Intranasal Sufentanil for Analgesia of Severe Sickle Cell Vaso-occlusive Pain Crisis in the Pediatric

Study Overview
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Brief Summary
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Sickle cell disease (SCD) is characterized by an abnormal hemoglobin, the main protein in the red blood cell. From the first months of life, acute obstruction of the vessels of the microcirculation manifests as intense and unpredictable recurrent episodes of severe pain. In the Emergency Department (ED), patients presenting with a vaso-occlusive crisis (VOC) required a rapid evaluation and administration of pain relief therapies and hydration. this strategy is based on an intranasal (IN) administration of Sufentanil at the initial management of children with VOC, followed by morphine intravenous (IV) relay as soon as possible, compared to the usual care procedure with IV morphine as soon as possible. The hypothesis is that the use of this IN opioid at the beginning of the management of children with VOC can reduce the time before being pain relieved. Indeed, the IN administration make it easier and faster to administer.

Detailed Description
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Sufentanil is a powerful opioid analgesic used intravenously by emergency physicians for the sedation of intensive care, intubated and ventilated patients. It is therefore already present in the pharmacopoeia of emergencies. As the duration of action of inztranasal Sufentanil is too short to completely replace the IV morphine, a very promising approach would be to use it during the initial phase of the management of severe pain in children with painful sickle cell crisis while waiting for a venous access. The INVOPE trial is a phase III trial evaluating the intranasal sufentanil in sickle cell disease children with severe VOC. The INVOPE trial is a randomized controlled, multicenter, double blind, two parallel-group in a 1:1 ratio, placebo-controlled superiority trial comparing the analgesic efficacy of the sufentanil IN + standard care IV morphine / versus placebo IN + IV morphine as soon as possible. Children will be randomized in two groups: Experimental group: IN Sufentanil procedure with IV administration of morphine as soon as possible Control group : IN placebo IN procedure with IV administration of morphine as soon as possible The objective of this trial is to compare a procedure consisting in IN Sufentanil followed by IV morphine, when compared to IN placebo followed by IV morphine alone, in children with severe vaso-occlusive crisis.

Official Title
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Intranasal Sufentanil for Analgesia of Severe Sickle Cell Vaso-occlusive Pain Crisis in the Pediatric Emergency Department: a Double Blind Randomized Versus Placebo Controlled Trial

Conditions
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Vaso-occlusive Crisis

Intervention / Treatment
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* Drug: Sufentanil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: At inclusion visit: Sickle-cell disease = Hemoglobin SS or SC or Sß-thalassemia Age < 18 years old Weight > 10 kgs Registered with the social security scheme (or State Medical Aid - AME) or his/her beneficiaries Informed consent of the holder (s) of the exercise of parental authority Age < 18 years old At randomisation visit Presenting to the ED with vaso-occlusive crisis: migratory bone pain, which may occur in the limbs, spine, thorax, pelvis, skull; or crisis known as such by the patient. Severe pain determined at triage, defined as: EVENDOL ≥ 10/15 in children aged 0-8 years or NRS-11 ≥ 7/10 in children aged 8 years to less than 18 years Informed consent of the holder (s) of the exercise of parental authority signed at inclusion visit Exclusion Criteria: At inclusion visit Known cirrhosis End-stage renal disease requiring kidney dialysis Known hypersensitivity or contraindication to sufentanil or any of the excipients Contraindication to morphine Facial malformation, epistaxis, blocked or traumatised nose Severe asthma Patient's or parent's refusal to participate Participation in another interventional trial Parents who do not speak French At randomization visit Known cirrhosis End-stage renal disease requiring kidney dialysis Known hypersensitivity or contraindication to sufentanil or any of the excipients Contraindication to morphine Facial malformation, epistaxis, blocked or traumatised nose Severe asthma Patient's or Parent's refusal to participate or withdrawal of parental consent Participation in another interventional trial Patient has already been randomised to the INVOPE trial during a previous VOC Strong opioids received <6 hours (morphine, oxycodone, hydromorphone, fentanyl, sufentanil, nalbuphine) Respiratory failure (tachypnea; bradypnea; paradoxical breathing; grunting; head-bobbing; nasal flaring; retractions (subcostal, suprasternal, intercostal, sternal)) Oxygen saturations below 95% on initial assessment Pneumonia requiring oxygen therapy Hemodynamic disorders: tachycardia, hypotension Altered conscious state as defined by a Glasgow Coma score less than 15 Positive urinary pregnancy test for woman of childbearing potential (postpubertal female with sexual activity) Nasal or sinus surgery within 6 months before randomisation High fever > 39°C Sign of intolerance of acute anaemia Description by the patient (or the parents) of the unusual nature of the attack

Ages Eligible for Study
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Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sufentanil IN + Morphine IV<br>Intranasal Sufentanil + IV morphine: | Drug: Sufentanil<br>* Administration of intranasal sufentanil<br>* Other names: sufentanil IN + morphine IV;|
| Placebo Comparator: Placebo IN + Morphine IV<br>Placebo of Sufentanil administered intranasally (IN) . One single administration +IV morphine similar to the experimental arm: | Drug: Sufentanil<br>* Administration of intranasal sufentanil<br>* Other names: sufentanil IN + morphine IV;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of the Efficacy of Intra-nasal Sufentanil for Analgesia of Vaso-occlusive Crisis in Sickle-cell in children | efficacy of the analgesia at 30 minutes after IN injection, in children with SCD presenting to the pediatric ED with a severe VOC with Pain relief is defined as EVENDOL score ≤ 5/15 or NRS-11 score ≤ 3/10 | at 30 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of children relieved (EVENDOL ≤ 5/15 or NRS-11 ≤ 3/10) at 10, 20, 40, 50 and 60 minutes after the IN injection inclusion | Proportion of children relieved (EVENDOL ≤ 5/15 or NRS-11 ≤ 3/10) at 10, 20, 40, 50 and 60 minutes after the IN injection inclusion | at 60 minutes | 
| Proportion of children with a moderate pain (EVENDOL ≤ 9/15 or NRS-11 ≤ 6/10) at 10, 20, 30, 40, 50 and 60 minutes after the IN injection | Proportion of children relieved (EVENDOL ≤ 5/15 or NRS-11 ≤ 3/10) at 10, 20, 40, 50 and 60 minutes after the IN spray; | EVENDOL ≤ 5/15 or NRS-11 ≤ 3/10 at 10, 20, 40, 50 and 60 minutes | 
| To demonstrate that {IN Sufentanil +IV morphine(as a standard of care)} procedure, when compared to {IN Placebo + IV morphine (as a standard of care)} procedure, is able to decrease the level of morphine consumption | Morphine consumption (mg). Assessed morphine consumption after treatment initiation, until 60 minutes | from randomisation to 60 minutes after | 
| To demonstrate the safety of the {IN Sufentanil +IV morphine} procedure, when compared to {IN Placebo + IV morphine } procedure, that is an absence of increase rate of hemodynamic and non-hemodynamic side effects of opiace | Rates of hypotension, hypoxia, bradycardia, respiratory distress, headache, nausea, vomiting, sleepiness and itchiness until 4 hours after the IN injection | until 4 hours after the IN injection | 
| To evaluate the safety of all children aged 0-18 years | This outcome is defined by the proportion of patients with at least one adverse events during the medical care, until 4 hours after treatment initiatio | From randomisaton to 4 hours after | 
| To demonstrate that the {IN Sufentanil +IV morphine (as a standard of care)} procedure, when compared to {IN Placebo + IV morphine (as a standard of care)} procedure, is able to improve the management of a VOC episode | Rate of admission after the ED visit | after 4 hours of randomisation | 
| To demonstrate that the {IN Sufentanil +IV morphine (as a standard of care)} procedure, when compared to {IN Placebo + IV morphine(as a standard of care)} procedure, is able to decrease the proportion of VOC complications | Rate of Acute chest syndrome: at hospital discharge Rate of admission in ICU, invasive ventilation, non-invasive ventilation, oxygene therapy: at hospital discharge Rate of Transfusion: at hospital discharge Rate of death: at hospital discharge | at hospital discharg, after 4 hours after randomisation |