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

NCT01938547 | Terminated Phase 4 Results DMC FDA Drug

• 1 other identifier: MDCO-CLV-12-01
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Pediatric Perioperative Blood Pressure Management

Keywords

perioperative; blood pressure; pediatrics; pediatric surgery

Outcome Measures

Primary Outcomes (11)

• 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 Outcomes (10)

• 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)

  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

  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

  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)

  From 30 minutes after infusion start (baseline) and up to 6 hours post-clevidipine infusion.

Study Arms (1)

clevidipine

EXPERIMENTAL

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

Interventions

clevidipine DRUG

Also known as: Cleviprex, clevidipine butyrate

clevidipine

Eligibility Criteria

• Age: Up to 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Chiesi Farmaceutici S.p.A.: lead

Study Sites (2)

Stanford Medical Center

Stanford, California, 94305, United States

Location

Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

Location

MeSH Terms

Interventions

clevidipine

Limitations and Caveats

After the study completion for Cohort 1 (adolescent patients 12 to less than 18 years), the PIONEER study was put 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.

Results Point of Contact

• Title: Clinical Trial Transparency
• Organization: Chiesi Farmaceutici S.p.A.

clinicaltrials_info@chiesi.com

+ 39 0521 2791

Study Officials

• Joseph D Tobias, MD

  Nationwide Children's Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 30, 2013
• First Posted: September 10, 2013
• Study Start: March 17, 2014
• Primary Completion: February 20, 2024
• Study Completion: February 20, 2024
• Last Updated: April 17, 2025
• Results First Posted: April 17, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)