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

Phase 4TerminatedNCT01938547

Chiesi Farmaceutici S.p.A.22 enrolled

Overview

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.

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

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Pediatric Perioperative Blood Pressure Management

Interventions

clevidipineDRUG

Eligibility

Sex: ALLMax age: 17 Years

Medical Language ↔ Plain English

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

Locations (2)

Stanford Medical Center

Stanford, California, United States

Nationwide Children's Hospital

Columbus, Ohio, United States

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Data from ClinicalTrials.gov

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Time frame: 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.