Conditions: Premedication Endotracheal Intubation
Keywords: Pain Newborn Anaesthesia opioids propofol neuromuscular blocker atropine
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 173
Healthy volunteers: no

Brief summary:
Multicenter double blind randomized controlled trial comparing "atropine+propofol" vs "atropine+atracurium+sufentanil" as a premedication prior to endotracheal intubation of the neonate.

Primary outcome: pulse oxymetry value \< 80% for more than 60 seconds. Secondary outcomes: number of attempts, duration of the procedure, changes in physiologic parameters, short- and long-term neurodevelopmental outcome.

Hypothesis: "atropine + propofol" compared to "atropine+atracurium+sufentanil" will significantly reduce the frequency of severe hypoxemia.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: atropine+ propofol intervention 2: atropine + atracurium + sufentanil
Intervention descriptions: intervention 1: Atropine bolus: 20 µg/kg Propofol injected over 60 seconds: 1 mg/kg for infants \< 1000g - Renewable once 2.5 mg/kg for infants \> 1000G - Possible additional dose of 1 mg/kg intervention 2: Atropine bolus: 20 µg/kg Atracurium: 0.3 mg/kg- Possible additional dose of 0.1 mg/kg Sufentanil: 0.1 µg/kg for infants \< 1000g 0.2 µg/kg for infants \> 1000g

Protocol document:
Prot_SAP_000.pdf: 
1
Premedication Trial for Tracheal Intubation of the NEOnate (PRETTINEO) 
 
A multicenter double blind randomized controlled trial comparing "atropine+propofol" vs 
"atropine+atracurium+sufentanil" as a premedication prior to endotracheal intubation of the 
neonate– English Version (translated from the original French version) 
ClinicalTrials.gov Identifier: NCT01490580 
Date : February 1st 2018 
 
Sponsor: Centre Hospitalier Intercommunal de Creteil, 40 avenue de Verdun, 94000 Créteil, 
France 
 
Coordinating investigator: Dr Xavier Durrmeyer, Médecine et réanimation néonatales, Centre 
Hospitalier Intercommunal de Creteil, 40 avenue de Verdun, 94000 Créteil, France 
 
Collaborators: 
Data management : ACTIV (Association Clinique et Thérapeutique du Val de Marne), Dr Corinne 
Levy, 27 rue d’Inkermann, 94100 St Maur, France 
Monitoring : CRC (Clinical Resaerch Center/Centre de Recherche Clinique), Dr Camille Jung, 
Centre Hospitalier Intercommunal de Creteil, 40 avenue de Verdun, 94000 Créteil, France 
 
Participating centers (all in France) 
 
Center 
Unit 
Principal 
investigator 
Address 
CHI Créteil 
Réanimation 
Néonatale 
Dr Claude Danan 
40 avenue de Verdun, 94010, Creteil Cedex 10 
CHU Tours 
Réanimation 
Pédiatrique et 
Néonatale 
Pr Elie Saliba 
49, Boulevard Béranger, 37044, Tours Cedex 9 
Hôpital mère-
enfant - Lyon 
Réanimation 
néonatale 
Pr Olivier Claris 
59 Bld Pinel, 69677, Bron cedex 
CHU Toulouse 
Réanimation 
Pédiatrique et 
Néonatale 
Dr Sophie Breinig 
330 avenue de Grande-Bretagne, 31059, Toulouse Cedex 9 
CHU Amiens 
Nord 
Médecine 
Néonatale 
Pr Pierre 
Tourneux 
1 place Victor Pauchet, 80054, Amiens Cedex 18 
CHU Rennes 
Unité de 
néonatologie 
Pr Alain Beuchee 
16 boulevard de Bulgarie, 35203, Rennes cedex 2 
CHU Caen 
Réanimation et 
médecine 
néonatale 
Dr Cénéric 
Alexandre 
Avenue de la Côte de Nacre, 14033, Caen Cedex 9 
 


2
 
Premedication Trial for Tracheal Intubation of the NEOnate (PRETTINEO) .............................. 1 
Scientific justification and general description of the research ................................................. 4 
Name and description of the experimental drug (s) ........................................................................... 4 
Scientific data from the literature ....................................................................................................... 4 
Predictable benefits and risks known to patients who are eligible for research ................................. 8 
Description and justification of the route of administration, dosage, administration schedule and 
duration of treatment .......................................................................................................................... 9 
Declaration of compliance with the protocol, good clinical practices and the legal and regulatory 
provisions in force ............................................................................................................................ 10 
Description of the population to be studied ...................................................................................... 10 
Purpose and outcomes ................................................................................................................. 12 
Purpose ........................................................................................................................................... 12 
Hypothesis ....................................................................................................................................... 12 
Primary outcome .............................................................................................................................. 12 
Secondary outcomes ....................................................................................................................... 12 
Methods .......................................................................................................................................... 13 
Trial design ...................................................................................................................................... 13 
Study proposal and consent from parents ....................................................................................... 13 
Data collection ................................................................................................................................. 13 
Intervention ...................................................................................................................................... 14 
Outcomes ........................................................................................................................................ 18 
Measures to reduce bias ................................................................................................................. 19 
Randomization ............................................................................................................................. 19 
Masking ........................................................................................................................................ 19 
Dosage and ways of administration of treatments. Unit shape, packaging and labeling ............. 19 
Duration of participation and follow-up ............................................................................................ 20 
Definitive or Temporary Termination Rules ..................................................................................... 20 
Treatment kits monitoring ................................................................................................................ 20 
Blinding maintenance and unblinding procedure ............................................................................. 20 
Source data ..................................................................................................................................... 21 
Participants .................................................................................................................................... 21 
Inclusion Criteria .............................................................................................................................. 21 
Non-Inclusion Criteria ...................................................................................................................... 21 
Procedures for premature termination of treatment administration and for patient’s exclusion ....... 22 
Criteria and procedures for discontinuing treatment and excluding a person from research ...... 22 
Method and timing of data collection ........................................................................................... 22 
Modality for the replacement of excluded patients ...................................................................... 22 
Follow-up ..................................................................................................................................... 22 
Treatments given to participants ................................................................................................. 23 
Description of the treatments needed to carry out the research ...................................................... 23 
Medicinal products and treatments authorized and prohibited under the Protocol .......................... 23 
Method for treatment follow-up and compliance .............................................................................. 23 
Storage conditions of experimental drugs ....................................................................................... 23 
Efficacy assessment ..................................................................................................................... 24 
Description of Efficacy Assessment Parameters ............................................................................. 24 


3
Method and timeline for measuring, collecting and analyzing efficacy endpoints ........................... 24 
Safety assessment ........................................................................................................................ 25 
Safety assessment Parameters ....................................................................................................... 25 
Methods and schedule for AE declaration ....................................................................................... 26 
Procedures for registration and notification of adverse reactions .................................................... 26 
Follow-up of persons following the occurrence of adverse events .................................................. 26 
Statistics ......................................................................................................................................... 27 
Statistical methods and timing of intermediate analysis .................................................................. 27 
Initial analysis plan (as of September 2011) ................................................................................ 27 
Final analysis plan (as of November 2016, established before data was released) .................... 27 
Sample size ..................................................................................................................................... 28 
Expected statistical significance ...................................................................................................... 28 
Statistical Criteria for Stopping the Research .................................................................................. 29 
Method for taking account of missing, unnecessary or invalid data ................................................ 29 
Management of changes to the initial strategy analysis plan .......................................................... 29 
Choice of subjects to include in analyzes ........................................................................................ 29 
Regulatory and Ethical aspects ................................................................................................... 29 
Right of access to data and source documents ............................................................................... 29 
Quality control and quality assurance .............................................................................................. 29 
Ethical Considerations ..................................................................................................................... 29 
National Agency for Numerical Data Safety (CNIL) ......................................................................... 30 
Data processing and retention of research documents and data .................................................... 30 
Funding and Insurance .................................................................................................................... 31 
Publication rules .............................................................................................................................. 31 
Feasibility of the study ..................................................................................................................... 31 
References ..................................................................................................................................... 33 
 


4
 
Scientific justification and general description of the research 
Name and description of the experimental drug(s) 
 
Propofol (2,6-diisopropylphenol) is a diisopropylphenol belonging to the class of general 
anesthetics. Anesthetic properties are likely mediated by depression of NMDA receptor neuro-
excitatory activity and activation of GABA A receptors 1. 
Atropine is a parasympatholytic used in pre-anesthesia as a protection against vagal 
manifestations. 
Sufentanil is a rapid, short-acting synthetic morphine used in anesthesia and resuscitation. 
Atracurium is a non-depolarizing, short-acting, fast-acting neuromuscular blocker used to facilitate 
tracheal intubation and artificial ventilation. 
 
Scientific data from the literature 
Prevention of pain in newborns should be a priority for all caregivers, as pain transmission 
pathways are present in the fetus as early as 22 weeks of gestation2. The management of newborn 
pain by pharmacological or non-pharmacological means was the subject of a consensus by the 
American Academy of Pediatrics and the Canadian Pediatric Society in 2000 3. A large 
observational study conducted in the Paris region in 2005-2006 reports that the median number of 
painful procedures in neonatal intensive care units is 16 per child per day of hospitalization 4. 
Beyond its ethically obvious nature, the management of newborn pain is important at many levels. 
Repeated exposure to pain during the neonatal period has adverse consequences on brain 
development5. In the long term, we observe in the former very premature infants an alteration of 
the sensitivity to the pain (which persists at least until the adolescence) 6 and behaviorial 
modifications (anticipatory fear for pain with reactions of withdrawal) 7. Premature newborns who 
have the highest risk of having neurological sequelae are also those who experience the most 
painful stimulation during their stay in neonatal resuscitation 8. Finally, pain contributes to parental 
stress, which is all the more important because separation is early and prolonged 9. 
Endotracheal intubation is commonly performed in the NICU and delivery room. A 
declarative survey conducted in France in 46 NICUS and 38 delivery rooms showed that only 74% 
of newborns were intubated with sedation and / or analgesia 10. A posteriori analysis of the 
EPIPPAIN study showed that in 12 out of 13 pediatric and neonatal ICUs in Ile de France, specific 
premedication was only administered in 56% of neonatal intubations 11. Yet this procedure is a 
painful and unpleasant experience 12,13 and there is a definite interest in intubating with 
premedication, as recently recommended by the American Academy of Pediatrics (AAP) 14. 
Premedication reduces the time and number of attempts necessary for intubation 15. Intubation 


5
without analgesia increases intracranial pressure and thus potentially increases the risk of 
intraventricular hemorrhage 16. In addition, laryngoscopy deforms the larynx and upper airways 
causing activation of the sympathetic and parasympathetic system responsible for bradycardia and 
increased intra-thoracic pressure 17. 
Reasons for not using analgesia may include lack of familiarity with premedication, fear of 
adverse effects, lack of sufficient evidence of efficacy, or lack of consensus on the optimal regimen 
of premedication. Several therapeutic classes have been evaluated for premedication before 
intubation and have been the subject of a recent comprehensive review 18. Barbiturates do not 
diminish the occurrence of desaturations 17,19. Midazolam seems dangerous if used alone 20. 
Opioids used without a neuromuscular blockerare associated with frequent desaturations 21,22. On 
the other hand, the combination of opioid and a neuromuscular blocker improves the conditions of 
intubation 22. This opioid+neuromuscular blocker combination is therefore considered the gold 
standard of premedication before intubation 23. 
Propofol is a diisopropylphenol which has many theoretical advantages. Its activity is 
observed in less than a minute after intravenous administration. The duration of action is brief, the 
half-life in adults is 1.8 to 4.1 minutes 24. The preparation of this drug is fast and easy because it is 
not necessary to dilute it, which decreases the risk of error. This drugcan be used alone because it 
has no vagolytic action. It decreases the pharyngeal reflex and muscle tone facilitating intubation 25 
and allows the maintenance of spontaneous breathing. Although it is not an analgesic, its 
effectiveness has been proven in many studies in children. It is commonly used as a premedication 
for bronchial 26or digestive 27fibroscopy in children. Propofol has also been shown to be effective 
for difficult intubations, for intubation in patients with vigil coma and for insertion of laryngeal and 
pharyngeal masks28,29. 
The use of propofol is common in adults and children, in intensive care and anesthesia. 
Reported adverse reactions of propofol are mild injection pain and systemic hypotension. From a 
hemodynamic point of view, propofol decreases cardiac pre-load and post-load that can lead to 
systemic hypotension due to a decrease in sympathetic tone and vascular resistance30 without any 
change in myocardial contractility31. In most cases, hypotension is brief without requiring volume 
expansion 32. In the respiratory system, it has been shown that propofol can reduce the diameter of 
the airways; this effect is completely reversible with continuous positive airway ventilation 33. In less 
than 2% of children undergoing endoscopy of the upper airway spontaneous ventilation under 
propofol, spontaneously resolving episodes of desaturation have been reported 34. Only continuous 
intravenous infusion of propofol at a dose greater than 5mg / kg / h has been associated in adults 
and children with severe complications associating zinc deficiency, metabolic acidosis, 
rhabdomyolysis, hyperkalemia and renal failure that may lead to deaths 35. Finally, maternal 
anesthesia with propofol for caesarean sections does not significantly alter the Apgar score in 
neonates compared to other analgesic protocols 36,37. 


6
Several animal studies have been conducted on the possible neurotoxicity of propofol. 
Indeed, propofol positively modulates the inhibitory function of GABA (gamma-amino-butyric 
acid)neurotransmitters causing a GABA accumulation by inhibition of reuptake and is an NMDA (N 
methyl D aspartate) receptor antagonist. In murine models, NMDA antagonists can induce massive 
neurodegeneration by apoptosis 38. However, these events are dependent on the dose 
administered, the chosen injection schedule (single dose or continuous infusion), the duration of 
exposure, stage of development and other anesthetic agents administered simultaneously39. Al-
Jadhari et al. in a dose-response study showed that exposure of neuronal growth cones from 
chicken embryos resulted in collapse of these embryos, which was reversible if the dose used was 
low and the exposure time was short39. The toxic doses used in this study are much higher than 
the doses used in humans. Vutskits et al identified an impairment of dendritic growth of rat neurons 
in vitro at doses considered clinically relevant 40. In contrast, propofol has beneficial effects 
described by its antioxidant properties in the adult animal where a model of cerebral ischemia-
reperfusion is observed to decrease neuronal apoptosis 41. The mechanism of action involves a 
decrease in lipid peroxidation 42and a decrease in the amount of free radicals 43. In animals, 
propofol also has immunomodulatory effects. There is a decrease in mortality in anesthetized rats 
after induction of septic shock by bacterial endotoxin 44. Propofol decreases the synthesis of pro-
inflammatory cytokines (TNFα and IL-6) in vivo and in vitro 45. It alters the immune functions of 
monocytes and polymorphonuclear neutrophils 46. It has a protective effect on the lungs after 
experimental induction of ARDS with oleic acid 47. 
The interpretation of such experimental results is delicate and experts recommend the 
utmost caution in the transposition of animal data to humans 48. All families of anesthetic drugs 
(opioids, benzodiazepines, GABA agonists, NMDA antagonists) have been implicated in the 
development of brain development disorders 48,49. However, the fight against pain must remain a 
priority in Neonatology while ensuring a rigorous and long-term evaluation of new practices. 
 
Researchers in San Diego and Dartmouth have previously studied the value of adding a 
fast-acting neuromuscular blocker to an opioid before intubation in an open randomized study 22. 
The atropine-fentanyl combination was compared to the atropine-fentanyl-mivacurium combination. 
The results of this study showed that the use of neuromuscular blocker combined with analgesia 
and anti-cholinergic decreased the time and number of attempts needed to intubate (confirmation 
of the secondary hypothesis) without significantly decreasing episodes of saturation lower than 
75% (reversal of the main hypothesis). In the mivacurium group (n = 21, mean weight: 1560g, 
mean age adjusted 31SA), 29% of children experienced a desaturation episode <75% with a 
duration greater than 30s. The total duration of the procedure was 31% shorter in the group 
receiving neuromuscular blocker and the total duration of laryngoscopy decreased by 41%. 
Créteil’s team carried out a prospective study for the evaluation of premedication with 
atropine, sufentanil and atracurium in newborns with less than 32 SA and / or less than 1500g (n = 


7
35 intubations, median birth weight: 850g, mean gestational age at birth: 27.6 weeks, median age 
at intubation: 10 days, (IQR [4-16]) 50.The intubation conditions reported by the operator were 
"good or excellent" in 94% of cases and the success rate at the first attempt of 75%. However, 
desaturations below 80% lasting at least one minute were observed in one out of two cases. 
Episodes of desaturation are therefore a common adverse event in this population during the 
intubation procedure with the atropine-opioid-neuromuscular blocker combination. The time 
required to prepare drugs is another disadvantage of this triple therapy since Ghanta et al. reported 
a preparation time of 960 seconds (900 to 1200s) 51. It is necessary to dilute the three products, 
each dilution exposing to a risk of error. Other notable adverse effects include the induction of 
thoracic rigidity or laryngospasm by fentanyl and its derivatives, making mechanical ventilation or 
intubation more difficult 52. The neuromuscular blockers, in turn, induce prolonged muscle 
relaxation and apnea requiring rapid initiation of assisted ventilation. But they do not always 
prevent the occurrence of chest blocking phenomena induced by sufentanil 50. These two 
phenomena can contribute to the occurrence of episodes of prolonged and/or severe desaturation. 
In neonates, the only prospective randomized trial evaluating propofol as premedication 
before intubation was performed in an Australian center 51. The hypothesis was that by allowing 
spontaneous breathing, the propofol-treated group would have fewer apneas and therefore 
potentially fewer episodes of hypoxemia during the procedure. The authors compared propofol at a 
dose of 2.5 mg / kg renewable as needed (n = 33) to a morphine-atropine-suxamethonium 
combination (n = 30) in neonates born at 25 to 31 weeks of gestation, with birth weights ranging 
from 759 to 1612g, intubation weight from 810 to 1972g, and age at intubation from 1 to 33 days. 
The results showed that sufficient muscle relaxation or sleep was achieved in 60 seconds in each 
group and that the intubation time was significantly shorter in the "propofol" group (120s versus 
260s). No difference in blood pressure and heart rate was observed between the groups. The 
median minimum oxygen saturation values during the procedure were significantly lower in the 
"morphine-atropine-suxamethonium" group (60 versus 80%). However, this minimum single 
saturation value does not necessarily indicate the duration or severity of hypoxia. The onset of 
anesthesia was faster in the "propofol" group (780 vs 1425s) and no serious adverse events were 
observed during the study, including no grade III or IV intraventricular hemorrhage. 
Other descriptive studies have been published on the use of propofol as premedication 
before neonatal intubation. Papoff et al. reported the use of fentanyl (1.5 µg / kg in 1 minute) and 
propofol (2 mg / kg in 20 seconds) in 21 term or near term neonates 53. The intubation conditions 
were good despite the occurrence of abrupt desaturations (> 60%) in 7 cases. In the majority of 
these cases, these desaturations were accompanied by a drop in blood pressure (undefined) that 
the authors treated with the administration of 10 ml / kg of normal saline bolus. In conclusion, the 
authors considered this association as safe and effective. 
More recently, Welzing et al. published a pilot study of 13 newborns less than 8 hours of life 
eligible for the INSURE procedure (INtubation SUrfactant Extubation) 54. This pilot study was 


8
prematurely interrupted due to the frequency of arterial hypotension defined by a mean arterial 
blood pressure <25 mm Hg. Propofol was administered as a bolus dose of 1 mg / kg in the first 6 
patients and over 60 seconds in the 7 following. In the first phase (bolus), 3 out of 6 patients 
experienced hypotension <25 mmHg 10 minutes after administration. In the second phase (1-
minute injection), two patients experienced hypotension <25 mm Hg. In these 7 infants, mean 
pressure decreased from 37 mmHg to 28 mmHg 5 minutes after propofol administration. No 
significant changes in heart rate and O2 saturation were observed. No complications such as 
intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, retinopathy or 
bronchopulmonary dysplasia were observed in the 13 children who participated in the study. 85% 
of intubations were performed under conditions deemed "good" or "excellent". 
In 2013, Simons et al. published their experience with propofol in 62 neonatal intubations 55. 
The initial dose of 2 mg / kg was sufficient for 37% of patients. Hypotension occurred in 39% and 
was more common in the first day of life. However, the diversity of associated pathologies 
(necrotizing enterocolitis, sepsis) could potentially have increased the risk of hypotension. 
Between March 2007 and December 2008, the NICU at the Centre Hospitalier 
Intercommunal de Creteil conducted an observational study of 33 intubations with propofol in 
infantsborn after 32 weeks of gestation56. The dose of 2.5 mg / kg was administered over 60 
seconds and could be repeated if necessary. Intubation conditions were rated as "good" or 
"excellent" in 91% of cases. Desaturation <80% for at least 1 minute occurred in 17 cases (52%) 
and bradycardia <100 / min for at least 1 minute in 5 cases (15%). Mean arterial blood pressure 
decreased at 5 and 10 minutes after injection (respectively -6.6 and -9.9 mmHg) but normalized 
spontaneously 15 minutes after injection. No significant changes in heart rate were observed. The 
identified risk factors for onset of desaturation were lower pre-intubation SpO2 (93% vs 98%) and 
longer duration of intubation (394 sec vs 167 sec). 
 
Predictable benefits and risks known to patients who are eligible for research 
 
The expected benefit for infants participating in this study is the systematic administration of a 
premedication before tracheal intubation except forlife-threatening situations. These infants will 
also benefit from sustained surveillance during and after the procedure. 
The expected risks are those commonly described during tracheal intubation in the newborn: 
bradycardia, desaturation, trauma to the upper airways. Premedication should avoid pain and 
discomfort, but expose children to the theoretical risk of chest stiffness and low blood pressure. 
The interpretation of arterial hypotension in preterm infants is extremely difficult 57. Indeed, it has 
been shown that the correlation between blood pressure and cardiac output is poor in these 
children 58. Upper vena cava flow was more predictive of neurodevelopmental outcome at 3 years 
than arterial hypotension in premature infants 59. However, routine measurement is difficult, 
especially during intubation. 


9
Concerning neurodevelopmental outcome, no evidence in human clinical research 
(exclusively retrospective data) allows to fear a possible toxicity of non-surgical anesthetic 
treatment in neonates hospitalized in NICU48,60,61. However, short and long term neurological 
monitoring will be performed. 
 
Description and justification of the route of administration, dosage, administration 
schedule and duration of treatment 
 
The drugs studied are strictly reserved for the intravenous route. These treatments will be 
evaluated for a single episode of intubation corresponding to a single administration of the 
treatments. 
Determination of doses 
All children will receive atropine at a dose of 0.02 mg / kg IVD, ie 0.08 ml / kg of the 1 ml solution = 
0.25 mg. This dose is routinely used in pre-anesthesia to prevent vagal bradycardias associated 
with the use of neuromuscular blockers62. Atropine will be routinely administered to prevent vagal 
stimulation associated with laryngoscopy 63. 
Regarding propofol, the dose of 2.5 mg / kg was used for intubation of the preterm infant with no 
significant side effects, especially hemodynamic51. This study allowed a second injection of 2.5 mg 
/ kg in case of failure of the first dose, which was necessary in 24% of cases 64. In addition, a 
pharmacological study in the term and premature newborn showed that a single injection of 3 mg / 
kg resulted in rapid elimination of the product 65. This same study established a slower elimination 
of the product in premature infants and children less than 10 days old. However, the occurrence of 
spontaneously resolving hypotension has been reported at a dose of 1 mg / kg in children younger 
than 8 hours 54. Therefore, for the current study, a dose of 1 mg / kg is proposed, ie 0.1 ml / kg of 
propofol 1% in infants under 1000 g and 2.5 mg / kg, ie 0.25 ml / kg of propofol 1% in children over 
1000 g, slow IV over 1 minute. If a satisfactory sedation (see criteria in chapter "Methods") is not 
obtained an additional dose of 1 mg / kg (ie 3.5 mg / kg maximum cumulative dose), or 0.1 ml / kg, 
may be administered. Propofol 1% will be increased to a volume of 1 ml in children under 1000 g to 
allow injection over 60 seconds. It will be used pure for children over 1000 g. 
 
If a patient is randomized to the atropine-sufentanil-atracurium group, he or she will receive 
atracurium after atropine to prevent the risk of sufentanil-related chest rigidity. A dose of 0.3 mg / 
kg of atracurium will be used. The dose of 0.5 mg / kg has been shown to be effective in neonates 
66,67, as is the dose of 0.3 mg / kg in only 10 patients 67. Efficient dose-finding studies have 
established an effective dose range of 0.3 to 0.7 mg / kg in neonates 68,69. Finally, the occurrence 
of rare accidents in the United Kingdom has recommended a dose of 0.25 mg / kg in newborns 70. 
We propose for this study a dose of 0.3 mg / kg corresponding to the local experience at Créteil’s 
NICU50. The atracurium besilate will be diluted according to the following modality: 1ml = 10 mg in 
9 ml of D5% resulting in a solution diluted to 1 ml = 1mg. 0.3 ml / kg (ie 0.3 mg / kg) of the IV 


10
diluted solution over 30 seconds will therefore be administered. In case of insufficient sedation, an 
additional dose of 0.1 ml / kg (ie 0.1 mg / kg) may be administered after the injection of sufentanil. 
Finally sufentanil will be injected. The loading dose of 0.2 µg / kg has been reported twice in the 
literature in neonates 71,72, with both efficacy and good tolerance. In addition, it is regularly used in 
Créteil’s NICU50. Very high doses (5 to 15 µg / kg) were administered in neonatal cardiac surgery 
with good tolerability and improvement in operative follow-up compared to the morphine-halothane 
group 73. However, in view of the pharmacokinetic peculiarities of extremely low birth weight 
neonates, a dose of 0.1 µg / kg should be used in infants <1000 g and 0.2 µg / kg in infants > 1000 
g. Sufentanil will first be diluted according to the following scheme: dilute 1 ml = 5 µg in 4 ml of 
D5% resulting in a solution diluted to 1 ml = 1 µg. 0.1 or 0.2 ml / kg (0.1 or 0.2 µg / kg) of the 
diluted IV solution will be administered depending on the weight groups over 60 seconds to reduce 
the risk of thoracic rigidity. In the group of infants<1000 g, the volume of the syringe will be 
increased to 1 ml to allow injection over 60 seconds. In infants> 1000g, the drug will be used 
diluted according to the above-mentioned modalities. 
With regard to the placebo for the studied drugs, the volumes of normal saline used in the 
propofol arm (0.5 ml maximum cumulative volume in children <1000 g and 0.6 ml / kg in children> 
1000 g) are considered negligible and without any effect on the blood volume or ionogram because 
they are lower than the flushing volumes currently used in daily practice. The volume of intralipids 
20% used in the sufentanil + atracurium arm represents a maximum of 0.2 ml / kg (<1000g) or 0.35 
ml / kg (> 1000 g) cumulative volume. These intakes correspond respectively to 0.04 g / kg (<1000 
g) and 0.07 g / kg of purified soybean oil. These minimal intakes do not affect global nutrient 
intakes of the order of 2 to 3 g / kg / 24h of lipids. 
 
Declaration of compliance with the protocol, good clinical practices and the legal and 
regulatory provisions in force 
 
The participating investigators undertake to respect the study protocol and to comply with the good 
practices in force. The legal and regulatory provisions in force will also be respected. 
The choice of the atropine-opioid-neuromuscular blocker combination for the control group 
corresponds to the recommendations of the literature 14,18,23. The choice of atropine-propofol is 
based on the pharmacological properties of propofol and the encouraging literature 51,55,56. 
 
Description of the population to be studied 
 
The study will include all premature or term neonates requiring tracheal intubation outside the 
context of the vital emergency and not presenting a contraindication to the use of the different 
experimental treatments (see criteria for non-inclusion). These children will be divided into two 
groups according to their weight at the time of intubation. 


11
 
 


12
 
Purpose and outcomes 
Purpose 
 
The aim is to compare two premedications: atropine-propofol and atropine-atracurium-sufentanil 
regarding desaturationsduring neonatal tracheal intubation on one hand, and regarding efficacy 
and tolerance.on the other hand  
 
Hypothesis 
 
"atropine + propofol" compared to "atropine+atracurium+sufentanil" will significantly reduce the 
frequency of severe hypoxemia. 
 
Primary outcome 
 
Pulse oxymetry value < 80% for more than 60 seconds.  
Since desaturation is defined as O2 saturation of less than 80% for at least 60 seconds, the main 
objective is to show that premedication with propofol decreases the frequency (percentage) of 
children with episodes of desaturation during tracheal intubation, the control group receiving 
atracurium-sufentanil. Both groups will receive atropine beforehand. 
 
Secondary outcomes 
 
Number of attempts, duration of the procedure, quality of sedation, time to spontaneous respiratory 
and limb’s movements’ recovery, changes in physiologic parameters, short- and long-term 
neurodevelopmental outcomes. 
The secondary objectives are to confirm the following assumptions: 
Compared to the atracurium-sufentanil association as premedication before intubation, 
- propofol will decrease the number of intubation attempts 
- propofol will reduce the duration of intubation 
- propofol will maintain the physiological parameters close to the basal state 
- Propofol will not cause short- and long-term neurological adverse events (2 years) 


13
Methods 
Trial design 
 
Study Type: Interventional, multicenter 
Allocation: Randomized 
Intervention Model: Parallel Assignment 
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) 
Primary Purpose: Treatment 
Study proposal and consent from parents 
 
The protocol will be exposed to the parents of all infants admitted to the to the neonatal intensive 
care unit.Parents will be informed about the objectives, methods, expected benefits and potential 
risks of the study and any inconvenience this may cause to their child. In cases where only one 
parent is present (absent father or mother hospitalized in another maternity and not immediately 
transportable), the written informed consent can be obtained from the present parent and the oral 
consent by telephone from the absent parent, who will sign the consent form as soon as he / she 
can move. This procedure should remain exceptional if no other solution to meet the parents 
directly is possible. Parents can also be approached if an upcoming intubation is planned and they 
are both present. Parents should be informed that they are free to revoke their consent at any time. 
The investigator will attest by affixing his / her signature at the bottom of the "Consent Form" that 
he / she has delivered all of the information contained in the information form. 
The parent (s) will certify by their signature on the same form that they have received this 
information and that they voluntarily participate in the project without any pressure being exerted 
on them. 
Once signed, the original will be archived by the investigator, a copy will be transmitted by the CRA 
monitor to Activ in sealed envelope in order to respect the anonymity of the subject and a copy will 
be given to the parents. In case of intubation in an eligible infant with signed parental consent, the 
child will be included in the study and the parents will be notified according to the usual local 
practices (telephone call or interview, immediately or after a delay). 
Data collection 
 
A team member who will not be directly involved in the intubation procedure will be designated as 
an "observer". He/she will be responsible for the collection of data. 
The child's birth date, age and corrected age, birth weight and current weight, sex, 5 minutes 
Apgar score, reason for intubation, personal history of intubation and last cranial ultrasound will be 
recorded before the start of the procedure. If the child had nocranial ultrasound performed within 
the previous 7 days, one should be performed before inclusion. 


14
The collection of the physiological parameters will begin 1 minute before the first injection and will 
be continued one hour after. Heart rate, pulse oximetry and blood pressure will be obtained one 
minute prior to injection of the first drug (atropine) and will be used as the baseline. Throughout the 
procedure, heart rate, transcutaneous CO2 partial pressure (TcPCO2) and oxygen saturation will 
be monitored continuously and blood pressure will be measured every three minutes by the 
monitoring system used in each service. O2 saturation will be measured by oximeters using 
Masimo technology 74 in all participating centers. Heart rate, blood pressure, O2 saturation, 
TcPCO2, cerebral activity via cerebral oximetry and ventilatory constants will be recorded 1 minute 
before the first injection, then 3, 6, 9, 12, 15, 30, 45 and 60 minutes after the start of the first 
injection. 
The observer will collect vital parameters before the procedure and then, during the procedure, the 
lowest heart rate, lowest saturation and the lowest and highest arterial pressures. He/she will 
measure the duration of intubation, the recovery time of spontaneous ventilation and the recovery 
time of spontaneous movements after the first drug injection. By controlling on the central monitor 
recordings, he/she will confirm the occurrence of the primary outcome (desaturation of less than 
80% for at least 60 seconds). This recording of physiological data will be stored and printed or 
saved in a digital format as source data. If no record can be made, the handwritten record sheet 
completed by the observer will serve as source data. 
The time will be measured from the insertion at the last ablation of the laryngoscope form the 
mouth after the success of the intubation. Intubation will be considered successful by clinical 
confirmation of bilateral lung sounds on auscultation, increased heart rate and saturation, and by 
the presence of an inspiratory and expiratory curve obtained through the respirator's spirometry 
sensor. In both groups, the duration of action of the drugs administered will be noted. 
A standardized collection sheet will indicate the level of training of the operator, the number of 
attempts for each operator, the total number of attempts required and the existence of any 
complications such as thoracic stiffness, lacerations of the mouth or lips. 
For neurological surveillance, aHUS will be performed within 7 days of intubation and will be 
compared to the pre-intubation examination if it exists. The follow-up of the children will be 
performed in each unit during outpatient visits at the corrected ages of one and two years. A 
questionnaire corresponding to the French version of the questionnaire Age and Stages 
Questionnaire (ASQ) 75will then be completed. In the absence of outpatient visits, parents will be 
called by telephone at the same dates and asked to complete the same questionnaire. 
Intervention 
 
After randomization and when the drugs are ready for use, the patient will be equipped with a pulse 
oxymetry sensor on his right hand. He/she will be positioned in the incubator and pre-oxygenated 
thanks to an artificial ventilation system connected to a face mask and delivering a positive 
expiratory pressure (PEP): respirator or bag equipped with a PEEP valve, with an FiO2 allowing to 


15
obtain an SpO2 ≥ 95%. The intubation will be performed by ajunior or senior doctor with a 
laryngoscope and an appropriately sized endotracheal tube (ETT)through the orotracheal or 
nasotracheal route according to usual local practices. The common practice in the departments 
participating in the study is to use the nasotracheal route as first-line and to favor junior doctors as 
the first operator if the condition of the child allows it and under the supervision of a Senior doctor. 
In case of failure, the second operator is usually a senior. There will be no rule imposed on the 
sequence of the operators because this trial aims to compare the premedications under the usual 
conditions of practice of the neonatal intubations. However, the level of experience of the operator 
(s) will be collected in order to allow a possible adjustment to this criterion if the distribution 
between the groups is different. 
weight ≤1000 g 
Syringe 
SufTrac group 
Prop Group 
N°1 
Atropine (1ml= 250 µg)  20 µg/kg 
0.08 ml/kg IV bolus 
Atropine (1ml= 250 µg): 20 µg/kg 
0,08 ml/kg IV bolus 
N°2 
Prepare 
syringe 
n°5 
simultaneously 
Atracurium 1 ml= 10 mg + 9 ml 5%D: 
0.3 mg/kg 
-> 1 ml= 1 mg : 0.3 ml/kg of the 
dilution IV 30 sec 
Normal saline 1 ml + 9 ml 5%D 
 
0.3 ml/kg of the dilution IV 30 sec 
N°3 
Sufentanil 1 ml =5µg + 4 ml 5%D: 0.1 
µg/kg 
-> 1ml =1µg : 0,1 ml/kg of the dilution 
The volume of the syringe will be 
increased to 1 ml with 5%D to allow 
injection over 60 seconds 
Normal saline 1 ml + 4 ml 5%D 
0.1 ml/kg de la dilution 
 
The volume of the syringe will be 
increased to 1 ml with 5%D to allow 
injection over 60 seconds 
N°4 
Prepare 
syringe 
n°6 
simultaneously 
Intralipids 20%: 0.1 ml/kg 
 
Increase the volume of the syringe 
with 5%D for injection over 60 
seconds, without exceeding 5 times 
the initial volume of the syringe 
Propofol 1%: 1 mg/kg 
0.1 ml/kg 
Increase the volume of the syringe with 
5%D for injection over 60 seconds, 
without exceeding 5 times the initial 
volume of the syringe 
N° 5 
If re-injection required : 
Same dilution as syringe N°2 : 0.1 
ml/kg 
If re-injection required : 
Same dilution as syringe N°2 : 0.1 
ml/kg 


16
The children will be randomized and 6 syringes will be prepared for each child: 4 syringes 
corresponding to the initial injections, 2 syringes for re-injections.  
The contents of the syringes are illustrated in the following tables according to weight at 
randomization: 
N° 6 
If re-injection required : 
Same dilution as syringe N°4 : 0.1 
ml/kg 
If re-injection required : 
Same dilution as syringe N°4 : 0.1 
ml/kg 


17
 
 
 
 
The first 4 syringes will be injected to all children. If acceptable sedation is not achieved, syringes 5 
and 6 will be injected. 
Sedation will be satisfactory if the following 3 criteria are satisfied: 
- Absence of facial expression, 
- Absence of spontaneous movement, 
- Absence of reaction to stimulation 
In each group, if the oxygen saturation falls below 60%, the procedure will be stopped and 
ventilation will be resumed with the mask, attempting to increase the saturation to more than 90% 
within a maximum of three minutes. Beyond these three minutes, or earlier according to the 
Syringe 
SufTrac group 
Prop Group 
N°1 
Atropine (1ml= 250 µg)  20 µg/kg 
0.08 ml/kg IV bolus 
Atropine (1ml= 250 µg): 20 µg/kg 
0,08 ml/kg IV bolus 
N°2 
Prepare 
syringe 
n°5 
simultaneously 
Atracurium 1 ml= 10 mg + 9 ml 5%D: 
0.3 mg/kg 
-> 1 ml= 1 mg : 0.3 ml/kg of the 
dilution IV 30 sec 
Normal saline 1 ml + 9 ml 5%D 
 
0.3 ml/kg of the dilution IV 30 sec 
N°3 
Sufentanil 1 ml =5µg + 4 ml 5%D 
0.2 µg/kg 
-> 1ml =1µg : 0.2 ml/kg of the dilution 
The volume of the syringe will be 
increased to 1 ml with 5%D to allow 
injection over 60 seconds 
Normal saline 1 ml + 4 ml 5%D 
0.2 ml/kg of the dilution 
 
The volume of the syringe will be 
increased to 1 ml with 5%D to allow 
injection over 60 seconds 
N°4 
Prepare 
syringe 
n°6 
simultaneously 
Intralipids 20%: 0.25 ml/kg 
 
Increase the volume of the syringe 
with 5%D for injection over 60 
seconds, without exceeding 5 times 
the initial volume of the syringe 
Propofol 1%: 2.5 mg/kg 
0.25 ml/kg 
Increase the volume of the syringe with 
5%D for injection over 60 seconds, 
without exceeding 5 times the initial 
volume of the syringe 
N° 5 
If re-injection required : 
Same dilution as syringe N°2 : 0.1 
ml/kg 
If re-injection required : 
Same dilution as syringe N°2 : 0.1 
ml/kg 
N° 6 
If re-injection required : 
Same dilution as syringe N°4 : 0.1 
ml/kg 
If re-injection required : 
Same dilution as syringe N°4 : 0.1 
ml/kg 


18
operator's judgment, a new intubation will be attempted. A "senior" will attend each intubation. 
 
Outcomes 
 
Primary Outcome Measure 
• Desaturation: Pulse oxymetry value measured by Masimo technology below 80% for 60 seconds 
or more. Intubation procedure is defined by the time between first laryngoscope insertion and last 
laryngoscope removal after successful intubation. Successful intubation is defined by clear bilateral 
breath sounds, increasing heart rate and saturation (if previously low) and appropriate flow curves 
on the ventilator. 
 
Secondary outcomes 
• Number of intubation attempts: each insertion of the laryngoscope in the mouth is considered an 
attempt. 
• Duration of intubation procedure: Duration of intubation is defined by the time between first 
laryngoscope insertion and last laryngoscope removal after successful intubation. Successful 
intubation is defined by clear bilateral breath sounds, increasing heart rate and saturation (if 
previously low) and appropriate flow curves on the ventilator. 
• Heart rate: Heart rate recordings 1 minute before the first injection and at 3, 6, 9, 12, 15, 30, 45 
and 60 minutes after the first injection  
• Pulse oxymetry: Pulse oxymetry recordings 1 minute before the first injection and at 3, 6, 9, 12, 
15, 30, 45 and 60 minutes after the first injection  
• Mean blood pressure: Blood pressure recordings 1 minute before the first injection and at 3, 6, 9, 
12, 15, 30, 45 and 60 minutes after the first injection  
• Transcutaneous PCO2 (TcPCO2) measurement: TcPCO2 recordings 1 minute before the first 
injection and at 3, 6, 9, 12, 15, 30, 45 and 60 minutes after the first injection 
• Time to spontaneous respiratory movements’ recovery: Time between the first syringe injection 
and the first onset of the trigger logo of the ventilator used for conventional ventilation if a 
synchronized mode is used or first inspiratory effort through direct observation if high frequency 
oscillation or ventilation is used.  
• Time to spontaneous limbs movements’ recovery: Time between the first syringe injection and 
the first spontaneous limb movements’ through direct observation of the neonate.  
• Quality of sedation: Assessed immediately after completion of the procedure by the operator 
who succeeded the intubation according to the following scale adapted from Hans 76 and Cooper 
77: 
Excellent: Relaxed jaw and open vocal cords and no movement when inserting ETT 
Good: Relaxed jaw and open vocal cords and mild movements when inserting ETT 
Acceptable: Mild jaw contraction and/or moving vocal cords and/or cough when inserting ETT 


19
Poor: Jaw contraction or closed vocal cords or intense cough or rigidity when inserting ETT. 
• Short term neurological outcome: Head ultrasound  
• Long term neurodevelopmental outcome: Age and stages questionnaire (ASQ) 
 
Measures to reduce bias 
 
Randomization 
 
Randomization will be centralized on line using a password. The randomization software will 
indicate the kit number to be used according to a pre-established randomization table stratified by 
center and by weight category. This assignment code will allow anonymization of the data. The 
programming of this randomization will be checked and validated by a second operator before 
putting it online. 
To prevent a center from making almost all inclusions, which would impair the representativeness 
of the results, the number of patients per center will be limited to 100. 
The number of inclusions may thus vary from one center to another, the important thing being that 
the two treatment groups remain balanced. 
 
Masking 
 
The placebo for propofol will be manufactured by Baccinex (Courroux, Switzerland) and will be 
sent to Theradis Pharma (Cagne-sur-mer, France). Kits containing 1 ampoule of atropine, 2 
ampoules filled with a transparentfluid and 1 bottle of 50 ml filled with a white emulsion will be 
packaged and manufactured by the company Theradis Pharma (Cagne-sur-mer, France) 
according to the regulatory rules. The ampoules and vials will have a strictly identical exterior 
appearance between the verum and the placebo. 
 
Dosage and ways of administration of treatments. Unit shape, packaging and labeling 
 
The atropine used will be atropine sulfate RENAUDIN 0.25mg / ml for injection. Each 1 ml ampoule 
contains 0.25 mg of atropine. 
Propofol Frésenius 1% is an injectable (oil-in-water, white and isotonic) emulsion in 50 ml vials. 
Each 50 ml vial contains 500 mg propofol, i.e. 1 ml contains 10 mg propofol. Excipients: soybean 
oil, egg lecithin, glycerol, oleic acid, sodium hydroxide, water ppi. 
The atracurium used will be the Tracrium® GLAXOSMITHKLINE solution for injection 10mg / ml 
containing atracurium besilate in vials of 5ml = 50mg. Excipients: 32% benzenesulfonic acid 
solution qs pH 3 to 3.8, water. 


20
Sufentanil JANSSEN (Sufenta®) 5µg / ml injectable solution is to be used. Each 10 ml vial 
contains 50 micrograms of sufentanil.Excipients: sodium chloride, sodium hydroxide qs pH4,5-7,0, 
hydrochloric acid qs pH4,5-7,0, water. 
Placebo for propofol will be a 20% Intralipid lipid emulsion packaged in 250 ml glass bottles 
(Frésenius Kasbi) used for parenteral nutrition in newborns. This product will be deconditioned in 
sterile conditions by Baccinex and reconditioned in sterile conditions in 50 ml vials. Baccinex will 
perform autoclaving and stability feasibility tests prior to the start of the study. 
The normal saline solution Lavoisier solution for injection will be packed in vials of 10 and 5 ml 
constituting respectively the placebo for sufentanil and atracurium. The "heads" of sufentanil and 
atracurium vials have specific colour linesthat do not appear on the "heads" of saline vials, 
Theradis Pharma will thus mask the heads of the 10 and 5 ml vials. 
Duration of participation and follow-up 
 
For the primary outcome, a patient will participate fromhis/her randomization to one hour after the 
first drug injection. For long-term follow-up, data collection is planned up to two-years corrected 
age. 
Definitive or Temporary Termination Rules 
 
For an included patient 
Since the trial involves a single prior administration of the medicinal product, participation may only 
be halted if there is a serious adverse reaction during the course of treatment or in case of 
sedation deemed insufficient by the operator: the operator will then administer the treatments 
deemed appropriate to the child's condition. However, data for this child will be analyzed (intention-
to-treat analysis). 
For the research 
The research will be interrupted on the advice of the safety committee, which will examine serious 
adverse events that may or may not be attributable to the experimental treatments and suspend 
the study according to predefined criteria (see appropriate paragraph). 
Treatment kits monitoring 
 
Theradis Pharmawill deliver treatment kits to local pharmacies of the participating centers. 
The distributed and administered treatments will be recorded on a list established by the center 
and containing the batch number of each kit as well as its expiry date. CTs and pharmacists will be 
responsible for updating this list and, in each center, the adequacy of treatments to inclusions. 
Blinding maintenance and unblinding procedure 
 
Unblinding will be performed at the request of the investigators or at the request of the supervisory 
committee. 


21
An investigator will have the possibility to unblind the allocated treatment for a patient only if he/she 
considers that the knowledge of the treatments administered is indispensable to the care of the 
patient. In this case, he/she will obtain from the local pharmacy the sealed envelope corresponding 
to the patient. He/she will have to warn within 48 hours the investigating coordinator of the 
unblinding procedure. 
 The Safety Committee will have the possibility to waive blinding for one or several patients if a pre-
defined number of serious adverse events occur, possibly or certainly attributable to the 
administration of drugs (see appropriate paragraph). 
In all other cases, blinding will be maintained. 
Source data 
 
The source data for each patient will be recorded on an anonymized clinical research form (CRF), 
in each center, by the designated investigators, and collected by and centralized at ACTIV. The 
CRF will be verified and validated by the designated investigators at each center and the CRA. 
These CRFs will be kept under lock at the CHIC and duplicates will be kept in each participating 
center. In case of missing data or for the purpose of verification, access to the medical chart of 
each included patient will be granted to the CRA while respecting medical confidentiality. 
 
Participants 
 
Inclusion Criteria 
 
Any newborn (corrected term <45 weeks of gestation) hospitalized in the neonatal intensive care 
unit and requiring non-urgent or semi-urgent intubation, equipped with a reliable and usable intra 
venous access, with parental consent, whowas never included in the study previously. 
Non-Inclusion Criteria 
 
- Lack of parental consent (failure to provide correct information to parents) 
- Parental refusal 
- Administration of sedative or anesthetic treatment in the previous 24 hours 
- Hemodynamic failure defined by a mean arterial pressure <corrected GA and / or capillaryrefill 
time> 3 seconds 
- Evidence of ENT malformation orobvious condition suggesting especially difficult intubation 
- Life-threatening situation requiring intubation without premedication 
- Participation in another exclusive clinical trial 
- Impossibility of placing intra venous access 
- Known intolerance to sufentanil or to opioids 


22
- Association with morphine antagonists: nalbuphine, buprenorphine, pentazocine 
- Risk of glaucoma  
- Paralytic Ileus 
- Urethro-prostatic disorders with risk of urinary retention 
- Known hypersensitivity to propofol, soybean, peanuts, or any of the excipients of the emulsion 
- Allergy to soya or peanuts 
- Hypersensitivity to atracurium, cisatracurium or benzene sulfonic acid 
- Acute shock 
- Severe dyslipidemia 
- Severe hepatic failure 
- Severe coagulation disorders, 
- Known or suspected hypersensitivity to egg phospholipids, soybean or peanut proteins or to any 
of the active substances or to any of the excipients contained in the intralipids. 
 
Procedures for prematuretermination of treatment administration and for patient’s 
exclusion 
 
Criteria and procedures for discontinuing treatment and excluding a person from research 
 
Premature discontinuation of treatment can only occur in the case of a serious adverse effect 
during treatment (exceptional situation). The criteria for the immediate cessation of intravenous 
injection during treatment are: 
- Sudden appearance of a lesion at the injection site 
- Central circulatory disorders with tachycardia> 200 / min or bradycardia <60 / min. In the event of 
a state of shock, volume expansion and inotropes must be readily available for each intubation. 
A patient will be excluded from the search if the parents withdraw consent. 
 
Method and timing of data collection 
 
Premature cessation of treatment or a patient’s exclusion should be transmitted within two working 
days to the coordinating investigator. A summary of these data will be made every 3 months. 
Modality for the replacement of excluded patients 
 
No alternative arrangements are planned, these circumstances being considered as exceptional. 
Follow-up 
 
In the short term, monitoring will be continuous (see methodology). 


23
In the medium term, a head ultrasound should be performed within 7 days after the patient's 
inclusion. All serious adverse events occurring within one week after inclusion of a patient should 
also be collected and reported (see appropriate paragraph). 
In the long term, neurodevelopmental follow-up will be carried out during outpatient visits or by 
phone. Clinical evaluation will be performed during outpatient visits within each participating center. 
The telephone assessment will be carried out at the corrected ages of one and two years 
according to the French version of the Age and Stage Questionnaire (ASQ)75. 
Treatments given to participants 
 
Description of the treatments needed to carry out the research 
 
The treatments used (atropine, propofol and atracurium-sufentanil combination) 
have been previously described in this Protocol. 
Medicinal products and treatments authorized and prohibited under the Protocol 
 
Administration of a sedative or anesthetic treatment within 24 hours prior to intubation constitutes a 
non-inclusion criteria in the study. 
The administration of a morphine agonist-antagonist treatment is contraindicated within 24 hours of 
inclusion. 
Any treatment deemed necessary for the patient is permitted. In the absence of extreme agitation 
or obvious pain, no sedative or anesthetic treatment should be administered within 1 hour of the 
study treatment. 
Method for treatment follow-up and compliance 
 
The treatment kit assignment will be done after randomization under the prescription of the doctor 
carrying out the study in each unit. 
The kit number assigned to each patient will be printed and included in the CRF. 
The volumes of each injected solution will be recorded during the study by direct observation. 
Given the uniqueness of the administration, no compliance problems are to be feared. 
The remaining quantities of unused product will be disposed of and empty vials will be sent to the 
local pharmacies at each center for posting and tracking of batches. 
Storage conditions of experimental drugs 
 
Propofol can be stored at a temperature not exceeding 25 ° C. It can also be stored at + 4 ° C, at 
which temperature its stability is 36 months. It must be used within 6 hours of its preparation. The 
unused quantity should be discarded. 
Atropine can be stored at room temperature or between + 4 ° C and + 8 ° C (lab advice Aguettant). 


24
Sufentanil may be stored at room temperature at a temperature not exceeding 25 ° C. It should be 
used within 24 hours of its preparation. The unused quantity should be discarded. 
Atracurium should be stored in the refrigerator (between + 2 ° C and + 8 ° C) and should not be 
frozen. The ampoules should be stored in the box in order to protect them from light. Once 
prepared, atracurium should be used immediately. The unused quantity should be discarded. 
Lavoisier sodium chloride 0.9 per cent solution for injection, packaged in glass vials requires no 
special storage precautions. 
Intralipids 20% Fresenius must be stored at a temperature below 25 ° C. 
The study kits will therefore be stored between + 2 ° C and + 8 ° C in a locked refrigerator provided 
to the centers by the sponsor for study purposes. The key of this refrigerator will be kept and made 
available in each pharmacy for internal use according to the same modalities as the key allowing 
the access to narcotics. 
Within Theradis Pharma, under the procedure "Management of narcotic drugs and psychotropic 
drugs": 
The narcotics are stored in a locked area, access to which is protected by a grid. This room 
contains nothing but narcotics. It is also equipped with a refrigerator and a freezer for special 
storage conditions. 
Only the Responsible Pharmacist and the Quality Assurance Manager of the Pharmaceutical 
Affairs know where the key is located. 
Efficacy assessment 
 
Description of Efficacy Assessment Parameters 
 
The efficacy of premedication will be evaluated according to the previously stated criteria for 
sedation to be achieved within two minutes of administration: 
- Absence of facial expression, 
- Absence of spontaneous movement 
- Absence of reaction to stimulation 
The efficacy of propofol compared to the atracurium-sufentanil combination will be evaluated by a 
significant decrease in the frequency (percentage) of children with desaturation <80% for at least 
60 seconds. 
Method and timeline for measuring, collecting and analyzing efficacy endpoints 
 
Episodes of desaturation <80% for at least 60 seconds will be identified by continuous monitoring 
analysis. The data collected for each patient, including the number of desaturations, will be 
collected every three months in each center by a CRA. The frequency of visits may be adapted to 
the inclusion rate of each center. 


25
At the end of the study, the analysis will cover all studied infants. 
 
Safety assessment 
 
Safety assessment Parameters 
 
An adverse event (AE) is defined as any adverse event in a patient in a clinical trial that is not 
necessarily linked to the treatment provided in the clinical trial. All adverse events encountered 
during the study will be recorded in the CRF in the dedicated section.This study falls within the 
scope of the law of 20 December 1988, as amended, protection of persons who lend themselves to 
biomedical research, the measures necessary to ensure that the provisions of Article L. 209-12 6th 
paragraph of the Public Health Code are respected, will be implemented. In particular, all serious 
adverse events likely to be related to the research will be reported. The investigators of each 
center will be responsible for establishing the accountability of the experimental treatment for the 
occurrence of the adverse event according to 3 modalities: 
- not attributable; 
- possibly attributable; 
- certainly attributable. 
A serious adverse event will be a serious adverse event that is either possibly or certainly 
attributable to one or more of the experimental drugs. 
The investigator is responsible for informing the sponsor of any serious adverse event. 
Responsibility for reporting such events to the supervisory authorities rests with the proponent. 
Serious adverse events (SAEs) are considered to occur when an AE: 
- Causes death, 
- Involves the vital prognosis, 
- Causes a temporary or permanent disability or incapacity, 
- Requires or extends the hospitalization of a patient. 
 
Some of the serious adverse events are listed in the following list, which is however not 
exhaustive: 
- Deaths 
- Heart failure 
- Pneumothorax 
- Sepsis 
- Necrotizing enterocolitis 
- Grade III or IV intraventricular haemorrhage 
- Neurological lesion (peri-ventricular leucomalacia, ischemia, haemorrhage) 


26
- Severe metabolic acidosis (pH <7.00, excess of base <15 mmol / l) 
 
Methods and schedule for AE declaration 
 
AEs will be collected within one hour of the start of treatment. 
Investigators will be required to report the occurrence of any SAE that appears within seven days 
of inclusion. The declaration of these SAEs must be made without delay to ACTIV as soon as the 
investigator of the center becomes aware of it. The SAEs will be analyzed in real time. 
Procedures for registration and notification of adverse reactions 
 
The AEs will be recorded in the CRF after the CRA has verified the data. 
- Serious adverse events (adverse events possibly or certainly attributable to experimental 
treatments) will be counted as they are notified and may lead to discontinuation of the study. The 
pharmacovigilance unit of For Drug Consulting is responsible for analysis and declarations to the 
competent authorities. The safety committee will be composed of Dr Sophie Saizy-Callaert, 
pharmacist at CHIC, Prof. Gilles Dhonneur, Anaesthesiologist- Intensivist at the CHU Henri 
Mondor and a Neonatologist, Dr. Elisabeth Walter, neonatology department, Hôpital Saint Joseph, 
Paris. The rules for stopping the study will be as follows: 
- 
Occurrence of two deaths directly attributable to the administration of drugs (frequency 1%); 
- 
Occurrence of three cardiac arrests requiring external cardiac massage and / or adrenaline 
administration directly attributable to drug administration (frequency 1.5%) 
- 
Occurrence of twelve new episodes of intraventricular haemorrhage grade III or IV and / or 
leucomalacia within 7 days of administration in the population of children under 1000 g 
(frequency 15%). 
These SAEs leading to study interruption will be communicated by the study coordinator via e-mail 
to the investigators of each center who will be responsible for their transmission to the rest of the 
team. 
The protocol, patient information note and consent may be amended if new safety information is 
updated. 
 
Follow-up of persons following the occurrence of adverse events 
 
Follow-up will be the one planned for the study. In case of a SAE, follow-up adapted to the 
patient's state of health and corresponding to the usual practices of the service will be offered. 
 


27
 
Statistics 
 
Statistical methods and timing of intermediate analysis 
 
Initial analysis plan (as of September 2011) not executed 
 
Pretreatment characteristics between groups (sex, gestational age, chronological age and 
corrected age, birth weight and present weight, 5-minute Apgar score, oxygen saturation, blood 
pressure, cardiac and respiratory rate, history of intubation, intubation) will be compared using 
Mantel and Haenzel tests (sex, gestational age, 5-minute Apgar score) or 2-factors variance 
analysis (all other variables). The randomization is stratified on the weight of the child at the time of 
intubation and on center, the two groups will be not be compared for these characteristics because 
of the randomization process. 
Analysis of primary and secondary outcomes (frequency of the children with desaturation, SpO2, 
blood pressure and heart rate, number of attempts and total duration of intubation) will also involve 
the Mantel and Haenszel test (frequency of the children with desaturation, indication for intubation 
and number of intubation attempts) and analysis of variance (for total duration of intubation). 
A subgroup analysis according to weight categories will be performed if the interaction test (chi2 
homogeneity) shows a difference in the effect of premedication on the primary outcome according 
to weight categories. 
No interim analysis is planned, the continuation of the study being based on the previously defined 
stopping rules. 
 
Final analysis plan (as of November 2016, established before data was released) executed 
 
Pretreatment characteristics (sex, gestational age, chronological age and corrected age, birth 
weight and present weight, 5-minute Apgar score, oxygen saturation, blood pressure, cardiac and 
respiratory rate, history of intubation, intubation) will be described by groups and no statistical test 
will be performed to compare the two groups at baseline. 
For the frequency of children with desaturation (primary outcome) and worsening of head 
ultrasound, the analysis will be conducted according to the intent to treat principle using a 
generalized mixed model with a log-binomial distribution adjusted on weight at inclusion (≤1000g, 
>1000g) accounting for randomization structure and treating center as a random effect 
(exchangeable within-center correlation  structure). Generalized linear mixed models are an 
extension of linear mixed models to allow response variables from different distributions, such as 
binary responses, which is the case for our primary outcome. In that type of model, we have to 


28
specify the distribution of the variable to explain (ie, the outcome). For the primary outcome, which 
is a binary outcome, we used a log-binomial distribution to obtain an adjusted relative risk.  
 
The number of intubation attempts will be analyzed using a generalized mixed model with a log-
Poisson distribution to account for the nature of variable (ie, counting with one or more several 
intubation attempts by patient). 
 Duration of intubation will also be evaluated using a generalized mixed linear model. The duration 
of intubation, the quality of sedation and the time to respiratory and limbs’ movements’ recovery 
will be compared between treatment groups using Kruskal-Wallis tests.  
The analysis of variations in physiological parameters recorded at the predefined time points will 
be performed using a generalized linear model for repeated data including treatment group, time, 
time by treatment interaction, baseline parameter value, weight at inclusion (≤ 1000g, >1000g) and 
treating center as a random effect (exchangeable within-center correlation structure). 
A subgroup analysis will be conducted according to weight at inclusion (≤1000g, >1000g). 
No interim analysis is planned, the study being based on pre-defined stopping rules. 
 
 
Sample size 
 
If one wants to show that the frequency of children showing at least one desaturation decreases 
significantly from 50% to 30% assuming a 2-sided α error of .05 and a power of 0.8, 93 children 
per group are required, ie 186 children in total . 
Given that 40% of children should weight less than 1000 g and 60% more than 2000 g, 37 and 56 
children in each group should be included in each stratum: for 5 participating centers, this would 
result in 8 children per group for weights ≤ 1000 g and 12 children per group for weights> 1000 g. 
Taking into account possible withdrawals of consent, recruitment could be carried out by 5 centers 
according to the following scheme: 
Center  
           weight ≤ 1000 g 
 
weight> 1000 g 
 
 
 
 
 
 
A 
B 
 
 
A 
B 
 
 
 
1 
 
8 
8 
 
 
12 
12 
 
 
 
2 
 
8 
8 
 
 
12 
12 
 
 
 
3 
 
8 
8 
 
 
12 
12 
 
 
 
4 
 
8 
8 
 
 
12 
12 
 
 
5 
 
8 
8 
 
 
12 
12 
 
 
 
which would eventually require 200 children. 
Expected statistical significance 
 


29
A difference observed between the two groups will be said to be significant if p <0.05. 
Statistical Criteria for Stopping the Research 
 
No interim analysis is planned. The rules for stopping the test are defined in another paragraph. 
Method for taking account of missing, unnecessary or invalid data 
 
Missing data will not be accounted for. 
 
Management of changes to the initial strategy analysis plan 
 
Not applicable to this study. 
 
Choice of subjects to include in analyzes 
 
The analysis will be on an intent-to-treat basis and will include all randomized children, even if 
incomplete treatment or ineffective sedation is used. 
 
Regulatory and Ethical aspects 
 
Right of access to data and source documents 
 
Access to data will be authorized for the CRA, the coordinating investigator and the sponsor in 
compliance with the rules of medical confidentiality. Direct access to source data will be authorized 
by the investigator in the event of an audit by the proponent or representatives of regulatory 
authorities. 
The source documents will be stored in each center inCRFs composed of single sheets. The copy 
will be collected by the CRAat each center and the original will be retrieved during the monitoring 
visits and stored in the Neonatal Resuscitation and Neonatal Department of CHIC, under lock. 
Quality control and quality assurance 
 
The completeness, consistency and quality of the data collected will be ensured by the 
investigators designated in each center and verified by the CRA. The principal investigator 
reserves the right to exclude from the study a center that does not conform to the protocol or does 
not ensure correct data collection 
Ethical Considerations 
 


30
This study will be carried out according to the national ethical rules for minors suitable for 
biomedical research. This protocol shall be submitted by the coordinating investigator to the 
opinion of the Comité de Protection des Personnes Ile de France III in accordance with the 
legislation in France at the start of the trial. Upon receipt of the favorable opinion issued by the 
Comité de Protection des Personnes and registration of the study at the General Direction of 
Health, the study may begin.  
Declaration of Helsinki 
This project was developed and will be carried out in accordance with the principles laid down by 
the 18th World Medical Assembly in Helsinki in 1964 and their amendments adopted in Tokyo, 
Venice, Hong Kong, South Africa and Edinburg - Ethical and legislative texts on Biomedical 
Research). 
It also complies with the legislation in France (Huriet Law No. 88-1138 of 20 December 1988, as 
amended, and Public Health Act No. 2004-806 of 9 August 2004) and the "Notice to Promoters 
and Investigators clinical trials of medicines "published by the Ministry of Health and Family in 
1987 (see Ethical and Legislative Texts on Biomedical Research). 
National Agency for Numerical Data Safety (CNIL) 
 
The study is subjectedto a declaration to the CNIL, and complies with the criteria for the 
methodology of reference. 
Data processing and retention of research documents and data 
 
Data processing: CRFs will be sent to ACTIV for validation, and dual input in real time. Requests 
for correction on the already monitored CRFs will be edited by ACTIV in the form of queries and 
handed over to CRA monitors in case of missing or incorrect data. Following the monitoring visits, 
the dated and signed investigator's responses will be entered on the basis, once refastened to 
ACTIV. 
The data will then be treated anonymously by Dr. Dechartres and Mrs Martin-Marchand (INSERM 
U 1153), respectively methodologist and statistician appointed for this study.  
The source documents will be kept in the participating centers and at the CHIC for a period of 15 
years. 
The documents to be kept by the investigator for a period of 15 years are as follows: 
- 
the final protocol signed by the investigator 
- 
any amendments to the protocol 
- 
one copy of the FIU for each patient 
- 
an information form 
- 
a patient identification list 
- 
Completed FIUs (yellow leaflets) 
- 
his CV together with an original copy of his financial agreement 


31
- 
signed (original) consents 
Funding and Insurance 
 
Funding for the study is based on funding through PHRC 2009, combined with an accepted 
supplement in September 2014. No other funding was requested for this study. The application for 
funding included in this study takes into account the cost of medical and paramedical time in all 
centers (two full-time equivalents for the entire study), the cost of the CRA and its regular 
movements. Regarding drugs, prices were evaluated with the CHIC pharmacy but will be fixed 
after the procedure respecting the code of the public contracts. Costs related to the double-blind 
procedure (pharmaceutical manufacturers) are based on a detailed quote from Crid Pharma, 
Theradis and Baccinex. Pharmacovigilance fees are based on quotes from the company ForDrug 
Consulting. 
The CRA of each site will ensure data entry. CRC monitors from CHI Créteil will monitor the study. 
Insurance has been taken out in accordance with the provisions of article L.1121-10 of the Code of 
Public Health. Issue 102.760 by the sponsor to SHAM. 
Publication rules 
 
The results of this study will be published in an international peer-reviewed English-language 
journal. 
Excluding the first and last author ranks reserved for the coordinating center, the rank will be 
proportional to the number of inclusions for each center. A representative of ACTIV will also be 
among the authors. 
Feasibility of the study 
 
Each participating center has a high annual recruitment. They all have solid experience in 
multicenter clinical trials. In the prospective study carried out in Creteil’s NICU in 2007, 35 
newborns (all gestational ages) were intubated over a period of 6 months (personal data), ie 70 
intubations per year. It can therefore be estimated that in each center - the number of annual 
neonatal admissions is close to that of the CHIC - an average of the lowest of 60 intubations per 
year will be achieved (90 over 18 months). The target of 40 inclusions per center over 18 months 
therefore requires an inclusion rate of 44% in the eligible population. This rate appears to be 
reasonably achievable given the experience of each of the participating centers. In each center, a 
part-time research technician will be allocated to identify eligible patients and provide first 
information to parents of potentially eligible children. These research technicians will also be 
responsible for the quality and completeness of the data collection, the appropriate reporting of 
AEs and SAEs by investigators and the keeping of screening logs. The inclusion rate of each 
center will be evaluated by the weekly collection of all the intubations carried out ("screening log") 
which will be transmitted by fax to the coordinating center. In case of difficulties of inclusion, the 


32
reasons for these difficulties will be discussed with each center and appropriate measures will be 
taken during on-site visits. 
The proper implementation of the study will be ensured by prior visits to each center explaining the 
objectives of the protocol, its conduct, the modeling with training in data collection, the declaration 
of AEs and SAEs and to plan the CRA's visits. 


33
 
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