A Randomized Trial of Outpatient Oxygen Weaning Strategies in Premature Infants

• ClinicalTrials.gov Identifier: NCT01994954
• Recruitment Status: Completed
• First Posted: November 26, 2013
• Results First Posted: October 2, 2019
• Last Update Posted: October 2, 2019
• Sponsor: University of Massachusetts, Worcester
• Collaborators: Bay State Medical Center; UConn Health; University of Vermont Medical Center; Connecticut Children's Medical Center; Patient-Centered Outcomes Research Institute; University of Kentucky; Boston Children's Hospital; Dartmouth-Hitchcock Medical Center; Tufts Medical Center; Westchester Medical Center
• Information provided by (Responsible Party): Lawrence Rhein, University of Massachusetts, Worcester

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Diagnostic
• Condition: Premature Infants
• Intervention: Other: RHO
• Enrollment: 196

Participant Flow

Recruitment Details	Eligible patients were screened from November 2013 to December 2017. Subjects were screened either before NICU discharge with anticipation of HOT therapy or at their first pulmonary clinic visit. Each subject was consented at their first outpatient pulmonary clinic or NICU follow-up clinic with a pulmonary component.
Pre-assignment Details

Arm/Group Title	Arm A:Standard Therapy	Arm B:RHO
Arm/Group Description	Infants' oxygen will be increased, decreased, or maintained based on brief structured assessments during monthly clinic visits. Polysomnograms will be utilized prior to final discontinuation of oxygen. RHO will only be utilized on the night prior to and during the polysomnogram to compare these two modalities.	Infants will have the same monthly clinic assessments as in Arm A, but also will utilize RHO to potentially increase, decrease or maintain oxygen between monthly visits. Parents will transmit a minimum of 4 days of stored RHO data (min 8 hrs per day) every 4-7 days. Changes in oxygen needs will be made based on standardized objective criteria. To determine discontinuation of oxygen, RHO will be utilized instead of polysomnography. RHO: Recorded oximetry data will be downloaded from home oximeters, analyzed, and used to assist in supplemental oxygen weaning decisions.
Period Title: Overall Study
Started	99	97
Completed	74	67
Not Completed	25	30
Reason Not Completed
Death	1	0
Withdrawal by Subject	9	14
Physician Decision	2	2
Lost to Follow-up	8	10
6 Month Follow-up Not Complete	5	4

Baseline Characteristics

Arm/Group Title		Arm A:Standard Therapy	Arm B:RHO	Total
Arm/Group Description		Infants' oxygen will be increased, decreased, or maintained based on brief structured assessments during monthly clinic visits. Polysomnograms will be utilized prior to final discontinuation of oxygen. RHO will only be utilized on the night prior to and during the polysomnogram to compare these two modalities.	Infants will have the same monthly clinic assessments as in Arm A, but also will utilize RHO to potentially increase, decrease or maintain oxygen between monthly visits. Parents will transmit a minimum of 4 days of stored RHO data (min 8 hrs per day) every 4-7 days. Changes in oxygen needs will be made based on standardized objective criteria. To determine discontinuation of oxygen, RHO will be utilized instead of polysomnography. RHO: Recorded oximetry data will be downloaded from home oximeters, analyzed, and used to assist in supplemental oxygen weaning decisions.	Total of all reporting groups
Overall Number of Baseline Participants		99	97	196
Baseline Analysis Population Description		[Not Specified]
Age, Customized; Measure Type: Count of Participants; Unit of measure: Participants
Less than 1 Year of Age	Number Analyzed	99 participants	97 participants	196 participants
		99 100.0%	97 100.0%	196 100.0%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	99 participants	97 participants	196 participants
	Female	41 41.4%	33 34.0%	74 37.8%
	Male	58 58.6%	64 66.0%	122 62.2%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	99 participants	97 participants	196 participants
	Hispanic or Latino	12 12.1%	6 6.2%	18 9.2%
	Not Hispanic or Latino	61 61.6%	65 67.0%	126 64.3%
	Unknown or Not Reported	26 26.3%	26 26.8%	52 26.5%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	99 participants	97 participants	196 participants
	American Indian or Alaska Native	0 0.0%	1 1.0%	1 0.5%
	Asian	1 1.0%	4 4.1%	5 2.6%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	12 12.1%	13 13.4%	25 12.8%
	White	57 57.6%	59 60.8%	116 59.2%
	More than one race	7 7.1%	5 5.2%	12 6.1%
	Unknown or Not Reported	22 22.2%	15 15.5%	37 18.9%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	99 participants	97 participants	196 participants
		99	97	196
Respiratory Support at 36 Weeks; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	99 participants	97 participants	196 participants
	Mechanical Ventilation	3 3.0%	6 6.2%	9 4.6%
	Non-Invasive Positive Pressure (CPAP/HFNC)	52 52.5%	48 49.5%	100 51.0%
	Low-Flow Nasal Cannula (LFNC)	36 36.4%	32 33.0%	68 34.7%
	Room Air	2 2.0%	5 5.2%	7 3.6%
	Unknown	6 6.1%	6 6.2%	12 6.1%
Diuretics; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	99 participants	97 participants	196 participants
	Yes	52 52.5%	51 52.6%	103 52.6%
	No	41 41.4%	38 39.2%	79 40.3%
	Unknowns	6 6.1%	8 8.2%	14 7.1%
Birth Weight; Mean (Standard Deviation); Unit of measure: Grams
	Number Analyzed	99 participants	97 participants	196 participants
		938.2 (439.1)	929.5 (442.6)	933.9 (439.6)
Gestational Age (wks); Mean (Standard Deviation); Unit of measure: Birth Gestational Age (Weeks)
	Number Analyzed	99 participants	97 participants	196 participants
		26.9 (2.6)	26.9 (2.7)	26.9 (2.6)
Length of NICU Stay (days); Mean (Standard Deviation); Unit of measure: Days
	Number Analyzed	99 participants	97 participants	196 participants
		97.7 (33.4)	104.4 (36.7)	101 (35.1)

Outcome Measures

1. Primary Outcome

Title	Duration of Home Oxygen Therapy
Description	Duration of home oxygen use from time of randomization (baseline visit) to successful discontinuation of home oxygen therapy (HOT).
Time Frame	NICU discharge date until successful discontinuation of home oxygen therapy (HOT), up to 26 months.

Outcome Measure Data

Analysis Population Description

A total of 166 infants were weaned successfully from HOT using one of our two methods, and a total of 140 subjects completed all study procedures through six months of follow-up post discontinuation of HOT. A total of 30 subjects were not weaned using either method due to being lost to follow-up, withdrawing, or parents self-weaning subject.

Arm/Group Title	Arm A:Standard Therapy	Arm B:RHO
Arm/Group Description:	Infants' oxygen will be increased, decreased, or maintained based on brief structured assessments during monthly clinic visits. Polysomnograms will be utilized prior to final discontinuation of oxygen. RHO will only be utilized on the night prior to and during the polysomnogram to compare these two modalities.	Infants will have the same monthly clinic assessments as in Arm A, but also will utilize RHO to potentially increase, decrease or maintain oxygen between monthly visits. Parents will transmit a minimum of 4 days of stored RHO data (min 8 hrs per day) every 4-7 days. Changes in oxygen needs will be made based on standardized objective criteria. To determine discontinuation of oxygen, RHO will be utilized instead of polysomnography. RHO: Recorded oximetry data will be downloaded from home oximeters, analyzed, and used to assist in supplemental oxygen weaning decisions.
Overall Number of Participants Analyzed	87	79
Median (90% Confidence Interval); Unit of Measure: Days
	66; (42 to 113)	58; (24 to 127)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A:Standard Therapy, Arm B:RHO
	Comments	The trial was designed to have 97% power at a type I error rate of 5% to detect a 25% intervention effect with respect to the primary outcome. this was done using an independent sample t-test. P-value was calculated, and a p-value of 0.05 or less was interpreted as statistically significant result.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.03
	Comments	A two-sided P-value of 0.05 or less was interpreted as a statistically significant result.
	Method	t-test, 2 sided
	Comments	[Not Specified]

2. Primary Outcome

Title	Caregiver Quality of Life
Description	We will compare the difference between survey-derived quality-of-life scores, comparing parent response averages while on home oxygen therapy (HOT) versus 3 months post oxygen discontinuation scores in both arms. The infant scale is composed of 36 items comprising 5 dimensions. The item scaling is a 5-point Likert scale from 0 (never) to 4 (almost always). Scores range from 0 to 100, with a higher score indicating a higher parent satisfaction and quality of life.
Time Frame	Monthly while on home oxygen therapy and at 3 months post discontinuation of therapy

Outcome Measure Data

Analysis Population Description

The final cohort included 196 infants, of those infants 105 parents completed at least one pre-parent satisfactory survey and one post-survey.

Arm/Group Title	Arm A:Standard Therapy	Arm B:RHO
Arm/Group Description:	Infants' oxygen will be increased, decreased, or maintained based on brief structured assessments during monthly clinic visits. Polysomnograms will be utilized prior to final discontinuation of oxygen. RHO will only be utilized on the night prior to and during the polysomnogram to compare these two modalities.	Infants will have the same monthly clinic assessments as in Arm A, but also will utilize RHO to potentially increase, decrease or maintain oxygen between monthly visits. Parents will transmit a minimum of 4 days of stored RHO data (min 8 hrs per day) every 4-7 days. Changes in oxygen needs will be made based on standardized objective criteria. To determine discontinuation of oxygen, RHO will be utilized instead of polysomnography. RHO: Recorded oximetry data will be downloaded from home oximeters, analyzed, and used to assist in supplemental oxygen weaning decisions.
Overall Number of Participants Analyzed	51	54
Mean (Standard Deviation); Unit of Measure: score on a scale
Pre-Wean from HOT	74.5 (16.3)	70.4 (15.0)
Post-Wean from HOT	78.6 (18.6)	75.9 (17.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A:Standard Therapy, Arm B:RHO
	Comments	Power calculations were based on the primary analysis (t-test comparing changes). A sample size of 130 would have given 80% power, with 0.05 two sided type 1 error rate, to detect a 20% absolute difference in emotional role limitation on the PedsQL v2.0, which we considered to be statistically significant.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.38
	Comments	[Not Specified]
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

3. Secondary Outcome

Title	Participants With Respiratory-related Emergency Department Visits and Rehospitalizations
Description	We will assess rates of rehospitalization or ED visit throughout the weaning process and continue to assess until 6 months post discontinuation.
Time Frame	WIthin 6 months of discontinuation of home oxygen

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A:Standard Therapy	Arm B:RHO
Arm/Group Description:	Infants' oxygen will be increased, decreased, or maintained based on brief structured assessments during monthly clinic visits. Polysomnograms will be utilized prior to final discontinuation of oxygen. RHO will only be utilized on the night prior to and during the polysomnogram to compare these two modalities.	Infants will have the same monthly clinic assessments as in Arm A, but also will utilize RHO to potentially increase, decrease or maintain oxygen between monthly visits. Parents will transmit a minimum of 4 days of stored RHO data (min 8 hrs per day) every 4-7 days. Changes in oxygen needs will be made based on standardized objective criteria. To determine discontinuation of oxygen, RHO will be utilized instead of polysomnography. RHO: Recorded oximetry data will be downloaded from home oximeters, analyzed, and used to assist in supplemental oxygen weaning decisions.
Overall Number of Participants Analyzed	99	97
Measure Type: Number; Unit of Measure: participants
All Events	41	25
Serious Adverse Event	28	19
Life Threatening, ICU admission or Intubation (G4)	7	6
Hospitalization (G3)	30	19
Intervention without hospitalization	39	26
Event During Respiratory Virus Season	29	17
Event During Non-Respiratory Season	26	15
Respiratory Related Events	26	20
Non-Respiratory Related Events	25	14

4. Secondary Outcome

Title	Growth Parameters
Description	Growth measurements were taken at each monthly clinic visit while on oxygen. The average for weight z-score change was calculated for each subject while on oxygen therapy. After oxygen discontinuation, growth measurements were taken at the 1 month and 6 month post wean visits. These two measurements were again averaged for each patient. The weight z-score change was found in both arms for pre and post weaning from home oxygen therapy. The weight z-score indicates the number of standard deviations away from the mean a participants weight is. A z-score of 0 is equal to the mean. Negative numbers indicate values lower than the mean and positive numbers indicate values higher than the mean.
Time Frame	Enrollment to 6 months post home oxygen therapy discontinuation

Outcome Measure Data

Analysis Population Description

We had data for 87 and 72 infants in the standard of care arm and RHO arm, respectively, during the O2 weaning process, and 80 and 73 infants after O2 discontinuation.

Arm/Group Title	Arm A: Standard of Care, Pre-Weaning	Arm B: Intervention Arm; Pre-Weaning	Arm A: Standard of Care; Post-Weaning	Arm B: Intervention Arm; Post-Weaning
Arm/Group Description:	Growth assessments were documented at each monthly clinic visit while on oxygen. Infants who had at least one assessment were included in the analysis.	Growth assessments were documented at each monthly clinic visit while on oxygen. Infants who had at least one assessment were included in the analysis.	Growth assessments were documented at the one and six month follow-up visits. Infants who had at least one assessment were included in the analysis.	Growth assessments were documented at the one and six month follow-up visits. Infants who had at least one assessment were included in the analysis.
Overall Number of Participants Analyzed	87	72	80	73
Mean (Standard Deviation); Unit of Measure: Weight z-score change
	-0.13 (0.03)	-0.01 (0.03)	0.02 (0.03)	0.03 (0.03)

5. Secondary Outcome

Title	Growth Parameters, Weight-for-length Z-score Change
Description	Growth measurements were taken at each monthly clinic visit while on oxygen. The average for weight for length z-score change was calculated for each subject while on oxygen therapy. After oxygen discontinuation, growth measurements were taken at the 1 month and 6 month post wean visits. These two measurements were again averaged for each patient. The weight for length z-score change was found in both arms for pre and post weaning from home oxygen therapy.The weight-for-length z-score indicates the number of standard deviations away from the mean a participants weight is. A z-score of 0 is equal to the mean. Negative numbers indicate values lower than the mean and positive numbers indicate values higher than the mean.
Time Frame	Enrollment through 6 months post discontinuation of home oxygen therapy

Outcome Measure Data

Analysis Population Description

We had data for 87 and 72 infants in the standard of care arm and RHO arm, respectively, during the O2 weaning process, and 80 and 73 infants after O2 discontinuation.

Arm/Group Title	Arm A: Standard of Care, Pre-Weaning	Arm B: Intervention Arm; Pre-Weaning	Arm A: Standard of Care; Post-Weaning	Arm B: Intervention Arm; Post-Weaning
Arm/Group Description:	Growth assessments were documented at each monthly clinic visit while on oxygen. Infants who had at least one assessment were included in the analysis.	Growth assessments were documented at each monthly clinic visit while on oxygen. Infants who had at least one assessment were included in the analysis.	Growth assessments were documented at the one month and six month post wean follow-up visits. Infants who had at least one assessment in the follow-up period were included in the analysis.	Growth assessments were documented at the one month and six month post wean follow-up visits. Infants who had at least one assessment in the follow-up period were included in the analysis.
Overall Number of Participants Analyzed	87	72	80	73
Mean (Standard Error); Unit of Measure: Weight-for-Length z-score change
	-0.17 (0.06)	-0.06 (0.07)	-0.14 (0.07)	0.01 (0.07)

Adverse Events

Time Frame	Adverse events were tracked from enrollment until 6 months post home oxygen therapy discontinuation.
Adverse Event Reporting Description	Grade 1: No Intervention Grade 2: Intervention without hospitalization concomitant-drug/non-drug therapy Grade 3: Hospitalization (Serious Adverse Event) Grade 4: Life Threatening, ICU Admission, Intubation (Serious Adverse Event) Grade 5: Death (Serious Adverse Event)
Arm/Group Title	Arm A:Standard Therapy		Arm B:RHO
Arm/Group Description	Infants' oxygen will be increased, decreased, or maintained based on brief structured assessments during monthly clinic visits. Polysomnograms will be utilized prior to final discontinuation of oxygen. RHO will only be utilized on the night prior to and during the polysomnogram to compare these two modalities.		Infants will have the same monthly clinic assessments as in Arm A, but also will utilize RHO to potentially increase, decrease or maintain oxygen between monthly visits. Parents will transmit a minimum of 4 days of stored RHO data (min 8 hrs per day) every 4-7 days. Changes in oxygen needs will be made based on standardized objective criteria. To determine discontinuation of oxygen, RHO will be utilized instead of polysomnography. RHO: Recorded oximetry data will be downloaded from home oximeters, analyzed, and used to assist in supplemental oxygen weaning decisions.
All-Cause Mortality
	Arm A:Standard Therapy		Arm B:RHO
	Affected / at Risk (%)		Affected / at Risk (%)
Total	41/99 (41.41%)		26/97 (26.80%)
Serious Adverse Events
	Arm A:Standard Therapy		Arm B:RHO
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	28/99 (28.28%)		19/97 (19.59%)
Gastrointestinal disorders
Feeding Issue/G-Tube Complication †	8/99 (8.08%)	8	1/97 (1.03%)	2
Respiratory, thoracic and mediastinal disorders
Viral Respiratory Event † [1]	16/99 (16.16%)	22	18/97 (18.56%)	20
Other † [2]	4/99 (4.04%)	10	0/97 (0.00%)	0
† Indicates events were collected by systematic assessment; [1] Former preterm infants are at an increased risk for respiratory adverse events and morbidity.; [2] Other serious adverse events related to prematurity
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Arm A:Standard Therapy		Arm B:RHO
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/99 (13.13%)		10/97 (10.31%)
Respiratory, thoracic and mediastinal disorders
Respiratory Related Event †	13/99 (13.13%)	15	10/97 (10.31%)	11
† 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: Dr. Lawrence Rhein
• Organization: University of Massachusetts Medical School
• Phone: 508-334-6206
• EMail: Lawrence.Rhein@umassmemorial.org

• Responsible Party: Lawrence Rhein, University of Massachusetts, Worcester
• ClinicalTrials.gov Identifier: NCT01994954
• Other Study ID Numbers: IP00009772
• First Submitted: November 20, 2013
• First Posted: November 26, 2013
• Results First Submitted: February 1, 2019
• Results First Posted: October 2, 2019
• Last Update Posted: October 2, 2019