OPTIMIST-A Trial: Minimally-invasive Surfactant Therapy in Preterm Infants 25-28 Weeks Gestation on CPAP

Bronchopulmonary Dysplasia Clinical Trial

— OPTIMIST-A  

Official title:

Multicentre Randomised Controlled Trial of Minimally-invasive Surfactant Therapy in Preterm Infants 25-28 Weeks Gestation on Continuous Positive Airways Pressure

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02140580
• Other study ID #: 4.3, 6th June 2013
• Status: Active, not recruiting
• Phase: Phase 4
• Start date: December 2011
• Est. completion date: June 2022

Study information

• Verified date: April 2020
• Source: Menzies Institute for Medical Research
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Trial question: Does administration of exogenous surfactant using a minimally-invasive technique improve outcome in preterm infants 25-28 weeks gestation treated with continuous positive airway pressure (CPAP)? Trial hypothesis: That early surfactant administration via a minimally-invasive technique to preterm infants on CPAP will result in a lesser duration of mechanical respiratory support, and a higher incidence of survival without bronchopulmonary dysplasia. Trial design: Multicentre, randomised, masked, controlled trial in inborn preterm infants 25-28 weeks gestation, aged less than 6 hours, requiring CPAP because of respiratory distress, with an FiO2 of >=0.3 and CPAP pressure 5-8. Infants randomised to surfactant treatment receive 200 mg/kg of poractant alfa (Curosurf) administered under direct laryngoscopy using a surfactant instillation catheter, followed by reinstitution of CPAP. Controls continue on CPAP. The intervention is masked from the clinical team. Care thereafter is as per usual in both groups, other than the requirement to adhere to intubation criteria. The primary outcome is incidence of death or BPD. Secondary outcomes include incidence of death, major neonatal morbidities (BPD, intraventricular haemorrhage, periventricular leukomalacia, retinopathy of prematurity, necrotising enterocolitis), pneumothorax and patent ductus arteriosus; need for intubation and surfactant therapy; durations of mechanical respiratory support, intubation, CPAP, intubation and CPAP, high flow nasal cannula (HFNC), oxygen therapy, intensive care stay and hospitalisation; hospitalisation cost; applicability and safety of the MIST procedure; and outcome at 2 years. The sample size is 303/group, allowing detection of a 33% difference in the primary outcome with 90% power. The trial commenced at Royal Hobart Hospital December 2011 and Royal Women's Hospital during 2012, and will ultimately be conducted over 5 years in multiple centres internationally.

Description:

1. OPTIMIST-A TRIAL SUMMARY RESEARCH QUESTION Does administration of exogenous surfactant using a minimally-invasive technique improve outcome in preterm infants 25-28 weeks gestation treated with continuous positive airway pressure (CPAP)?

BACKGROUND Nasal CPAP is often very effective in preterm infants as the initial means of respiratory support, but a sub-group of infants, most with features of respiratory distress syndrome, fail on CPAP and require intubation and ventilation in the first 72 hours. When compared to those in whom CPAP is successful, infants failing CPAP have a substantially longer duration of respiratory support, and a higher risk of adverse outcomes. Decreasing the risk of CPAP failure would thus seem advantageous, and may be achievable with minimally invasive surfactant therapy (MIST), in which surfactant is administered to a spontaneously breathing infant who then remains on CPAP. A technique of MIST (the "Hobart method") using a semi-rigid surfactant instillation catheter has been shown to be feasible in preterm infants on CPAP, and appears to have the potential to alter respiratory course and outcome. This method of MIST now requires evaluation in randomised controlled trials.

RESEARCH DESIGN Multicentre, randomised, masked, controlled trial.

RECRUITMENT Entry criteria Inborn preterm infants 25-28 weeks gestation, aged less than 6 hours, who were not intubated at birth but require CPAP or NIPPV because of respiratory distress, with a CPAP pressure of 5-8 cm H2O and FiO2 ≥0.30.

Exclusion criteria Infants will be excluded if in imminent need of intubation, or if there is a congenital anomaly or alternative cause for respiratory distress.

RANDOMISATION With parental consent, eligible infants will be randomly allocated using a web-based randomisation server, with stratification by study centre, to receive exogenous surfactant via the Hobart MIST technique, or to continue on CPAP.

INTERVENTION Infants randomised to surfactant treatment will receive a dose of poractant alfa (Curosurf) administered under direct laryngoscopy using a surfactant instillation catheter, at a dosage of 200 mg/kg. CPAP will thereafter be reinstituted. Controls will continue on CPAP. The intervention will be masked from the clinical team.

POST-INTERVENTION MANAGEMENT Other than the requirement to adhere to intubation criteria in the first week, and in some cases perform a room air trial at 36 weeks corrected gestation, management after intervention will be at the discretion of the clinical team. Titration of CPAP pressure is encouraged, with a permitted maximum of 8 cm H2O. Nasal IPPV (bi-level CPAP) is allowable. Early caffeine therapy is expected.

Criteria for intubation: Enrolled infants on CPAP will be intubated if FiO2 ≥0.45, or if there is unremitting apnoea or persistent acidosis. These criteria apply during the first week of life, and to the first episode of intubation only.

FOLLOWUP: At 2 years corrected age, parents of each infant will complete a brief health assessment and a validated child development assessment (PARCA-R, Dev Med Child Neurol 2004;46:389-97) administered as a web-based questionnaire located on a secure server. The infant-specific link to the questionnaire, and reminders where necessary, will be sent electronically to the parents by research personnel at each Site, thus maintaining confidentiality. No identifying details will be revealed in the completion of the questionnaire.

OUTCOMES Primary outcome: Incidence of composite outcome of death or physiological bronchopulmonary dysplasia (BPD).

Secondary outcomes: Incidence of death, major neonatal morbidities (BPD, intraventricular haemorrhage, periventricular leukomalacia, retinopathy of prematurity, necrotising enterocolitis), pneumothorax and patent ductus arteriosus; need for intubation and surfactant therapy; durations of mechanical respiratory support, intubation, CPAP, intubation and CPAP, high flow nasal cannula (HFNC), oxygen therapy, intensive care stay and hospitalisation; hospitalisation cost; applicability and safety of the MIST procedure; and outcome at 2 years.

SAMPLE SIZE 606 infants (303 per group), giving 90% power to detect a 33% reduction in death or BPD from the anticipated rate of 38% in the control arm, α = 0.05.

TRIAL PLAN The OPTIMIST trials will commence at RHH Hobart and RWH Melbourne during 2011. All Australasian neonatal units, and selected international centres including those in the Vermont- Oxford Network, will be invited to join the trials. A full complement of participating centres is expected by early 2014. Recruitment will thereafter proceed at full rate until completion, which is estimated to take up to 4 years.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 486
• Est. completion date: June 2022
• Est. primary completion date: May 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 6 Hours

Eligibility

Inclusion Criteria:

• Gestational age 25-28 completed weeks

• Requiring CPAP or non-invasive positive pressure ventilation with signs of early respiratory distress.

• CPAP pressure of 5-8 cm H2O and FiO2 >=0.30.

• Less than 6 hours of age.

• Agreement of the Treating Physician in charge of the infant's care.

• Signed parental consent.

Exclusion Criteria:

• Previously intubated, or in imminent need of intubation

• Congenital anomaly or condition that might adversely affect breathing.

• Identifiable alternative cause for respiratory distress (e.g. congenital pneumonia or pulmonary hypoplasia).

• Lack of availability of an OPTIMIST treatment team.

Related Conditions & MeSH terms

• Bronchopulmonary Dysplasia

Intervention

Device:
• Minimally invasive surfactant therapy
Active Comparator

Other:
• Continuation on CPAP
Sham Comparator

Locations

Country	Name	City	State
Australia	Royal Hobart Hospital	Hobart	Tasmania
Australia	Mercy Hospital for Women	Melbourne	Victoria
Australia	Monash Medical Centre	Melbourne	Victoria
Australia	Royal Womens Hospital	Melbourne	Victoria
Israel	Bnai Zion Medical Center	Haifa
Israel	Ziv Medical Center	Tsefat
New Zealand	Auckland City Hospital	Auckland
New Zealand	Middlemore Hospital	Auckland
Slovenia	University Medical Center, Ljubljana	Zaloska	Ljubljana
Turkey	Zekai Tahir Burak Hospital	Ankara
Turkey	Uludag University Hospital	Gorukle	Bursa
United States	Cooper University Hospital	Camden	New Jersey
United States	NorthShore Health University HealthSystem Evanston Hospital	Evanston	Illinois
United States	Kapi'olani Medical Center for Women and Children	Honolulu	Hawaii
United States	West Virginia University Hospital	Morgantown	West Virginia
United States	Yale-New Haven Children's Hospital	New Haven	Connecticut

Sponsors (21)

Lead Sponsor

Collaborator

Menzies Institute for Medical Research

Auckland City Hospital, Bnai Zion Medical Center, Dunedin Hospital, Kanuni Sultan Suleyman Training and Research Hospital, Kapiolani Medical Center For Women & Children, Mercy Hospital for Women, Australia, Middlemore Hospital, New Zealand, Monash Medical Centre, NorthShore University HealthSystem, Royal Hobart Hospital, Royal Women's Hospital, Melbourne, Australia, The Cooper Health System, Uludag University Hospital, University Medical Center Groningen, University Medical Centre Ljubljana, University of Southern California, West Virginia University Hospital, Yale University, Zekai Tahir Burak Women's Health Research and Education Hospital, Ziv Medical Center

Countries where clinical trial is conducted

United States,  Australia,  Israel,  New Zealand,  Slovenia,  Turkey, 

References & Publications (3)

Dargaville PA, Aiyappan A, Cornelius A, Williams C, De Paoli AG. Preliminary evaluation of a new technique of minimally invasive surfactant therapy. Arch Dis Child Fetal Neonatal Ed. 2011 Jul;96(4):F243-8. doi: 10.1136/adc.2010.192518. Epub 2010 Oct 21. — View Citation

Dargaville PA, Aiyappan A, De Paoli AG, Kuschel CA, Kamlin CO, Carlin JB, Davis PG. Minimally-invasive surfactant therapy in preterm infants on continuous positive airway pressure. Arch Dis Child Fetal Neonatal Ed. 2013 Mar;98(2):F122-6. doi: 10.1136/archdischild-2011-301314. Epub 2012 Jun 9. — View Citation

Dargaville PA. Innovation in surfactant therapy I: surfactant lavage and surfactant administration by fluid bolus using minimally invasive techniques. Neonatology. 2012;101(4):326-36. doi: 10.1159/000337346. Epub 2012 Jun 1. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Hospitalisation cost	The mean of patient billings and mean cost of hospitalisation per patient will be determined, and compared between groups.	First hospitalisation (average assessment period 14 weeks)
Primary	Death or physiological bronchopulmonary dysplasia	Composite outcome of death by 36 weeks or physiological bronchopulmonary dysplasia (BPD). Physiological BPD is assessed at 36 weeks post-menstrual age, and is defined as either need for respiratory support (intubation / CPAP / high flow nasal cannula > 2 L/min) or need for FiO2 >=0.3 or failure of a room air trial conducted at 36 weeks post-menstrual age. This will be assessed by the research nurse at each centre.	36 weeks post menstrual age
Secondary	Mortality		36 weeks post menstrual age
Secondary	Major morbidity	Major morbidity, defined as one or more of BPD, grade III or IV intraventricular haemorrhage, periventricular leukomalacia or retinopathy of prematurity > stage 2, occurring at any time up to 36 weeks post menstrual age. Screening for intraventricular haemorrhage, periventricular leukomalacia and retinopathy of prematurity will be performed as routine care, and the results taken from the medical record.	36 weeks post menstrual age
Secondary	Pneumothorax	Pneumothorax at any time up to 36 weeks post menstrual age, as documented in medical record.	36 weeks post menstrual age
Secondary	Duration of respiratory support	Duration of respiratory support, defined as cumulative hours of all episodes of intubation, nasal CPAP and high flow nasal cannula oxygen (flow rate >= 2 litres/min). This information will be derived from medical record or unit database.	During first hospitalisation (average assessment period 14 weeks)
Secondary	Bronchopulmonary dysplasia	Bronchopulmonary dysplasia (BPD) will be assessed both clinically (need for mechanical respiratory support and/or an oxygen requirement at 36 weeks corrected gestation), and by a physiological definition. Physiological BPD is assessed at 36 weeks post-menstrual age, and is defined as either need for respiratory support (intubation / CPAP / high flow nasal cannula > 2 L/min) or need for FiO2 >=0.3 or failure of a room air trial conducted at 36 weeks post-menstrual age. This will be assessed by the research nurse at each centre.	36 weeks post menstrual age
Secondary	Duration of bradycardia and hypoxaemia during intervention	Heart rate and oxygen saturation will be monitored continuously during the intervention. The severity and duration of bradycardia and hypoxia will thus be documented during delivery of exogenous surfactant via brief tracheal catheterisation.	During intervention
Secondary	Discomfort during intervention	The incidence of apparent discomfort, as judged by the nurse assisting in the surfactant delivery procedure, will be ascertained in the group randomised to receive surfactant via brief tracheal catheterisation.	During intervention