Bronchodilator Response in 4-12 Years Chinese Controller Naive Asthmatic Children

• Sponsor: Capital Institute of Pediatrics, China (Other)
• Overall Status: Completed
• CT.gov ID: NCT01500525
• Collaborator: Merck Sharp & Dohme Corp. (Industry)
• Enrollment: 587
• Location: 1
• Duration (Months): 40
• Patients Per Site Per Month: 14.7

Study Details

Study Description

Brief Summary

Objectives:

1. To observe BDR distribution curve for Chinese non-asthmatic and controller-naïve asthmatic children from 4-12 years respectively

2. To compare BDR values between non-asthmatic group and controller-naïve asthmatic group, and analyze appropriate cut-off point value

Background and rationale:

According to the guidelines spirometry, including baseline forced expiratory volume in 1 second (FEV1) and the bronchodilator response (BDR) to short acting beta agonists (SABA), should be used in children as objective measures to establish the diagnosis and severity of bronchial asthma. Baseline FEV1 is usually in the normal range (greater than 80% predicted) in children, regardless of asthma severity, so several other objective measures have been suggested for diagnosis in children, including the response to a bronchodilator, which reflects airway reversibility.

The current definition for a positive BDR is >12% reversibility. In the study carried out by Galant et al among 51 non-asthmatic children and 346 controller naïve asthmatic children between 4-17 years, the BDR value could achieve 12% in only 30.6% asthmatic children, across all severity. Also, in a study among 142 children between 5-10 years in UK, 9% increase in FEV1 after bronchodilator use was suggested as the cutoff point with good sensitivity and specificity.

Difference between the proposed study to be carried out in our hospital and the one in Anhui Province is that we will tentatively calculate a BDR cutoff point by using receiver operating characteristic (ROC curve). And the cutoff point can be used as a reference indicator in asthma diagnosis and long-term management.

The current BDR cutoff point of 12% that is not ideal for children can also be reflected in the clinical management. It has been shown that a persistent BDR value, even less than 12%, in asthmatic children suggests poor clinical outcome. In a 4 years study among 1041 asthmatic children in America carried out by Sharma et al, it showed that compared with individuals who had a BDR of 12% and 200ml, individuals who had a BDR of 10% had similar poor clinical outcomes (e.g. more hospital visits, more prednisone bursts, increased nocturnal awakenings, and missing more days of school). Same results were also obtained in Galant et al study among 679 asthmatic children among 5-18 years.

Condition or Disease	Intervention/Treatment	Phase
Asthma

Detailed Description

This is a prospective observational non-interventional clinical study.

1. Patient population:

300 non-asthmatic and 300 asthmatic children will be recruited.

1. Non-asthmatic group: healthy children from 4-12 years will be recruited from the Capital Institute of Pediatrics nearby schools

Inclusion criteria:

1. Willingly attend this investigation 2) Chest physical tests are normal

Exclusion criteria:

1. The child had been hospitalized for any severe respiratory condition 2) A physician had ever stated that the child had asthma, reactive airway diseases, or the child had taken antiasthma medications for symptoms 3) The child was diagnosed with congenital heart disease requiring surgery or medications for management 4) There are positive responses concerning other serious chest problems, chest surgery, chronic productive cough, recurrent intractable wheezing, and shortness of breath 5) The children can not finish the test that met American Thoracic Society criteria for preschool children in a maximum of 6 attempts and are unable to successfully complete post-bronchodilator (BD) spirometry

1. Asthmatic group: 4-12 years old asthmatic children will be recruited from the asthma clinic of the Capital Institute of Pediatrics

Inclusion criteria:

1. Diagnose asthma by specialist of asthma (based on symptoms): criteria for the diagnosis of asthma made by the asthma specialist included a history of recurrent coughing, wheezing, or shortness of breath at rest or with exercise, symptomatic improvement after bronchodilator use, and exclusion of other diagnoses 2) Asymptomatic or mild symptomatic with no physical signs of wheeze at the time of testing 3) Not receiving controller medication 6 weeks prior to the initial evaluation 4) Willing to attend this investigation

Exclusion criteria:

1. Using short β2 agonists within 6 hours

2. Using long acting β2 agonists within 24 hours

3. Can not finish the test that met American Thoracic Society criteria for preschool children in a maximum of 6 attempts and are unable to successfully complete post-bronchodilator spirometry.

4. Preparation before tests

5. Sign the consent form.

6. Fill the asthma severity form according to NEAPP guideline (asthmatic group).

7. Chest physical test, record on the form of test.

8. Standing height and weight will be measured.

9. Calculation of age: The date of test subtracts the date of birth.

10. Pulmonary function tests

Standardized pulmonary function tests will be conducted.

Contents of tests:

Pre and post flow volume: forced volume vital capacity (FVC), FEV0.5, FEV1, FEV1/FVC ratio, PEF, forced expiratory flow 25 (FEF25), FEF50, FEF75, FEF25-75, forced expiratory time (FET), back-extrapolated volume (VBE), VBE/FVC.

The BDR is based on pulmonary function measurements before and after administration of 2.5 mg albuterol by nebulizer. BDR is calculated as [(postbronchodilator FEV1- baseline FEV1)/baseline FEV1] x 100%.

Study Procedures:

1. Spirometry preparation The spirometry was purchased from VIASYS Healthcare, Hochberg Germany (MasterScope).

2. Check: Before switch on, check the conjunction between flow sensor and the hand knob, ensure that the black compact is tightness.

3. Calibration: Before calibration, the room temperature, pressure, humidity should be tested and recorded and all of the parameter should be reconciled to BTPS condition.

Using 2 liters scalar to calibrate flow. Every day do the even flow calibration. Every week do the flow linear calibration, include high, media and low flow these three different flow calibration. The variety should be less than 3%.

The record of calibration should be printed, and the technician should be signed on it and save it.

1. Test method The training process is the same as Eigen H. et al (ref 8). The entire instruction and testing session for each child is strictly limited to 15 min, during which time children are instructed in the techniques of spirometry and performed at least three forced vital capacity maneuvers. A highly experienced children's pulmonary function technologist does the instruction for each child. At the time of testing, each child is given an explanation of the testing procedure individually and then tested using coaching techniques used in our pulmonary function laboratory in evaluating younger children.

2. Criteria for accepting Data (ATS/ERS 2005) The principles of spirometry quality control in preschool children are the same as for adults.

3. It is necessary to visually inspect the flow-volume and volume-time traces, and exclude maneuvers that are visibly inadequate. Maneuvers should be excluded if the flow-volume curve does not demonstrate a rapid rise to peak flow, or a smooth descending limb, with no evidence of cough or glottis closure.

4. The start of test should be quantified by calculating the VBE. Some investigators reported that more than 80% of the studied preschool population achieved a VBE of less than or equal to 80 ml or less than 12.5% of the FVC. Alternative criteria are presented, but these should be viewed as a guide to assist visual inspection, rather than as exclusion criteria.

5. The end of test should be quantified by reporting the point of cessation of flow. It is known that many preschool children cannot sustain forced expiration for 1 second, let alone the 6 seconds previously stipulated for adults (ref 9) , and the forced expired time should be reported but should not be used to exclude maneuvers. This pattern should not be misinterpreted as early termination (ref 10).

Study Design

• Study Type: Observational
• Actual Enrollment: 587 participants
• Observational Model: Case-Control
• Time Perspective: Prospective
• Official Title: A Prospective Observational Study in a Tertiary Pediatric Hospital in Beijing to Understand the Accuracy of Bronchodilator Response (BDR) in Chinese Controller Naive Asthmatic Children Between the Age of 4~12 Years Old
• Study Start Date: Dec 1, 2011
• Actual Primary Completion Date: Jan 1, 2014
• Actual Study Completion Date: Apr 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
asthmatic children children diagnosed by a specialist as asthmatic patients
non-asthmatic children children who are healthy and who do not have respiratory syndrom

Outcome Measures

Primary Outcome Measures

1. Bronchodilator Response in Asthmatic Children [3 years]

   To observe bronchodilator response(BDR) distribution curve for Chinese non-asthmatic children from 4-12 years, BDR calculated as: (FEV 1 L post-bronchodilator - FEV 1 L pre-bronchodilator)/FEV 1 L pre-bronchodilator × 100%. To observe BDR distribution curve for Chinese controller-naïve asthmatic children from 4-12 years To compare BDR values between non-asthmatic group and controller-naïve asthmatic group, and analyze appropriate cut-off point value

Eligibility Criteria

Criteria

• Ages Eligible for Study: 4 Years to 12 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

-Non-asthmatic group: healthy children from 4-12 years will be recruited from the Capital Institute of Pediatrics nearby schools

Inclusion criteria:

1. Willingly attend this investigation

2. Chest physical tests are normal

Exclusion criteria:

1. The child had been hospitalized for any severe respiratory condition

2. A physician had ever stated that the child had asthma, reactive airway diseases, or the child had taken antiasthma medications for symptoms

3. The child was diagnosed with congenital heart disease requiring surgery or medications for management

4. There are positive responses concerning other serious chest problems, chest surgery, chronic productive cough, recurrent intractable wheezing, and shortness of breath

5. The children can not finish the test that met American Thoracic Society criteria for preschool children in a maximum of 6 attempts and are unable to successfully complete post-bronchodilator (BD) spirometry

• Asthmatic group: 4-12 years old asthmatic children will be recruited from the asthma clinic of the Capital Institute of Pediatrics

Inclusion criteria:

1. Diagnose asthma by specialist of asthma (based on symptoms): criteria for the diagnosis of asthma made by the asthma specialist included a history of recurrent coughing, wheezing, or shortness of breath at rest or with exercise, symptomatic improvement after bronchodilator use, and exclusion of other diagnoses

2. Asymptomatic or mild symptomatic with no physical signs of wheeze at the time of testing

3. Not receiving controller medication 6 weeks prior to the initial evaluation

4. Willing to attend this investigation

Exclusion criteria:

1. Using short β2 agonists within 6 hours

2. Using long acting β2 agonists within 24 hours

3. Can not finish the test that met American Thoracic Society criteria for preschool children in a maximum of 6 attempts and are unable to successfully complete post-bronchodilator spirometry.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Capital Institute of Pediatrics	Beijing	Beijing	China

Sponsors and Collaborators

• Capital Institute of Pediatrics, China
• Merck Sharp & Dohme Corp.

Investigators

• Principal Investigator: Ling Cao, MD, Capital Institute of Pediatrics, China

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: caoling, Director of Pulmonary Department, Director of Asthma Center, Capital Institute of Pediatrics, China
• ClinicalTrials.gov Identifier: NCT01500525
• Other Study ID Numbers: MISP 40467
• First Posted: Dec 28, 2011
• Last Update Posted: Sep 28, 2021
• Last Verified: Sep 1, 2021

• Keywords provided by caoling, Director of Pulmonary Department, Director of Asthma Center, Capital Institute of Pediatrics, China: asthma; children; accuracy of bronchodilator response
• Additional relevant MeSH terms: Asthma

Study Results

Participant Flow

Arm/Group Title	Asthmatic Children	Non-asthmatic Children
Arm/Group Description	children diagnosed by a specialist as asthmatic patients	children who are healthy and who do not have respiratory syndrom
Period Title: Overall Study
STARTED	286	301
COMPLETED	286	301
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Asthmatic Children	Non-asthmatic Children	Total
Arm/Group Description	children diagnosed by a specialist as asthmatic patients	children who are healthy and who do not have respiratory syndrom	Total of all reporting groups
Overall Participants	286	301	587
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	7.22 (2.44)	7.56 (2.41)	7.41 (2.43)
Sex: Female, Male (Count of Participants)
Female	92 32.2%	141 46.8%	233 39.7%
Male	194 67.8%	160 53.2%	354 60.3%

Outcome Measures

1. Primary Outcome

Title	Bronchodilator Response in Asthmatic Children
Description	To observe bronchodilator response(BDR) distribution curve for Chinese non-asthmatic children from 4-12 years, BDR calculated as: (FEV 1 L post-bronchodilator - FEV 1 L pre-bronchodilator)/FEV 1 L pre-bronchodilator × 100%. To observe BDR distribution curve for Chinese controller-naïve asthmatic children from 4-12 years To compare BDR values between non-asthmatic group and controller-naïve asthmatic group, and analyze appropriate cut-off point value
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

asthmatic group : children diagnosed by a specialist as asthmatic patients; Non-asthmatic Children: children who are healthy and who do not have respiratory syndrom

Arm/Group Title	Asthmatic Children	Non-asthmatic Children
Arm/Group Description	children diagnosed by a specialist as asthmatic patients	children who are healthy and who do not have respiratory syndrom
Measure Participants	286	301
Mean (Standard Deviation) [percentage of BDR]	9.45 (9.15)	3.30 (3.85)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Asthmatic Children, Non-asthmatic Children
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3
	Confidence Interval	(1-Sided) 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	30 minutes
Arm/Group Title	Asthmatic Children		Non-asthmatic Children
Arm/Group Description	children diagnosed by a specialist as asthmatic patients		children who are healthy and who do not have respiratory syndrom
All Cause Mortality
	Asthmatic Children		Non-asthmatic Children
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/286 (0%)		0/301 (0%)
Serious Adverse Events
	Asthmatic Children		Non-asthmatic Children
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/286 (0%)		0/301 (0%)
Other (Not Including Serious) Adverse Events
	Asthmatic Children		Non-asthmatic Children
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/286 (0%)		0/301 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.