Clinical trial NCT06181695: Intranasal Sufentanil for Analgesia of Severe Sickle Cell Vaso-occlusive Pain Crisis in the Pediatric
Official title: 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
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Vaso-occlusive Crisis
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2023-12-26
Enrollment: 182
Sex: ALL
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Evaluation of the Efficacy of Intra-nasal Sufentanil for Analgesia of Vaso-occlusive Crisis in Sickle-cell in children
timeFrame: at 30 minutes
Secondary outcomes:
measure: 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
timeFrame: at 60 minutes
measure: 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
timeFrame: EVENDOL ≤ 5/15 or NRS-11 ≤ 3/10 at 10, 20, 40, 50 and 60 minutes
measure: 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
timeFrame: from randomisation to 60 minutes after
measure: 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
timeFrame: until 4 hours after the IN injection
measure: To evaluate the safety of all children aged 0-18 years
timeFrame: From randomisaton to 4 hours after
measure: 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
timeFrame: after 4 hours of randomisation
measure: 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
timeFrame: at hospital discharg, after 4 hours after randomisation
Other outcomes:
Locations:
Study officials:
affiliation: Assistance Publique des Hopitaux de Paris
name: Camille AUPIAIS, Pre
role: PRINCIPAL_INVESTIGATOR
References:
citation: Prise en charge de la drépanocytose chez l'enfant et l'adolescent. Haute Autorité de Santé. Accessed March 3, 2021. https://www.has-sante.fr/jcms/c_272479/fr/prise-en-charge-de-la-drepanocytose-chez-l-enfant-et-l-adolescent
citation: Yawn BP, Buchanan GR, Afenyi-Annan AN, Ballas SK, Hassell KL, James AH, Jordan L, Lanzkron SM, Lottenberg R, Savage WJ, Tanabe PJ, Ware RE, Murad MH, Goldsmith JC, Ortiz E, Fulwood R, Horton A, John-Sowah J. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014 Sep 10;312(10):1033-48. doi: 10.1001/jama.2014.10517.
citation: Gonzalez ER, Bahal N, Hansen LA, Ware D, Bull DS, Ornato JP, Lehman ME. Intermittent injection vs patient-controlled analgesia for sickle cell crisis pain. Comparison in patients in the emergency department. Arch Intern Med. 1991 Jul;151(7):1373-8.
citation: Dampier CD, Smith WR, Wager CG, Kim HY, Bell MC, Miller ST, Weiner DL, Minniti CP, Krishnamurti L, Ataga KI, Eckman JR, Hsu LL, McClish D, McKinlay SM, Molokie R, Osunkwo I, Smith-Whitley K, Telen MJ; Sickle Cell Disease Clinical Research Network (SCDCRN). IMPROVE trial: a randomized controlled trial of patient-controlled analgesia for sickle cell painful episodes: rationale, design challenges, initial experience, and recommendations for future studies. Clin Trials. 2013 Apr;10(2):319-31. doi: 10.1177/1740774513475850.
citation: Treadwell MJ, Bell M, Leibovich SA, Barreda F, Marsh A, Gildengorin G, Morris CR. A Quality Improvement Initiative to Improve Emergency Department Care for Pediatric Patients with Sickle Cell Disease. J Clin Outcomes Manag. 2014 Feb;21(2):62-70.
citation: Shenoi R, Ma L, Syblik D, Yusuf S. Emergency department crowding and analgesic delay in pediatric sickle cell pain crises. Pediatr Emerg Care. 2011 Oct;27(10):911-7. doi: 10.1097/PEC.0b013e3182302871.
citation: Kavanagh PL, Sprinz PG, Wolfgang TL, Killius K, Champigny M, Sobota A, Dorfman D, Barry K, Miner R, Moses JM. Improving the Management of Vaso-Occlusive Episodes in the Pediatric Emergency Department. Pediatrics. 2015 Oct;136(4):e1016-25. doi: 10.1542/peds.2014-3470. Epub 2015 Sep 21.
citation: Brandow AM, Nimmer M, Simmons T, Charles Casper T, Cook LJ, Chumpitazi CE, Paul Scott J, Panepinto JA, Brousseau DC. Impact of emergency department care on outcomes of acute pain events in children with sickle cell disease. Am J Hematol. 2016 Dec;91(12):1175-1180. doi: 10.1002/ajh.24534. Epub 2016 Sep 3.
citation: Mathias MD, McCavit TL. Timing of opioid administration as a quality indicator for pain crises in sickle cell disease. Pediatrics. 2015 Mar;135(3):475-82. doi: 10.1542/peds.2014-2874. Epub 2015 Feb 9.
citation: Galeotti C, Courtois E, Carbajal R. How French paediatric emergency departments manage painful vaso-occlusive episodes in sickle cell disease patients. Acta Paediatr. 2014 Dec;103(12):e548-54. doi: 10.1111/apa.12773. Epub 2014 Oct 2.
citation: Corrigan M, Wilson SS, Hampton J. Safety and efficacy of intranasally administered medications in the emergency department and prehospital settings. Am J Health Syst Pharm. 2015 Sep 15;72(18):1544-54. doi: 10.2146/ajhp140630.
citation: Dale O. Intranasal administration of opioids/fentanyl - Physiological and pharmacological aspects. European Journal of Pain Supplements. 2010;4(3):187-190. doi:10.1016/j.eujps.2010.06.001
citation: Dale O, Hjortkjaer R, Kharasch ED. Nasal administration of opioids for pain management in adults. Acta Anaesthesiol Scand. 2002 Aug;46(7):759-70. doi: 10.1034/j.1399-6576.2002.460702.x.
citation: Wolfe TR, Braude DA. Intranasal medication delivery for children: a brief review and update. Pediatrics. 2010 Sep;126(3):532-7. doi: 10.1542/peds.2010-0616. Epub 2010 Aug 9.
citation: Helmers JH, Noorduin H, Van Peer A, Van Leeuwen L, Zuurmond WW. Comparison of intravenous and intranasal sufentanil absorption and sedation. Can J Anaesth. 1989 Sep;36(5):494-7. doi: 10.1007/BF03005373.
citation: Haynes G, Brahen NH, Hill HF. Plasma sufentanil concentration after intranasal administration to paediatric outpatients. Can J Anaesth. 1993 Mar;40(3):286. doi: 10.1007/BF03037044. No abstract available.
citation: Nielsen BN, Friis SM, Romsing J, Schmiegelow K, Anderson BJ, Ferreiros N, Labocha S, Henneberg SW. Intranasal sufentanil/ketamine analgesia in children. Paediatr Anaesth. 2014 Feb;24(2):170-80. doi: 10.1111/pan.12268. Epub 2013 Oct 1.
citation: Murphy A, O'Sullivan R, Wakai A, Grant TS, Barrett MJ, Cronin J, McCoy SC, Hom J, Kandamany N. Intranasal fentanyl for the management of acute pain in children. Cochrane Database Syst Rev. 2014 Oct 10;2014(10):CD009942. doi: 10.1002/14651858.CD009942.pub2.
citation: Lemoel F, Contenti J, Cibiera C, Rapp J, Occelli C, Levraut J. Intranasal sufentanil given in the emergency department triage zone for severe acute traumatic pain: a randomized double-blind controlled trial. Intern Emerg Med. 2019 Jun;14(4):571-579. doi: 10.1007/s11739-018-02014-y. Epub 2019 Jan 1.
citation: Setlur A, Friedland H. Treatment of pain with intranasal fentanyl in pediatric patients in an acute care setting: a systematic review. Pain Manag. 2018 Sep 1;8(5):341-352. doi: 10.2217/pmt-2018-0016. Epub 2018 Oct 3.
citation: Hronova K, Pokorna P, Posch L, Slanar O. Sufentanil and midazolam dosing and pharmacogenetic factors in pediatric analgosedation and withdrawal syndrome. Physiol Res. 2016 Dec 21;65(Suppl 4):S463-S472. doi: 10.33549/physiolres.933519.
citation: Bayrak F, Gunday I, Memis D, Turan A. A comparison of oral midazolam, oral tramadol, and intranasal sufentanil premedication in pediatric patients. J Opioid Manag. 2007 Mar-Apr;3(2):74-8. doi: 10.5055/jom.2007.0043.
citation: Crellin D, Ling RX, Babl FE. Does the standard intravenous solution of fentanyl (50 microg/mL) administered intranasally have analgesic efficacy? Emerg Med Australas. 2010 Feb;22(1):62-7. doi: 10.1111/j.1742-6723.2010.01257.x.
citation: Borland M, Jacobs I, King B, O'Brien D. A randomized controlled trial comparing intranasal fentanyl to intravenous morphine for managing acute pain in children in the emergency department. Ann Emerg Med. 2007 Mar;49(3):335-40. doi: 10.1016/j.annemergmed.2006.06.016. Epub 2006 Oct 25.
citation: Sin B, Jeffrey I, Halpern Z, Adebayo A, Wing T, Lee AS, Ruiz J, Persaud K, Davenport L, de Souza S, Williams M. Intranasal Sufentanil Versus Intravenous Morphine for Acute Pain in the Emergency Department: A Randomized Pilot Trial. J Emerg Med. 2019 Mar;56(3):301-307. doi: 10.1016/j.jemermed.2018.12.002. Epub 2019 Jan 9.
citation: Fantacci C, Fabrizio GC, Ferrara P, Franceschi F, Chiaretti A. Intranasal drug administration for procedural sedation in children admitted to pediatric Emergency Room. Eur Rev Med Pharmacol Sci. 2018 Jan;22(1):217-222. doi: 10.26355/eurrev_201801_14120.
citation: Chiaretti A, Barone G, Rigante D, Ruggiero A, Pierri F, Barbi E, Barone G, Riccardi R. Intranasal lidocaine and midazolam for procedural sedation in children. Arch Dis Child. 2011 Feb;96(2):160-3. doi: 10.1136/adc.2010.188433. Epub 2010 Oct 27.
citation: Inthavong K, Fung MC, Yang W, Tu J. Measurements of droplet size distribution and analysis of nasal spray atomization from different actuation pressure. J Aerosol Med Pulm Drug Deliv. 2015 Feb;28(1):59-67. doi: 10.1089/jamp.2013.1093. Epub 2014 Jun 10.
citation: Barrett MJ, Cronin J, Murphy A, McCoy S, Hayden J, an Fhaili S, Grant T, Wakai A, McMahon C, Walsh S, O'Sullivan R. Intranasal fentanyl versus intravenous morphine in the emergency department treatment of severe painful sickle cell crises in children: study protocol for a randomised controlled trial. Trials. 2012 May 30;13:74. doi: 10.1186/1745-6215-13-74.