The primary objective is to quantify the remimazolam exposure-response relationship with and without remifentanil in regard to various stages of MOAA/S for procedural and ICU sedation and general anaesthesiaSecondary objectives are:- Quantification…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
general anesthesia
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
An exposure-response model describing the relationship between effect-site
concentrations of remimazolam and plasma concentrations of remifentanil and
MOAA/S corresponding to mild, moderate and deep sedation
Secondary outcome
Pharmacokinetics
An exposure-response model describing the relationship between effect-site
concentrations of remimazolam and plasma concentrations of remifentanil and BIS
corresponding to mild, moderate and deep sedation
Performance characteristics for the TCI models used (RMZ and remifentanil)
according to Varvel et al. [1]. These include median absolute prediction error,
median prediction error, wobble and divergence.
Pharmacodynamics
Exposure response models for:
1. tolerance to laryngoscopy,
2. tolerance to tetanic stimulus,
3. BIS,
4. hemodynamic alterations in terms of heart rate, arterial blood pressure
(ABP), mean arterial pressure (MAP), stroke volume and cardiac output.
5. respiratory depression.
6. raw EEG data will be used for explorative comparison with the listed PD
parameters
Safety
* Heart rate and arterial blood pressure
* Number and incidence of adverse events by drug-relatedness, seriousness, and
severity during each treatment period.
* Clinical laboratory parameters (at screening, prior to each period and End of
Trial), ECG, vital signs, physical examination at Screening and End-of-Trial
(end of Treatment Period 3). Modified Aldrete score (prior to discharge after
each treatment period).
Background summary
This trial is designed to quantify the pharmacodynamic (PD) and pharmacokinetic
(PK) interaction(s) between an anaesthetic drug (remimazolam) and an opioid
(remifentanil). Remimazolam is a new anaesthetic drug with a sedative effect,
which, in combination with an opioid can be used to achieve general
anaesthesia.
Remimazolam exhibits its anaesthetic effects via the benzodiazepine binding
site at the GABAA receptor, as does midazolam. The compound is rapidly
metabolised and inactivated by tissue esterases that are abundantly distributed
throughout the body. Remimazolam was found to be generally safe and well
tolerated in all clinical trials conducted to date. Safety results from the
completed trials show a lower overall incidence of hypotension compared to both
midazolam and propofol.
To date, however, no clinical trials have been conducted to specifically assess
the potential for drug-drug interactions between remimazolam and remifentanil.
A better characterization of this drug-drug interaction will lead to more
precise dosing regimens, which in turn, will lead to a reduction in the
occurrence of over sedation, side effects and recovery times.
Study objective
The primary objective is to quantify the remimazolam exposure-response
relationship with and without remifentanil in regard to various stages of
MOAA/S for procedural and ICU sedation and general anaesthesia
Secondary objectives are:
- Quantification of the remimazolam exposure-response relationship with and
without remifentanil in regard to various BIS values for procedural and ICU
sedation and general anaesthesia.
- Validation of the Remimazolam (RMZ) 3-compartmental PK model (Final PopPK
model from Nuventra*s *procedural sedation* report, NPS2981) under TCI
conditions based on arterial blood samples taken during steady-state and
non-steady-state conditions.
- Evaluation of various haemodynamic parameters of this combination under
various concentrations at steady state.
- Explorative pharmacokinetic comparison of remimazolam alone and with
different remifentanil concentrations.
- Evaluation of standard safety assessments of this combination under various
concentrations at steady state.
Study design
This is a single-centre, open-label, three-period, randomised treatment
sequence, trial
Subjects will be screened up to 28 days before Day 1 of Treatment Period 1.
Each subject will be randomised to a sequence of 3 consecutive treatment
periods. In each treatment period, subjects will enter the clinic on the late
afternoon/evening before dosing (Day 1) for a restricted screening (see
7.2.2). They will return early in the next morning and remain in the unit until
completely recovered on the evening of the treatment (Day 1). There will be at
least 5 days between each of the 3 treatment periods. A follow-up visit will be
performed just before discharge after recovery in Period 3. A follow-up per
telephone will be performed one day after each treatment period .
Intervention
In each cohort, 2 males and 2 females will be randomised to each Treatment
Sequence (1 or 2, respectively). Sequences 1 and 2 will be identical for
Periods 1 and 2. Dosing for remifentanil will be randomised in Period 3.
In each period, remifentanil will be dosed to a fixed effect concentration (EC)
throughout:
Period 1: 0 ng/mL,
Period 2: 0.5 ng/mL,
Period 3: 0.1 ng/mL [Sequence 1] or 1.0 ng/mL [Sequence 2]).
In each period, remimazolam will be dosed in a series of up to 11 predefined 30
minute EC dose steps (6 ascending steps followed by 5 descending steps).
Study burden and risks
Small risks in this trial are associated with the administration of the IMP and
remifentanil (see 2.3.1 of protocol), the catheterization of the A. radialis,
the insertion of venous cannulae, the bladder catheterization and with the
total blood loss of up to 275 mL over the 3 treatment periods.
Furthermore, subjects will:
- need to refrain from alchol, nicotine and recreational drugs prior to and
during study participation,
- fast before the study days (6 hours concerning solid food, 2 hours concerning
clear liquids)
- need to use highly effective birth control from the last menstrual cycle
prior to the start of the IMP until the end of the trial follow-up procedures
(females) or prevent their partner from becoming pregnant during the study
procedure (males)
Kew Road 5
Richmond TW92PR
GB
Kew Road 5
Richmond TW92PR
GB
Listed location countries
Age
Inclusion criteria
* Healthy male or female adults *18 to *70 years old
* American Society of Anesthesiologists (ASA) Physical Status 1
* Body mass index (BMI) >18 or <30 kg/m2
* Bilateral patent a. radialis
* For female volunteers of childbearing potential: Negative results of 2
pregnancy tests, the first test taken at the start of Screening and the second
test taken from the morning urine within 3 hours before the start of the
administration of the IMP as well as consent to use highly effective birth
control from the last menstrual cycle prior to the start of the IMP until the
end of the trial follow-up procedures. For definition of childbearing potential
and highly effective birth control, see protocol.
* For male participants, their partner must not become pregnant during the
trial. They should inform their partner about this.
* Subject agrees not to use alcohol for 2 days, not to use nicotine for 1 week,
and not to use recreational drugs for 2 weeks prior to the first period until
End of Trial
* Understanding of the trial procedures and be willing to follow the
instructions of the Investigator or centre staff during the course of the
clinical trial
* Written informed consent obtained from the subject
Exclusion criteria
* Known intolerance to benzodiazepines, flumazenil, opioids or any ingredients
of the remimazolam drug products (e.g., dextran, lactose)
* Pregnancy, or currently breastfeeding
* Have current neurological disorder(s) (epilepsy, the presence of a brain
tumour, 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).
* Have a disease(s) involving the cardiovascular system (hypertension, coronary
artery disease, prior acute myocardial infarction, any valvular and/or
myocardial disease involving decrease in ejection fraction, arrhythmias, which
are either symptomatic or require continuous medication/pacemaker/automatic
internal cardioverter defibrillator)
* Recent (<3 months) use of psycho-active medication (benzodiazepines,
anti-epileptic drugs, Parkinson*s medication, neuroleptics, anxiolytics,
anti-depressant drugs, opioid analgesics)
* A history of illicit drug or alcohol abuse within two years prior to screening
* Any ongoing condition considered by the Investigator as potentially relevant
to the trial
* Any medical history considered by the Investigator as potentially relevant to
the trial
* An employee or direct relative of an employee of the trial site, the CRO or
the Sponsor.
* Resting HR <45 bpm or *90 bpm OR resting SABP <90 mmHg or *140 mmHg OR
resting DABP <50 mmHg or *90 mmHg, except for those cases of mild hypertension
or tachycardia which is considered to be secondary to anxiety or known white
coat hypertension.
* Positive urine drug screening test (amphetamines, methamphetamines,
benzodiazepines, barbiturates, marijuana, cocaïne, and opioids).
* Positive Covid-19 screening test
* Any participant as judged by the PI or Sub-Investigator to be inappropriate
for the trial for any other reason
* Clinically significant, as judged by the Investigator abnormal ECG
* Clinically significant abnormal laboratory values
* Participation in a clinical trial of an Investigational Drug or Medical
Device within three months prior to the Screening Visit
* Blood donation of *500mL within three months prior to Screening Visit
* Prior participation in this clinical trial. However, non-dosed drop-outs can
participate in the trial again but will need to be-rescreened.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-003806-30-NL |
| ClinicalTrials.gov | NCT04670471 |
| CCMO | NL75782.056.20 |