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TerminatedNCT03199976Updated Sep 19, 2024Results posted

Efficacy of Intermittent Tiotropium in Early Childhood Wheezing

A Phase 4 interventional study of Tiotropium Bromide and Fluticasone Propionate in Wheezy Bronchitis, Asthmatic Bronchitis and Wheezing, sponsored by Helsinki University Central Hospital. Terminated at 1 site in Finland. Open to participants aged 6 Months to 35 Months. Per ClinicalTrials.gov, last updated 2024-09-19.

Sponsored by Helsinki University Central Hospital · Phase 4, Interventional, and Treatment

Why this study was terminated
Subjects in the Salbutamol group discontinued the intervention more often due to troublesome respiratory symptoms
Phase
Phase 4
Study type
Interventional
Enrollment
80
Allocation
Randomized
Ages
6 Months to 35 Months
Sex
All
01

Study summary

This study evaluates the effect of intermittent tiotropium bromide and salbutamol as needed versus intermittent fluticasone propionate and salbutamol as needed, or solely, salbutamol as needed on episode-free days in infants and toddlers with recurrent episodes of wheeze and/or shortness of breath.

Read the detailed description

Up to 30% of all children suffer from episodic wheeze or shortness of breath, i.e. asthmatic bronchitis, during the first three years of life. The condition is usually induced by viral respiratory infections, and short-acting beta-agonists are recommended as a monotherapy for symptoms unless there are at least four physician-confirmed episodes of wheeze or shortness of breath, or three episodes plus asthma risk factors. There is a current need for new therapeutic agents to treat asthmatic bronchitis in young children.

In viral-induced wheeze, increased parasympathetic nerve activity results in increased acetylcholine release from nerve endings. Tiotropium bromide, an inhaled anticholinergic agent, prevents the acetylcholine function and achieves mild bronchodilatation and decrease in mucus secretion from the submucosal glands.

The aim of the study is to find out the effect of intermittent tiotropium bromide and salbutamol as needed versus intermittent fluticasone propionate and salbutamol as needed, or solely, salbutamol as needed on episode-free days in infants and toddlers with recurrent episodes of wheeze and/or shortness of breath. Episode-free days are defined as those days during which there are no symptoms of wheeze and/or shortness of breath, no unscheduled medical visits for wheeze and/or shortness of breath, and no use of rescue or supplementary controller medications.

02

Conditions studied

  • Wheezy Bronchitis
  • Asthmatic Bronchitis
  • Wheezing
  • Obstruction Airway

Keywords

  • wheeze
  • shortness of breath
03

Who can participate

Ages eligible
6 Months to 35 Months
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  1. Children at the age of 6 to 35 months.
  2. Two to four physician-confirmed episodes of wheeze and/or shortness of breath.
  3. Parents/legal representatives with sufficient written and spoken skills in Finnish language.

Exclusion criteria

Exclusion Criteria:

  1. Birth before 36th week of gestation.
  2. Suspected/diagnosed chronic parenchymal lung disease or a structural airway defect, or a history of thoracotomy with pulmonary resection.
  3. A history of congenital or acquired heart disease, including any unstable or life-threatening cardiac arrhythmia.
  4. Constipation with a need of regular medication, or a diagnosed/suspected structural defect in the gastrointestinal tract.
  5. A history of malignancy, or other significant chronic disorder, disease, or defect.
04

Study design

Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
None (open label)
Enrollment
80 participants (actual)

Study arms

  • Experimental
    Tiotropium Bromide & Salbutamol

    Inhaled Tiotropium Bromide 5 µg once a day, beginning at the onset of an upper respiratory tract infection and continuing for 7 to 14 days as needed, and inhaled Salbutamol 0.2 mg 4 to 6 times a day as needed for wheeze and shortness of breath

    Drug: Tiotropium Bromide · Drug: Salbutamol

  • Active comparator
    Fluticasone Propionate & Salbutamol

    Inhaled Fluticasone Propionate 125 µg twice a day, beginning at the onset of an upper respiratory tract infection and continuing for 7 to 14 days as needed, and inhaled Salbutamol 0.2 mg 4 to 6 times a day as needed for wheeze and shortness of breath

    Drug: Fluticasone Propionate · Drug: Salbutamol

  • Active comparator
    Salbutamol

    Inhaled Salbutamol 0.2 mg 4 to 6 times a day as needed for wheeze and shortness of breath

    Drug: Salbutamol

Interventions

  • DrugTiotropium Bromide

    Tiotropium Bromide 2.5 µg/dose inhaled aerosol

    Also known as: Spiriva Respimat

  • DrugFluticasone Propionate

    Fluticasone Propionate 125 µg/dose inhaled aerosol

    Also known as: Flixotide Evohaler

  • DrugSalbutamol

    Salbutamol 0.1 mg/dose inhaled aerosol

    Also known as: Ventoline Evohaler

05

What researchers measure

Primary outcomes

  1. Percentage of Episode-Free Days

    Effect on the episode-free days defined as the days during which there are no symptoms of wheeze and/or shortness of breath, no unscheduled medical visits for wheeze and/or shortness of breath, and no use of rescue or supplementary controller medications.

    Time frame: Up to 48 weeks

Secondary outcomes

  1. Number of Participants With Unscheduled Physician Visits

    Effect on the number of unscheduled physician visits for episodes of wheeze and/or shortness of breath.

    Time frame: Up to 48 weeks

  2. Percentage of Days Participants Needed Rescue Medication

    Effect of the treatment on the need for bronchochilative and/or supplementary controller medication.

    Time frame: Up to 48 weeks

  3. Number of Participants With Adverse Events

    Occurrence of adverse events in treatment groups.

    Time frame: Up to 48 weeks

06

Results

Posted Sep 19, 2024
Limitations and caveats
Early termination leading to small numbers of subjects analyzed.

Participant flow

Participant flow — Overall Study
MilestoneTiotropium Bromide & SalbutamolFluticasone Propionate & SalbutamolSalbutamol
Started272528
Completed231814
Not completed4714
Withdrew: Lack of efficacy3613
Withdrew: Withdrawal by subject100
Withdrew: Lost to follow-up011

Outcome measures

PrimaryPercentage of Episode-Free Days

Effect on the episode-free days defined as the days during which there are no symptoms of wheeze and/or shortness of breath, no unscheduled medical visits for wheeze and/or shortness of breath, and no use of rescue or supplementary controller medications.

Time frame:
Up to 48 weeks
Reported as:
Median · percentage of episode-free days
Percentage of Episode-Free Days
percentage of episode-free daysTiotropium Bromide & SalbutamolFluticasone Propionate & SalbutamolSalbutamol
Percentage of Episode-Free Days97 (93 to 99)87 (78 to 93)88 (79 to 95)
Statistical analysis
  • Tiotropium Bromide & Salbutamol vs Fluticasone Propionate & Salbutamol vs Salbutamol · Wilcoxon (Mann-Whitney) · p = <0.01 (Bonferroni correction was applied in pairwise analyses.)
SecondaryNumber of Participants With Unscheduled Physician Visits

Effect on the number of unscheduled physician visits for episodes of wheeze and/or shortness of breath.

Time frame:
Up to 48 weeks
Reported as:
Count of participants · Participants
Number of Participants With Unscheduled Physician Visits
ParticipantsTiotropium Bromide & SalbutamolFluticasone Propionate & SalbutamolSalbutamol
Number of Participants With Unscheduled Physician Visits101014
Statistical analysis
  • Tiotropium Bromide & Salbutamol vs Fluticasone Propionate & Salbutamol vs Salbutamol · Chi-squared · p = 0.595
SecondaryPercentage of Days Participants Needed Rescue Medication

Effect of the treatment on the need for bronchochilative and/or supplementary controller medication.

Time frame:
Up to 48 weeks
Reported as:
Median · percentage of days
Percentage of Days Participants Needed Rescue Medication
percentage of daysTiotropium Bromide & SalbutamolFluticasone Propionate & SalbutamolSalbutamol
Percentage of Days Participants Needed Rescue Medication2 (0 to 7)13 (6 to 21)12 (6 to 20)
Statistical analysis
  • Tiotropium Bromide & Salbutamol vs Fluticasone Propionate & Salbutamol vs Salbutamol · Wilcoxon (Mann-Whitney) · p = <0.01 (Bonferroni correction was applied in pairwise analyses.)
SecondaryNumber of Participants With Adverse Events

Occurrence of adverse events in treatment groups.

Time frame:
Up to 48 weeks
Reported as:
Count of participants · Participants
Number of Participants With Adverse Events
ParticipantsTiotropium Bromide & SalbutamolFluticasone Propionate & SalbutamolSalbutamol
Number of Participants With Adverse Events232526
Statistical analysis
  • Tiotropium Bromide & Salbutamol vs Fluticasone Propionate & Salbutamol vs Salbutamol · Chi-squared · p = <0.05

Adverse events

Collected over 48 weeks. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Tiotropium Bromide & Salbutamol0/27 (0%)4/27 (14.8%)19/27 (70.4%)
Fluticasone Propionate & Salbutamol0/25 (0%)3/25 (12%)22/25 (88%)
Salbutamol0/28 (0%)3/28 (10.7%)23/28 (82.1%)
Most frequent serious events
Most frequent serious events
EventTiotropium Bromide & SalbutamolFluticasone Propionate & SalbutamolSalbutamol
Wheezy bronchitisInfections and infestations3/271/251/28
Wheezy bronchitis and laryngitisInfections and infestations0/271/250/28
Wheezy bronchitis and anaphylaxis to cashewInfections and infestations0/271/250/28
PneumoniaInfections and infestations1/270/250/28
Wheezy bronchitis and pneumoniaInfections and infestations0/270/251/28
EnteritisInfections and infestations0/270/251/28
Most frequent other events
Most frequent other events
EventTiotropium Bromide & SalbutamolFluticasone Propionate & SalbutamolSalbutamol
Otitis mediaInfections and infestations16/279/2512/28
Upper respiratory tract infectionInfections and infestations13/2713/259/28
Wheezy bronchitisInfections and infestations7/277/2512/28
ConjunctivitisInfections and infestations4/271/257/28
EnteritisInfections and infestations3/273/252/28
Minor traumaInjury, poisoning and procedural complications2/273/252/28
EczemaSkin and subcutaneous tissue disorders1/273/251/28
TonsillitisInfections and infestations1/271/253/28
ExanthemaSkin and subcutaneous tissue disorders1/272/252/28
PharyngitisInfections and infestations2/270/252/28

Baseline characteristics

Age, Continuous
Age, Continuous(months)Tiotropium Bromide & SalbutamolFluticasone Propionate & SalbutamolSalbutamolTotal
Mean21.4 ± 7.020.0 ± 6.822.1 ± 6.021.2 ± 6.6
Sex: Female, Male
Sex: Female, Male(Participants)Tiotropium Bromide & SalbutamolFluticasone Propionate & SalbutamolSalbutamolTotal
Female991028
Male18161852
Race and Ethnicity Not Collected
Race and Ethnicity Not Collected(Participants)Tiotropium Bromide & SalbutamolFluticasone Propionate & SalbutamolSalbutamolTotal
Count of participants———0
Region of Enrollment
Region of Enrollment(Participants)Tiotropium Bromide & SalbutamolFluticasone Propionate & SalbutamolSalbutamolTotal
Finland27252880
07

Study locations

1 site
  • Skin and Allergy Hospital, Helsinki University Hospital, Helsinki, Finland
    Helsinki, FI-00029 HUS, Finland
08

References and documents

Publications

  • Kotaniemi-Syrjanen A, Klemola T, Koponen P, Jauhola O, Aito H, Malmstrom K, Malmberg LP, Rahiala E, Sarna S, Pelkonen AS, Makela MJ. Intermittent Tiotropium Bromide for Episodic Wheezing: A Randomized Trial. Pediatrics. 2022 Sep 1;150(3):e2021055860. doi: 10.1542/peds.2021-055860. PubMed 35942814 ↗

Study documents

  • Protocol and statistical analysis plan · Nov 1, 2018

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No — Deidentified individual participant data will not be made available.

09

Registry details

Key details

Study ID
NCT03199976
Lead sponsor
Helsinki University Central Hospital
Responsible party
Anne Kotaniemi-Syrjänen (MD, PhD, Helsinki University Central Hospital) — Principal investigator
First posted
Jun 27, 2017
Start date
Apr 20, 2016
Primary completion
Nov 18, 2020
Completion
Nov 18, 2020
Results posted
Sep 19, 2024
Last update
Sep 19, 2024

Study contacts

Mika J Mäkelä, Professor
study director · Skin and Allergy Hospital, Helsinki University Hospital, Helsinki, Finland

Oversight

Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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