Pulmonary Hypertension
Conditions
Keywords
Sedation, Pulmonary Hypertension, Pediatric, Cardiac Catheterization, Pulmonary Vascular Resistance
Brief summary
Clinical dose escalation drug trial to evaluate the effect of 3 different doses of dexmedetomidine on the pulmonary vascular bed in pediatric subjects with elevated pulmonary vascular resistance (PVR). The study will be conducted in 2 parts, with part 1 incorporating stopping rules to optimize safety of the drug in this population. The second part of this study will evaluate if the lowest safest dose, as determined in part 1, is adequate to provide effective sedation during a cardiac catheterization procedure.
Detailed description
Clinical dose escalation drug trial to evaluate the effect of 3 different doses of dexmedetomidine on the pulmonary vascular bed in pediatric subjects with elevated pulmonary vascular resistance. The study will be conducted in 2 parts, with a pilot phase incorporating stopping rules to optimize safety of the drug in this population. Study subjects will include pediatric subjects with Pulmonary Hypertension (PHTN). Part 1: This will be the dose escalation phase of the study. Twenty four evaluable subjects will be enrolled. Subjects will include pediatric subjects with pulmonary hypertension (PVR\>4WU) undergoing hemodynamic cardiac catheterization and vasoreactivity drug testing. Cohorts of 8 evaluable subjects will receive dose level 1, dose level 2, or dose level 3 of Dexmedetomidine (DEX). The dose will be escalated to the next dose of DEX once all subjects have been enrolled in the preceding DEX dose cohort, and safety has been established at that level. Inadequate sedation despite the highest dose of DEX at each level will be considered a treatment failure on an intention to treat basis. Part 2: This part of the study will be conducted after the pilot phase is safely completed, and the full complement of subjects will be recruited.
Interventions
DRUGDexmedetomidine
This is a single center, dose escalation study of Dexmedetomidine in pediatric subjects with pulmonary hypertension (PVR\>4WU) undergoing hemodynamic cardiac catheterization and vasoreactivity drug testing. Cohorts of 8 evaluable subjects will receive dose level 1, dose level 2, or dose level 3 of Dexmedetomidine.
Sponsors
Children's Hospital of Philadelphia
Aruna Nathan
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
8 Years to 21 Years
Healthy volunteers
No
Inclusion criteria
1. Subjects with a diagnosis of pulmonary hypertension 2. Procedure - Planned cardiac catheterization procedure with spontaneous ventilation and natural airway 3. Patients who want sedation or general anesthetic for the procedure. 4. Age: Subjects ≥8 years and \< 21 years 5. Adequate Renal Function defined As:Serum creatinine ≤ 1 mg/dL 6. Adequate Liver Function defined As:Total bilirubin ≤ 1.5 mg/dL alanine aminotransferase (ALT) ≤ 2 times the upper limit of normal 7. Informed Consent: All parents or legal guardians must sign a written informed consent. 8. Signed assent when developmentally appropriate 9. Negative pregnancy test in menstruating females and all females ≥ 12 yr
Exclusion criteria
1. Refusal of Informed Consent/Assent 2. Subjects with single ventricle physiology 3. Pregnant or lactating females 4. Subjects with syndromes e.g. Trisomy 21 will be excluded due to variability in pharmacodynamic responses and airway instability during sedation 5. Inappropriate clinical or developmental status to undergo cardiac catheterization under conditions of spontaneous ventilation with a natural airway 6. Second or third degree heart block 7. Moderate - severe right ventricular dysfunction/failure 8. Subjects who, in the opinion of the investigator, are not appropriate candidates for an investigational drug study e.g. behavioral or anxiety disorders, inability to lie supine 9. Concomitant Medications - Investigational Drugs: Subjects who have received another investigational drug protocol 30 days prior to enrollment in this study 10. Subjects who in the opinion of the investigator may be non compliant with study schedules or procedures. 11. Non-English speaking subjects will be excluded due to need for direct communication from clinical and study staff during study procedures and the ability to complete study tools.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Primary Endpoint Will be the Change in PVR in Wood Units | For each subject PVR will be measured by cardiac catheterization at T0 ( baseline measurement) , after DEX bolus (T1) which is given over 10 minutes and after 30 mins after start of the DEX infusion (T2) - Maximum upto 4 hours | Pulmonary vascular resistance (PVR) in Wood units calculated during cardiac catheterization; |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of Sedation With DEX | Subjects will participate in a dose escalation study which will define minimal effective dose that results in effective sedation in ≥ 7 out of 8 patients in that dose cohort. Maximum upto 4 hours | The study was terminated early due to increased pulmonary vascular resistance (PVR) in one subject from To-T1 reaching the level of a predetermined stopping rule. Investigators suggested that it is premature to conclude that DEX does not adversely affect PVR |
| Quantify the Effect of DEX on PVR in Pediatric Subjects With Pulmonary Hypertension (PHTN) and Its Dependence on Baseline PVR | Every individual patient will be studied over maximum of 4 hours during the dose escalation phase. This part of the study will be completed in 1 year | The study was terminated early due to increased pulmonary vascular resistance (PVR) in one subject from To-T1 reaching the level of a predetermined stopping rule. Investigators suggested that it is premature to conclude that DEX does not adversely affect PVR |
| Obtain Pharmacokinetic Data in This Population | 6 hours | The study was terminated early due to increased pulmonary vascular resistance (PVR) in one subject from To-T1 reaching the level of a predetermined stopping rule. Investigators suggested that it is premature to conclude that DEX does not adversely affect PVR |
| Demonstrate That DEX is a Safe Sedative in Pediatric Subjects With PHTN | 24 hours | The study was terminated early due to increased pulmonary vascular resistance (PVR) in one subject from To-T1 reaching the level of a predetermined stopping rule. Investigators suggested that it is premature to conclude that DEX does not adversely affect PVR. |
Countries
United States
Participant flow
Pre-assignment details
22 patients were screened, but 18 were determined to be not feasible, only 4 participants were enrolled and started the study at drug level 1 (bolus of 1mcg/kg and infusion at 0.7mcg/kg/hr); There was no escalation to either dose level 2 or dose level 3 as we did not reach enrollment target of 8 subjects in dose level 1
Participants by arm
| Arm | Count |
|---|---|
| Dexmedetomidine To study safety of DEX with regard to effect on PVR; There will be 3 study groups (n=8 per group). The groups will be based on DEX doses as follows- Group 1 - Bolus 1 mcg/kg followed by infusion 0.7 mcg/kg/hr Group 2 - Bolus 1.5 mcg/kg followed by infusion 1.05 mcg/kg/hr Group 3 - Bolus 2 mcg/kg followed by infusion 1.4 mcg/kg/hr
Dexmedetomidine: This is a single center, dose escalation study of Dexmedetomidine in pediatric subjects with pulmonary hypertension (PVR\>4WU) undergoing hemodynamic cardiac catheterization and vasoreactivity drug testing. Cohorts of 8 evaluable subjects will receive dose level 1, dose level 2, or dose level 3 of Dexmedetomidine. | 4 |
| Total | 4 |
Baseline characteristics
| Characteristic | Dexmedetomidine |
|---|---|
| Age, Categorical <=18 years | 3 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 4 |
| serious Total, serious adverse events | 0 / 4 |
Outcome results
Primary
The Primary Endpoint Will be the Change in PVR in Wood Units
Pulmonary vascular resistance (PVR) in Wood units calculated during cardiac catheterization;
Time frame: For each subject PVR will be measured by cardiac catheterization at T0 ( baseline measurement) , after DEX bolus (T1) which is given over 10 minutes and after 30 mins after start of the DEX infusion (T2) - Maximum upto 4 hours
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Subject 1 | The Primary Endpoint Will be the Change in PVR in Wood Units | T0 | 8.9 wood units |
| Subject 1 | The Primary Endpoint Will be the Change in PVR in Wood Units | T2 | 7.1 wood units |
| Subject 1 | The Primary Endpoint Will be the Change in PVR in Wood Units | T1 | 9.7 wood units |
| Subject 2 | The Primary Endpoint Will be the Change in PVR in Wood Units | T0 | 13.7 wood units |
| Subject 2 | The Primary Endpoint Will be the Change in PVR in Wood Units | T2 | 15.5 wood units |
| Subject 2 | The Primary Endpoint Will be the Change in PVR in Wood Units | T1 | 15.5 wood units |
| Subject 3 | The Primary Endpoint Will be the Change in PVR in Wood Units | T1 | 6.52 wood units |
| Subject 3 | The Primary Endpoint Will be the Change in PVR in Wood Units | T0 | 5.45 wood units |
| Subject 3 | The Primary Endpoint Will be the Change in PVR in Wood Units | T2 | 7.0 wood units |
| Subject 4 | The Primary Endpoint Will be the Change in PVR in Wood Units | T0 | 8.57 wood units |
| Subject 4 | The Primary Endpoint Will be the Change in PVR in Wood Units | T2 | 2.27 wood units |
| Subject 4 | The Primary Endpoint Will be the Change in PVR in Wood Units | T1 | 13.18 wood units |
Secondary
Demonstrate That DEX is a Safe Sedative in Pediatric Subjects With PHTN
The study was terminated early due to increased pulmonary vascular resistance (PVR) in one subject from To-T1 reaching the level of a predetermined stopping rule. Investigators suggested that it is premature to conclude that DEX does not adversely affect PVR.
Time frame: 24 hours
Population: The study was terminated early due to increased pulmonary vascular resistance (PVR) in one subject from To-T1 reaching the level of a predetermined stopping rule. Investigators suggested that it is premature to conclude that DEX does not adversely affect PVR.
Secondary
Efficacy of Sedation With DEX
The study was terminated early due to increased pulmonary vascular resistance (PVR) in one subject from To-T1 reaching the level of a predetermined stopping rule. Investigators suggested that it is premature to conclude that DEX does not adversely affect PVR
Time frame: Subjects will participate in a dose escalation study which will define minimal effective dose that results in effective sedation in ≥ 7 out of 8 patients in that dose cohort. Maximum upto 4 hours
Population: The study was terminated early due to increased pulmonary vascular resistance (PVR) in one subject from To-T1 reaching the level of a predetermined stopping rule. Investigators suggested that it is premature to conclude that DEX does not adversely affect PVR.
Secondary
Obtain Pharmacokinetic Data in This Population
The study was terminated early due to increased pulmonary vascular resistance (PVR) in one subject from To-T1 reaching the level of a predetermined stopping rule. Investigators suggested that it is premature to conclude that DEX does not adversely affect PVR
Time frame: 6 hours
Population: The study was terminated early due to increased pulmonary vascular resistance (PVR) in one subject from To-T1 reaching the level of a predetermined stopping rule. Investigators suggested that it is premature to conclude that DEX does not adversely affect PVR.
Secondary
Quantify the Effect of DEX on PVR in Pediatric Subjects With Pulmonary Hypertension (PHTN) and Its Dependence on Baseline PVR
The study was terminated early due to increased pulmonary vascular resistance (PVR) in one subject from To-T1 reaching the level of a predetermined stopping rule. Investigators suggested that it is premature to conclude that DEX does not adversely affect PVR
Time frame: Every individual patient will be studied over maximum of 4 hours during the dose escalation phase. This part of the study will be completed in 1 year
Population: The study was terminated early due to increased pulmonary vascular resistance (PVR) in one subject from To-T1 reaching the level of a predetermined stopping rule. Investigators suggested that it is premature to conclude that DEX does not adversely affect PVR