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The investigators propose to evaluate premedication with Propofol compared to a control strategy including a placebo with a possible rescue treatment with ketamine to ensure pain control before LISA Procedure . Investigators hypothesize that sedation with Propofol is safe and non-inferior to placebo for the risk of Mechanical Ventilation in the 72 hours following the procedure.
Non-inferiority trial comparing Propofol versus placebo during the intra tracheal Less Invasive Surfactant Administration (LISA) in preterm babies < 32 weeks of gestation for the need for mechanical ventilation after the procedure. An open-label ketamine treatment as rescue is possible in each group.
In each participating unit, information will be given to parents of preterm babies <32 wGA upon their admission to the delivery room or to the NICU (neonatal intensive care unit), and informed consent will be sought as soon as possible. Eligible babies presenting a RDS (respiratory distress syndrome) will be included and randomized to the control (placebo) group or Propofol group. While benefiting from Nasal Intermittent Positive Pressure Ventilation (NIPPV) the newborn will be prepared as usual for tracheal intubation. Trialists will be blinded to treatment allocation.
The drug administration in the two groups will be titrated according to weight (0.5mg/kg per dose of Propofol or a similar volume of placebo). Before and after each dose, a pain score (FANS) will be quickly evaluated within 2 minutes of the injection, to assess the need for a supplementary dose (up to a predefined limit) or rescue treatment by Ketamine, also according to the clinician's clinical impression .
After the steps of sedation, the LISA procedure will be performed, with detailed data collection of per procedure events up to 72 hours of life. Babies will be subsequently managed as usual in each NICU and data will be collected about respiratory, neurological and hemodynamic outcomes during the hospital stay, and especially at discharge, 28 days, and 36 weeks. At two years of corrected age, a final examination will be performed to evaluate neurodevelopmental outcomes.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Propofol | Experimental | Propofol (Propofol LIPURO 1% 100mL), Pharmacologic form: 10mg/ml. Considering the birthweight of most preterm babies, Propofol will be diluted to a final concentration of 1mg/ml by the nurse. Treatment initiation: the 1st dose will be injected following usual management of LISA procedure included the installation of the newborn and the atropine and caffeine injections and sugar solution administration Dose per administration: 0.5mg/kg per dose of Propofol. Number of administrations: Several administrations of 0.5 mg/kg are possible, according the level of sedation achieved, as evaluated by the FANS score and the physician feeling. If the FANS score is ≥6 AND the baby is not comfortable, a new dose will be injected up to a total of two (before 28 wGA) or 3 (between 28 - 31 wGA) administrations of the drug. |
|
| medialipide | Placebo Comparator | Name of treatment for placebo: Medialipide® (B. BRAUN) Pharmacological form: 20g/100ml Medialipide 20% will be used as the placebo. This is an emulsion of medium and long triglycerides based on soya oil and having same appearance organoleptic characteristics as Propofol. Dose per administration: Same volume as for the Propofol administration Number of administrations: according the same protocol that for the Propofol administration. Modalities of preparation : The same dilution procedure as Propofol lipuro 1% SPC (Summary of Product Characteristics):1 part of Medialipide 20% with 9 parts of 5% w/v glucose solution or 0.9% w/v sodium chloride solution as shown in parenteral nutrition which is in accordance with medialipide 20% SPC |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Propofol-Lipuro | Drug | sedation of babies < 32wGA with propofol / placebo before a LISA Procedure |
|
| Measure | Description | Time Frame |
|---|---|---|
| need for mechanical ventilation after the procedure | Rate of mechanical ventilation from the start of the LISA procedure up to 72 hours of life Pain before procedure (need of ketamine administration) or within 1 hour following first injection of propofol/placebo (FANS score ≥ 6) | 72hours |
| Measure | Description | Time Frame |
|---|---|---|
| Rate of MV (mechanical ventilation ) in each class of GA (<28, 28-31wGA) | Rate of MV (mechanical ventilation ) from the start of the LISA procedure up to 72 hours of life in each class of GA (<28, 28-31wGA) | 72hours |
| FANS during LISA and 1h after LISA |
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Inclusion Criteria:
Preterm Infants < 32 wGA (weeks of gestational age)
Presenting a RDS (respiratory distress syndrome)
in the first 48 hours of life
treated by CPAP (continuous positive airway pressure) or BiPAP (Bilevel Positive Airway Pressure)
requiring surfactant :
FIO2 : (fraction of inspired oxygen)
SpO2 (arterial oxygen saturation) : to obtain a SpO2 between ≥88 and ≤ 95%
Available IntraVenous line (peripheral, umbilical or central catheter)
Recipient of the French Social Security
Informed consent form signed
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Thierry DEBILLON, MD PHD | CHU de Grenoble Alpes | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| centre hospitalier deTroyes | Troyes | Aube | 10000 | France | ||
| CHU Grenoble Alpes |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32384914 | Background | Chevallier M, Durrmeyer X, Ego A, Debillon T; PROLISA Study Group. Propofol versus placebo (with rescue with ketamine) before less invasive surfactant administration: study protocol for a multicenter, double-blind, placebo controlled trial (PROLISA). BMC Pediatr. 2020 May 8;20(1):199. doi: 10.1186/s12887-020-02112-x. | |
| 26907795 |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Feb 17, 2026 |
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| Placebos | Drug | injected to babies < 32wGA with propofol / placebo before a LISA Procedure |
|
|
Faceless acute neonatal pain scale (FANS) assessed during LISA and 1 hour after the procedure by an independent operator. |
| 1hour |
| number of ketamine administrations for rescue | Number of ketamine administrations for rescue in order to obtain a FANS score <6 and to be able to proceed to LISA. | before LISA Procedure |
| Number of laryngoscopies | Number of laryngoscopies needed to perform LISA | during LISA Procedure (T0) |
| Tolerance and efficacy (Per procedure events): Apnea | Apnea requiring bag mask ventilation | during LISA Procedure (T0) |
| Tolerance and efficacy (Per procedure events): emergency intubation | Emergency intubation after the drug injection before the LISA procedure can be performed or within 1h following the drug injection | from drug injection to 1hour after |
| Tolerance and efficacy (Per procedure events): Viby Mogensen score | Clinician's satisfaction during laryngoscopy with the Viby Mogensen score : Item Score 1 Score 2 Score 3 Score 4 Laryngoscopy Easy Fair Difficult Impossible Vocal cords Open Moving Closing Closed Coughing None Slight Moderate Severe Jaw relaxation Complete Slight Stiff Rigid Limb movements None Slight Moderate Severe the total score is calculated adding each item scores. min score = 5. max score = 20. An easy intubation would obtain a low score and a difficult intubation would have a high score. | during LISA Procedure |
| BPD (bronchopulmonary dysplasia) at 36 weeks of Gestational Age | Broncho Pulmonary Dysplasia at 36 weeks of Gestational Age | equivalent to 36 weeks of Gestational Age |
| In-hospital morbidity and mortality: pneumothorax | Pneumothorax within 72hours | 72hours post LISA Procedure |
| In-hospital morbidity and mortality: Necrotizing Enterocolitis | necrotizing enterocolitis during hospitalization | the day of discharge from hospital (the day depends to each participant : between 36-45 weeks of Gestational Age) |
| In-hospital morbidity and mortality : sepsis | proven sepsis during hospitalization | the day of discharge from hospital (the day depends to each participant : between 36-45 weeks of Gestational Age) |
| In-hospital morbidity and mortality: retinopathy | retinopathy of prematurity during hospitalization | the day of discharge from hospital (the day depends to each participant : between 36-45weeks of gestational ageGA) |
| In-hospital morbidity and mortality | periventricular leukomalacia or grade 3 or 4 intraventricular hemorrhage during hospitalization | the day of discharge from hospital (the day depends to each participant : between 36-45weeks of Gestational Age) |
| In-hospital morbidity and mortality: patent ductus arteriosus | treatment of a patent ductus arteriosus during hospitalization | the day of discharge from hospital (the day depends to each participant : between 36-45 weeks of Gestational Age) |
| In-hospital morbidity and mortality: death 36weeks of Gestational Age | Death at 36 weeks of Gestational Age | equivalent to 36 weeks of Gestational Age |
| In-hospital morbidity and mortality: death during hospitalization | in-hospital mortality | the day of discharge from hospital (the day depends to each participant : between 36-45weeks of Gestational Age) |
| At two years of corrected age: ASQ (Ages and Stages Questionnaire) | ASQ (Ages and Stages Questionnaire) questionnaire is a general developmental screening tool (5 areas are evaluated: Communication, gross motor, fine motor, problem solving, and personal-social). Total score is the sum of each of the 5 area scores (wich are between 0-60. Total score is between 0 and 300. The higher the score is, the best developed the children is. | 2 years (corrected age) |
| At two years of corrected age: motor function | Gross Motor Function Classification Scale (GMFCS) looks at movements such as sitting, walking and use of mobility devices. It is helpful because it provides families and clinicians with a clear description of a child's current motor function, and an idea of what equipment or mobility aids a child may need in the future, e.g. crutches, walking frames or wheelchairs. Participant will be assignated to one of the 5 levels by the clinicians : a patient who is in level 5 has more motor impairments than a patient in level 1. | 2 years (corrected age) |
| At two years of corrected age: vision | Visual functions : a clinical examination will conclude if the participant has a visual deficit or not. And in the deficit case, what kind of vision pathology. | 2 years (corrected age) |
| At two years of corrected age: audition | Hearing functions : a clinical examination will conclude if the participant has a hearing deficit or not. And in the deficit case, what kind of audition pathology. | 2 years (corrected age) |
| Grenoble |
| Isère |
| 38043 |
| France |
| Chu Amiens | Amiens | 80000 | France |
| Chu Angers | Angers | 49000 | France |
| Chu Brest | Brest | 29200 | France |
| Chu Chambery | Chambéry | 73000 | France |
| Chi Creteil | Créteil | 94000 | France |
| Chu Limoges | Limoges | 87000 | France |
| Ap-H Marseille | Marseille | 13000 | France |
| Chu Nantes | Nantes | 44000 | France |
| Chu Nimes | Nîmes | 30000 | France |
| Chi Poissy St Germain | Poissy | 78300 | France |
| Ch Rennes | Rennes | 35000 | France |
| Dekker J, Lopriore E, Rijken M, Rijntjes-Jacobs E, Smits-Wintjens V, Te Pas A. Sedation during Minimal Invasive Surfactant Therapy in Preterm Infants. Neonatology. 2016;109(4):308-13. doi: 10.1159/000443823. Epub 2016 Feb 24. |
| 25164872 | Result | Dargaville PA, Kamlin CO, De Paoli AG, Carlin JB, Orsini F, Soll RF, Davis PG. The OPTIMIST-A trial: evaluation of minimally-invasive surfactant therapy in preterm infants 25-28 weeks gestation. BMC Pediatr. 2014 Aug 27;14:213. doi: 10.1186/1471-2431-14-213. |
| 21963186 | Result | Gopel W, Kribs A, Ziegler A, Laux R, Hoehn T, Wieg C, Siegel J, Avenarius S, von der Wense A, Vochem M, Groneck P, Weller U, Moller J, Hartel C, Haller S, Roth B, Herting E; German Neonatal Network. Avoidance of mechanical ventilation by surfactant treatment of spontaneously breathing preterm infants (AMV): an open-label, randomised, controlled trial. Lancet. 2011 Nov 5;378(9803):1627-34. doi: 10.1016/S0140-6736(11)60986-0. Epub 2011 Sep 29. |
| 30068669 | Result | Dekker J, Lopriore E, van Zanten HA, Tan RNGB, Hooper SB, Te Pas AB. Sedation during minimal invasive surfactant therapy: a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed. 2019 Jul;104(4):F378-F383. doi: 10.1136/archdischild-2018-315015. Epub 2018 Aug 1. |
| 22250028 | Result | Berde CB, Walco GA, Krane EJ, Anand KJ, Aranda JV, Craig KD, Dampier CD, Finkel JC, Grabois M, Johnston C, Lantos J, Lebel A, Maxwell LG, McGrath P, Oberlander TF, Schanberg LE, Stevens B, Taddio A, von Baeyer CL, Yaster M, Zempsky WT. Pediatric analgesic clinical trial designs, measures, and extrapolation: report of an FDA scientific workshop. Pediatrics. 2012 Feb;129(2):354-64. doi: 10.1542/peds.2010-3591. Epub 2012 Jan 16. |
| 29532502 | Result | Bourgoin L, Caeymaex L, Decobert F, Jung C, Danan C, Durrmeyer X. Administering atropine and ketamine before less invasive surfactant administration resulted in low pain scores in a prospective study of premature neonates. Acta Paediatr. 2018 Jul;107(7):1184-1190. doi: 10.1111/apa.14317. Epub 2018 Apr 16. |
| 17485450 | Result | Ghanta S, Abdel-Latif ME, Lui K, Ravindranathan H, Awad J, Oei J. Propofol compared with the morphine, atropine, and suxamethonium regimen as induction agents for neonatal endotracheal intubation: a randomized, controlled trial. Pediatrics. 2007 Jun;119(6):e1248-55. doi: 10.1542/peds.2006-2708. Epub 2007 May 7. |
| 26922562 | Result | Owen LS, Manley BJ. Nasal intermittent positive pressure ventilation in preterm infants: Equipment, evidence, and synchronization. Semin Fetal Neonatal Med. 2016 Jun;21(3):146-53. doi: 10.1016/j.siny.2016.01.003. Epub 2016 Feb 26. |
| 23439457 | Result | Durrmeyer X, Daoud P, Decobert F, Boileau P, Renolleau S, Zana-Taieb E, Saizou C, Lapillonne A, Granier M, Durand P, Lenclen R, Coursol A, Nicloux M, de Saint Blanquat L, Shankland R, Boelle PY, Carbajal R. Premedication for neonatal endotracheal intubation: results from the epidemiology of procedural pain in neonates study. Pediatr Crit Care Med. 2013 May;14(4):e169-75. doi: 10.1097/PCC.0b013e3182720616. |
| 23359581 | Result | Kanmaz HG, Erdeve O, Canpolat FE, Mutlu B, Dilmen U. Surfactant administration via thin catheter during spontaneous breathing: randomized controlled trial. Pediatrics. 2013 Feb;131(2):e502-9. doi: 10.1542/peds.2012-0603. Epub 2013 Jan 28. |
| 28483817 | Result | Descamps CS, Chevallier M, Ego A, Pin I, Epiard C, Debillon T. Propofol for sedation during less invasive surfactant administration in preterm infants. Arch Dis Child Fetal Neonatal Ed. 2017 Sep;102(5):F465. doi: 10.1136/archdischild-2017-312791. Epub 2017 May 8. No abstract available. |
| 27942865 | Result | Klotz D, Porcaro U, Fleck T, Fuchs H. European perspective on less invasive surfactant administration-a survey. Eur J Pediatr. 2017 Feb;176(2):147-154. doi: 10.1007/s00431-016-2812-9. Epub 2016 Dec 9. |
| Jun 1, 2026 |
| Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D047928 | Premature Birth |
| ID | Term |
|---|---|
| D007752 | Obstetric Labor, Premature |
| D007744 | Obstetric Labor Complications |
| D011248 | Pregnancy Complications |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
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| ID | Term |
|---|---|
| D015742 | Propofol |
| ID | Term |
|---|---|
| D010636 | Phenols |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
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