Preterm Infant Inhaled Albuterol Dosing

• ClinicalTrials.gov Identifier: NCT02447250
• Recruitment Status: Completed
• First Posted: May 18, 2015
• Results First Posted: May 23, 2019
• Last Update Posted: May 23, 2019
• Sponsor: Oregon Health and Science University
• Information provided by (Responsible Party): Cynthia McEvoy, Oregon Health and Science University

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Diagnostic
• Conditions: Bronchopulmonary Dysplasia; Very Low Birth Weight
• Intervention: Drug: Varied albuterol dose response
• Enrollment: 14

Participant Flow

Recruitment Details
Pre-assignment Details	1 subject was consented into the study, but then became too clinically unstable to participate in the study and remained unstable throughout the eligibility period.

Arm/Group Title	Single Arm: Varied Albuterol Dose Response
Arm/Group Description	Subjects will be evaluated in three sessions within a 7 day time span, beginning after 14 days of age and at 28w0d to 33w6d corrected gestational age. In each session, pulmonary function tests (PFTs) will be performed prior to and 15 minutes after a dose of albuterol. The dose will be different in each session. In the first session, a single dose of 180 micrograms (2 puffs) of albuterol sulfate via metered dose inhaler. The dose will be 270 micrograms in the second session and 360 micrograms in the third session. PFTs will be performed during quiet sleep while the baby is spontaneously breathing or while the baby is intubated and receiving mechanical ventilation. Resistance and compliance will be measured using the single breath occlusion technique. Varied albuterol dose response: Subjects will be evaluated in three sessions. The sessions will occur within a 7 day time span, beginning between 14 or more days from birth and at a corrected gestational age of 2
Period Title: First Dose (180 mcg Albuterol)
Started	14
Completed	14
Not Completed	0
Period Title: Second Dose (270 mcg Albuterol)
Started	14
Completed	13
Not Completed	1
Reason Not Completed
elevated HR with first dose	1
Period Title: Third Dose (360 mcg Albuterol)
Started	13
Completed	8
Not Completed	5
Reason Not Completed
Clinically unstable, unable to do PFT	1
Elevated HR with 2nd dose	4

Baseline Characteristics

Arm/Group Title		Single Arm: Varied Albuterol Dose Response
Arm/Group Description		Subjects will be evaluated in three sessions within a 7 day time span, beginning after 14 days of age and at 28w0d to 33w6d corrected gestational age. In each session, pulmonary function tests (PFTs) will be performed prior to and 15 minutes after a dose of albuterol. The dose will be different in each session. In the first session, a single dose of 180 micrograms (2 puffs) of albuterol sulfate via metered dose inhaler. The dose will be 270 micrograms in the second session and 360 micrograms in the third session. PFTs will be performed during quiet sleep while the baby is spontaneously breathing or while the baby is intubated and receiving mechanical ventilation. Resistance and compliance will be measured using the single breath occlusion technique. Varied albuterol dose response: Subjects will be evaluated in three sessions. The sessions will occur within a 7 day time span, beginning between 14 or more days from birth and at a corrected gestational age of 2
Overall Number of Baseline Participants		14
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Full Range); Unit of measure: Days
	Number Analyzed	14 participants
		36; (17 to 66)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	14 participants
	Female	10 71.4%
	Male	4 28.6%
birthweight; Mean (Full Range); Unit of measure: Grams
	Number Analyzed	14 participants
		895; (350 to 1293)
gestational age at birth; Mean (Full Range); Unit of measure: Weeks
	Number Analyzed	14 participants
		26.9; (24.1 to 29.9)
respiratory support at study entry, CPAP; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	14 participants
		12 85.7%
respiratory support at study entry, mechanical ventilation; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	14 participants
		2 14.3%
history of any mechanical ventilation; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	14 participants
		8 57.1%
received surfactant; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	14 participants
		7 50.0%
received antenatal corticosteroids; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	14 participants
		13 92.9%
ever received albuterol prior to study entry; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	14 participants
		0 0.0%
received diuretics prior to study entry; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	14 participants
		3 21.4%
reason for preterm delivery: preterm labor; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	14 participants
		6 42.9%
maternal age, years (mean); Mean (Full Range); Unit of measure: Years
	Number Analyzed	14 participants
		26.4; (17 to 36)
maternal BMI (mean, range); Median (Full Range); Unit of measure: Kg/ m^2
	Number Analyzed	14 participants
		25.5; (18.7 to 47)
maternal diabetes mellitus (pregestational or gestational); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	14 participants
		4 28.6%
family history of asthma; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	14 participants
		2 14.3%
maternal smoking during pregnancy; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	14 participants
		4 28.6%
second hand smoke exposure during pregnancy; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	14 participants
		6 42.9%

Outcome Measures

1. Primary Outcome

Title	Change in Respiratory Resistance
Description	The primary outcome is the percentage of subjects who show a positive response to each dose of albuterol. A positive response is defined as a greater than or equal to 10% decrease in respiratory resistance (Rrs). The change in RRs was measured at baseline and again after each dose of albuterol. All measurements were taken within a 7 day time frame for each subject such that each subject would have up to 3 results measured during a 7 day period, if he/she were able to complete three sets of PFTs according to study protocol. The change in Rrs was calculated by subtracting the baseline Rrs from the post-albuterol Rrs.
Time Frame	Within one week of performing pulmonary function tests

Outcome Measure Data

Analysis Population Description

Some subjects did not receive all 3 doses (based on how they tolerated initial dose(s))

Arm/Group Title		Single Arm: Varied Albuterol Dose Response
Arm/Group Description:		Subjects will be evaluated in 3 sessions. The sessions will occur within a 7 day time span, beginning after 14 days of age and at 28w0d to 33w6d corrected gestational age. In each session, pulmonary function tests (PFTs) will be performed prior to and 15 minutes after a dose of albuterol. The dose will be different in each session. In the first session, a single dose of 180 micrograms (2 puffs) of albuterol sulfate via metered dose inhaler. The dose will be 270 micrograms in the second session and 360 micrograms in the third session. PFTs will be performed during quiet sleep while the baby is spontaneously breathing or while the baby is intubated and receiving mechanical ventilation. Resistance and compliance will be measured using the single breath occlusion technique. Varied albuterol dose response: Subjects will be evaluated in three sessions. The sessions will occur within a 7 day time span, beginning between 14 or more days from birth and at a corrected gestational age of 2
Overall Number of Participants Analyzed		11
Mean (Standard Deviation); Unit of Measure: cm h2o/mL/sec
dose 1	Number Analyzed	11 participants
		0.011 (0.016)
dose 2	Number Analyzed	10 participants
		0.006 (0.008)
dose 3	Number Analyzed	6 participants
		0.014 (0.014)

2. Secondary Outcome

Title	Number of Participants With Positive Response at Different Albuterol Doses
Description	Compare number of subjects who have a positive response (greater than or equal to 10% decrease in respiratory resistance) to each dose of albuterol
Time Frame	Data collected 15 minutes after dose in each session. Study includes 3 sessions within a 7 day period.

Outcome Measure Data

Analysis Population Description

Measuring Rrs can be technically challenging, particularly in premature infants, and we did not have measurable Rrs for every subject at every time point, therefore the denominator here is not the same as the total number of participants. For example, we have missing/unmeasurable Rrs for 3 subjects at the lowest albuterol dose.

Arm/Group Title		Single Arm: Varied Albuterol Dose Response
Arm/Group Description:		Subjects will be evaluated in 3 sessions. The sessions will occur within a 7 day time span, beginning after 14 days of age and at 28w0d to 33w6d corrected gestational age. In each session, pulmonary function tests (PFTs) will be performed prior to and 15 minutes after a dose of albuterol. The dose will be different in each session. In the first session, a single dose of 180 micrograms (2 puffs) of albuterol sulfate via metered dose inhaler. The dose will be 270 micrograms in the second session and 360 micrograms in the third session. PFTs will be performed during quiet sleep while the baby is spontaneously breathing or while the baby is intubated and receiving mechanical ventilation. Resistance and compliance will be measured using the single breath occlusion technique. Varied albuterol dose response: Subjects will be evaluated in 3 sessions. The sessions will occur within a 7 day time span, beginning between 14 or more days from birth and at a corrected gestational age of 28w0d to
Overall Number of Participants Analyzed		14
Measure Type: Number; Unit of Measure: participants
positive Rrs response at 180 mcg albuterol	Number Analyzed	11 participants
		6
positive Rrs response at 270 mcg albuterol	Number Analyzed	10 participants
		4
positive Rrs response at 360 mcg albuterol	Number Analyzed	6 participants
		4

3. Secondary Outcome

Title	Birth Weight of Albuterol Responders vs Non Responders
Description	birth weight in grams of each subject was recorded at time of enrollment
Time Frame	within one week of entering study

Outcome Measure Data

Analysis Population Description

This data included 10 subjects who responded to albuterol at at least one dose, and 3 subjects who did not show a positive response to albuterol at any dose

Arm/Group Title		Single Arm: Varied Albuterol Dose Response
Arm/Group Description:		Subjects will be evaluated in 3 sessions. The sessions will occur within a 7 day time span, beginning after 14 days of age and at 28w0d to 33w6d corrected gestational age. In each session, pulmonary function tests (PFTs) will be performed prior to and 15 minutes after a dose of albuterol. The dose will be different in each session. In the first session, a single dose of 180 micrograms (2 puffs) of albuterol sulfate via metered dose inhaler. The dose will be 270 micrograms in the second session and 360 micrograms in the third session. PFTs will be performed during quiet sleep while the baby is spontaneously breathing or while the baby is intubated and receiving mechanical ventilation. Resistance and compliance will be measured using the single breath occlusion technique. Varied albuterol dose response: Subjects will be evaluated in 3 sessions. The sessions will occur within a 7 day time span, beginning between 14 or more days from birth and at a corrected gestational age of 28w0d to
Overall Number of Participants Analyzed		13
Mean (Standard Deviation); Unit of Measure: grams
albuterol responders	Number Analyzed	10 participants
		847.2 (296)
albuterol non responders	Number Analyzed	3 participants
		1147.7 (216)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Single Arm: Varied Albuterol Dose Response
	Comments	comparison of mean birth weights between responders and non-responders
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.14
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]

4. Secondary Outcome

Title	Gestational Age at Birth
Description	Average gestational age (GA) in weeks at birth for subjects who responded to albuterol versus subjects without a positive response
Time Frame	within one week of entering study

Outcome Measure Data

Analysis Population Description

We have data for 10 subjects who responded to albuterol and 3 subjects who did not respond.

Arm/Group Title		Single Arm: Varied Albuterol Dose Response
Arm/Group Description:		Subjects will be evaluated in 3 sessions. The sessions will occur within a 7 day time span, beginning after 14 days of age and at 28w0d to 33w6d corrected gestational age. In each session, pulmonary function tests (PFTs) will be performed prior to and 15 minutes after a dose of albuterol. The dose will be different in each session. In the first session, a single dose of 180 micrograms (2 puffs) of albuterol sulfate via metered dose inhaler. The dose will be 270 micrograms in the second session and 360 micrograms in the third session. PFTs will be performed during quiet sleep while the baby is spontaneously breathing or while the baby is intubated and receiving mechanical ventilation. Resistance and compliance will be measured using the single breath occlusion technique. Varied albuterol dose response: Subjects will be evaluated in 3 sessions. The sessions will occur within a 7 day time span, beginning between 14 or more days from birth and at a corrected gestational age of 28w0d to
Overall Number of Participants Analyzed		13
Mean (Standard Deviation); Unit of Measure: weeks
birth GA albuterol responders, weeks	Number Analyzed	10 participants
		26.7 (1.9)
birth GA albuterol non responders	Number Analyzed	3 participants
		28.5 (1.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Single Arm: Varied Albuterol Dose Response
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.16
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]

5. Secondary Outcome

Title	Etiology of Preterm Delivery
Description	Reason for each subject's preterm delivery was classified as either preterm labor or delivery for maternal indications (eg pre-eclampsia).
Time Frame	within one week of entering study

Outcome Measure Data

Analysis Population Description

5 subjects were delivered due to preterm labor, and 8 delivered prematurely due to maternal indications

Arm/Group Title		Single Arm: Varied Albuterol Dose Response
Arm/Group Description:		Subjects will be evaluated in 3 sessions. The sessions will occur within a 7 day time span, beginning after 14 days of age and at 28w0d to 33w6d corrected gestational age. In each session, pulmonary function tests (PFTs) will be performed prior to and 15 minutes after a dose of albuterol. The dose will be different in each session. In the first session, a single dose of 180 micrograms (2 puffs) of albuterol sulfate via metered dose inhaler. The dose will be 270 micrograms in the second session and 360 micrograms in the third session. PFTs will be performed during quiet sleep while the baby is spontaneously breathing or while the baby is intubated and receiving mechanical ventilation. Resistance and compliance will be measured using the single breath occlusion technique. Varied albuterol dose response: Subjects will be evaluated in three sessions. The sessions will occur within a 7 day time span, beginning between 14 or more days from birth and at a corrected gestational age of 2
Overall Number of Participants Analyzed		13
Measure Type: Count of Participants; Unit of Measure: Participants
preterm labor, responsive to albuterol	Number Analyzed	5 participants
		4 80.0%
maternal indicated delivery, responsive to albuter	Number Analyzed	8 participants
		6 75.0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Single Arm: Varied Albuterol Dose Response
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.0
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

6. Other Pre-specified Outcome

Title	Family History of Asthma and Likelihood to Respond to Albuterol
Description	Family history was obtained from verbal history by subject's mother at time of enrollment in study. A positive family history was noted if a first degree relative of the subject (infant) had a diagnosis of asthma.
Time Frame	History collected at enrollment, albuterol response assessed within one week

Outcome Measure Data

Analysis Population Description

only 2 subjects had a history of a first-degree relative (parent or sibling) with asthma

Arm/Group Title		Single Arm: Varied Albuterol Dose Response
Arm/Group Description:		Subjects will be evaluated in 3 sessions. The sessions will occur within a 7 day time span, beginning after 14 days of age and at 28w0d to 33w6d corrected gestational age. In each session, pulmonary function tests (PFTs) will be performed prior to and 15 minutes after a dose of albuterol. The dose will be different in each session. In the first session, a single dose of 180 micrograms (2 puffs) of albuterol sulfate via metered dose inhaler. The dose will be 270 micrograms in the second session and 360 micrograms in the third session. PFTs will be performed during quiet sleep while the baby is spontaneously breathing or while the baby is intubated and receiving mechanical ventilation. Resistance and compliance will be measured using the single breath occlusion technique. Varied albuterol dose response: Subjects will be evaluated in three sessions. The sessions will occur within a 7 day time span, beginning between 14 or more days from birth and at a corrected gestational age of 2
Overall Number of Participants Analyzed		14
Measure Type: Number; Unit of Measure: participants
family hx of asthma, respond to albuterol	Number Analyzed	2 participants
		1
no fam hx asthma, respond to albuterol	Number Analyzed	12 participants
		9

7. Other Pre-specified Outcome

Title	Maternal BMI at Time of Pregnancy and Likelihood of Positive Response to Albuterol
Description	Maternal BMI will be obtained from her medial record, and she will be asked about weight gain during pregnancy at time of enrollment. Results will be compared for infants born to women with a normal BMI vs. those with obese BMI (>30).
Time Frame	Maternal information collected at enrollment; albuterol response assessed within one week

Outcome Measure Data

Analysis Population Description

We have BMI data on 13 mothers.

Arm/Group Title		Single Arm: Varied Albuterol Dose Response
Arm/Group Description:		Subjects will be evaluated in 3 sessions. The sessions will occur within a 7 day time span, beginning after 14 days of age and at 28w0d to 33w6d corrected gestational age. In each session, pulmonary function tests (PFTs) will be performed prior to and 15 minutes after a dose of albuterol. The dose will be different in each session. In the first session, a single dose of 180 micrograms (2 puffs) of albuterol sulfate via metered dose inhaler. The dose will be 270 micrograms in the second session and 360 micrograms in the third session. PFTs will be performed during quiet sleep while the baby is spontaneously breathing or while the baby is intubated and receiving mechanical ventilation. Resistance and compliance will be measured using the single breath occlusion technique. Varied albuterol dose response: Subjects will be evaluated in 3 sessions. The sessions will occur within a 7 day time span, beginning between 14 or more days from birth and at a corrected gestational age of 28w0d to
Overall Number of Participants Analyzed		13
Mean (Standard Deviation); Unit of Measure: kg/m^2
mean BMI mothers of albuterol-responders , any dos	Number Analyzed	10 participants
		27.4 (8.6)
mean BMI mothers of albuterol non-responders	Number Analyzed	3 participants
		27.3 (3.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Single Arm: Varied Albuterol Dose Response
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.0
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]

8. Other Pre-specified Outcome

Title	Association of Smoke Exposure During Pregnancy and Neonatal Response to Albuterol
Description	Mothers who smoked cigarettes during pregnancy and the rate of albuterol response of their infants
Time Frame	Smoking and second hand smoke exposure history will be obtained at enrollment. Albuterol response will be obtained within one week.

Outcome Measure Data

Analysis Population Description

We have data for 9 subjects whose mothers did not smoke and 4 subjects whose mothers smoked

Arm/Group Title		Single Arm: Varied Albuterol Dose Response
Arm/Group Description:		Subjects will be evaluated in 3 sessions. The sessions will occur within a 7 day time span, beginning after 14 days of age and at 28w0d to 33w6d corrected gestational age. In each session, pulmonary function tests (PFTs) will be performed prior to and 15 minutes after a dose of albuterol. The dose will be different in each session. In the first session, a single dose of 180 micrograms (2 puffs) of albuterol sulfate via metered dose inhaler. The dose will be 270 micrograms in the second session and 360 micrograms in the third session. PFTs will be performed during quiet sleep while the baby is spontaneously breathing or while the baby is intubated and receiving mechanical ventilation. Resistance and compliance will be measured using the single breath occlusion technique. Varied albuterol dose response: Subjects will be evaluated in 3 sessions. The sessions will occur within a 7 day time span, beginning between 14 or more days from birth and at a corrected gestational age of 28w0d to
Overall Number of Participants Analyzed		13
Measure Type: Number; Unit of Measure: participants
albuterol responders of mothers who smoked	Number Analyzed	4 participants
		4
albuterol responders of non-smoker mothers %	Number Analyzed	9 participants
		6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Single Arm: Varied Albuterol Dose Response
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.50
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Single Arm: Varied Albuterol Dose Response
Arm/Group Description	Subjects will be evaluated in 3 sessions. The sessions will occur within a 7 day time span, beginning after 14 days of age and at 28w0d to 33w6d corrected gestational age. In each session, pulmonary function tests (PFTs) will be performed prior to and 15 minutes after a dose of albuterol. The dose will be different in each session. In the first session, a single dose of 180 micrograms (2 puffs) of albuterol sulfate via metered dose inhaler. The dose will be 270 micrograms in the second session and 360 micrograms in the third session. Resistance and compliance will be measured using the single breath occlusion technique. Varied albuterol dose response: Subjects will be evaluated in 3 sessions. The sessions will occur within a 7 day time span, beginning between 14 or more days from birth and at a corrected gestational age of 28w0d to
All-Cause Mortality
	Single Arm: Varied Albuterol Dose Response
	Affected / at Risk (%)
Total	0/14 (0.00%)
Serious Adverse Events
	Single Arm: Varied Albuterol Dose Response
	Affected / at Risk (%)	# Events
Total	0/14 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Single Arm: Varied Albuterol Dose Response
	Affected / at Risk (%)	# Events
Total	1/14 (7.14%)
Cardiac disorders
elevated heart rate above predefined criteria †	1/14 (7.14%)	1
† Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.

Results Point of Contact

• Name/Title: Cindy McEvoy, MD
• Organization: OHSU
• Phone: 5034940223
• EMail: mcevoyc@ohsu.edu

Publications:

Blake K, Madabushi R, Derendorf H, Lima J. Population pharmacodynamic model of bronchodilator response to inhaled albuterol in children and adults with asthma. Chest. 2008 Nov;134(5):981-989. doi: 10.1378/chest.07-2991. Epub 2008 Jun 26.

Ng G, da Silva O, Ohlsson A. Bronchodilators for the prevention and treatment of chronic lung disease in preterm infants. Cochrane Database Syst Rev. 2012 Jun 13;(6):CD003214. doi: 10.1002/14651858.CD003214.pub2.

Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2001 Jun;163(7):1723-9. doi: 10.1164/ajrccm.163.7.2011060. No abstract available.

• Responsible Party: Cynthia McEvoy, Oregon Health and Science University
• ClinicalTrials.gov Identifier: NCT02447250
• Other Study ID Numbers: IRB00009883
• First Submitted: May 14, 2015
• First Posted: May 18, 2015
• Results First Submitted: October 16, 2018
• Results First Posted: May 23, 2019
• Last Update Posted: May 23, 2019