Clinical trial NCT04164264: Genetic Differences in Propofol Pharmacodynamics in Children
Official title: Genetic Differences in Pharmacodynamic Safety Endpoints With Propofol Anaesthesia in Children
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE4
Conditions: Anesthesia
Keywords: Propofol
Lead sponsor: University of British Columbia
Sponsor class: OTHER
Collaborators: name: BC Children's Hospital Research Institute
First posted: 2019-11-15
Enrollment: 360
Sex: ALL
Minimum age (years): 3
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: SUPPORTIVE_CARE

Brief summary: Propofol is an extensively utilized intravenous sedative and general anesthetic. However, propofol has a narrow therapeutic index, and this means that there is only a small difference in the dose required to produce loss of consciousness and the dose required to produce potentially life-threatening effects such as loss of protective airway reflexes and cessation of spontaneous breathing. Moreover, there is substantial variation between individuals in the doses required to achieve these pharmacodynamic endpoints.

Given the inexorable rise in demand for pediatric sedation and the increasing use of propofol in sedation protocols by non-anaesthesiologists, the purpose of this study is to refine the propofol dosing recommendations to account for pharmacogenomic variability to make procedural sedation safer for children. Experienced users already adjust for age and body weight. This study may enable further refinements according to sex and - novelly - ancestry.

Detailed description: Hypothesis:

The investigators hypothesize that examination of genome-wide association study (GWAS) findings will enable the investigators to provide pharmacogenomic insights into clinically observed - and, with this study, quantified - differences in propofol requirements for loss of consciousness (LOC) and apnea in children. It is further hypothesized that the distribution of allelic variants in these pharmacogenes may differ between children of different genomic ancestry.

Objectives:

Primary: (i) To describe and quantify doses of propofol required to produce loss of consciousness and apnea in children of differing ages, sex and self-identified countries of origin. (ii) To identify genomic associations that may explain variability, and generate hypotheses for further study. (iii) To identify genomic ancestry and examine how pharmacogene allele variants that may explain the findings of (i) above are distributed across genomic ancestries.

Secondary: To examine the correlation between self-identified countries of family origin and genomic ancestry.

Methods:

Prospective, non-randomized, single cohort study of two pharmacodynamic endpoints (loss of consciousness and apnea), in children requiring propofol anesthesia, with subsequent genome-wide association study (GWAS) and principal component analysis (PCA) to examine, respectively, pharmacogenomic explanations for pharmacodynamic variability and genomic ancestry.

Eligibility criteria: Inclusion Criteria:

* Age ≥ 3 to ≤ 18
* ASA physical status classification I-III
* Intravenous induction resulting in apnea clinically appropriate and indicated

Exclusion Criteria:

* Age \< 3 or \>18
* ASA physical status IV-V
* Propofol induction to apnea not indicated or feasible
* Sedative premedication
* Severe neurological impairment, expected to reduce propofol requirement as judged by the clinical experience of the anaesthetist
* Weight \<3%ile or \>97%ile for age

Primary outcomes:
measure: Dose of propofol required to produce loss of consciousness
timeFrame: Loss of consciousness will be expected to occur somewhere between 120-180 seconds after commencing the induction infusion.
measure: Dose of propofol required to produce apnea
timeFrame: Apnea will be expected to occur within 10 min after commencing the induction infusion.
Secondary outcomes:
measure: Self-identified countries of family origin up to grandparents
timeFrame: Within 10 minutes after consent to participate.
measure: A genotyped/imputed dataset of 8 million genetic variants aggregated using SHAPEIT (v2), IMPUTE2 (v2.3.2), Phase 3 1000 Genomes Project reference panel, SNP2HLA (v1.0.2), and the Type 1 Diabetes Genetics Consortium reference panel.
timeFrame: Saliva sample collected immediately after apnea, within 10min of propofol infusion start. Genomic analysis will be performed post-hoc.
Other outcomes:
Locations:
city: Vancouver
country: Canada
facility: BC Children's Hospital - Department of Anesthesia
state: British Columbia
Study officials:
affiliation: BC Children's Hospital, Department of Anesthesia
name: Simon Whyte, MBBS, FRCA
role: PRINCIPAL_INVESTIGATOR
References: