Trial of Late Surfactant for Prevention of Bronchopulmonary Dysplasia (TOLSURF)
Primary Purpose
Bronchopulmonary Dysplasia
Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Infasurf surfactant (ONY, Inc.)
Sham (No Treatment)
Sponsored by
About this trial
This is an interventional prevention trial for Bronchopulmonary Dysplasia focused on measuring nitric oxide, surfactant, BPD, prematurity, neonates, iNO, pulmonary outcome, neurodevelopmental outcome, Infasurf, lung function, Surfactant Dysfunction, Bronchopulmonary Dysplasia
Eligibility Criteria
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
Sites / Locations
- University of Arkansas - Arkansas Childrens Hospital
- Alta Bates Medical Center
- Oakland Children's Hospital
- University of California, San Francisco
- Wolfson Children's Hospital and Shands HospitaL
- Florida Hospital for Children
- All Children's Hospital
- Northwestern Memorial Hospital
- Children's Memorial Hospital
- Childrens Hospital and Clinics of Minnesota- Minneapolis
- University of Minnesota Medical School
- Children's Hospital and Clinics of Minnesota - St Paul
- Children's Mercy Hospital
- Women's and Children's Hospital of Buffalo
- Stony Brook University Medical Center
- Wake Forest University- Forsyth Hospital and Brenner Hospital
- Medical University of South Carolina(MUSC)
- UT Memphis- Memphis Medical Center
- UT Houston Health Science Center
- Texas Children's Hospital
- University of Washington, Seattle
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Sham Comparator
Arm Label
Infasurf surfactant (ONY, Inc.)
Sham (No Treatment)
Arm Description
Infants already receiving inhaled nitric oxide will receive scheduled doses of late surfactant (Infasurf) on study days 0, 2, 4, 6 and 8.
Infants already receiving inhaled nitric oxide will receive "Sham (no treatment)" doses on study days 0,2,4,6, and 8.
Outcomes
Primary Outcome Measures
Survival Without BPD at 36 Weeks Post Menstrual Age.
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
Survival Without BPD at 40 Weeks
BPD was diagnosed as need for respiratory support with either positive pressure and/or oxygen as evaluated by physiological oxygen/flow reduction.
Respiratory Outcomes of TOLSURF Infants at 1 Year Corrected Age
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.
Pulmonary Outcomes Through 2 Years of Age
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.
Percentage of Participants With Neurodevelopmental Impairment (NDI) at 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.
Full Information
NCT ID
NCT01022580
First Posted
November 19, 2009
Last Updated
April 21, 2021
Sponsor
Roberta Ballard
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
1. Study Identification
Unique Protocol Identification Number
NCT01022580
Brief Title
Trial of Late Surfactant for Prevention of Bronchopulmonary Dysplasia
Acronym
TOLSURF
Official Title
Trial of Late Surfactant for Prevention of Bronchopulmonary Dysplasia: A Study in Ventilated Preterm Infants Receiving Inhaled Nitric Oxide
Study Type
Interventional
2. Study Status
Record Verification Date
April 2021
Overall Recruitment Status
Completed
Study Start Date
January 2010 (undefined)
Primary Completion Date
December 2013 (Actual)
Study Completion Date
January 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Roberta Ballard
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
4. Oversight
Data Monitoring Committee
Yes
5. 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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Bronchopulmonary Dysplasia
Keywords
nitric oxide, surfactant, BPD, prematurity, neonates, iNO, pulmonary outcome, neurodevelopmental outcome, Infasurf, lung function, Surfactant Dysfunction, Bronchopulmonary Dysplasia
7. Study Design
Primary Purpose
Prevention
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
511 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Infasurf surfactant (ONY, Inc.)
Arm Type
Active Comparator
Arm Description
Infants already receiving inhaled nitric oxide will receive scheduled doses of late surfactant (Infasurf) on study days 0, 2, 4, 6 and 8.
Arm Title
Sham (No Treatment)
Arm Type
Sham Comparator
Arm Description
Infants already receiving inhaled nitric oxide will receive "Sham (no treatment)" doses on study days 0,2,4,6, and 8.
Intervention Type
Drug
Intervention Name(s)
Infasurf surfactant (ONY, Inc.)
Other Intervention Name(s)
Treatment
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Sham (No Treatment)
Other Intervention Name(s)
Control
Intervention Description
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.
Primary Outcome Measure Information:
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
Secondary Outcome Measure Information:
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
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
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
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
10. Eligibility
Sex
All
Minimum Age & Unit of Time
7 Days
Maximum Age & Unit of Time
14 Days
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Roberta A Ballard, MD
Organizational Affiliation
University of California, San Francisco
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Arkansas - Arkansas Childrens Hospital
City
Little Rock
State/Province
Arkansas
ZIP/Postal Code
72202
Country
United States
Facility Name
Alta Bates Medical Center
City
Berkeley
State/Province
California
ZIP/Postal Code
94705
Country
United States
Facility Name
Oakland Children's Hospital
City
Oakland
State/Province
California
ZIP/Postal Code
94609
Country
United States
Facility Name
University of California, San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States
Facility Name
Wolfson Children's Hospital and Shands HospitaL
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32207
Country
United States
Facility Name
Florida Hospital for Children
City
Orlando
State/Province
Florida
ZIP/Postal Code
32803
Country
United States
Facility Name
All Children's Hospital
City
Saint Petersburg
State/Province
Florida
ZIP/Postal Code
33701
Country
United States
Facility Name
Northwestern Memorial Hospital
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Children's Memorial Hospital
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60614
Country
United States
Facility Name
Childrens Hospital and Clinics of Minnesota- Minneapolis
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55404
Country
United States
Facility Name
University of Minnesota Medical School
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Facility Name
Children's Hospital and Clinics of Minnesota - St Paul
City
Saint Paul
State/Province
Minnesota
ZIP/Postal Code
55102
Country
United States
Facility Name
Children's Mercy Hospital
City
Kansas City
State/Province
Missouri
ZIP/Postal Code
64108
Country
United States
Facility Name
Women's and Children's Hospital of Buffalo
City
Buffalo
State/Province
New York
ZIP/Postal Code
14222
Country
United States
Facility Name
Stony Brook University Medical Center
City
Stony Brook
State/Province
New York
ZIP/Postal Code
11794
Country
United States
Facility Name
Wake Forest University- Forsyth Hospital and Brenner Hospital
City
Winston-Salem
State/Province
North Carolina
ZIP/Postal Code
27103
Country
United States
Facility Name
Medical University of South Carolina(MUSC)
City
Charleston
State/Province
South Carolina
ZIP/Postal Code
29403
Country
United States
Facility Name
UT Memphis- Memphis Medical Center
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38103-2807
Country
United States
Facility Name
UT Houston Health Science Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030-1503
Country
United States
Facility Name
Texas Children's Hospital
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
University of Washington, Seattle
City
Seattle
State/Province
Washington
ZIP/Postal Code
98195-6320
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
16870913
Citation
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. doi: 10.1056/NEJMoa061088. Erratum In: N Engl J Med. 2007 Oct 4;357(14):1444-5.
Results Reference
background
PubMed Identifier
17671061
Citation
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. doi: 10.1542/peds.2007-0095.
Results Reference
background
PubMed Identifier
17403837
Citation
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. doi: 10.1542/peds.2006-2683.
Results Reference
background
PubMed Identifier
26500107
Citation
Ballard RA, Keller RL, Black DM, Ballard PL, Merrill JD, Eichenwald EC, Truog WE, Mammel MC, Steinhorn RH, Rogers EE, Ryan RM, Durand DJ, Asselin JM, Bendel CM, Bendel-Stenzel EM, Courtney SE, Dhanireddy R, Hudak ML, Koch FR, Mayock DE, McKay VJ, O'Shea TM, Porta NF, Wadhawan R, Palermo L; TOLSURF Study Group. Randomized Trial of Late Surfactant Treatment in Ventilated Preterm Infants Receiving Inhaled Nitric Oxide. J Pediatr. 2016 Jan;168:23-29.e4. doi: 10.1016/j.jpeds.2015.09.031. Epub 2015 Oct 21.
Results Reference
result
PubMed Identifier
29627188
Citation
Wai KC, Hibbs AM, Steurer MA, Black DM, Asselin JM, Eichenwald EC, Ballard PL, Ballard RA, Keller RL; Trial of Late Surfactant (TOLSURF) Study Group. Maternal Black Race and Persistent Wheezing Illness in Former Extremely Low Gestational Age Newborns: Secondary Analysis of a Randomized Trial. J Pediatr. 2018 Jul;198:201-208.e3. doi: 10.1016/j.jpeds.2018.02.032. Epub 2018 Apr 4.
Results Reference
result
PubMed Identifier
28100402
Citation
Keller RL, Eichenwald EC, Hibbs AM, Rogers EE, Wai KC, Black DM, Ballard PL, Asselin JM, Truog WE, Merrill JD, Mammel MC, Steinhorn RH, Ryan RM, Durand DJ, Bendel CM, Bendel-Stenzel EM, Courtney SE, Dhanireddy R, Hudak ML, Koch FR, Mayock DE, McKay VJ, Helderman J, Porta NF, Wadhawan R, Palermo L, Ballard RA; TOLSURF Study Group. The Randomized, Controlled Trial of Late Surfactant: Effects on Respiratory Outcomes at 1-Year Corrected Age. J Pediatr. 2017 Apr;183:19-25.e2. doi: 10.1016/j.jpeds.2016.12.059. Epub 2017 Jan 16.
Results Reference
result
PubMed Identifier
27583380
Citation
Wai KC, Keller RL, Lusk LA, Ballard RA, Chan DK; Trial of Late Surfactant (TOLSURF) Study Group. Characteristics of Extremely Low Gestational Age Newborns Undergoing Tracheotomy: A Secondary Analysis of the Trial of Late Surfactant Randomized Clinical Trial. JAMA Otolaryngol Head Neck Surg. 2017 Jan 1;143(1):13-19. doi: 10.1001/jamaoto.2016.2428.
Results Reference
derived
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Trial of Late Surfactant for Prevention of Bronchopulmonary Dysplasia
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