Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02022592
Recruitment Status : Completed
First Posted : December 30, 2013
Last Update Posted : May 27, 2020
Sponsor:
Information provided by (Responsible Party):
Claudia Spies, Charite University, Berlin, Germany

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.


Condition or disease Intervention/treatment Phase
Sedation in Intensive Care Unit Patients Drug: Lormetazepam Drug: Midazolam Phase 4

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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 84 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Comparison of Lormetazepam and Midazolam Used as Sedatives for Patients That Require Intensive Care
Actual Study Start Date : July 17, 2014
Actual Primary Completion Date : December 12, 2019
Actual Study Completion Date : March 12, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Lormetazepam
The patient is treated on ICU not longer than 2 days. Dosage requirements according to Summary of product characteristics (Sedalam®).
Drug: Lormetazepam
Active Comparator: Midazolam
The patient is treated on ICU not longer than 2 days. Dosage requirements according to Summary of product characteristics (Midazolam-ratiopharm®, Midazolam-hameln®).
Drug: Midazolam



Primary Outcome Measures :
  1. Controllability of sedation [ Time Frame: Up to 8 days ]
    Controllability of sedation is defined as the percentage share of measures where the actual depth of sedation (measured with the Richmond Agitation and Sedation Scale) (RASS)) matches the target depths of sedation. The individual sedation target is defined by the attending physician. It will be measured until 5 days after termination of study drug.


Secondary Outcome Measures :
  1. SOFA (Sequential Organ Failure Assessment) [ Time Frame: Up to 8 days ]
  2. Pain-Scores [ Time Frame: Up to 28 days ]

    NRS-V (Numeric Rating Scale -V) and FPS-R (Faces Pain Scale-Revised) and BPS (Behavioral Pain Scale) and BPS-NI (Non-Intubated BPS)

    according to German consensus guidelines


  3. Anxiety-Score [ Time Frame: Up to 28 days ]
    Faces Anxiety Scale score

  4. Concurrent medication for Analgesia and Sedation [ Time Frame: up to 8 days ]
    dose/time. It will be measured until 5 days after termination of study drug.

  5. Delirium-screening-Instruments [ Time Frame: Up to 28 days ]
    CAM-ICU (Confusion Assessment Method for Intensive Care Unit) ICDSC ( Intensive Care Delirium Screening Checklist) Nu-DESC (Nursing Delirium Screening Scale)

  6. Mortality [ Time Frame: Up to 90 days ]
  7. Duration of mechanical ventilation and weaning from mechanical ventilation [ Time Frame: During intensive care unit stay, an average of 14 days ]
  8. Length of intensive care unit stay [ Time Frame: During intensive care unit stay, an average of 14 days ]
  9. Length of hospital stay [ Time Frame: During hospital stay, an average of 28 days ]
  10. Follow-up treatment regarding Patient- Documentation-Management-System [ Time Frame: During hospital stay, an average of 28 days ]
    Discharge Mode

  11. Length of sedation [ Time Frame: During intensive care unit stay, an average of 14 days ]
  12. Number of changes in target Richmond agitation sedation scale (RASS) [ Time Frame: Up to 3 days ]
    During administration of study drug

  13. Wake-up-time [ Time Frame: Up to 3 days ]
    During administration of study drug

  14. Deviation from target Richmond agitation sedation scale (RASS) [ Time Frame: Up to 3 days ]
    During administration of study drug

  15. Quality of Life [ Time Frame: Up to 90 days ]
    Questionnaire designed to measure health status (EQ-5D)

  16. Cognition [ Time Frame: Up to 28 days, at hospital discharge ]
    Minimental State Examination (MMSE) and Cambridge Cognition - computerised cognitive testing (CANTAB®), Mehrfachwahl-Wortschatz-Intelligenztest (MWT) and Fragebogen erlebter Aufmerksamkeitsdefizite (FEDA)

  17. Posttraumatic stress disorder [ Time Frame: Up to 90 days ]
    The Post-Traumatic Stress Syndrome 14-Questions Inventory

  18. Bedside measurement of Acetylcholinesterase activity (U/gHb) [ Time Frame: Up to 8 days ]
    The Acetylcholinesterase activity will be measured on every study day out of a blood sample (10µl); It will be measured until 5 days after termination of study drug.

  19. Organ dysfunctions [ Time Frame: Up to 8 days ]
    It will be measured until 5 days after termination of study drug.

  20. Depth of sedation [ Time Frame: During the operation ]
    Depth of sedation is measured by Electroencephalography and Electromyography (only surgical patients in the Centers Charité and Gießen, intensive care unit patients only Center Charité)

  21. Photomotor reflex [ Time Frame: During intensive care unit stay, an average of 14 days ]
    Photo motor reflex variations are measured by video pupillometry (only Center Charité)

  22. Pain threshold measurement [ Time Frame: Up to 3 days ]
    Automatic measurement of specific pain reflexes

  23. micro ribonucleic acid (rna) [ Time Frame: Up to 3 days ]
    micro rna panel is analysed (only Center Charité)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02022592


Locations
Layout table for location information
Germany
Clinic for Anesthesiology, Intensive Care Medicine and Painmanagement, Johann-Wolfgang-Goethe-University
Frankfurt, Frankfurt Am Main, Germany, 60590
Clinic for Operative Intensive Care Medicine and Intermediate Care, University of RWTH
Aachen, Germany, 52056
Department of Anesthesiology and Intensive Care Medicine, Charité - University Medicine
Berlin, Germany, 13353
Sponsors and Collaborators
Claudia Spies
Investigators
Layout table for investigator information
Study Chair: Claudia Spies, MD, Univ.- Prof. Charite University, Berlin, Germany
Study Director: Gernot Marx, MD, Univ.-Prof. University RWTH Aachen
Layout table for additonal information
Responsible Party: Claudia Spies, Univ.-Prof. Dr. med. C. Spies, Charite University, Berlin, Germany
ClinicalTrials.gov Identifier: NCT02022592    
Other Study ID Numbers: LoveMi
First Posted: December 30, 2013    Key Record Dates
Last Update Posted: May 27, 2020
Last Verified: May 2020
Additional relevant MeSH terms:
Layout table for MeSH terms
Midazolam
Lormetazepam
Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action