Assessment of Efficacy, Safety and Dosing of Clevidipine in Pediatric Participants Undergoing Surgery (PIONEER) (PIONEER)

Open Label Study to Assess the Efficacy, Safety and Dosing of Clevidipine in Pediatric Patients Undergoing Surgery

Evaluate the efficacy, safety, and dosing of clevidipine as an intravenous (IV) infusion for blood pressure (BP) management in paediatric participants in the perioperative setting.

Study Overview

• Status: Terminated
• Conditions: Pediatric Perioperative Blood Pressure Management
• Intervention / Treatment: Drug: clevidipine

Detailed Description

This was an open-label study to assess, in a stepwise approach across 4 age cohorts from oldest to youngest (birth to <age 18), the efficacy and safety of clevidipine exposure for a minimum of 30 minutes and up to a maximum of 96 hours in pediatric participants undergoing a surgical procedure with anesthesia for greater than or equal to 1 hour and for whom parenteral IV infusion of antihypertensive therapy for the management of blood pressure was expected.

The reason for initiating clevidipine administration was to keep blood pressure within a pre-specified range during surgery.

After the study completion for Cohort 1 (adolescent patients 12 to less than 18 years), the PIONEER study was placed on partial clinical hold by the FDA; later, the study was terminated by the sponsor. Enrolment of the subsequent cohorts did not take place; results are presented for Cohort 1 only.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford Medical Center
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 17 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Less than 18 years of age
• Written informed consent obtained before initiation of any study-related procedures
• The enrolling physician determines that the participant will likely require a 15% reduction in BP during the perioperative course
• Intra-arterial line is available for blood pressure monitoring
• Surgical procedure requiring a minimum of 1 hour of anesthesia, in which IV antihypertensive therapy to control BP for at least 30 minutes is anticipated

Exclusion Criteria:

• Administration of an IV or oral antihypertensive agent within 2 hours prior to study drug administration
• Congenital heart disease described as single ventricle
• Evidence of liver failure, severe liver disease, pulmonary disease (e.g. uncontrolled asthma), hyperlipidemia, lipoid nephrosis, lipid dysfunction or acute pancreatitis
• Allergy to soya bean oil or egg lecithin
• Known to be intolerant to calcium channel blockers
• Hemophilia or blood coagulation disorders
• Any serious medical condition which, in the opinion of the investigator, is likely to interfere with study procedures
• Clinically significant abnormal physical findings at the screening evaluation
• Any serious surgical or medical condition which, in the opinion of the investigator, is likely to interfere with study procedures or with the pharmacokinetics or pharmacodynamics of the study drug
• Participant is terminally ill (death likely to occur within 48 hours)
• Use of Methylphenidate, calcium channel blockers, Aripiprazole and other atypical anti- psychotics and antihypertensives used for BP control within 2 hours prior to study drug initiation
• Positive serum or urine pregnancy test for any female of child bearing potential
• Participation in other clinical research studies involving the evaluation of other investigational drugs or devices within 30 days of enrollment
• Participants who, for any reason, are deemed by the Investigator to be inappropriate for this study
• Participant is a relative of the Investigator or his/her deputy, research assistant, pharmacist, study coordinator, other staff directly involved in the conduct of the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: clevidipine; An initial clevidipine IV infusion dose for the adolescent cohort has been specified per protocol. The initial dose for each of the subsequent age cohorts could be modified if necessary, based on the recommendation of the Data and Safety Monitoring Board (DSMB). Following the initial dose, clevidipine will be up-titrated every 1.5 minutes, according to participant need, to achieve a systolic blood pressure (SBP) within the pre-specified SBP target range. Doses may be increased by less than doubling, and the time between dose adjustments may be lengthened, as the target blood pressure is approached. The infusion rate may be maintained for up to 96 hours, once the participant's SBP is within the target range, and titrated as necessary to maintain blood pressure within the range.

Drug: clevidipine; Other Names: Cleviprex; clevidipine butyrate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy: Median Time to Attain the Initial Pre-specified Target SBP Range	Efficacy: Median time to attain the initial pre-specified target SBP range (≥20 mm Hg and ≤ 40 mm Hg apart). The reason for initiating clevidipine administration was to keep blood pressure within a pre-specified range during surgery. Time to first achieve SBP target range within first 30 minutes. A target systolic blood pressure (SBP) range was specified for each patient prior to study drug initiation and could not be changed for the first 30 minutes of the treatment period. Adolescent patients received an initial weight-based dose of 0.4 μg/kg/minute, to be maintained for the first 1.5 minutes. Treatment period: from study drug initiation to termination of infusion (up to 96 hours) was: Phase 1: initial dosing (0 to 1.5 minutes); Phase 2: titration and maintenance phase (>1.5 minutes up to 96 hours); Phase 3: transition and termination phase where the study drug is ceased, and the patient is transitioned to an alternative IV or oral antihypertensive if required.	During the first 30 minutes of clevidipine infusion start (baseline).
Efficacy: Number and Percentage of Participants Achieving the Initial Pre-specified Target SBP Range -- During First 30 Min of Clevidipine Infusion	Efficacy: Number and percentage of participants achieving the initial pre-specified target SBP range within first 30 minutes of clevidipine infusion.	During the first 30 minutes of clevidipine infusion start (baseline).
Efficacy: Total Dose to Attain the Initial Pre-specified Target SBP Range	Efficacy: Total dose infused to attain the initial pre-specified target SBP range (≥20 mm Hg and ≤ 40 mm Hg apart) within the first 30 min.	During the first 30 minutes of clevidipine infusion start (baseline).
Pharmacology: Pharmacodynamic Variable -- Infusion Rate	Pharmacodynamic (PD) variable: infusion rate. A target systolic blood pressure (SBP) range was specified for each patient prior to study drug initiation by the Investigator and could not be changed for the first 30 minutes of the treatment period. Adolescent patients received an initial weight-based dose of 0.4 μg/kg/minute, to be maintained for the first 1.5 minutes.	Duration of clevidipine infusion (minimum of 30 minutes up to a maximum 96 hours).
Pharmacology: Clevidipine -- Tmax	Pharmacology: Pharmacokinetic (PK) variables for clevidipine were established by non-compartmental analysis and non-linear mixed effects modelling (NONMEM). PK results represent those that were obtained during and after the infusion of clevidipine, started at infusion rate of 0.4 µg/kg/min and then titrated according to the study protocol. Tmax: The time it takes for a drug to reach the maximum concentration after administration of a drug.	From 30 minutes before start of infusion up to termination of infusion (minimum of 9 hours up to a maximum of 96 hours).
Pharmacology: Clevidipine -- Cmax	Pharmacology: Pharmacokinetic (PK) variables for clevidipine were established by non-compartmental analysis and non-linear mixed effects modelling (NONMEM). PK results represent those that were obtained during and after the infusion of clevidipine, started at infusion rate of 0.4 µg/kg/min and then titrated according to the study protocol. Cmax: Highest concentration of a drug reached after administration.	From 30 minutes before start of infusion up to termination of infusion (minimum of 9 hours up to a maximum of 96 hours).
Pharmacology: Clevidipine -- Area Under the Concentration Curve (AUCall)	Pharmacology: Pharmacokinetic (PK) variables for clevidipine were established by non-compartmental analysis and non-linear mixed effects modelling (NONMEM). PK results represent those that were obtained during and after the infusion of clevidipine, started at infusion rate of 0.4 µg/kg/min and then titrated according to the study protocol. AUC all: Area under the curve, represents the total drug exposure integrated over time.	From 30 minutes before start of infusion up to termination of infusion (minimum of 9 hours up to a maximum of 96 hours).
Pharmacology: Clevidipine -- Area Under the Concentration Curve Infinity (AUCinf)	Pharmacology: Pharmacokinetic (PK) variables for clevidipine were established by non-compartmental analysis and non-linear mixed effects modelling (NONMEM). PK results represent those that were obtained during and after the infusion of clevidipine, started at infusion rate of 0.4 µg/kg/min and then titrated according to the study protocol. AUC inf: Area under the curve of the blood concentration from time zero and extrapolated to infinity.	From 30 minutes before start of infusion up to termination of infusion (minimum of 9 hours up to a maximum of 96 hours).
Pharmacology: Clevidipine -- Volume of Distribution (Vd)	Pharmacology: Pharmacokinetic (PK) variables for clevidipine were established by non-compartmental analysis and non-linear mixed effects modelling (NONMEM). PK results represent those that were obtained during and after the infusion of clevidipine, started at infusion rate of 0.4 µg/kg/min and then titrated according to the study protocol. Vd: Volume of distribution is defined as the total amount of drug in the body divided by its concentration in plasma.	From 30 minutes before start of infusion up to termination of infusion (minimum of 9 hours up to a maximum of 96 hours).
Pharmacology: Clevidipine -- Total Clearance (CL)	Pharmacology: Pharmacokinetic (PK) variables for clevidipine were established by non-compartmental analysis and non-linear mixed effects modelling (NONMEM). PK results represent those that were obtained during and after the infusion of clevidipine, started at infusion rate of 0.4 µg/kg/min and then titrated according to the study protocol. CL: Total Clearance is defined as the rate at which a drug is removed from plasma (mg/min) divided by the concentration of that drug in the plasma (mg/mL).	From 30 minutes before start of infusion up to termination of infusion (minimum of 9 hours up to a maximum of 96 hours).
Pharmacology: Clevidipine -- Half-Life (T1/2)	Pharmacology: Pharmacokinetic (PK) variables for clevidipine were established by non-compartmental analysis and non-linear mixed effects modelling (NONMEM). PK results represent those that were obtained during and after the infusion of clevidipine, started at infusion rate of 0.4 µg/kg/min and then titrated according to the study protocol. T1/2: The half-life of a drug is the time it takes for the amount of a drug's active substance in your body to reduce by half.	From 30 minutes before start of infusion up to termination of infusion (minimum of 9 hours up to a maximum of 96 hours).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy: Percent Change in SBP From Baseline at Each Time Point -- During First 30 Min of Infusion Start (Baseline)	Efficacy: Percent Change in SBP From Baseline at Each Time Point -- During First 30 Min of Infusion Start (Baseline).	From infusion start (baseline) to 30 minutes post baseline.
Efficacy: Percent Change From Baseline in SBP -- Hourly Measurements -- From 30 Min to 6 Hours of Infusion Start (Baseline)	Efficacy: Percent change from baseline (infusion start) in SBP at each hour after the first 30 minutes of clevidipine infusion up to the cessation of infusion (up to 6 hours from baseline).	At each hour from 30 minutes post-clevidipine infusion start (baseline) to 6 hours from baseline.
Efficacy: Percent Change in SBP From Baseline at Each Time Point -- From Cessation of Study Drug Infusion up to 12 Hours	Efficacy: Percent change in SBP from baseline at each time point -- from cessation of study drug infusion and up to 12 hours.	During the first 12 hours (measured at each hour) after cessation of clevidipine infusion.
Efficacy: Number and Percentage of Patients Falling Below the Target Systolic Blood Pressure Range Lower Limit -- During the First 30 Minutes and During the Entire Drug Treatment Period of Clevidipine Infusion	Efficacy: Number and percentage of patients falling below the target systolic blood pressure range lower limit -- during the first 30 minutes and during the entire drug treatment period of clevidipine infusion.	During the first 30 minutes and during the entire drug treatment period (up to a maximum of 96 hours of clevidipine infusion).
Efficacy: Number and Percentage of Participants in Whom the SBP Was Within Target Range at Each Hour After the First 30 Minutes of Clevidipine Infusion (up to 6 Hours)	The number and percentage of participants in whom the SBP was within target range at each hour after the first 30 minutes of clevidipine infusion (up to 6 hours).	From 30 minutes after infusion start (baseline) and up to 6 hours post-clevidipine infusion.
Efficacy: Percent Change From Baseline in Heart Rate (HR) -- During First 30 Min of Infusion	Efficacy: Percent change from baseline in heart rate (HR). From infusion start (baseline) to 30 minutes post baseline.	From infusion start (baseline) to 30 minutes post baseline.
Efficacy: Percent Change From Baseline in Heart Rate (HR).	Efficacy: Percent change from baseline in heart rate (HR) -- From 30 Min to 6 Hours From Baseline.	At each hour after 30 minutes post-clevidipine infusion start (baseline) and up to 6 hours.
Efficacy: Percent Change From Baseline in Heart Rate (HR) -- From Cessation of Study Drug Infusion up to 12 Hours	Efficacy: Percent change from baseline in heart rate. At each hour after cessation of clevidipine infusion (up to 12 hours).	At each hour after cessation of clevidipine infusion (up to 12 hours).
Efficacy: Number and Percentage of Participants Requiring Rescue Therapy	Efficacy: Number and percentage of participants who require rescue therapy (i.e. receive any alternative IV antihypertensive drug) at any time during the study drug treatment period.	Minimum of 30 minutes up to a maximum of 96 hours post infusion start (baseline).
Efficacy: Number and Percentage of Participants Discontinuing Due to Adverse Events	Number and percentage of participants discontinuing the study due to adverse events.	Minimum of 30 minutes up to a maximum of 96 hours post infusion start (baseline).

Collaborators and Investigators

• Sponsor: Chiesi Farmaceutici S.p.A.
• Investigators: Principal Investigator: Joseph D Tobias, MD, Nationwide Children's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): March 17, 2014
• Primary Completion (Actual): February 20, 2024
• Study Completion (Actual): February 20, 2024

Study Registration Dates

• First Submitted: August 30, 2013
• First Submitted That Met QC Criteria: September 4, 2013
• First Posted (Estimated): September 10, 2013

Study Record Updates

• Last Update Posted (Actual): April 17, 2025
• Last Update Submitted That Met QC Criteria: April 16, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: pediatrics; blood pressure; pediatric surgery; perioperative
• Additional Relevant MeSH Terms: Calcium-Regulating Hormones and Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Membrane Transport Modulators; Calcium Channel Blockers; Clevidipine
• Other Study ID Numbers: MDCO-CLV-12-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No