Individualized Therapy For Asthma in Toddlers (INFANT)

• ClinicalTrials.gov Identifier: NCT01606306
• Recruitment Status: Completed
• First Posted: May 25, 2012
• Results First Posted: March 16, 2017
• Last Update Posted: March 16, 2017
• Sponsor: Milton S. Hershey Medical Center
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): dave mauger, Milton S. Hershey Medical Center

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Conditions: Asthma; Wheezing
• Interventions: Drug: daily fluticasone propionate; Drug: Montelukast; Drug: as-needed fluticasone propionate
• Enrollment: 300

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Crossover Sequence 1	Crossover Sequence 2	Crossover Sequence 3	Crossover Sequence 4	Crossover Sequence 5	Crossover Sequence 6
Arm/Group Description	daily fluticasone propionate, followed by daily montelukast, followed by as needed fluticasone propionate	daily fluticasone propionate, followed by as needed fluticasone propionate, followed by daily montelukast	daily montelukast, followed by as needed fluticasone propionate, followed by daily fluticasone propionate	daily montelukast, followed by daily fluticasone propionate, followed by as needed fluticasone propionate	as needed fluticasone propionate, followed by daily fluticasone propionate, followed by daily montelukast	as needed fluticasone propionate, followed by daily montelukast, followed by daily fluticasone propionate
Period Title: Overall Study
Started	50	49	51	51	52	47
Completed First Treatment Period	43	47	47	45	47	44
Completed Second Treatment Period	41	38	43	44	46	41
Completed Third Treatment Period	35	39	37	38	41	36
Completed	35	39	37	38	41	36
Not Completed	15	10	14	13	11	11
Reason Not Completed
Lack of Efficacy	2	1	4	4	1	2
Adverse Event	1	0	1	1	2	0
Lost to Follow-up	7	4	5	4	3	5
Withdrawal by Subject	4	3	4	4	5	4
Physician Decision	1	2	0	0	0	0

Baseline Characteristics

Arm/Group Title		Crossover Sequence 1	Crossover Sequence 2	Crossover Sequence 3	Crossover Sequence 4	Crossover Sequence 5	Crossover Sequence 6	Total
Arm/Group Description		daily fluticasone propionate, followed by daily montelukast, followed by as needed fluticasone propionate	daily fluticasone propionate, followed by as needed fluticasone propionate, followed by daily montelukast	daily montelukast, followed by as needed fluticasone propionate, followed by daily fluticasone propionate	daily montelukast, followed by daily fluticasone propionate, followed by as needed fluticasone propionate	as needed fluticasone propionate, followed by daily fluticasone propionate, followed by daily montelukast	as needed fluticasone propionate, followed by daily montelukast, followed by daily fluticasone propionate	Total of all reporting groups
Overall Number of Baseline Participants		50	49	51	51	52	47	300
Baseline Analysis Population Description		All randomized participants
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	50 participants	49 participants	51 participants	51 participants	52 participants	47 participants	300 participants
	<=18 years	50 100.0%	49 100.0%	51 100.0%	51 100.0%	52 100.0%	47 100.0%	300 100.0%
	Between 18 and 65 years	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	>=65 years	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Months
	Number Analyzed	50 participants	49 participants	51 participants	51 participants	52 participants	47 participants	300 participants
		38.3 (13.6)	40.7 (12.4)	38.7 (11.6)	38.6 (15.1)	41.7 (12.7)	41.2 (14.0)	39.9 (13.2)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	50 participants	49 participants	51 participants	51 participants	52 participants	47 participants	300 participants
	Female	20 40.0%	20 40.8%	19 37.3%	21 41.2%	18 34.6%	23 48.9%	121 40.3%
	Male	30 60.0%	29 59.2%	32 62.7%	30 58.8%	34 65.4%	24 51.1%	179 59.7%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	50 participants	49 participants	51 participants	51 participants	52 participants	47 participants	300 participants
	Hispanic or Latino	17 34.0%	12 24.5%	10 19.6%	11 21.6%	12 23.1%	10 21.3%	72 24.0%
	Not Hispanic or Latino	33 66.0%	37 75.5%	41 80.4%	40 78.4%	40 76.9%	37 78.7%	228 76.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	50 participants	49 participants	51 participants	51 participants	52 participants	47 participants	300 participants
	American Indian or Alaska Native	1 2.0%	1 2.0%	0 0.0%	2 3.9%	0 0.0%	1 2.1%	5 1.7%
	Asian	2 4.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	2 0.7%
	Native Hawaiian or Other Pacific Islander	1 2.0%	0 0.0%	0 0.0%	1 2.0%	1 1.9%	0 0.0%	3 1.0%
	Black or African American	11 22.0%	15 30.6%	20 39.2%	13 25.5%	20 38.5%	18 38.3%	97 32.3%
	White	25 50.0%	27 55.1%	24 47.1%	30 58.8%	21 40.4%	21 44.7%	148 49.3%
	More than one race	10 20.0%	6 12.2%	7 13.7%	5 9.8%	10 19.2%	7 14.9%	45 15.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	50 participants	49 participants	51 participants	51 participants	52 participants	47 participants	300 participants
		50	49	51	51	52	47	300
Parental Asthma; Measure Type: Number; Unit of measure: Participants	Number Analyzed	50 participants	49 participants	51 participants	51 participants	52 participants	47 participants	300 participants
Present		30	29	29	32	35	23	178
Not Present		20	20	22	19	17	24	122
Systemic corticosteroids in past 12 monts; Measure Type: Number; Unit of measure: Participants	Number Analyzed	50 participants	49 participants	51 participants	51 participants	52 participants	47 participants	300 participants
Used		37	35	37	40	39	36	224
Not used		13	14	14	11	13	11	76
Hospitalized in past 12 months; Measure Type: Number; Unit of measure: Participants	Number Analyzed	50 participants	49 participants	51 participants	51 participants	52 participants	47 participants	300 participants
Hospitalized		9	14	11	6	13	12	65
Not hospitalized		41	35	40	45	39	35	235
Allergen Test; Measure Type: Number; Unit of measure: Participants	Number Analyzed	50 participants	49 participants	51 participants	51 participants	52 participants	47 participants	300 participants
Positive test		18	20	20	21	25	17	121
Negative test		32	29	31	30	27	30	179
Eczema; Measure Type: Number; Unit of measure: Participants	Number Analyzed	50 participants	49 participants	51 participants	51 participants	52 participants	47 participants	300 participants
Present		21	28	27	28	26	30	160
Not Present		29	21	24	23	26	17	140
Blood eosinophils; Median (Inter-Quartile Range); Unit of measure: Number of cells per micro-liter
	Number Analyzed	50 participants	49 participants	51 participants	51 participants	52 participants	47 participants	300 participants
		183; (111 to 435)	234; (153 to 572)	258; (133 to 460)	255; (175 to 457)	308; (184 to 496)	310; (182 to 536)	258; (158 to 492)
Serum IgE; Median (Inter-Quartile Range); Unit of measure: International units per liter
	Number Analyzed	50 participants	49 participants	51 participants	51 participants	52 participants	47 participants	300 participants
		67; (25 to 212)	106.5; (22 to 463)	64; (21 to 141)	64; (31 to 143)	87; (19 to 237)	84; (19 to 348)	70; (22 to 208)

Outcome Measures

1. Primary Outcome

Title	Differential Response to the Three Therapies Based on Fixed Threshold Criteria for the Following Asthma Control Measures: Use of Oral Prednisone for Acute Asthma Exacerbations and Asthma Control Days.
Description	The primary outcome was differential response to the three therapies on the basis of fixed threshold criteria for the following asthma control measures, which encompassed domains of risk and impairment: the time from the start of the treatment period to an asthma exacerbation treated with systemic corticosteroids, and the annualized number of asthma control days (ACDs) from within that period. ACDs were defined as full calendar days without symptoms, rescue medication use, or unscheduled healthcare visits. Children were defined as differential responders if, first, the time to an asthma exacerbation was at least four weeks longer, or second, if the number of annualized ACDs was at least 31 days more for one treatment than another, in that order. If neither threshold was met, the participant was considered a non differential responder. Differential response was determined in children completing at least two treatment periods and at least 50% of the daily diary entries for each period.
Time Frame	The last 14 weeks of each 16-week treatment period

Outcome Measure Data

Analysis Population Description

Differential response was determined in children completing at least two treatment periods and at least 50% of the daily diary entries for each period.

Arm/Group Title	All Evaluable Participants
Arm/Group Description:	Differential response was determined in children completing at least two treatment periods and at least 50% of the daily diary entries for each period. Because placebo washouts were not performed, the data collected during the first two weeks of each period were not included in the analysis of ACDs. Days with missing diary data were also excluded from ACD determination.
Overall Number of Participants Analyzed	230
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: probability
Non-differential responders	.26; (.26 to .26)
Responded best to daily ICS	.40; (.33 to .47)
Responded best to daily LTRA	.18; (.13 to .23)
Responded best to as-needed ICS	.16; (.11 to .21)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Evaluable Participants
	Comments	The primary analysis tested the null hypothesis of all three treatments having equal probability to yield the best response as defined by the criteria defining the primary outcome. A sample size of 300 participants was selected to test the primary null hypothesis of all three treatments having equal probability (one-third) to yield the best response with statistical power of at least 0.90 if any one of the three treatments actually has probability of at least one-half to yield the best response.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Rank-ordered logistic regression (ROLR) was used to model the probability of best response for each treatment and bootstrapping was used to calculate confidence intervals.
	Method	rank-order logistic regression
	Comments	ROLR is in the class of Discrete Choice models, which seek to estimate the probability that an individual responds best to a specific treatments.
Other Statistical Analysis		The probabilistic construct of the Discrete Choice (DC) model does not reflect individual behavior that is intrinsically probabilistic, but rather population heterogeneity. DC models rely on stochastic assumptions to account for unobserved factors related to the treatments themselves and to characteristics of study participants. Specifically, that each treatment has an underlying utility that may differ from one individual to another. Mathematically, these utilities are represented by U_t, where t denotes the treatment. Utility can be thought of as a latent variable quantifying treatment response where higher values indicate better response. The U_t can be used to find the probability (P) of best response for each treatment by the following equation: P_t = exp(U_t) / [exp(U_A) + exp(U_B) + exp(U_C)], where A, B, and C, denote the three study treatments. The primary analysis tested whether the three treatments have equal utility and, thus, equal probability of best response.

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Daily ICS		As-needed ICS		Daily LTRA
Arm/Group Description	Daily inhaled corticosteroid (ICS) treatment		As-needed ICS plus short-acting beta agonist (as-needed ICS/SABA) rescue treatment.		Daily leukotriene receptor antagonist (LTRA) treatment
All-Cause Mortality
	Daily ICS		As-needed ICS		Daily LTRA
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--		--/--
Serious Adverse Events
	Daily ICS		As-needed ICS		Daily LTRA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/300 (0.67%)		8/300 (2.67%)		8/300 (2.67%)
Gastrointestinal disorders
Constipation	0/300 (0.00%)	0	1/300 (0.33%)	1	0/300 (0.00%)	0
Injury, poisoning and procedural complications
Simple laceration	1/300 (0.33%)	1	0/300 (0.00%)	0	0/300 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Influenza	1/300 (0.33%)	1	0/300 (0.00%)	0	0/300 (0.00%)	0
Penumonia	0/300 (0.00%)	0	1/300 (0.33%)	1	0/300 (0.00%)	0
asthma exacerbation	0/300 (0.00%)	0	4/300 (1.33%)	4	8/300 (2.67%)	8
bronchitis	0/300 (0.00%)	0	1/300 (0.33%)	1	0/300 (0.00%)	0
Surgical and medical procedures
tonsilitis	0/300 (0.00%)	0	1/300 (0.33%)	1	0/300 (0.00%)	0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Daily ICS		As-needed ICS		Daily LTRA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	212/300 (70.67%)		206/300 (68.67%)		212/300 (70.67%)
Ear and labyrinth disorders
Otitis media	22/300 (7.33%)	27	24/300 (8.00%)	27	28/300 (9.33%)	29
General disorders
Fever	100/300 (33.33%)	127	89/300 (29.67%)	111	109/300 (36.33%)	146
Headache	16/300 (5.33%)	20	14/300 (4.67%)	17	11/300 (3.67%)	17
Respiratory, thoracic and mediastinal disorders
Acute upper respiratory tract infection	39/300 (13.00%)	45	41/300 (13.67%)	53	54/300 (18.00%)	65
Allergic rhinitis	11/300 (3.67%)	15	16/300 (5.33%)	21	26/300 (8.67%)	36
Cough	27/300 (9.00%)	31	35/300 (11.67%)	42	26/300 (8.67%)	32
Wheezing	41/300 (13.67%)	47	59/300 (19.67%)	70	68/300 (22.67%)	84

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: David Mauger, PhD
• Organization: Penn State University Dept of Public Health Sciences
• Phone: 717.573.0336
• EMail: dmauger@psu.edu

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Fitzpatrick AM, Jackson DJ, Mauger DT, Boehmer SJ, Phipatanakul W, Sheehan WJ, Moy JN, Paul IM, Bacharier LB, Cabana MD, Covar R, Holguin F, Lemanske RF Jr, Martinez FD, Pongracic JA, Beigelman A, Baxi SN, Benson M, Blake K, Chmiel JF, Daines CL, Daines MO, Gaffin JM, Gentile DA, Gower WA, Israel E, Kumar HV, Lang JE, Lazarus SC, Lima JJ, Ly N, Marbin J, Morgan W, Myers RE, Olin JT, Peters SP, Raissy HH, Robison RG, Ross K, Sorkness CA, Thyne SM, Szefler SJ; NIH/NHLBI AsthmaNet. Individualized therapy for persistent asthma in young children. J Allergy Clin Immunol. 2016 Dec;138(6):1608-1618.e12. doi: 10.1016/j.jaci.2016.09.028. Epub 2016 Oct 21.

• Responsible Party: dave mauger, Milton S. Hershey Medical Center
• ClinicalTrials.gov Identifier: NCT01606306
• Other Study ID Numbers: AsthmaNet 004; 1U10HL098115 ( U.S. NIH Grant/Contract )
• First Submitted: May 23, 2012
• First Posted: May 25, 2012
• Results First Submitted: September 15, 2016
• Results First Posted: March 16, 2017
• Last Update Posted: March 16, 2017