Efficacy and Safety of Increasing Doses of Inhaled Albuterol in Children With Acute Wheezing Episodes

This study has been completed.
Sponsor:
Collaborator:
Fundação de Amparo à Pesquisa do Estado de São Paulo
Information provided by (Responsible Party):
Luiz Vicente Ribeiro Ferreira da Silva Filho, University of Sao Paulo
ClinicalTrials.gov Identifier:
NCT01323010
First received: March 24, 2011
Last updated: February 15, 2016
Last verified: February 2016
  Purpose
Metered dose inhalers with spacers are devices capable of providing higher rates of lung deposition of drugs such as beta agonists when compared to conventional nebulizers, but there is no consensus about the optimal dose when this is the device of choice and there is evidence that younger children need proportionally higher doses of albuterol (in μg/kg) when compared to older children. Other factors that may interfere with response to albuterol treatment include the genetics of the beta adrenergic receptor (ADRβ2) and infectious etiology of the wheezing attack. This study will assess the effectiveness of a dose regimen that prioritizes higher doses of albuterol, with doses in μg/kg higher for younger children. Security of this new dosing regimen will be assessed by monitoring clinical side effects and serum levels of albuterol, but the investigators will also examine the presence of 12 different respiratory viruses in these patients and evaluate the influence of ADRβ2 receptor genetics in the response to albuterol. The primary outcome measure will be the need for hospitalization. Secondary outcomes will include a change in clinical score, respiratory rate and forced expiratory volume in the first second, the need for additional treatments and length of stay in the emergency room for those not hospitalized.

Condition Intervention
Asthma
Children
Drug: Albuterol - Experimental
Drug: Albuterol - Control

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Efficacy and Safety of Increasing Doses of Inhaled Albuterol Administered by Metered Dose Inhalers in Children With Acute Wheezing Episodes

Resource links provided by NLM:


Further study details as provided by University of Sao Paulo:

Primary Outcome Measures:
  • Hospital Admission [ Time Frame: Starting at 4 hours post-treatment ] [ Designated as safety issue: No ]
    Hospital admission was defined as the need to stay in the emergency room for more than 4 hours, due to the failure to meet the discharge criteria (PRAM score ≤ 3 and pulse oximetry, ≥ 92%)


Secondary Outcome Measures:
  • Forced Expiratory Volume in the First Second [ Time Frame: One hour post-treatment in comparison with baseline ] [ Designated as safety issue: No ]
    Change in FEV1 one hour post-treatment in comparison with baseline. Spirometry was performed only in subjects older than 6 years and who could perform the maneuver properly.

  • Change in PRAM Score After One Hour [ Time Frame: One hour post-treatment ] [ Designated as safety issue: No ]

    Change in the Pediatric Respiratory Assessment Measure (PRAM) score one hour post-treatment in comparison with baseline.

    The PRAM score is used to assess the severity of asthma attacks, it ranges from 0 to 15, and the higher the score, the greater the severity of the attack.

    We calculated the difference between the PRAM score measured one hour post treatment and the PRAM score at baseline (PRAM score 1 hour - PRAM score baseline).

    The larger the absolute value of the difference, the better the outcome (e.g., a difference of -4 indicates a better outcome that a difference of -2).

    minimum value of the difference (Albuterol - Higher Dose, experimental group): -8 maximum value of the difference (Albuterol - Higher Dose, experimental group): 0

    minimum value of the difference (Albuterol - Lower Dose, control group): -8 maximum value of the difference (Albuterol - Lower Dose, control group): 0


  • Albuterol Determination in the Plasma [ Time Frame: at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment) ] [ Designated as safety issue: Yes ]
    Albuterol determination in the plasma was carried out at at discharge or hospital admission (up to 4 hours post treatment), dosage was accomplished by High Performance Liquid Chromatography.

  • Changes in Glucose Serum Levels [ Time Frame: at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment) in comparison with baseline. ] [ Designated as safety issue: Yes ]
    Changes in glucose serum levels at discharge or hospital admission (up to 4 hours post treatment) in comparison with baseline.

  • Electrocardiogram at Baseline [ Time Frame: at baseline ] [ Designated as safety issue: Yes ]
    Electrocardiogram performed at baseline

  • Changes in Respiratory Rate After One Hour [ Time Frame: One hour post-treatment in comparison with baseline ] [ Designated as safety issue: No ]
    Change in respiratory rate one hour post-treatment in comparison with baseline.

  • Need for Additional Therapies [ Time Frame: at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment) ] [ Designated as safety issue: No ]
    The need for additional therapies such as magnesium sulphate or intravenous albuterol were recorded

  • Changes in PRAM Score at Discharge or Hospital Admission [ Time Frame: at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment) in comparison with baseline. ] [ Designated as safety issue: No ]

    Change in the Pediatric Respiratory Assessment Measure (PRAM) score at discharge or hospital admission (up to 4 hours post treatment) in comparison with baseline.

    The PRAM score is used to assess the severity of asthma attacks, it ranges from 0 to 15, and the higher the score, the greater the severity of the attack.

    We calculated the difference between the PRAM score measured at discharge or admission and the PRAM score at baseline (PRAM score discharge or admission - PRAM score baseline).

    The larger the absolute value of the difference, the better the outcome (e.g., a difference of -4 indicates a better outcome that a difference of -2).

    minimum value of the difference (Albuterol - Higher Dose, experimental group): -9 maximum value of the difference (Albuterol - Higher Dose, experimental group): 0

    minimum value of the difference (Albuterol - Lower Dose, control group): -9 maximum value of the difference (Albuterol - Lower Dose, control group): 1


  • Changes in Potassium Serum Levels [ Time Frame: at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment) in comparison with baseline. ] [ Designated as safety issue: Yes ]
    Changes in potassium serum levels at discharge or hospital admission (up to 4 hours post treatment) in comparison with baseline.

  • Changes in Bicarbonate Serum Levels [ Time Frame: at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment) in comparison with baseline. ] [ Designated as safety issue: Yes ]
    Changes in bicarbonate serum levels at discharge or hospital admission (up to 4 hours post treatment) in comparison with baseline.

  • Changes in Respiratory Rate at at Discharge or Hospital Admission. [ Time Frame: at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment) in comparison with baseline. ] [ Designated as safety issue: No ]
    Changes in respiratory rate at discharge or hospital admission (up to 4 hours post treatment) in comparison with baseline.

  • Change in Pulse Oximetry One Hour Post-treatment [ Time Frame: One hour post-treatment in comparison with baseline ] [ Designated as safety issue: No ]
    Change in pulse oximetry one hour post-treatment in comparison with baseline

  • Changes in Pulse Oximetry at Discharge or Hospital Admission. [ Time Frame: at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment) in comparison with baseline. ] [ Designated as safety issue: No ]
    Changes in pulse oximetry at discharge or hospital admission (up to 4 hours post treatment) in comparison with baseline.

  • Changes in Heart Rate After One Hour [ Time Frame: One hour post-treatment in comparison with baseline ] [ Designated as safety issue: Yes ]
    Change in heart rate one hour post-treatment in comparison with baseline.

  • Changes in Heart Rate at Discharge or Hospital Admission [ Time Frame: at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment) ] [ Designated as safety issue: Yes ]
    Changes in heart rate at discharge or hospital admission (up to 4 hours post treatment) in comparison with baseline.

  • Electrocardiogram One Hour Post-treatment. [ Time Frame: One hour post-treatment ] [ Designated as safety issue: Yes ]
    Electrocardiogram one hour post-treatment to identify possible rhythm disturbances.

  • Electrocardiogram at Discharge or Hospital Admission [ Time Frame: at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment) ] [ Designated as safety issue: Yes ]
    Electrocardiogram at discharge or hospital admission to identify possible rhythm disturbances.

  • Lengths of Stay in the Emergency Room [ Time Frame: one to four hours ] [ Designated as safety issue: No ]
    lengths of stay in the emergency room for discharged patients

  • Admission Rates in Patients With and Without Any Virus Detected [ Time Frame: at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment) ] [ Designated as safety issue: No ]
    Admission rates in patients with and without any of the following viruses detected by PCR in nasal lavage samples: Adenovirus; Bocavirus; Coronavirus; Enterovirus (Echovirus); Influenza (A H3N2, A H1N1/2009, B and C); Metapneumovirus (subtypes A and B); Parainfluenza 1, 2, 3 and 4 (subtypes A and B); Rhinovirus; Respiratory Syncytial Virus type A and Respiratory Syncytial Virus type B.

  • Admission Rates in Patients With and Without Rhinovirus Detect [ Time Frame: at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment) ] [ Designated as safety issue: No ]
    Admission rates in patients with and without rhinovirus detected by PCR in nasal lavage samples.

  • Admission Rates in Patients With the Arg16Gly Polymorphisms [ Time Frame: at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment) ] [ Designated as safety issue: No ]
    Admission rates in patients with the Arg16Gly polymorphisms of the beta-2 adrenergic receptor (Arg16Gly, Arg16Arg and Gly16Gly genotypes).


Enrollment: 119
Study Start Date: September 2011
Study Completion Date: April 2014
Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Albuterol - Experimental
Albuterol dosages during the first hour include 900 mcg (up to 15 kg), 1200 mcg (> 15 to 20 kg), 1500 mcg (> 20 to 25 kg) and 1800 mcg (> 25 kg).
Drug: Albuterol - Experimental
The Experimental group will receive higher doses of albuterol in the first hour: 900 mcg (up to 15 kg), 1200 mcg (> 15 to 20 kg), 1500 mcg (> 20 to 25 kg) and 1800 mcg (> 25 kg).
Other Name: Ventolin
Active Comparator: Albuterol - Control
Albuterol dosages during the first hour include either 600 mcg (up to 25 kg) or 1200 mcg (> 25 kg).
Drug: Albuterol - Control
The Control group will receive the following doses of albuterol in the first hour 600 mcg (up to 25 kg) or 1200 mcg (> 25 kg)
Other Name: Ventolin

Detailed Description:

This is a prospective, randomized, double blinded, controlled study. The patients will be randomly assigned to one of the treatment groups (experimental or control groups).

The patients will be assessed 1 hour later and every 30 minutes thereafter until discharge. Following 4 hours in the emergency room, any patient who do not meet the discharge criteria (PRAM score ≤ 3 and SpO2 ≥ 92%) will be admitted to the hospital. Each patient's attending physician will determine the need for additional therapies following the first hour.

Identification of respiratory viruses in the nasal lavage samples wil be performed using the CLART PneumoVir® kit.

Albuterol plasmatic levels will be analyzed via HPLC (High Performance Liquid Chromatography).

To genotype the ADBR2 receptor (blood samples), the gene regions encompassing the Arg16Gly, Gln27Glu, and Arg19Cys Thr164Ile polymorphisms will be amplified via PCR. The resultant amplimers were then sequenced.

A sample of 124 patients (62 in each group) was calculated to provide an 80% power with which to detect a significant difference of at least 30 minutes in the lengths of stay between the groups. The chi-square test will be used to compare hospital admission rates and tremor rates. For all other outcomes, t-tests for mean comparisons (variables with a normal distribution), a Mann Whitney test (nonparametric data) and ANOVA with repeated measures will be used.

  Eligibility

Ages Eligible for Study:   2 Years to 18 Years   (Child, Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Aged 2 to 18 years;
  2. History of two or more previous episodes of wheezing treated with bronchodilators in the last year;
  3. Wheezing attacks characterized by coughing, difficulty breathing and auscultation of expiratory wheezing or prolonged expiration;
  4. Intensity of wheezing attacks defined by PRAM score as moderate or severe (PRAM ≥ 5).

Exclusion Criteria:

  1. Pre-existing chronic diseases such as bronchopulmonary dysplasia, cystic fibrosis, bronchiolitis obliterans or other chronic pulmonary or cardiovascular disease;
  2. Initial clinical status indicating immediate ventilatory support, need for subcutaneous or intravenous bronchodilators;
  3. Decreased level of consciousness;
  4. Using a β-agonist in the four hours prior to arrival.
  5. Use of corticosteroids in the last 24h.
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01323010

Locations
Brazil
Instituto da Crianca HCFMUSP
Sao Paulo, Brazil, 05403-010
Sponsors and Collaborators
University of Sao Paulo
Fundação de Amparo à Pesquisa do Estado de São Paulo
Investigators
Principal Investigator: Luiz Vicente RF Silva Filho, MD University of São Paulo
  More Information

Responsible Party: Luiz Vicente Ribeiro Ferreira da Silva Filho, MD PhD, University of Sao Paulo
ClinicalTrials.gov Identifier: NCT01323010     History of Changes
Other Study ID Numbers: Hidalba 
Study First Received: March 24, 2011
Results First Received: September 14, 2015
Last Updated: February 15, 2016
Health Authority: Brazil: Ethics Committee

Keywords provided by University of Sao Paulo:
asthma
albuterol
metered dose inhalers

Additional relevant MeSH terms:
Respiratory Sounds
Signs and Symptoms, Respiratory
Signs and Symptoms
Albuterol
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Tocolytic Agents
Reproductive Control Agents
Adrenergic beta-2 Receptor Agonists
Adrenergic beta-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 24, 2016