Clinical trial NCT04684238: Effect & Safety of Inhaled Isoflurane vs IV Midazolam for Sedation in Mechanically Ventilated Children 3-17 Years Old
Official title: A Randomised Active-controlled Study to Compare Efficacy & Safety of Inhaled Isoflurane Delivered by the AnaConDa-S (Anaesthetic Conserving Device) vs IV Midazolam for Sedation in Mechanically Ventilated Paediatric Patients 3-17 Years Old
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Sedation
Keywords: sedation
isoflurane
mechanically ventilation
pediatric
midazolam
Lead sponsor: Sedana Medical
Sponsor class: INDUSTRY
First posted: 2020-12-24
Enrollment: 94
Sex: ALL
Minimum age (years): 3
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a study to compare safety and efficacy of inhaled isoflurane delivered by the AnaConDa-S (Anaesthetic Conserving Device (ACD)) versus intravenous midazolam for sedation in mechanically ventilated children admitted to an intensive care unit.

Detailed description: This is a phase III, multi-centre, prospective, randomized, active-controlled, assessor-blind study. Primary endpoint: percentage of time of adequately maintained sedation, in absence of rescue sedation, within the COMFORT-B interval (light, moderate, or deep sedation) prescribed at randomization, monitored every 2 hours for an expected minimum of 12 hours (up to 48 hours).

Eligibility criteria: Inclusion Criteria:

* Patients at least 3 years to 17 (less than 18) years at the time of randomization, admitted to an ICU/with planned ICU admission.
* Expected mechanical (invasive) ventilation and sedation for at least 12 hours.
* Informed consent obtained from the patient, patient's legal guardian(s)

Exclusion Criteria:

* Ongoing seizures requiring acute treatment.
* Continuous sedation for more than 72 hours at time of randomization.
* Less than 24 hours post cardiopulmonary resuscitation.
* Uncompensated circulatory shock.
* Known or suspected genetic susceptibility to malignant hyperthermia.
* Patients with acute asthma or obstructive lung disease symptoms requiring treatment at inclusion.
* Patient with tidal volume below 30 mL or above 800 mL.
* Inability to perform reliable COMFORT-B assessment in the opinion of the Investigator
* Patients with intracranial pressure (ICP) monitoring or with suspected increase in ICP
* Patients with treatment-induced whole-body hypothermia.
* Patients with pheochromocytoma.
* Patients with prolonged QT interval or with significant risk for prolonged QT interval.
* Patient not expected to survive next 48 hours or not committed to full medical care.

Primary outcomes:
measure: Percentage of Time of Adequately Maintained Sedation Depth up to 48 Hours (± 6 Hours)
timeFrame: Minimum of 12 hours up to 48 hours (± 6 hours).
Secondary outcomes:
measure: Compare the Use of Opioids
timeFrame: From first blinded COMFORT-B assessment (at +2 h from start of study drug initiation) to end of the study treatment period
measure: Compare the Use of Opioids
timeFrame: Last 4 hours of study treatment compared to first 4 hours of study treatment after first blinded COMFORT-B assessment (at +2 h from start of study drug initiation).
measure: Compare Time From End of Study Drug Administration to Extubation
timeFrame: From end of study drug administration to extubation or end of extubation attempt
measure: Compare the Proportion of Time With Spontaneous Breathing
timeFrame: From initiation of study drug treatment to End of study treatment (up to 48h +/- 6h)
measure: Evaluate Haemodynamic Effect as Indicated by Need for Additional Inotropic/Vasopressor Agent
timeFrame: From start of study treatment to end of study treatment (up to 48h +/- 6h)
measure: Evaluate the Number of Patients With Withdrawal Symptom
timeFrame: From > 96 hours sedation (including pre-study sedation period) until the end of the 48-hour post study treatment monitoring or ICU discharge, whichever comes first.
measure: Evaluate the Frequency of Delirium
timeFrame: Patients admitted to the ICU ≥48 hours (including period prior to study enrolment) until the end of the 48-hour post study treatment monitoring or ICU discharge, whichever comes first.
measure: Evaluate the Frequency of Neurological Symptoms or Psychomotor Dysfunction
timeFrame: During study treatment and up to 48 hours after discontinuation of isoflurane and midazolam
measure: Compare the 30 Days/Hospital Mortality
timeFrame: From start of study treatment up to 30 days
measure: Compare Ventilator-free Days
timeFrame: From start of study treatment up to 30 days
measure: Compare the Time in ICU/Hospital
timeFrame: From start of study treatment up to 30 days
measure: Compare ICU-free Days
timeFrame: From start of study treatment up to 30 days
Other outcomes:
Locations:
city: Lyon
country: France
facility: Hôpital Femme-Mère-Enfant Groupe Hospitalier Est
city: Nantes
country: France
facility: CHU de NANTES, Hôpital Mère-Enfant
city: Paris
country: France
facility: Hôpital Robert-Debré AP-HP
city: Paris
country: France
facility: Hôpitaux Universitaires Paris Sud Site Bicetre
city: Reims
country: France
facility: Centre Hospitalier Universitaire de Reims
city: Strasbourg
country: France
facility: Hôpitaux Universitaires de Strasbourg Hôpital de Hautepierre
city: Cologne
country: Germany
facility: Universitätsklinikum Köln
city: Freiburg
country: Germany
facility: Universitätsklinik Freiburg
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf (UKE)
city: Jena
country: Germany
facility: Universitätsklinikum Jena
city: Barcelona
country: Spain
facility: Hospital Materno Infantil Sant Joan de Deu Hospital
city: Córdoba
country: Spain
facility: Hospital Universitario Reina Sofía
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañón
city: Madrid
country: Spain
facility: Hospital Infantil Universitario Niño Jesús Pediatric Intensive Care Unit
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Málaga
country: Spain
facility: Hospital Regional Universitario, Carlos Haya
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio de Sevilla
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe
city: Solna
country: Sweden
facility: Karolinska Universitetssjukhus Solna
city: Leeds
country: United Kingdom
facility: Leeds Teaching Hospitals NHS Trust
city: Leicester
country: United Kingdom
facility: University Hospitals of Leicester NHS Trust
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust
city: Manchester
country: United Kingdom
facility: Royal Manchester Children's Hospital
Study officials:
affiliation: Sedana Medical
name: Peter Sackey, MD, PhD
role: STUDY_DIRECTOR
References:
citation: Eifinger F, Hunseler C, Roth B, Vierzig A, Oberthuer A, Mehler K, Kribs A, Menzel C, Trieschmann U. Observations on the effects of inhaled isoflurane in long-term sedation of critically Ill children using a modified AnaConDa(c)-system. Klin Padiatr. 2013 Jul;225(4):206-11. doi: 10.1055/s-0033-1345173. Epub 2013 Jun 24.
citation: Ariyama J, Hayashida M, Shibata K, Sugimoto Y, Imanishi H, O-oi Y, Kitamura A. Risk factors for the development of reversible psychomotor dysfunction following prolonged isoflurane inhalation in the general intensive care unit. J Clin Anesth. 2009 Dec;21(8):567-73. doi: 10.1016/j.jclinane.2009.01.011.
citation: Grant MJ, Balas MC, Curley MA; RESTORE Investigative Team. Defining sedation-related adverse events in the pediatric intensive care unit. Heart Lung. 2013 May-Jun;42(3):171-6. doi: 10.1016/j.hrtlng.2013.02.004.
citation: Hoemberg M, Vierzig A, Roth B, Eifinger F. Plasma fluoride concentrations during prolonged administration of isoflurane to a pediatric patient requiring renal replacement therapy. Paediatr Anaesth. 2012 Apr;22(4):412-3. doi: 10.1111/j.1460-9592.2012.03814.x. No abstract available.
citation: Kruessell MA, Udink ten Cate FE, Kraus AJ, Roth B, Trieschmann U. Use of propofol in pediatric intensive care units: a national survey in Germany. Pediatr Crit Care Med. 2012 May;13(3):e150-4. doi: 10.1097/PCC.0b013e3182388a95.
citation: Kudchadkar SR, Yaster M, Punjabi NM. Sedation, sleep promotion, and delirium screening practices in the care of mechanically ventilated children: a wake-up call for the pediatric critical care community*. Crit Care Med. 2014 Jul;42(7):1592-600. doi: 10.1097/CCM.0000000000000326.
citation: Nolent P, Laudenbach V. [Sedation and analgesia in the paediatric intensive care unit]. Ann Fr Anesth Reanim. 2008 Jul-Aug;27(7-8):623-32. doi: 10.1016/j.annfar.2008.04.014. Epub 2008 Jul 9. French.
citation: Meiser A, Laubenthal H. Inhalational anaesthetics in the ICU: theory and practice of inhalational sedation in the ICU, economics, risk-benefit. Best Pract Res Clin Anaesthesiol. 2005 Sep;19(3):523-38. doi: 10.1016/j.bpa.2005.02.006.
citation: Meyburg J, Dill ML, von Haken R, Picardi S, Westhoff JH, Silver G, Traube C. Risk Factors for the Development of Postoperative Delirium in Pediatric Intensive Care Patients. Pediatr Crit Care Med. 2018 Oct;19(10):e514-e521. doi: 10.1097/PCC.0000000000001681.
citation: Mody K, Kaur S, Mauer EA, Gerber LM, Greenwald BM, Silver G, Traube C. Benzodiazepines and Development of Delirium in Critically Ill Children: Estimating the Causal Effect. Crit Care Med. 2018 Sep;46(9):1486-1491. doi: 10.1097/CCM.0000000000003194.
citation: Playfor S, Jenkins I, Boyles C, Choonara I, Davies G, Haywood T, Hinson G, Mayer A, Morton N, Ralph T, Wolf A; United Kingdom Paediatric Intensive Care Society Sedation; Analgesia and Neuromuscular Blockade Working Group. Consensus guidelines on sedation and analgesia in critically ill children. Intensive Care Med. 2006 Aug;32(8):1125-36. doi: 10.1007/s00134-006-0190-x. Epub 2006 May 13.
citation: Sackey PV, Martling CR, Granath F, Radell PJ. Prolonged isoflurane sedation of intensive care unit patients with the Anesthetic Conserving Device. Crit Care Med. 2004 Nov;32(11):2241-6. doi: 10.1097/01.ccm.0000145951.76082.77.
citation: Sackey PV, Martling CR, Radell PJ. Three cases of PICU sedation with isoflurane delivered by the 'AnaConDa'. Paediatr Anaesth. 2005 Oct;15(10):879-85. doi: 10.1111/j.1460-9592.2005.01704.x.
citation: Tobias JD. Tolerance, withdrawal, and physical dependency after long-term sedation and analgesia of children in the pediatric intensive care unit. Crit Care Med. 2000 Jun;28(6):2122-32. doi: 10.1097/00003246-200006000-00079.
citation: Vet NJ, Ista E, de Wildt SN, van Dijk M, Tibboel D, de Hoog M. Optimal sedation in pediatric intensive care patients: a systematic review. Intensive Care Med. 2013 Sep;39(9):1524-34. doi: 10.1007/s00134-013-2971-3. Epub 2013 Jun 19.