Sedation in Intensive Care Unit PatientsPhase 4NCT02022592
Comparison of Lormetazepam and Midazolam Used as Sedatives for Patients That Require Intensive Care
A Phase 4 study testing Lormetazepam and Midazolam in people with Sedation in Intensive Care Unit Patients, run by Claudia Spies at 3 sites in Germany.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Sedation in Intensive Care Unit Patients
- What is being tested?
- Lormetazepam and Midazolam
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 84 participants
- Where
- 3 sitesGermany
- Study dates
- 17 Jul 2014to 12 Mar 2020
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 26Show fewer
- 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
Trial locations and contacts
3 sites in 1 country.
Germany3 sites
Clinic for Operative Intensive Care Medicine and Intermediate Care, University of RWTH
Aachen, 52056
Department of Anesthesiology and Intensive Care Medicine, Charité - University Medicine
Berlin, 13353
Clinic for Anesthesiology, Intensive Care Medicine and Painmanagement, Johann-Wolfgang-Goethe-University
Frankfurt, Frankfurt Am Main, 60590
About this study
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.
Read the 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
- Being tested
- Lormetazepam, Midazolam
- Keywords
- Sedation management, Midazolam, Lormetazepam, Intensive care unit
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LormetazepamDrug
MidazolamDrug
| Study group | Role | What they receive |
|---|---|---|
| Lormetazepam | Experimental | The patient is treated on ICU not longer than 2 days. Dosage requirements according to Summary of product characteristics (Sedalam®). Receives: Drug: Lormetazepam |
| Midazolam | Active comparator | The patient is treated on ICU not longer than 2 days. Dosage requirements according to Summary of product characteristics (Midazolam-ratiopharm®, Midazolam-hameln®). Receives: Drug: Midazolam |
What is being measured
The primary outcome is the main question the study is designed to answer.
Controllability of sedation
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 terminationduring administration of study drug until 2 hours after its termination.
Measured: Up to 50 hours
Secondary outcomes (25)
SOFA (Sequential Organ Failure Assessment)
Measured: Up to 8 days
Pain-Scores
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
Measured: Up to 28 days
Anxiety-Score
Faces Anxiety Scale score
Measured: Up to 28 days
Concurrent medication for Analgesia and Sedation
dose/time.
Measured: Up to 8 days
Delirium-screening-Instruments
CAM-ICU (Confusion Assessment Method for Intensive Care Unit) ICDSC ( Intensive Care Delirium Screening Checklist) Nu-DESC (Nursing Delirium Screening Scale)
Measured: Up to 28 days
Mortality
Measured: Up to 90 days
Duration of mechanical ventilation and weaning from mechanical ventilation
Measured: Up to 8 days
Length of intensive care unit stay
Measured: During intensive care unit stay, an average of 14 days
Length of hospital stay
Measured: During hospital stay, an average of 28 days
Follow-up treatment regarding Patient- Documentation-Management-System
Discharge Mode
Measured: During hospital stay, an average of 28 days
Length of sedation
During administration of study drug until 8 hours after its termination.
Measured: Up to 56 hours
Number of changes in target Richmond agitation sedation scale (RASS)
During administration of study drug
Measured: Up to 56 hours
Wake-up-time
During administration of study drug until 5 days after its termination
Measured: Up to 8 days
Deviation from target Richmond agitation sedation scale (RASS)
During administration of study drug
Measured: Up to 8 days
Quality of Life
Questionnaire designed to measure quality of life (EQ-5D-3L)
Measured: Up to 90 days
Cognition 1
Minimental State Examination (MMSE)
Measured: Up to 28 days
Cognition 2
Mehrfach-Wortschatz-Intelligenztest (MWT)
Measured: Up to 90 days
Posttraumatic stress disorder
The Post-Traumatic Stress Syndrome 14-Questions Inventory
Measured: Up to 90 days
Bedside measurement of Acetylcholinesterase activity (U/gHb)
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.
Measured: Up to 8 days
Organ dysfunctions
It will be measured until 5 days after termination of study drug.
Measured: Up to 8 days
Depth of sedation 1
Depth of sedation is measured by Electroencephalography and Electromyography (only surgical patients in the Centers Charité and Gießen)
Measured: During the operation
Depth of sedation 2
Depth of sedation 2 is measured by Electroencephalography and Electromyography (intensive care unit patients only Center Charité)
Measured: Up to 3 days
Photomotor reflex
Photo motor reflex variations are measured by video pupillometry (only Center Charité)
Measured: Up to 8 days
Pain threshold measurement
Automatic measurement of specific pain reflexes
Measured: Up to 3 days
micro ribonucleic acid (rna)
micro rna panel is analysed (only Center Charité)
Measured: Up to 24 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Dec 2013 (estimated)
- Study start17 Jul 2014
- Primary completion12 Dec 2019
- Study completion12 Mar 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Sedation in Intensive Care Unit PatientsStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 84 participants (actual)
Sponsor and investigators
- Lead sponsor
- Claudia Spies
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Claudia Spies, Charite University, Berlin, Germany
- Investigators
- Claudia Spies, MD, Univ.- Prof., Study chair, Charite University, Berlin, GermanyGernot Marx, MD, Univ.-Prof., Study director, University RWTH Aachen
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02022592
- Sponsor's protocol ID
- LoveMi
- Status last verified
- Apr 2022
- First submitted
- 12 Dec 2013
- Last updated
- 13 Apr 2022
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 13 Apr 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Comparison of Lormetazepam and Midazolam Used as Sedatives for Patients That Require Intensive Care
- ClinicalTrials.gov ID
- NCT02022592
- Acronym / sponsor ID
- LoveMi
- Conditions
- Sedation in Intensive Care Unit Patients
- Keywords
- Sedation management, Midazolam, Lormetazepam, Intensive care unit
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 84 participants (actual)
- Lead sponsor
- Claudia SpiesUniversity, hospital or other
- Study start
- 17 Jul 2014 (actual)
- Primary completion
- 12 Dec 2019 (actual)
- Study completion
- 12 Mar 2020 (actual)
- First posted
- 30 Dec 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Lormetazepam | Experimental | Drug: LormetazepamThe patient is treated on ICU not longer than 2 days. Dosage requirements according to Summary of product characteristics (Sedalam®). |
| Midazolam | Active comparator | Drug: MidazolamThe patient is treated on ICU not longer than 2 days. Dosage requirements according to Summary of product characteristics (Midazolam-ratiopharm®, Midazolam-hameln®). |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (26 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Lormetazepam | Drug | Lormetazepam |
| Midazolam | Drug | Midazolam |
Primary outcome
Controllability of sedation
Time frame: Up to 50 hours
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 terminationduring administration of study drug until 2 hours after its termination.
25 secondary outcomes
SOFA (Sequential Organ Failure Assessment)
Time frame: Up to 8 days
Pain-Scores
Time frame: Up to 28 days
Anxiety-Score
Time frame: Up to 28 days
Concurrent medication for Analgesia and Sedation
Time frame: Up to 8 days
Delirium-screening-Instruments
Time frame: Up to 28 days
Mortality
Time frame: Up to 90 days
Duration of mechanical ventilation and weaning from mechanical ventilation
Time frame: Up to 8 days
Length of intensive care unit stay
Time frame: During intensive care unit stay, an average of 14 days
Length of hospital stay
Time frame: During hospital stay, an average of 28 days
Follow-up treatment regarding Patient- Documentation-Management-System
Time frame: During hospital stay, an average of 28 days
Length of sedation
Time frame: Up to 56 hours
Number of changes in target Richmond agitation sedation scale (RASS)
Time frame: Up to 56 hours
Wake-up-time
Time frame: Up to 8 days
Deviation from target Richmond agitation sedation scale (RASS)
Time frame: Up to 8 days
Quality of Life
Time frame: Up to 90 days
Cognition 1
Time frame: Up to 28 days
Cognition 2
Time frame: Up to 90 days
Posttraumatic stress disorder
Time frame: Up to 90 days
Bedside measurement of Acetylcholinesterase activity (U/gHb)
Time frame: Up to 8 days
Organ dysfunctions
Time frame: Up to 8 days
Depth of sedation 1
Time frame: During the operation
Depth of sedation 2
Time frame: Up to 3 days
Photomotor reflex
Time frame: Up to 8 days
Pain threshold measurement
Time frame: Up to 3 days
micro ribonucleic acid (rna)
Time frame: Up to 24 hours
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Apr 2022.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Claudia Spies, MD, Univ.- Prof. study chair
Charite University, Berlin, Germany
Gernot Marx, MD, Univ.-Prof. study director
University RWTH Aachen
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Lormetazepam and Midazolam in people with Sedation in Intensive Care Unit Patients, run by Claudia Spies at 3 sites in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 Apr 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Controllability of sedation (time frame: Up to 50 hours). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Apr 2022.