Progression of Airway Obstruction in Childhood Asthma

• Sponsor: National Jewish Health (Other)
• Overall Status: Completed
• CT.gov ID: NCT00873873
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 55
• Location: 1
• Duration (Months): 33
• Patients Per Site Per Month: 1.7

Study Details

Study Description

Brief Summary

Distinct patterns of loss in pulmonary function were identified in children with mild to moderate asthma participating in a 10-year observation period during the NHLBI Childhood Asthma Management Program. This loss in pulmonary function is likely related to ongoing inflammation unresponsive to current therapy. This study will measure indicators of airway inflammation which are associated with structural and physiologic changes in the lung and provide insight into mechanisms of asthma progression in adolescence and early adulthood.

Condition or Disease	Intervention/Treatment	Phase
Asthma

Detailed Description

The Childhood Asthma Management Program Continuation Study/Phase 2 is a 3.25 year observational follow-up study of the children enrolled in the Childhood Asthma Management Program (CAMP) randomized trial. CAMPCS/2 is a multicenter National Heart, Lung and Blood Institute program. The objective of the CAMPCS/2 is to determine the consequences of childhood asthma and its treatment on asthma outcomes in young adulthood. This separate ancillary study will extend the core CAMP/CAMPCS work by focusing on progression of airway obstruction in childhood asthma to evaluate mechanisms of progression and describe the differences in the four separate patterns in airway obstruction that have evolved over time. The four patterns of airway obstruction which have been identified are as follows: (1) abnormal obstruction present in early childhood which remained abnormal (Low/Low group) and (2) initially normal ratios, which worsened into the abnormal range over time (Normal/Low group). These patterns with unfavorable outcomes can be compared to two other patterns with favorable outcomes: (3) initially abnormal ratios improving with time (Low/Normal group) and (4) normal ratios throughout follow-up (Normal/Normal group).

Based on these four patterns, three specific hypotheses related to immunology, structure, and physiology are identified:

1. Among school-aged children with mild to moderate asthma, those children with increased airflow limitation (i.e. low FEV1/FVC) at the end of CAMPCS (Normal/Low and Low/Low groups) have elevated markers of inflammation related to proteolysis (i.e. neutrophil elastase, matrix metalloproteinase-9 (MMP9), and tissue inhibitor of metalloproteinase-1 (TIMP1) and neutrophils in sputum).

2. Subjects who show a pattern of early progression and failure to resolve (Low/Low group) have clinical evidence of steroid insensitivity compared to those with slow progression (Normal/Low group). They also have in vitro evidence of steroid resistance compared to the Normal/Low or Normal/Normal groups. This pattern of obstruction may be due to irreversible changes consistent with airway remodeling and inflammation that are relatively refractory to steroid therapy.

3. Children with ongoing airflow limitation (Normal/Low and Low/Low groups) have more prominent structural changes related to increased air trapping and airway thickening compared to those with normal FEV1/FVC at the end of CAMPCS (Low/Normal and Normal/Normal groups).

Each participant will be studied at varying times over the 2-year study period. Researchers will complete a collection of sputum, blood, urine, and exhaled breath condensate samples; exhaled nitric oxide; and spirometry from CAMPCS/3 participants, representing each of the four phenotypes (n = 20 for a total of 80).

Study Design

• Study Type: Observational
• Actual Enrollment: 55 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Progression of Airway Obstruction in Childhood Asthma
• Study Start Date: Sep 1, 2008
• Actual Primary Completion Date: Jun 1, 2011
• Actual Study Completion Date: Jun 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Persistent obstruction (pattern of asthma progression)
Late obstruction (pattern of asthma progression)
Late normal (pattern of asthma progression)
Persistent normal (pattern of asthma progression)

Outcome Measures

Primary Outcome Measures

1. Airway Wall Thickness [Measured at Year 2]

   Segmental average airway wall thickness

Secondary Outcome Measures

1. Protease/Antiprotease [Measured at Year 2]

   MMP9/TIMP 1 molar ratio MMP9 is matrix metalloproteinse 9 and is a protease enzyme that is responsible for tissue degradation of extracellular matrix and could be a factor in airway remodeling. TIMP 1 is an abbreviation for tissue inhibitor of metalloproteinase-1 and is an inhibitor of MMP9 and would serve to balance the activity protease activity of MMP9 and this it is an anti-protease. Therefore the ratio of MMP9 and TIMP1 is used to assess the relative balance of protease and antiprotease activity.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years to 40 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Must be enrolled in the CAMPCS/3 study; individuals enrolled in this study will represent four different patterns of asthma progression, as defined by forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) levels

Exclusion Criteria:

• Unwilling to comply with study procedures

• Physical state does not allow the study procedures to be performed (e.g., low pulmonary function for induced sputum, pregnancy for computerized tomography [CT] scan)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Jewish Health	Denver	Colorado	United States	80206

Sponsors and Collaborators

• National Jewish Health
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Stanley J. Szefler, MD, National Jewish Health

Study Documents (Full-Text)

None provided.

More Information

Publications

• Childhood Asthma Management Program Research Group, Szefler S, Weiss S, Tonascia J, Adkinson NF, Bender B, Cherniack R, Donithan M, Kelly HW, Reisman J, Shapiro GG, Sternberg AL, Strunk R, Taggart V, Van Natta M, Wise R, Wu M, Zeiger R. Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med. 2000 Oct 12;343(15):1054-63.
• Covar RA, Spahn JD, Murphy JR, Szefler SJ; Childhood Asthma Management Program Research Group. Progression of asthma measured by lung function in the childhood asthma management program. Am J Respir Crit Care Med. 2004 Aug 1;170(3):234-41. Epub 2004 Mar 17.
• Strunk RC, Weiss ST, Yates KP, Tonascia J, Zeiger RS, Szefler SJ; CAMP Research Group. Mild to moderate asthma affects lung growth in children and adolescents. J Allergy Clin Immunol. 2006 Nov;118(5):1040-7.

• Responsible Party: National Jewish Health
• ClinicalTrials.gov Identifier: NCT00873873
• Other Study ID Numbers: 645; R21HL087811-01
• First Posted: Apr 2, 2009
• Last Update Posted: Oct 22, 2020
• Last Verified: Oct 1, 2020

• Keywords provided by National Jewish Health: Asthma Progression; Airway Wall Thickness; Corticosteroid Resistance; Biomarkers; Pulmonary Physiology
• Additional relevant MeSH terms: Asthma; Airway Obstruction; Disease Progression

Study Results

Participant Flow

Recruitment Details	The NHLBI Childhood Asthma Management Program (CAMP) and CAMP Continuation Studies afforded a unique opportunity to investigate four newly described, distinct patterns of airway obstruction associated with childhood asthma, including two that have been associated with significant and potentially irreversible loss in pulmonary function.
Pre-assignment Detail	Analysis of serial pulmonary function measures in participants in CAMP and CAMPCS over time showed 4 patterns of airway obstruction developing during childhood and adolescence based on measurements of pre-bronchodilator FEV1/FVC at the time of enrollment in CAMP and again at the end of the observational phase.

Arm/Group Title	Persistent Obstruction	Late Obstruction in Pulmonary Physiology	Late Normal in Pulmonary Physiology	Persistent Normal in Pulmonary Physiology
Arm/Group Description	This group represents those that have persistent obstruction from baseline at entry into the NHLBI CAMP study until end of the CAMP Continuation study, 9 years later.	This group represents those that had normal pulmonary function from baseline at entry into the NHLBI CAMP study and then has evidence of obstruction, as defined by FEV1/FVC criteria, at end of the CAMP Continuation study, 9 years later.	This group represents those that has evidence of obstruction, as defined by FEV1/FVC criteria, from baseline at entry into the NHLBI CAMP study and then has normal pulmonary function at end of the CAMP.	This groups has normal pulmonary function at the time of entry into the CAMP study and normal pulmonary function 9 years later.
Period Title: Overall Study
STARTED	20	8	9	18
COMPLETED	20	8	9	18
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Persistent Obstruction	Late Obstruction in Pulmonary Physiology	Late Normal in Pulmonary Physiology	Persistent Normal in Pulmonary Physiology	Total
Arm/Group Description	This group represents those that have persistent obstruction from baseline at entry into the NHLBI CAMP study until end of the CAMP Continuation study, 9 years later.	This group represents those that had normal pulmonary function from baseline at entry into the NHLBI CAMP study and then has evidence of obstruction, as defined by FEV1/FVC criteria, at end of the CAMP Continuation study, 9 years later.	This group represents those that has evidence of obstruction, as defined by FEV1/FVC criteria, from baseline at entry into the NHLBI CAMP study and then has normal pulmonary function at end of the CAMP.	This groups has normal pulmonary function at the time of entry into the CAMP study and normal pulmonary function 9 years later.	Total of all reporting groups
Overall Participants	20	8	9	18	55
Age (Count of Participants)
<=18 years	3 15%	2 25%	1 11.1%	3 16.7%	9 16.4%
Between 18 and 65 years	17 85%	6 75%	8 88.9%	15 83.3%	46 83.6%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	20.0 (2.1)	18.9 (2.0)	20.8 (2.4)	19.9 (2.0)	20.0 (2.1)
Sex: Female, Male (Count of Participants)
Female	8 40%	2 25%	6 66.7%	11 61.1%	27 49.1%
Male	12 60%	6 75%	3 33.3%	7 38.9%	28 50.9%
Region of Enrollment (participants) [Number]
United States	20 100%	8 100%	9 100%	18 100%	55 100%

Outcome Measures

1. Primary Outcome

Title	Airway Wall Thickness
Description	Segmental average airway wall thickness
Time Frame	Measured at Year 2

Outcome Measure Data

Analysis Population Description

There were 43 participants with Chest CT data; 1 was excluded from the analysis due to incidental finding of an anatomical congenital anomaly.

Arm/Group Title	Persistent Obstruction	Late Obstruction	Late Normal	Persistent Normal
Arm/Group Description	This group represents those that have persistent obstruction from baseline at entry into the NHLBI CAMP study until end of the CAMP Continuation study, 9 years later.	This group represents those that had normal pulmonary function from baseline at entry into the NHLBI CAMP study and then has evidence of obstruction, as defined by FEV1/FVC criteria, at end of the CAMP Continuation study, 9 years later.	This group represents those that has evidence of obstruction, as defined by FEV1/FVC criteria, from baseline at entry into the NHLBI CAMP study and then has normal pulmonary function at end of the CAMP.	This groups has normal pulmonary function at the time of entry into the CAMP study and normal pulmonary function 9 years later.
Measure Participants	15	7	8	12
Mean (Standard Deviation) [mm]	1.5 (0.2)	1.5 (0.2)	1.4 (0.1)	1.6 (0.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Persistent Obstruction, Late Obstruction, Persistent Normal
	Comments	Is there a difference in airway wall thickness among the 4 groups?
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.2
	Comments
	Method	ANOVA
	Comments

2. Secondary Outcome

Title	Protease/Antiprotease
Description	MMP9/TIMP 1 molar ratio MMP9 is matrix metalloproteinse 9 and is a protease enzyme that is responsible for tissue degradation of extracellular matrix and could be a factor in airway remodeling. TIMP 1 is an abbreviation for tissue inhibitor of metalloproteinase-1 and is an inhibitor of MMP9 and would serve to balance the activity protease activity of MMP9 and this it is an anti-protease. Therefore the ratio of MMP9 and TIMP1 is used to assess the relative balance of protease and antiprotease activity.
Time Frame	Measured at Year 2

Outcome Measure Data

Analysis Population Description

54 participants had induced sputum data but 1 was excluded due to congenital anatomical anomaly (bronchial atresia).

Arm/Group Title	Persistent Obstruction	Late Obstruction	Late Normal	Persistent Normal
Arm/Group Description	This group represents those that have persistent obstruction from baseline at entry into the NHLBI CAMP study until end of the CAMP Continuation study, 9 years later.	This group represents those that had normal pulmonary function from baseline at entry into the NHLBI CAMP study and then has evidence of obstruction, as defined by FEV1/FVC criteria, at end of the CAMP Continuation study, 9 years later.	This group represents those that has evidence of obstruction, as defined by FEV1/FVC criteria, from baseline at entry into the NHLBI CAMP study and then has normal pulmonary function at end of the CAMP.	This groups has normal pulmonary function at the time of entry into the CAMP study and normal pulmonary function 9 years later.
Measure Participants	19	7	9	18
Mean (Standard Deviation) [ratio]	34.1 (58.8)	29.3 (31.3)	9.9 (8.4)	12.1 (9.0)

Adverse Events

Arm/Group Title	Persistent Obstruction		Late Obstruction in Pulmonary Physiology		Late Normal in Pulmonary Physiology		Persistent Normal in Pulmonary Physiology
Arm/Group Description	This group represents those that have persistent obstruction from baseline at entry into the NHLBI CAMP study until end of the CAMP Continuation study, 9 years later.		This group represents those that had normal pulmonary function from baseline at entry into the NHLBI CAMP study and then has evidence of obstruction, as defined by FEV1/FVC criteria, at end of the CAMP Continuation study, 9 years later.		This group represents those that has evidence of obstruction, as defined by FEV1/FVC criteria, from baseline at entry into the NHLBI CAMP study and then has normal pulmonary function at end of the CAMP.		This groups has normal pulmonary function at the time of entry into the CAMP study and normal pulmonary function 9 years later.
All Cause Mortality
	Persistent Obstruction		Late Obstruction in Pulmonary Physiology		Late Normal in Pulmonary Physiology		Persistent Normal in Pulmonary Physiology
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Persistent Obstruction		Late Obstruction in Pulmonary Physiology		Late Normal in Pulmonary Physiology		Persistent Normal in Pulmonary Physiology
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/7 (0%)		0/9 (0%)		0/18 (0%)
Other (Not Including Serious) Adverse Events
	Persistent Obstruction		Late Obstruction in Pulmonary Physiology		Late Normal in Pulmonary Physiology		Persistent Normal in Pulmonary Physiology
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/7 (0%)		0/9 (0%)		0/18 (0%)

Limitations/Caveats

We had planned to extend invitations to the remaining 55 participants in a streamlined version of this protocol after analyzing the preliminary data and an additional cycle of CAMP was funded in 2007.

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.