TOLSURF: Trial of Late Surfactant for Prevention of Bronchopulmonary Dysplasia

• Sponsor: Roberta Ballard (Other)
• Overall Status: Completed
• CT.gov ID: NCT01022580
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 511
• Locations: 21
• Arms: 2
• Duration (Months): 72
• Patients Per Site: 24.3
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if late doses of Infasurf surfactant given when patients are receiving inhaled nitric oxide will interact to improve surfactant function and increase survival without BPD in treated infants.

Condition or Disease	Intervention/Treatment	Phase
Bronchopulmonary Dysplasia	Drug: Infasurf surfactant (ONY, Inc.); Drug: Sham (No Treatment)	Phase 3

Detailed Description

This is a multi-center, blinded, randomized controlled clinical trial to evaluate the effects of booster doses of exogenous surfactant (Infasurf®, calfactant) in addition to inhaled nitric oxide (iNO) on the outcome of survival without bronchopulmonary dysplasia (BPD, or chronic lung disease of prematurity, characterized by chronic lung dysfunction) at 36 weeks' post-menstrual age (PMA) in extremely low gestational age (ELGAN) infants that are at high risk of the development of BPD. This multi-center trial, with a planned enrollment of 524 infants, will also enable us to evaluate for any adverse effects of late surfactant treatment on short- and long-term outcomes, as we will be collecting data on effects of dosing of late surfactant, co-morbidities of prematurity and neurodevelopmental and pulmonary outcome at 1 year and 24 months corrected age. In addition, we will collect biological specimens for evaluation of the effects of late surfactant replacement therapy (administered as described in this trial) on surfactant function and inflammatory markers.

Study Design

• Study Type: Interventional
• Actual Enrollment: 511 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Trial of Late Surfactant for Prevention of Bronchopulmonary Dysplasia: A Study in Ventilated Preterm Infants Receiving Inhaled Nitric Oxide
• Study Start Date: Jan 1, 2010
• Actual Primary Completion Date: Dec 1, 2013
• Actual Study Completion Date: Jan 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Infasurf surfactant (ONY, Inc.) Infants already receiving inhaled nitric oxide will receive scheduled doses of late surfactant (Infasurf) on study days 0, 2, 4, 6 and 8.	Drug: Infasurf surfactant (ONY, Inc.); Late doses of Infasurf 3ml/kg will be given to infants on study days 0, 2, 4, 6 and 8 as long as infant remains intubated.; Other Names: Treatment
Sham Comparator: Sham (No Treatment) Infants already receiving inhaled nitric oxide will receive "Sham (no treatment)" doses on study days 0,2,4,6, and 8.	Drug: Sham (No Treatment); Late doses of Sham (No treatment) will be given to infants on study days 0, 2, 4, 6 and 8 as long as infant remains intubated.; Other Names: Control

Outcome Measures

Primary Outcome Measures

1. Survival Without BPD at 36 Weeks Post Menstrual Age. [36 weeks post menstrual age +/- 1 week]

   BPD was diagnosed as need for respiratory support with either positive pressure and/or oxygen as evaluated by physiological oxygen/flow reduction.

Secondary Outcome Measures

1. Survival Without BPD at 40 Weeks [40 weeks PMA +/- 1 week]

   BPD was diagnosed as need for respiratory support with either positive pressure and/or oxygen as evaluated by physiological oxygen/flow reduction.

2. Respiratory Outcomes of TOLSURF Infants at 1 Year Corrected Age [1 year]

   Evaluation of respiratory outcome through the first 12 months after birth. questionnaires were administered by phone at 3,6,9 and 12 months to determine respiratory resource use (medications, home support, and hospitalization) No Pulmonary Morbidity (NoPM) was reported for infants who had no resource use in any quarter and Persistent PM was reported for infants having resource use in 3 or 4 quarters.

3. Pulmonary Outcomes Through 2 Years of Age [2 years]

   Evaluation of pulmonary outcome at 24 months of age. Evaluation of persistent wheezing based on reported wheezing during both first and second year of life.

4. Percentage of Participants With Neurodevelopmental Impairment (NDI) at 2 Years. [2 years]

   At 24 months corrected age, children underwent neuropsychological testing with the Bayley Scales of Infant Development-Third Edition (Bayley-3), and composite cognitive, language, and motor scores were collected as well as subscale scores in receptive and expressive speech and fine and gross motor. Infants with greater than one impairment as identified by testing were classified as having neurodevelopmental impairment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 7 Days to 14 Days
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• <=28 0/7 weeks gestational age

• Day of life 7-14

• Intubated and mechanically ventilated

• Plan to treat with inhaled nitric oxide

Exclusion Criteria:

• Serious congenital malformations or chromosomal abnormalities

• Life expectancy <7 days from enrollment

• Clinically unstable

• Less tha 48 hours since last dose surfactant

• Ability to obtain 36 week primary outcome information is unlikely

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Arkansas - Arkansas Childrens Hospital	Little Rock	Arkansas	United States	72202
2	Alta Bates Medical Center	Berkeley	California	United States	94705
3	Oakland Children's Hospital	Oakland	California	United States	94609
4	University of California, San Francisco	San Francisco	California	United States	94143
5	Wolfson Children's Hospital and Shands HospitaL	Jacksonville	Florida	United States	32207
6	Florida Hospital for Children	Orlando	Florida	United States	32803
7	All Children's Hospital	Saint Petersburg	Florida	United States	33701
8	Northwestern Memorial Hospital	Chicago	Illinois	United States	60611
9	Children's Memorial Hospital	Chicago	Illinois	United States	60614
10	Childrens Hospital and Clinics of Minnesota- Minneapolis	Minneapolis	Minnesota	United States	55404
11	University of Minnesota Medical School	Minneapolis	Minnesota	United States	55455
12	Children's Hospital and Clinics of Minnesota - St Paul	Saint Paul	Minnesota	United States	55102
13	Children's Mercy Hospital	Kansas City	Missouri	United States	64108
14	Women's and Children's Hospital of Buffalo	Buffalo	New York	United States	14222
15	Stony Brook University Medical Center	Stony Brook	New York	United States	11794
16	Wake Forest University- Forsyth Hospital and Brenner Hospital	Winston-Salem	North Carolina	United States	27103
17	Medical University of South Carolina(MUSC)	Charleston	South Carolina	United States	29403
18	UT Memphis- Memphis Medical Center	Memphis	Tennessee	United States	38103-2807
19	UT Houston Health Science Center	Houston	Texas	United States	77030-1503
20	Texas Children's Hospital	Houston	Texas	United States	77030
21	University of Washington, Seattle	Seattle	Washington	United States	98195-6320

Sponsors and Collaborators

• Roberta Ballard
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Roberta A Ballard, MD, University of California, San Francisco

Study Documents (Full-Text)

None provided.

More Information

Publications

• Ballard PL, Merrill JD, Truog WE, Godinez RI, Godinez MH, McDevitt TM, Ning Y, Golombek SG, Parton LA, Luan X, Cnaan A, Ballard RA. Surfactant function and composition in premature infants treated with inhaled nitric oxide. Pediatrics. 2007 Aug;120(2):346-53.
• Ballard RA, Truog WE, Cnaan A, Martin RJ, Ballard PL, Merrill JD, Walsh MC, Durand DJ, Mayock DE, Eichenwald EC, Null DR, Hudak ML, Puri AR, Golombek SG, Courtney SE, Stewart DL, Welty SE, Phibbs RH, Hibbs AM, Luan X, Wadlinger SR, Asselin JM, Coburn CE; NO CLD Study Group. Inhaled nitric oxide in preterm infants undergoing mechanical ventilation. N Engl J Med. 2006 Jul 27;355(4):343-53. Erratum in: N Engl J Med. 2007 Oct 4;357(14):1444-5.
• Truog WE, Ballard PL, Norberg M, Golombek S, Savani RC, Merrill JD, Parton LA, Cnaan A, Luan X, Ballard RA; Nitric Oxide (to Prevent) Chronic Lung Disease Study Investigators. Inflammatory markers and mediators in tracheal fluid of premature infants treated with inhaled nitric oxide. Pediatrics. 2007 Apr;119(4):670-8.

• Responsible Party: Roberta Ballard, Professor of Pediatrics, University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT01022580
• Other Study ID Numbers: H10842-33541-01A; U01HL094338
• First Posted: Dec 1, 2009
• Last Update Posted: May 13, 2021
• Last Verified: Apr 1, 2021

• Keywords provided by Roberta Ballard, Professor of Pediatrics, University of California, San Francisco: nitric oxide; surfactant; BPD; prematurity; neonates; iNO; pulmonary outcome; neurodevelopmental outcome; Infasurf; lung function; Surfactant Dysfunction; Bronchopulmonary Dysplasia
• Additional relevant MeSH terms: Bronchopulmonary Dysplasia; Hyperplasia; Pulmonary Surfactants; Calfactant

Study Results

Participant Flow

Arm/Group Title	Infasurf Surfactant (ONY, Inc.)	Sham
Arm/Group Description	Infants already receiving inhaled nitric oxide will receive scheduled doses of late surfactant (Infasurf) on study days 0, 2, 4, 6 and 8. Infasurf surfactant (ONY, Inc.): Late doses of Infasurf 3ml/kg will be given to infants on study days 0, 2, 4, 6 and 8.	Infants already receiving inhaled nitric oxide will not receive additional doses of late surfactant (Infasurf).
Period Title: Overall Study
STARTED	252	259
COMPLETED	234	237
NOT COMPLETED	18	22

Baseline Characteristics

Arm/Group Title	Infasurf Surfactant (ONY, Inc.)	Sham	Total
Arm/Group Description	Infants already receiving inhaled nitric oxide will receive scheduled doses of late surfactant (Infasurf) on study days 0, 2, 4, 6 and 8. Infasurf surfactant (ONY, Inc.): Late doses of Infasurf 3ml/kg will be given to infants on study days 0, 2, 4, 6 and 8.	Infants already receiving inhaled nitric oxide will not receive additional doses of late surfactant (Infasurf).	Total of all reporting groups
Overall Participants	252	259	511
Age (weeks) [Mean (Standard Deviation) ]
Gestational Age Weeks	25.2 (1.2)	25.2 (1.2)	25.2 (1.2)
Sex: Female, Male (Count of Participants)
Female	109 43.3%	121 46.7%	230 45%
Male	143 56.7%	138 53.3%	281 55%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	23 9.1%	33 12.7%	56 11%
Not Hispanic or Latino	227 90.1%	225 86.9%	452 88.5%
Unknown or Not Reported	2 0.8%	1 0.4%	3 0.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 0.8%	3 1.2%	5 1%
Asian	9 3.6%	5 1.9%	14 2.7%
Native Hawaiian or Other Pacific Islander	1 0.4%	0 0%	1 0.2%
Black or African American	99 39.3%	91 35.1%	190 37.2%
White	134 53.2%	157 60.6%	291 56.9%
More than one race	3 1.2%	1 0.4%	4 0.8%
Unknown or Not Reported	4 1.6%	2 0.8%	6 1.2%
Respiratory Severity Score (RSS) - MAP x FiO2 (score on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [score on a scale]	3.7 (2.3)	3.8 (2.2)	3.75 (3.25)
Birthweight (grams) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [grams]	700.1 (173.2)	702.3 (156.0)	701 (160)

Outcome Measures

1. Primary Outcome

Title	Survival Without BPD at 36 Weeks Post Menstrual Age.
Description	BPD was diagnosed as need for respiratory support with either positive pressure and/or oxygen as evaluated by physiological oxygen/flow reduction.
Time Frame	36 weeks post menstrual age +/- 1 week

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Infasurf Surfactant (ONY, Inc.)	Sham
Arm/Group Description	Infants already receiving inhaled nitric oxide will receive scheduled doses of late surfactant (Infasurf) on study days 0, and repeated Q24-72 hours as long as infant remains ventilated. Infasurf surfactant (ONY, Inc.): Late doses of Infasurf 3ml/kg will be given to infants on study days 0, and repeated Q24-72 hours as long as infant remains ventilated.	Infants already receiving inhaled nitric oxide will receive scheduled sham (nothing done) doses of late surfactant (nothing done). Sham (nothing done) doses will be given to infants on study days 0,and repeated Q24-72 hours as long as infant remains ventilated.
Measure Participants	252	259
Count of Participants [Participants]	79 31.3%	82 31.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Infasurf Surfactant (ONY, Inc.), Sham
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.89
	Comments
	Method	unadj GEE
	Comments

2. Secondary Outcome

Title	Survival Without BPD at 40 Weeks
Description	BPD was diagnosed as need for respiratory support with either positive pressure and/or oxygen as evaluated by physiological oxygen/flow reduction.
Time Frame	40 weeks PMA +/- 1 week

Outcome Measure Data

Analysis Population Description

Infants who were No BPD at 36 wk were imputed to be No BPD at 40 wk. Infants discharged on oxygen without a challenge test were assigned Yes BPD.

Arm/Group Title	Infasurf Surfactant (ONY, Inc.)	Sham
Arm/Group Description	Infants already receiving inhaled nitric oxide will receive scheduled doses of late surfactant (Infasurf) upon entry into study. Repeat Infasurf surfactant (ONY, Inc.) doses will be given to infants still ventilated on study days (+/- 24 hours): 2, 4, 6 and 8.	Infants already receiving inhaled nitric oxide will receive Sham (no treatment) upon entry into study. Repeat Sham doses will be given to infants still ventilated on study days (+/- 24 hours): 2, 4, 6 and 8.
Measure Participants	252	259
Count of Participants [Participants]	148 58.7%	140 54.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Infasurf Surfactant (ONY, Inc.), Sham
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.33
	Comments
	Method	unadj GEE
	Comments

3. Secondary Outcome

Title	Respiratory Outcomes of TOLSURF Infants at 1 Year Corrected Age
Description	Evaluation of respiratory outcome through the first 12 months after birth. questionnaires were administered by phone at 3,6,9 and 12 months to determine respiratory resource use (medications, home support, and hospitalization) No Pulmonary Morbidity (NoPM) was reported for infants who had no resource use in any quarter and Persistent PM was reported for infants having resource use in 3 or 4 quarters.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Infants who survived to discharge and had data from questionaires available

Arm/Group Title	Infasurf Surfactant (ONY, Inc.)	Sham
Arm/Group Description	Infants who received inhaled nitric oxide and late doses of surfactant will have respiratory questionaires administered by phone at 3,6,9 and 12 months.	Infants who received only inhaled nitric oxide will have respiratory questionaires administered by phone at 3,6,9 and 12 months
Measure Participants	208	240
Home respiratory support	80 31.7%	118 45.6%
No PM	54 21.4%	47 18.1%
Persistent PM	74 29.4%	75 29%

4. Secondary Outcome

Title	Pulmonary Outcomes Through 2 Years of Age
Description	Evaluation of pulmonary outcome at 24 months of age. Evaluation of persistent wheezing based on reported wheezing during both first and second year of life.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Infasurf Surfactant (ONY, Inc.)	Sham
Arm/Group Description	Infants already receiving inhaled nitric oxide will receive scheduled doses of late surfactant (Infasurf) on study days 0, 2, 4, 6 and 8. Infasurf surfactant (ONY, Inc.): Late doses of Infasurf 3ml/kg will be given to infants on study days 0, 2, 4, 6 and 8.	Infants already receiving inhaled nitric oxide will not receive additional doses of late surfactant (Infasurf).
Measure Participants	203	217
Count of Participants [Participants]	91 36.1%	98 37.8%

5. Secondary Outcome

Title	Percentage of Participants With Neurodevelopmental Impairment (NDI) at 2 Years.
Description	At 24 months corrected age, children underwent neuropsychological testing with the Bayley Scales of Infant Development-Third Edition (Bayley-3), and composite cognitive, language, and motor scores were collected as well as subscale scores in receptive and expressive speech and fine and gross motor. Infants with greater than one impairment as identified by testing were classified as having neurodevelopmental impairment.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Neurodevelopmental testing occurred with only 322 participants.

Arm/Group Title	Infasurf Surfactant (ONY, Inc.)	Sham
Arm/Group Description	Infants already receiving inhaled nitric oxide will receive scheduled doses of late surfactant (Infasurf) on study days 0, 2, 4, 6 and 8. Infasurf surfactant (ONY, Inc.): Late doses of Infasurf 3ml/kg will be given to infants on study days 0, 2, 4, 6 and 8.	Infants already receiving inhaled nitric oxide will not receive additional doses of late surfactant (Infasurf).
Measure Participants	154	168
Number [percentage of participants]	28 11.1%	32 12.4%

Adverse Events

Arm/Group Title	Infasurf Surfactant (ONY, Inc.)		Sham (No Treatment)
Arm/Group Description	Infants already receiving inhaled nitric oxide will receive scheduled doses of late surfactant (Infasurf) on study days 0, 2, 4, 6 and 8. Infasurf surfactant (ONY, Inc.): Late doses of Infasurf 3ml/kg will be given to infants on study days 0, 2, 4, 6 and 8 as long as infant remains intubated.		Infants already receiving inhaled nitric oxide will receive "Sham (no treatment)" doses on study days 0,2,4,6, and 8. Sham (No Treatment): Late doses of Sham (No treatment) will be given to infants on study days 0, 2, 4, 6 and 8 as long as infant remains intubated.
All Cause Mortality
	Infasurf Surfactant (ONY, Inc.)		Sham (No Treatment)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	29/252 (11.5%)		24/259 (9.3%)
Serious Adverse Events
	Infasurf Surfactant (ONY, Inc.)		Sham (No Treatment)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	29/252 (11.5%)		24/259 (9.3%)
Investigations
Death	29/252 (11.5%)	29	24/259 (9.3%)	24
Other (Not Including Serious) Adverse Events
	Infasurf Surfactant (ONY, Inc.)		Sham (No Treatment)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	141/252 (56%)		153/259 (59.1%)
Cardiac disorders
PDA Requiring Treatment	89/252 (35.3%)	89	95/259 (36.7%)	95
Eye disorders
ROP Class 4-5 or surgery	34/252 (13.5%)	34	29/259 (11.2%)	29
Gastrointestinal disorders
NEC	27/252 (10.7%)	27	24/259 (9.3%)	24
General disorders
IVH New or Worsened	33/252 (13.1%)	33	35/259 (13.5%)	35
Infections and infestations
Sepsis	141/252 (56%)	141	153/259 (59.1%)	153

Limitations/Caveats

Possible limitations of the trial: Infants 1) may not have had enough surfactant dysfunction to benefit from replacement; or 2) had irreversible lung damage prior to enrollment; or 3) The dose/frequency of replacement surfactant was inadequate.

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.