Pharmacokinetics and Clinical Effects of Escalating Doses of Clonidine in ICU Patients

Critical Illness Clinical Trial

— Clokin1  

Official title:

Pharmacokinetics and Clinical Effects of Escalating Doses of Clonidine in ICU Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02466373
• Other study ID #: Clonidine kinetics 1.1
• Status: Completed
• Phase: Phase 3
• Start date: December 2016
• Est. completion date: April 5, 2018

Study information

• Verified date: July 2018
• Source: Deventer Ziekenhuis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 32
• Est. completion date: April 5, 2018
• Est. primary completion date: April 5, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Critical Illness
• Delirium

Intervention

Drug:
• Clonidine (Catapresan®) 0,150 mg/ml, ampoule 1 ml
clonidine intravenous

Locations

Country	Name	City	State
Netherlands	Deventer Hospital	Deventer

Sponsors (1)

Lead Sponsor	Collaborator
Deventer Ziekenhuis

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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=?+8, t=?+16, t=?+24 h, and t=?+48 h (?= end of infusion).	up to 7 days
Secondary	heart rate	Heart rate 2-hrly for the first 12 h, 8-hrly thereafter	up to 7 days
Secondary	blood pressure	Blood pressure 2-hrly for the first 12 h, 8-hrly thereafter	up to 7 days
Secondary	delirium	delirium rating scale, CAM-ICU 3 times daily	up to 7 days
Secondary	use of antipsychotics	additional use of haloperidol or sedatives, measured in total amount during the investigational period	up to 7 days