Comparison of Lormetazepam and Midazolam Used as Sedatives for Patients That Require Intensive Care

NCT ID: NCT02022592

Last Updated: 2022-04-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 84 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-07-17
• Study Completion Date: 2020-03-12

Brief Summary

A goal directed , demand-driven administration of sedative drugs is an integral part of every intensive care treatment. During long-term application of sedatives, Midazolam is the most commonly used sedative in Europe.

One major objective is the problem of oversedation and agitation during an intensive care treatment due to the lack of controllability of available substances.

The Love-Mi RCT investigates the clinical controllability of Midazolam versus the newly available intravenous drug Lormetazepam.

Detailed Description

Midazolam is almost exclusively metabolized intrahepatically. The methyl-group at position 1 of the imidazole ring is oxidized by liver enzymes. The product is a-OH-midazolam. This reaction is catalyzed by a p450-dependent oxidase in the liver.

Active a-OH-midazolam is inactivated by a biotransformation type II reaction after conjugation. The water soluble, conjugated midazolam can be excreted by the kidney.

During an intensive care treatment, the p450 dependent metabolization is known to be a "bottleneck of elimination" as many drugs are inactivated by this pathway.

As the phase II (glucuronidation) is non-saturable in practice - the phase I reaction limits the metabolic capacity. This leads to unpredictable prolongation of midazolam effects.

In contrast, Lormetazepam is glucuronized directly at its OH-group during a phase II reaction. Since the glucuronidation is non-saturable, Lormetazepam is metabolized with nearly constant kinetics even if repeatedly administered.

Due to the pharmacokinetics we hypothesize that Lormetazepam has an improved controllability compared to midazolam. As this leads to less frequent agitation and over-sedation, we hypothesize that there are multiple beneficial clinical outcomes for patients treated with lormetazepam instead of midazolam.

Conditions

Sedation in Intensive Care Unit Patients

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Lormetazepam

The patient is treated on ICU not longer than 2 days. Dosage requirements according to Summary of product characteristics (Sedalam®).

Group Type: EXPERIMENTAL

Lormetazepam

Intervention Type: DRUG

Midazolam

The patient is treated on ICU not longer than 2 days. Dosage requirements according to Summary of product characteristics (Midazolam-ratiopharm®, Midazolam-hameln®).

Group Type: ACTIVE_COMPARATOR

Midazolam

Intervention Type: DRUG

Interventions

Lormetazepam

Intervention Type: DRUG

Midazolam

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Mechanically ventilated ICU patients with the need for sedatives to achieve or maintain the intended target-RASS (surgical/ nonsurgical).
• Age ≥ 18 years
• Patients who are incapable of giving consent at study inclusion: Written informed consent by patient's legal representative or an independent medical consultant, patients give informed consent subsequent if they are capable.
• Patients who are able to give informed consent at study inclusion: Written informed consent by patients for planned postoperative prolonged ventilatory support who undergo heart surgery
• Consensable patients for inclusion: with necessary intubation with analgosedation

Exclusion Criteria

• Any bolus administration of benzodiazepines until 72hrs before inclusion (except from premedication due to anaesthesia).
• Continuous administration of benzodiazepines within the last 7 days before start of study drug application
• Titration phase: No way that a target RASS between -3 and 0 can be determined by the attending physician
• Known drug intolerance or allergy against lormetazepam, midazolam or one of the additional components.
• Addictive disorder
• Increased intracranial pressure
• Acute intoxication with alcohol, analgesics, sedatives, antipsychotics (neuroleptics, anti-depressives, lithium).
• Patients with cerebrale Pathology, which changes the controllability of sedation or die consciousness (e.g. patients known mental retardation due to syndromatic disorders or an infantile brain damage)
• Patients with a suspected or secured hypoxic brain damage
• Patients with intracranial surgery during actual hospital care
• Tetraplegic patients
• Myasthenia Gravis
• Cerebellar or spinal Ataxia
• Moribund patients with an expected lifespan of less than 24 hours.
• Sickle cell anaemia
• Thallassemia
• Enzyme related disorders that are associated with a severe decreased activity of UDP-glucoronyltransferase (e.g. M. Crigler- Najjar)
• Chronic liver insufficiency CHILD C with MELD Score > 17 before access to intensive care unit
• Diagnosed propofol intolerance/anamnestic propofol infusion Syndrome
• Known depression/suicidality
• Pregnancy (positive beta-HCG test from urine or positive beta-HCG laboratory test from serum (in anuric patients the serum beta-HCG test is obliged) or lactation
• Woman of child-bearing potential who are not using a highly effective contraception (Pearl - Index <1) until 3 months after study inclusion and during this trial
• Referral following an order of official authorities (court order or administrative decision) according to German Drug Law (AMG)

§40 (1) 4

• Participation in clinical trials according to the German Drug Law (AMG) 30 days to and during the study
• Local staff

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Claudia Spies

OTHER

Sponsor Role: lead

Responsible Party

Claudia Spies

Univ.-Prof. Dr. med. C. Spies

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Claudia Spies, MD, Univ.- Prof.

Role: STUDY_CHAIR

Charite University, Berlin, Germany

Gernot Marx, MD, Univ.-Prof.

Role: STUDY_DIRECTOR

University RWTH Aachen

Locations

Clinic for Anesthesiology, Intensive Care Medicine and Painmanagement, Johann-Wolfgang-Goethe-University

Frankfurt, Frankfurt Am Main, Germany

Clinic for Operative Intensive Care Medicine and Intermediate Care, University of RWTH

Aachen, , Germany

Department of Anesthesiology and Intensive Care Medicine, Charité - University Medicine

Berlin, , Germany

Countries

Germany

Other Identifiers

LoveMi

Identifier Type: -

Identifier Source: org_study_id