Pharmacokinetics and Clinical Effects of Escalating Doses of Clonidine in ICU Patients (Clokin1)

This study is developed for assessing the pharmacodynamic and pharmacokinetic properties of intravenous (IV) clonidine in critically ill patients on the ICU, and to estimate the optimal dosing strategy for IV clonidine.

Study Overview

• Status: Completed
• Conditions: Delirium; Critical Illness
• Intervention / Treatment: Drug: Clonidine (Catapresan®) 0,150 mg/ml, ampoule 1 ml

Detailed Description

Many patients in intensive care units (ICU's) require sedation and analgesia to tolerate mechanical ventilation and other ICU procedures. Commonly used GABA-ergic anaesthetics like propofol, midazolam and morphine have potential adverse effects that may increase morbidity, prolong ICU stay and provoke delirium. Recent studies have shown that sedation with alpha-2-adrenergic agonists may lead to a reduction of the total amount of gamma-aminobutyric acid (GABA) -ergic anaesthetics and reduction of delirium1In clinical practice the alpha-2-adrenergic agent clonidine is widely used off label as an add-on sedative in mechanically ventilated patients who suffer from delirium, but there are no large studies proving that this therapy is effective and safe. Limited information exists on the pharmacokinetics of iv clonidine, especially in ICU patients. Besides, dosing regimens of clonidine differ widely among ICU's in the Netherlands, and in the literature.

The sample size required for pharmacokinetic modelling with an acceptable level of precision is inversely related to the number of blood samplings taken from each individual. Population pharmacokinetic experiments that have been published have generally used 50 or more subjects. However, in the investigators study a relatively large number of blood samples are taken (>10 per subject when the protocol is completed, see section 6.3). THe investigators estimate that sufficient precision can be obtained with a sample size of 24 subjects, generating an estimated 240 to 360 blood samples.

In a recent publication of a computer simulated population pharmacokinetics of an absorption model using a design that involved 6 samplings per subject, it was estimated that a two-compartment first-order model would need 50 subjects (i.e. 300 blood samplings) to obtain a model with 50% precision and a power of 0.8.

The investigators 24 subjects will be treated with 3 different doses of clonidine (600, 1200 and 1800 µg/day), that is 8 per treatment arm.

On top of this, 8 patients receiving no clonidine will serve as a reference group, in order to interpret hemodynamic and safety data, and to illustrate dose-response relationships.

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 3

Contacts and Locations

Study Locations

• Netherlands
  • Deventer, Netherlands
    • Deventer Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

In order to be eligible to participate in this study, a subject must be:

• at least 18 years of age
• intubated
• sedated at the start of the study. Because of the high incidence of delirium on the ICU in all age categories, all age groups > 18 years will be included

Exclusion Criteria:

• Severe neurotrauma,
• Severe dementia (living in a nursing home)
• Inability to speak Dutch or English, which is one of the causes of not being able to use the CAM-ICU.
• The use of clonidine during the 96 hours before the start of the study.
• Bradycardia (<50/min)
• Severe hypotension (MAP < 65 after volume resuscitation and vasopressors)
• Pregnancy and lactation (pregnancy test are routinely performed in premenopausal women on the ICU).
• Epilepsy
• Known clonidine intolerance
• Liver cirrhosis (Child Pugh class C)
• Recent and acute myocardial infarction
• Severe heart failure (LVEF < 30%)
• Second or third degree atrioventricular (AV)-block without a permanent pacemaker
• Expected transfer to another hospital.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: No clonidine; No clonidine is administered. The outcome measures are recorded, to compare them with the outcome measures of the other clonidine arms
Experimental: Clonidine 600mcg; 4 patients receive 600 µg/day of clonidine without loading schedule. 4 patients receive 600 µg/day of clonidine with a loading schedule of 300 µg in 4 h.	Drug: Clonidine (Catapresan®) 0,150 mg/ml, ampoule 1 ml; clonidine intravenous; Other Names: Boehringer Ingelheim, RVG 06055
Experimental: Clonidine 1200mcg; 4 patients receive 1200 µg/day of clonidine without loading schedule.; 4 patients receive 1200 µg/day of clonidine with a loading schedule of 600 µg in 4 h.	Drug: Clonidine (Catapresan®) 0,150 mg/ml, ampoule 1 ml; clonidine intravenous; Other Names: Boehringer Ingelheim, RVG 06055
Experimental: Clonidine 1800mcg; 4 patients receive 1800 µg/day of clonidine without loading schedule.; 4 patients receive 1800 µg/day of clonidine with a loading schedule of 900 µg in 4 h.	Drug: Clonidine (Catapresan®) 0,150 mg/ml, ampoule 1 ml; clonidine intravenous; Other Names: Boehringer Ingelheim, RVG 06055

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
clonidine plasma concentrations	pharmacokinetic and pharmacodynamic properties of intravenous clonidine in ICU patients Clonidine plasma concentration at start of infusion at t=2, t=4, t=8 and t=12 h Clonidine plasma concentration during study, once daily Clonidine plasma concentration after stopping infusion at t=ω+8, t=ω+16, t=ω+24 h, and t=ω+48 h (ω= end of infusion).	up to 7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
heart rate	Heart rate 2-hrly for the first 12 h, 8-hrly thereafter	up to 7 days
blood pressure	Blood pressure 2-hrly for the first 12 h, 8-hrly thereafter	up to 7 days
delirium	delirium rating scale, CAM-ICU 3 times daily	up to 7 days
use of antipsychotics	additional use of haloperidol or sedatives, measured in total amount during the investigational period	up to 7 days

Collaborators and Investigators

• Sponsor: Deventer Ziekenhuis
• Investigators: Principal Investigator: Huub Oever v/d, Deventer Ziekenhuis

Study record dates

Study Major Dates

• Study Start: December 1, 2016
• Primary Completion (Actual): April 5, 2018
• Study Completion (Actual): April 5, 2018

Study Registration Dates

• First Submitted: April 21, 2015
• First Submitted That Met QC Criteria: June 4, 2015
• First Posted (Estimate): June 9, 2015

Study Record Updates

• Last Update Posted (Actual): July 30, 2018
• Last Update Submitted That Met QC Criteria: July 27, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: delirium; pharmacokinetics; intensive care; pharmacodynamics; clonidine
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Nervous System Diseases; Neurologic Manifestations; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Disease Attributes; Delirium; Critical Illness; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Autonomic Agents; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Sympatholytics; Clonidine
• Other Study ID Numbers: Clonidine kinetics 1.1

Plan for Individual participant data (IPD)

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