of FEV1 and/or \>= 2 other parameters - Forced Vital Capacity (FVC; liters \[L\]), Peak Expiratory Flow (PEF; liters per second \[L/s\]), and Forced Expiratory Flow between 25% and 75% of Forced Vital Capacity (FEF25-75; liters per second \[L/s\]).) below -1.65 SD. * Positive bronchodilatation test, defined as an increase in FEV₁ or FVC of more than 10% of the corresponding GLI-predicted value following administration of ipratropium bromide. Bronchodilator responsiveness will be calculated separately for FEV₁ and FVC as: \[(post-bronchodilator value - pre-bronchodilator value) / predicted value\] × 100. FEV₁ and FVC will be measured in litres (L) after ipratropium administration. * Acceptable spirometry performance in accordance with American Thoracic Society/European Respiratory Society (ATS/ERS) 2019 standards. * No long-term inhalation therapy (such as a long-acting beta₂-agonist (LABA) or a combination of an inhaled corticosteroid and a long-acting beta₂-agonist (ICS/LABA)) within the last month prior to study enrollment.
Exclusion criteria
* Other chronic respiratory diseases (e.g., asthma, cystic fibrosis). * Anatomical abnormalities of the respiratory tract or presence of glaucoma. * Congenital malformations of the uropoetic tract or cardiac arrhythmias/congenital heart defects. * Concomitant use of anticholinergic medications for enuresis nocturna. * Pregnancy (mandatory urine screening required for all female participants aged 13 years and older). * Insufficient cooperation or inability to properly perform spirometry maneuvers.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute change from Baseline in Forced Expiratory Volume in 1 Second (FEV1) expressed in liters (L) | At the end of the 3-month treatment period and at the end of the 3-month control period (specifically at Week 12 and Week 28 for Sequence A, or at Week 12 and Week 24 for Sequence B) | The outcome will be the within-participant difference in forced expiratory volume in 1 second (FEV₁), expressed in litres (L) and Forced Vital Capacity in liters - FVC, between the end of the 3-month tiotropium treatment period and the end of the 3-month control observation period. FEV₁ and FVC will also be expressed as a z-score and percentage of the predicted value calculated using the applicable Global Lung Function Initiative (GLI) reference equations. The treatment effect will be calculated as: FEV₁ after the tiotropium treatment period (L) - FEV₁ after the control observation period (L). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change from Baseline in Secondary Spirometric Parameters (FVC expressed in liters [L], PEF in liters per second [L/s], and MEF25-75 in liters per second [L/s]) | At the end of the 3-month treatment period and at the end of the 3-month control period (specifically at Week 12 and Week 28 for Sequence A, or at Week 12 and Week 24 for Sequence B) | The absolute changes in Forced Vital Capacity (FVC, expressed in liters \[L\]), Peak Expiratory Flow (PEF, expressed in liters per second \[L/s\],), and Forced Expiratory Flow at 25%, 50%, and 75% of FVC (FEF25-75, expressed in liters per second \[L/s\],) evaluated between the end of the 3-month tiotropium treatment period and the end of the 3-month control observation period. |
| Frequency of Acute Respiratory Exacerbations and Rescue Medication Use | Continuously throughout both 3-month periods (treatment and control) and the 4-week washout phase, evaluated over a total span of up to 7 months per participant. | The total number of acute respiratory exacerbations and the frequency of rescue medication (Short-acting Beta-2 Agonist - SABA) usage tracked via daily patient/parent diaries during the 3-month tiotropium treatment period compared to the 3-month control observation period. |
Countries
Czechia
Contacts
CONTACTMartina Racková, Mgr., MBA
CONTACTPavel Michálek, Prof., MUDr.
PRINCIPAL_INVESTIGATORJana Tuková, MUDr., Ph.D.
General University Hospital, Prague
Outcome results
None listed