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

Asthma Clinical Trial

Official title:

Efficacy and Safety of Increasing Doses of Inhaled Albuterol Administered by Metered Dose Inhalers in Children With Acute Wheezing Episodes

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01323010
• Other study ID #: Hidalba
• Status: Completed
• Phase: N/A
• First received: March 24, 2011
• Last updated: February 15, 2016
• Start date: September 2011
• Est. completion date: April 2014

Study information

• Verified date: February 2016
• Source: University of Sao Paulo
• Contact: n/a
• Is FDA regulated: No
• Health authority: Brazil: Ethics Committee
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 119
• Est. completion date: April 2014
• Est. primary completion date: December 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 2 Years to 18 Years

Eligibility

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 ß-agonist in the four hours prior to arrival.

5. Use of corticosteroids in the last 24h.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Asthma
• Children

Intervention

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).
• 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)

Locations

Country	Name	City	State
Brazil	Instituto da Crianca HCFMUSP	Sao Paulo

Sponsors (2)

Lead Sponsor	Collaborator
University of Sao Paulo	Fundação de Amparo à Pesquisa do Estado de São Paulo

Country where clinical trial is conducted

Brazil, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Hospital Admission	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%)	Starting at 4 hours post-treatment	No
Secondary	Forced Expiratory Volume in the First Second	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.	One hour post-treatment in comparison with baseline	No
Secondary	Change in PRAM Score After One Hour	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	One hour post-treatment	No
Secondary	Albuterol Determination in the Plasma	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.	at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment)	Yes
Secondary	Changes in Glucose Serum Levels	Changes in glucose serum levels at discharge or hospital admission (up to 4 hours post treatment) in comparison with baseline.	at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment) in comparison with baseline.	Yes
Secondary	Electrocardiogram at Baseline	Electrocardiogram performed at baseline	at baseline	Yes
Secondary	Changes in Respiratory Rate After One Hour	Change in respiratory rate one hour post-treatment in comparison with baseline.	One hour post-treatment in comparison with baseline	No
Secondary	Need for Additional Therapies	The need for additional therapies such as magnesium sulphate or intravenous albuterol were recorded	at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment)	No
Secondary	Changes in PRAM Score at Discharge or Hospital Admission	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	at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment) in comparison with baseline.	No
Secondary	Changes in Potassium Serum Levels	Changes in potassium serum levels at discharge or hospital admission (up to 4 hours post treatment) in comparison with baseline.	at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment) in comparison with baseline.	Yes
Secondary	Changes in Bicarbonate Serum Levels	Changes in bicarbonate serum levels at discharge or hospital admission (up to 4 hours post treatment) in comparison with baseline.	at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment) in comparison with baseline.	Yes
Secondary	Changes in Respiratory Rate at at Discharge or Hospital Admission.	Changes in respiratory rate at discharge or hospital admission (up to 4 hours post treatment) in comparison with baseline.	at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment) in comparison with baseline.	No
Secondary	Change in Pulse Oximetry One Hour Post-treatment	Change in pulse oximetry one hour post-treatment in comparison with baseline	One hour post-treatment in comparison with baseline	No
Secondary	Changes in Pulse Oximetry at Discharge or Hospital Admission.	Changes in pulse oximetry at discharge or hospital admission (up to 4 hours post treatment) in comparison with baseline.	at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment) in comparison with baseline.	No
Secondary	Changes in Heart Rate After One Hour	Change in heart rate one hour post-treatment in comparison with baseline.	One hour post-treatment in comparison with baseline	Yes
Secondary	Changes in Heart Rate at Discharge or Hospital Admission	Changes in heart rate at discharge or hospital admission (up to 4 hours post treatment) in comparison with baseline.	at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment)	Yes
Secondary	Electrocardiogram One Hour Post-treatment.	Electrocardiogram one hour post-treatment to identify possible rhythm disturbances.	One hour post-treatment	Yes
Secondary	Electrocardiogram at Discharge or Hospital Admission	Electrocardiogram at discharge or hospital admission to identify possible rhythm disturbances.	at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment)	Yes
Secondary	Lengths of Stay in the Emergency Room	lengths of stay in the emergency room for discharged patients	one to four hours	No
Secondary	Admission Rates in Patients With and Without Any Virus Detected	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.	at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment)	No
Secondary	Admission Rates in Patients With and Without Rhinovirus Detect	Admission rates in patients with and without rhinovirus detected by PCR in nasal lavage samples.	at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment)	No
Secondary	Admission Rates in Patients With the Arg16Gly Polymorphisms	Admission rates in patients with the Arg16Gly polymorphisms of the beta-2 adrenergic receptor (Arg16Gly, Arg16Arg and Gly16Gly genotypes).	at discharge or admission (up to 4 hours post treatment, minimum 1 hour, maximum 4 hours post treatment)	No