Congenital Heart Disease, Dexmedetomidine
Conditions
Keywords
Intranasal, Pharmacokinetic, Pediatric
Brief summary
The main objectives of the study are to determine peak plasma drug concentration levels and corresponding time of dexmedetomidine following intranasal administration in children age ≥1 mo to ≤ 6 yr with congenital heart disease undergoing an elective diagnostic or interventional cardiac catheterization procedure.
Detailed description
The high anxiety levels that children may experience during the preoperative period may be associated with negative medical, psychological, and social consequences. To reduce this stress, and to facilitate separation from parents and the induction of anesthesia, children are often given a sedative prior to undergoing a procedure. Dexmedetomidine is a highly selective a2-adrenergic receptor agonist with sedative, anxiolytic, and analgesic properties. While off-label in its use, the administration of dexmedetomidine by the intranasal route has become a popular and effective technique for sedation in children because it is non-invasive, easy to administer, well tolerated, and relatively fast in onset. Despite this, little consistent data have been published on its onset time, duration of action, or optimal dose. The only available pharmacokinetic (PK) data on dexmedetomidine in pediatric patients is in children who were administered IV dexmedetomidine. We are proposing a prospective open-label inter-subject cohort dose-escalation pharmacokinetic study to obtain peak dexmedetomidine drug concentration level in plasma and the corresponding time point following intranasal administration in the pediatric patient with cardiac disease.
Interventions
DRUGDexmedetomidine
Dose-escalation of atomized intranasal dexmedetomidine
Sponsors
Children's Hospital of Philadelphia
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Months to 6 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female subjects age ≥1 mo to ≤6 yo. 2. Subjects must have congenital heart disease. 3. American Society of Anesthesiology (ASA) Physical Status 1-3. 4. Subjects scheduled for elective cardiac interventional or diagnostic catheterization anticipated to last ≥ 3hours. 5. Subjects spontaneously ventilating with a natural airway scheduled for elective cardiac interventional or diagnostic catheterization anticipated to last ≥ 2 hours. 6. Subjects must have reliable intravascular access from which to draw blood samples.
Exclusion criteria
1. History of allergic reaction or sensitivity to dexmedetomidine. 2. Nasal pathology preventing the administration of drug. 3. Patients that are on maintenance medications that could inhibit or induce the CYP2A6 enzyme. 4. Cardiac conduction abnormalities defined as second or third degree heart block or pacemaker dependence. 5. Bradycardia, defined by age, upon arrival in the preoperative care area. 6. Hepatic dysfunction defined as a history of hepatic dysfunction AND an Alanine Aminotransferase (ALT) value greater than 2 times normal in the 6 months prior to study drug administration. 7. The subject has received dexmedetomidine or clonidine within 1 week of the study date. 8. BMI \>30. 9. Patients previously enrolled in this study. 10. Any investigational drug use within 30 days prior to enrollment. 11. Wards will not be eligible.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Samples Obtained Per Subject | Up to 5 hours - 0, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, and 300 minutes post drug administration | Following the administration of atomized intranasal dexmedetomidine, serum samples will be drawn at 0, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240 and 300 minutes post drug administration. This is the number of samples obtained per subject. |
| Time of Peak Drug Concentration Level of Dexmedetomidine | Up to 5 hours - 0, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, and 300 minutes post drug administration | Following the administration of atomized intranasal dexmedetomidine, serum samples will be drawn at 0, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240 and 300 minutes post drug administration. The time of peak drug concentration will be determined based on this data. |
| Serum Drug Concentration Levels of Dexmedetomidine | Up to 5 hours - 0, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, and 300 minutes post drug administration | Following administration of atomized intranasal dexmedetomidine, serum samples will be obtained at the following times post administrations: 0, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, and 300 minutes. Peak concentration will be determined based on this data. |
| Dose-limiting Toxicities (DLT) and/or Maximum Plasma Level > 1000 pg/mL | Subjects were monitored for 6 hours after the administration of study drug. | Dose-limiting toxicities (DLT) include bradycardia, hypotension, new intraventricular conduction abnormality or any serious adverse event possibly, probably, or definitely related to intranasal dexmedetomidine administration that occured after the administration of the intranasal dexmedetomidine and through the completion of PK sampling. Bradycardia, hypotension, or new intraventricular conduction abnormalities that occured after the administration of intravenous dexmedetomidine given by the primary anesthesia team as part of usual clinical care were not considered DLTs but were considered an adverse event. Any events that could not be explained by the intervention that the patient was undergoing were assumed to be related to the study drug. |
Countries
United States
Participant flow
Recruitment details
Prospective open-label inter-subject cohort dose escalation PK and PD study performed at a since center in a pediatric cardiac catheterization laboratory. Study was approved by IRB on 4/23/18 and the FDA initiation date was 11/29/17. Subjects were enrolled from 06/14/18 through 8/23/21. All study related activities were completed on 10/13/21.
Pre-assignment details
Some of our subjects were scheduled for a cardiac MRI prior to their heart catheterization. If the MRI answered the clinical question, the heart catheterization was not performed and therefore study drug was not administered.
Participants by arm
| Arm | Count |
|---|---|
| 2 μg/kg; Subjects Age >2 yo and ≤ 6 yo Cohort 1A:
* Dexmedetomidine 2 μg/kg, atomized intranasal
* Under general oral endotracheal anesthesia
* Subjects age \>2 yo and ≤ 6 yo | 10 |
| 2 ug/kg; Subjects Age ≥1 mo and ≤2 yo Cohort 1a:
* Dexmedetomidine 2 μg/kg, atomized intranasal
* Under general oral endotracheal anesthesia
* Subjects age ≥1 mo and ≤2 yo | 5 |
| 4 μg/kg; Subjects Age >2 yo and ≤ 6 yo Cohort 2
* Dexmedetomidine 4 μg/kg, atomized intranasal
* Under general oral endotracheal anesthesia
* 7 subjects age \>2 yo and ≤ 6 yo | 13 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Inadequate study staff available to process samples | 0 | 0 | 1 |
| Overall Study | Met exclusion criteria after obtaining consent | 0 | 0 | 1 |
| Overall Study | Procedure cancelled; subject did not receive study drug | 2 | 0 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | 2 μg/kg; Subjects Age >2 yo and ≤ 6 yo | Total | 4 μg/kg; Subjects Age >2 yo and ≤ 6 yo | 2 ug/kg; Subjects Age ≥1 mo and ≤2 yo |
|---|---|---|---|---|
| Age, Continuous | 44.5 months | 38.5 months | 40 months | 14 months |
| Age, Customized ≥1 mo and ≤2 yo | 0 Participants | 5 Participants | 0 Participants | 5 Participants |
| Age, Customized >2 yo and ≤ 6 yo | 10 Participants | 23 Participants | 13 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 8 Participants | 4 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 20 Participants | 9 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Mixing lesion present | 5 Participants | 15 Participants | 8 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 2 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 3 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized More than one race | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 8 Participants | 5 Participants | 2 Participants |
| Race/Ethnicity, Customized Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White or Caucasian | 7 Participants | 14 Participants | 6 Participants | 1 Participants |
| Region of Enrollment United States | 10 participants | 28 participants | 13 participants | 5 participants |
| Sex: Female, Male Female | 5 Participants | 16 Participants | 8 Participants | 3 Participants |
| Sex: Female, Male Male | 5 Participants | 12 Participants | 5 Participants | 2 Participants |
| Weight | 15.2 kilograms | 14.7 kilograms | 16.1 kilograms | 8.8 kilograms |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 5 | 0 / 9 |
| other Total, other adverse events | 1 / 7 | 2 / 5 | 3 / 9 |
| serious Total, serious adverse events | 0 / 7 | 0 / 5 | 0 / 9 |
Outcome results
Primary
Dose-limiting Toxicities (DLT) and/or Maximum Plasma Level > 1000 pg/mL
Dose-limiting toxicities (DLT) include bradycardia, hypotension, new intraventricular conduction abnormality or any serious adverse event possibly, probably, or definitely related to intranasal dexmedetomidine administration that occured after the administration of the intranasal dexmedetomidine and through the completion of PK sampling. Bradycardia, hypotension, or new intraventricular conduction abnormalities that occured after the administration of intravenous dexmedetomidine given by the primary anesthesia team as part of usual clinical care were not considered DLTs but were considered an adverse event. Any events that could not be explained by the intervention that the patient was undergoing were assumed to be related to the study drug.
Time frame: Subjects were monitored for 6 hours after the administration of study drug.
Population: Population includes any subject who received study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 2 μg/kg; Subjects Age >2 yo and ≤ 6 yo | Dose-limiting Toxicities (DLT) and/or Maximum Plasma Level > 1000 pg/mL | 0 Events |
| 2 ug/kg; Subjects Age ≥1 mo and ≤2 yo | Dose-limiting Toxicities (DLT) and/or Maximum Plasma Level > 1000 pg/mL | 2 Events |
| 4 μg/kg; Subjects Age >2 yo and ≤ 6 yo | Dose-limiting Toxicities (DLT) and/or Maximum Plasma Level > 1000 pg/mL | 3 Events |
Primary
Number of Samples Obtained Per Subject
Following the administration of atomized intranasal dexmedetomidine, serum samples will be drawn at 0, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240 and 300 minutes post drug administration. This is the number of samples obtained per subject.
Time frame: Up to 5 hours - 0, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, and 300 minutes post drug administration
Population: Population includes all subjects who received study drug. This included evaluable and non-evaluable subjects.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 2 μg/kg; Subjects Age >2 yo and ≤ 6 yo | Number of Samples Obtained Per Subject | 10 Samples |
| 2 ug/kg; Subjects Age ≥1 mo and ≤2 yo | Number of Samples Obtained Per Subject | 9 Samples |
| 4 μg/kg; Subjects Age >2 yo and ≤ 6 yo | Number of Samples Obtained Per Subject | 10 Samples |
Primary
Serum Drug Concentration Levels of Dexmedetomidine
Following administration of atomized intranasal dexmedetomidine, serum samples will be obtained at the following times post administrations: 0, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, and 300 minutes. Peak concentration will be determined based on this data.
Time frame: Up to 5 hours - 0, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, and 300 minutes post drug administration
Population: Analysis population includes subjects who received study drug and had at least 90 minutes of sampling time to ensure that Cmax had been achieved. There was one subject in Cohort 1a who had BLQ for all samples obtained for unknown reasons. This subject's data could also not be evaluated.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 2 μg/kg; Subjects Age >2 yo and ≤ 6 yo | Serum Drug Concentration Levels of Dexmedetomidine | 413 pg/mL |
| 2 ug/kg; Subjects Age ≥1 mo and ≤2 yo | Serum Drug Concentration Levels of Dexmedetomidine | 570 pg/mL |
| 4 μg/kg; Subjects Age >2 yo and ≤ 6 yo | Serum Drug Concentration Levels of Dexmedetomidine | 1000 pg/mL |
Primary
Time of Peak Drug Concentration Level of Dexmedetomidine
Following the administration of atomized intranasal dexmedetomidine, serum samples will be drawn at 0, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240 and 300 minutes post drug administration. The time of peak drug concentration will be determined based on this data.
Time frame: Up to 5 hours - 0, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, and 300 minutes post drug administration
Population: Analysis population includes subjects who received study drug and had at least 90 minutes of sampling time to ensure that Tmax had been achieved. There was one subject in Cohort 1a who had BLQ for all samples obtained for unknown reasons. This subject's data also not be evaluated.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 2 μg/kg; Subjects Age >2 yo and ≤ 6 yo | Time of Peak Drug Concentration Level of Dexmedetomidine | 91 minutes |
| 2 ug/kg; Subjects Age ≥1 mo and ≤2 yo | Time of Peak Drug Concentration Level of Dexmedetomidine | 30 minutes |
| 4 μg/kg; Subjects Age >2 yo and ≤ 6 yo | Time of Peak Drug Concentration Level of Dexmedetomidine | 54 minutes |