Pharmacodynamic Interaction of REMI and DMED

NCT ID: NCT03143972

Last Updated: 2024-04-18

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE4

Total Enrollment

30 participants

Study Classification

INTERVENTIONAL

Study Start Date

2017-06-28

Study Completion Date

2018-02-23

Brief Summary

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The objective is to map the pharmacokinetic / pharmacodynamic interaction between dexmedetomidine and remifentanil by observing changes in anesthetic depth. These changes will be related to drug concentrations using pharmacokinetic/pharmacodynamic (PKPD) modeling.

Detailed Description

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This study is designed to investigate whether the use of a combination of dexmedetomidine and remifentanil is clinically useful to provide anesthesia during surgical and diagnostic procedures and whether it could be used for anesthetic induction. Furthermore the aim is to gain better insights in the required dosing regimens, the inter-individual variability in response towards the combination and the associated side effects. Better characterization of this drug-drug interaction will presumably lead to more precise dosing regimens, which in turn, will lead to a reduction in the occurrence of oversedation, side effects and recovery times.

The objective is to map the pharmacokinetic / pharmacodynamic interaction between dexmedetomidine and remifentanil by observing changes in anesthetic depth, measured by hypnotic and analgesic endpoints such as modified observer's assessment of alertness and sedation scale (MOAA/S), response to electrical stimuli, response to laryngoscopy and electroencephalogram (EEG) derived indices. These effects will be related to drug concentrations using pharmacokinetic/pharmacodynamic (PKPD) modeling.

Conditions

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Anesthesia

Study Design

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Allocation Method

NON_RANDOMIZED

Intervention Model

CROSSOVER

All volunteers will receive 2 standardized anesthesia sessions with a washout period of at least one week between sessions. During the first session volunteers will receive dexmedetomidine, during the second session they will first receive remifentanil and afterwards the combination of drugs will be administered. Anesthetic depth will be evaluated by MOAA/S scores (see table 2), testing of tolerance to electrical stimuli and laryngoscopy. Furthermore multichannel EEG-data will be collected to get insight in the drug dependent characteristics. Measured effects will be related to drug plasma concentrations.
Primary Study Purpose

SUPPORTIVE_CARE

Blinding Strategy

NONE

Study Groups

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Dexmedetomidine only

Dexmedetomidine will be administered by effect-site TCI according to the Hannivoort model extended with an effect-site rate constant of 0.0428min-1.

A stepwise increasing dosing regimen will be given, with concentrations targeting an effect site concentration of 1 ng/ml (40 min), 3 ng/ml (50 min), 4 ng/ml (40 min), 5 ng/ml (40 min) and 8 ng/ml (70 min).

Group Type EXPERIMENTAL

Dexmedetomidine

Intervention Type DRUG

Single drug administration

Remifentanil only

Remifentanil will be administered by effect-site TCI according to the Eleveld model. A stepwise increasing dosing regimen will be given, with concentrations targeting an effect site concentration of 1 ng/ml (12 min), 2 ng/ml (12 min), 3 ng/ml (12 min), 5 ng/ml (12 min) and 7 ng/ml (12 min).

Group Type EXPERIMENTAL

Remifentanil

Intervention Type DRUG

Single drug administration

Dexmedetomidine-Remifentanil interaction

A fixed background dose of dexmedetomidine will be given, this will be calculated after the first 5 subjects completed the dexmedetomidine only session. It will be set to 50% of the observed mean EC50TOL (Tolerance of Laryngoscopy).

Remifentanil infusion will be administered by effect site TCI with stepwise increasing targets of 0.5 - 1.0 - 1.5 - 2.0 - 2.5 - 3.0 - 4.0 ng/ml, each lasting for 15 minutes.

Group Type EXPERIMENTAL

Dexmedetomidine

Intervention Type DRUG

Single drug administration

Remifentanil

Intervention Type DRUG

Single drug administration

Interventions

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Dexmedetomidine

Single drug administration

Intervention Type DRUG

Remifentanil

Single drug administration

Intervention Type DRUG

Other Intervention Names

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Dexdor Ultiva

Eligibility Criteria

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Inclusion Criteria

* American Society of Anesthesiologists (ASA) Physical Status 1
* No medical history of significance
* No chronic use of medication, drugs, tobacco or more than 20 gr alcohol daily (oral contraceptives excluded).
* Concerning the cognitive function: Volunteers are considered to have sufficient cognitive reserve if they are able to read and comprehend the patient information form, if they can adequately answer the anamnestic questions during the screening process and if they are allowed to provide legitimate written informed consent.
* No selection will be made regarding ethnic background
* No exclusion criterium is present

Exclusion Criteria

* Known intolerance to dexmedetomidine or remifentanil
* Volunteer refusal
* Age \< 18 years or \>70 years
* Pregnancy, or currently nursing
* Hairstyle with dreadlocks (EEG-monitoring will not be possible)
* Body mass index (BMI) \<18 or \>30 kg/m2.
* Neurological disorder (epilepsy, the presence of a brain tumor, a history of brain surgery, hydrocephalic disorders, depression needing treatment with anti-depressive drugs, a history of brain trauma, a subarachnoidal bleeding, TIA or cerebral infarct, psychosis or dementia , schizophrenia, alcohol or drug abuse).
* Diseases involving the cardiovascular system (hypertension, coronary artery disease, prior acute myocardial infarction, any valvular and/or myocardial disease involving
Minimum Eligible Age

18 Years

Maximum Eligible Age

70 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes

Sponsors

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University Medical Center Groningen

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Michel MR Struys, Prof.Dr.

Role: PRINCIPAL_INVESTIGATOR

University Medical Center Groningen

Locations

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University Medical Center Groningen

Groningen, , Netherlands

Site Status

Countries

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Netherlands

References

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Hannivoort LN, Eleveld DJ, Proost JH, Reyntjens KM, Absalom AR, Vereecke HE, Struys MM. Development of an Optimized Pharmacokinetic Model of Dexmedetomidine Using Target-controlled Infusion in Healthy Volunteers. Anesthesiology. 2015 Aug;123(2):357-67. doi: 10.1097/ALN.0000000000000740.

Reference Type BACKGROUND
PMID: 26068206 (View on PubMed)

Su H, Koomen JV, Eleveld DJ, Struys MMRF, Colin PJ. Pharmacodynamic mechanism-based interaction model for the haemodynamic effects of remifentanil and propofol in healthy volunteers. Br J Anaesth. 2023 Aug;131(2):222-233. doi: 10.1016/j.bja.2023.04.043. Epub 2023 Jun 22.

Reference Type DERIVED
PMID: 37355412 (View on PubMed)

Ramaswamy SM, Kuizenga MH, Weerink MAS, Vereecke HEM, Struys MMRF, Belur Nagaraj S. Frontal electroencephalogram based drug, sex, and age independent sedation level prediction using non-linear machine learning algorithms. J Clin Monit Comput. 2022 Feb;36(1):121-130. doi: 10.1007/s10877-020-00627-3. Epub 2020 Dec 14.

Reference Type DERIVED
PMID: 33315176 (View on PubMed)

Ramaswamy SM, Weerink MAS, Struys MMRF, Nagaraj SB. Dexmedetomidine-induced deep sedation mimics non-rapid eye movement stage 3 sleep: large-scale validation using machine learning. Sleep. 2021 Feb 12;44(2):zsaa167. doi: 10.1093/sleep/zsaa167.

Reference Type DERIVED
PMID: 32860500 (View on PubMed)

Belur Nagaraj S, Ramaswamy SM, Weerink MAS, Struys MMRF. Predicting Deep Hypnotic State From Sleep Brain Rhythms Using Deep Learning: A Data-Repurposing Approach. Anesth Analg. 2020 May;130(5):1211-1221. doi: 10.1213/ANE.0000000000004651.

Reference Type DERIVED
PMID: 32287128 (View on PubMed)

Ramaswamy SM, Kuizenga MH, Weerink MAS, Vereecke HEM, Struys MMRF, Nagaraj SB. Novel drug-independent sedation level estimation based on machine learning of quantitative frontal electroencephalogram features in healthy volunteers. Br J Anaesth. 2019 Oct;123(4):479-487. doi: 10.1016/j.bja.2019.06.004. Epub 2019 Jul 18.

Reference Type DERIVED
PMID: 31326088 (View on PubMed)

Other Identifiers

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PIRAD-001

Identifier Type: -

Identifier Source: org_study_id

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