AnesthesiaPhase 1NCT04670471
Assessment of the Pharmacodynamic and Pharmacokinetic Interaction of Remimazolam and Remifentanil
A Phase 1 study testing Remimazolam and Remifentanil in people with Anesthesia, run by Paion UK Ltd. at 1 site in Netherlands.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 70 yearsHealthy volunteers can take part
- Conditions the study is for
- Anesthesia
- What is being tested?
- Remimazolam and Remifentanil
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 28 participants
- Where
- 1 siteNetherlands
- Study dates
- 13 Apr 2021to 28 Jan 2022
- Phase
- Phase 1
- 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 to 70 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Healthy male or female adults ≥18 to ≤70 years old
- American Society of Anesthesiologists (ASA) Physical Status 1
- Body mass index (BMI) >18 to <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. Highly effective methods of birth control include:
- Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral/intravaginal/transdermal)
Show all 17Show fewer
- Progestogen-only hormonal contraception associated with inhibition of ovulation (oral/injectable/implantable)
- Intrauterine device (IUD)
- Intrauterine hormone-releasing system (IUS)
- Bilateral tubal occlusion
- Vasectomised partner (provided that the partner is the sole sexual partner of the female patient of childbearing potential and that the vasectomised partner has received medical assessment of the surgical success).
- Sexual abstinence
- Women who had their last menstruation at least two years ago or who underwent surgical interventions (surgical birth control, bilateral oophorectomy, hysterectomy, etc.) are regarded as having no childbearing potential.
- For male participants, their partner must not become pregnant during the trial. They should inform their partner about this. They must also agree to use of barrier methods of contraception during the trial.
- 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
Who cannot join
- 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, and opioid analgesics)
- A history of illicit drug or alcohol abuse within two years prior to screening
Show all 18Show fewer
- 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 where hypertension is accompanied by tachycardia as judged by the screening physician.
- Positive urine drug screening test (amphetamines, methamphetamines, benzodiazepines, barbiturates, marijuana, cocaine, 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 re-screened.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Single-centre, Randomised, Prospective, Open-label, Three-period, Phase 1 Clinical Trial for Assessment of the Pharmacodynamic and Pharmacokinetic Interaction of Remimazolam and Remifentanil
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. To date, however, no clinical trials have been conducted to specifically assess the potential for drug-drug interactions between remimazolam and remifentanil. Greater understanding of the potential for such interactions will help define more appropriate dosing regimens with less over-sedation and associated side effects.
- Conditions
- Anesthesia
- Being tested
- Remimazolam, Remifentanil
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RemimazolamDrug
Also called Byfavo, CNS7056
Remimazolam is an intravenous anaesthetic and sedative drug. Remimazolam exhibits its anaesthetic effects via the benzodiazepine binding site at the GABAA receptor.
RemifentanilDrug
Also called Ultiva
Remifentanil is a commonly used opioid in anaesthetic practice. It is a potent and fast-acting analgesic.
| Study group | Role | What they receive |
|---|---|---|
| Remimazolam + Remifentanil plasma concentration of 2.0 ng/mL | Experimental | Each participant will receive study medication on three different occasions:
Session 1: remimazolam alone Session 2: remimazolam plus remifentanil 0.5 ng/mL Session 3 : remimazolam plus reminfentanil 2.0 ng/mL During each session remimazolam will be dosed in a step-up / step-down manner while the remifentanil target concentration will be kept constant. Receives: Drug: Remimazolam; Drug: Remifentanil |
| Remimazolam + Remifentanil plasma concentration of 4.0 ng/mL | Experimental | Each participant will receive study medication on three different occasions:
Session 1: remimazolam alone Session 2: remimazolam plus remifentanil 0.5 ng/mL Session 3 : remimazolam plus reminfentanil 4.0 ng/mL During each session remimazolam will be dosed in a step-up / step-down manner while the remifentanil target concentration will be kept constant. Receives: Drug: Remimazolam; Drug: Remifentanil |
| Remimazolam + Remifentanil plasma concentration of 0.1 ng/mL | Experimental | Each participant will receive study medication on three different occasions:
Session 1: remimazolam alone Session 2: remimazolam plus remifentanil 0.5 ng/mL Session 3 : remimazolam plus reminfentanil 0.1 ng/mL During each session remimazolam will be dosed in a step-up / step-down manner while the remifentanil target concentration will be kept constant. Receives: Drug: Remimazolam; Drug: Remifentanil |
| Remimazolam + Remifentanil plasma concentration of 1.0 ng/ml | Experimental | Each participant will receive study medication on three different occasions:
Session 1: remimazolam alone Session 2: remimazolam plus remifentanil 0.5 ng/mL Session 3 : remimazolam plus reminfentanil 1.0 ng/mL During each session remimazolam will be dosed in a step-up / step-down manner while the remifentanil target concentration will be kept constant. Receives: Drug: Remimazolam; Drug: Remifentanil |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Through study completion, approximately 3 weeks
Secondary outcomes (7)
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.
Measured: Through study completion, approximately 3 weeks
Performance characteristics for the TCI models used (remimazolam and remifentanil) according to Varvel et al. These include median absolute performance error, median performance error, wobble and divergence.
Measured: Through study completion, approximately 3 weeks
Exposure response models for tolerance to laryngoscopy
Measured: Through study completion, approximately 3 weeks
Exposure response models for tolerance to tetanic stimulus
Measured: Through study completion, approximately 3 weeks
Exposure response models for BIS
Measured: Through study completion, approximately 3 weeks
Exposure response models for hemodynamic alterations in terms of heart rate, arterial blood pressure (ABP), mean arterial pressure (MAP), stroke volume and cardiac output
Measured: Through study completion, approximately 3 weeks
Exposure response models for respiratory depression
Measured: Through study completion, approximately 3 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Dec 2020
- Study start13 Apr 2021
- Primary completion28 Jan 2022
- Study completion28 Jan 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for AnesthesiaStudies 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 1
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 28 participants (actual)
Sponsor and investigators
- Lead sponsor
- Paion UK Ltd.
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- University Medical Center Groningen, QPS Holdings LLC
- Responsible party
- Sponsor
- Investigators
- Remco Vellinga, MD, Principal investigator, University Medical Center Groningen (UMCG)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04670471
- Sponsor's protocol ID
- CNS7056-025
- Other IDs
- 2020-003806-30
- Status last verified
- Sep 2023
- First submitted
- 25 Nov 2020
- Last updated
- 11 Sep 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Varvel JR, Donoho DL, Shafer SL. Measuring the predictive performance of computer-controlled infusion pumps. J Pharmacokinet Biopharm. 1992 Feb;20(1):63-94. doi: 10.1007/BF01143186.
PubMed 1588504Vellinga R, Koomen JV, Eleveld DJ, Stohr T, Pesic M, Struys MMRF, Colin PJ. Influence of Remifentanil on the Pharmacokinetics and Pharmacodynamics of Remimazolam in Healthy Volunteers. Anesthesiology. 2025 Apr 1;142(4):666-679. doi: 10.1097/ALN.0000000000005348. Epub 2025 Jan 15.
PubMed 40067039
Study at a glance
From the registry record, last updated by the sponsor on 11 Sep 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Single-centre, Randomised, Prospective, Open-label, Three-period, Phase 1 Clinical Trial for Assessment of the Pharmacodynamic and Pharmacokinetic Interaction of Remimazolam and Remifentanil
- ClinicalTrials.gov ID
- NCT04670471
- Acronym / sponsor ID
- CNS7056-025
- Conditions
- Anesthesia
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 28 participants (actual)
- Lead sponsor
- Paion UK Ltd.Industry (pharma, biotech, devices)
- Collaborators
- University Medical Center Groningen, QPS Holdings LLC
- Study start
- 13 Apr 2021 (actual)
- Primary completion
- 28 Jan 2022 (actual)
- Study completion
- 28 Jan 2022 (actual)
- First posted
- 17 Dec 2020 (actual)
- 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.
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. To date, however, no clinical trials have been conducted to specifically assess the potential for drug-drug interactions between remimazolam and remifentanil. Greater understanding of the potential for such interactions will help define more appropriate dosing regimens with less over-sedation and associated side effects.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Remimazolam + Remifentanil plasma concentration of 2.0 ng/mL | Experimental | Drug: Remimazolam, Drug: RemifentanilEach participant will receive study medication on three different occasions: Session 1: remimazolam alone Session 2: remimazolam plus remifentanil 0.5 ng/mL Session 3 : remimazolam plus reminfentanil 2.0 ng/mL During each session remimazolam will be dosed in a step-up / step-down manner while the remifentanil target concentration will be kept constant. |
| Remimazolam + Remifentanil plasma concentration of 4.0 ng/mL | Experimental | Drug: Remimazolam, Drug: RemifentanilEach participant will receive study medication on three different occasions: Session 1: remimazolam alone Session 2: remimazolam plus remifentanil 0.5 ng/mL Session 3 : remimazolam plus reminfentanil 4.0 ng/mL During each session remimazolam will be dosed in a step-up / step-down manner while the remifentanil target concentration will be kept constant. |
| Remimazolam + Remifentanil plasma concentration of 0.1 ng/mL | Experimental | Drug: Remimazolam, Drug: RemifentanilEach participant will receive study medication on three different occasions: Session 1: remimazolam alone Session 2: remimazolam plus remifentanil 0.5 ng/mL Session 3 : remimazolam plus reminfentanil 0.1 ng/mL During each session remimazolam will be dosed in a step-up / step-down manner while the remifentanil target concentration will be kept constant. |
| Remimazolam + Remifentanil plasma concentration of 1.0 ng/ml | Experimental | Drug: Remimazolam, Drug: RemifentanilEach participant will receive study medication on three different occasions: Session 1: remimazolam alone Session 2: remimazolam plus remifentanil 0.5 ng/mL Session 3 : remimazolam plus reminfentanil 1.0 ng/mL During each session remimazolam will be dosed in a step-up / step-down manner while the remifentanil target concentration will be kept constant. |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (17 listed)
- Healthy male or female adults ≥18 to ≤70 years old
- American Society of Anesthesiologists (ASA) Physical Status 1
- Body mass index (BMI) >18 to <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. Highly effective methods of birth control include:
Key exclusion criteria (18 listed)
- 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, and opioid analgesics)
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 |
|---|---|---|
| RemimazolamAlso: Byfavo, CNS7056Remimazolam is an intravenous anaesthetic and sedative drug. Remimazolam exhibits its anaesthetic effects via the benzodiazepine binding site at the GABAA receptor. | Drug | Remimazolam + Remifentanil plasma concentration of 0.1 ng/mL, Remimazolam + Remifentanil plasma concentration of 1.0 ng/ml, Remimazolam + Remifentanil plasma concentration of 2.0 ng/mL, Remimazolam + Remifentanil plasma concentration of 4.0 ng/mL |
| RemifentanilAlso: UltivaRemifentanil is a commonly used opioid in anaesthetic practice. It is a potent and fast-acting analgesic. | Drug | Remimazolam + Remifentanil plasma concentration of 0.1 ng/mL, Remimazolam + Remifentanil plasma concentration of 1.0 ng/ml, Remimazolam + Remifentanil plasma concentration of 2.0 ng/mL, Remimazolam + Remifentanil plasma concentration of 4.0 ng/mL |
Primary outcome
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.
Time frame: Through study completion, approximately 3 weeks
7 secondary outcomes
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.
Time frame: Through study completion, approximately 3 weeks
Performance characteristics for the TCI models used (remimazolam and remifentanil) according to Varvel et al. These include median absolute performance error, median performance error, wobble and divergence.
Time frame: Through study completion, approximately 3 weeks
Exposure response models for tolerance to laryngoscopy
Time frame: Through study completion, approximately 3 weeks
Exposure response models for tolerance to tetanic stimulus
Time frame: Through study completion, approximately 3 weeks
Exposure response models for BIS
Time frame: Through study completion, approximately 3 weeks
Exposure response models for hemodynamic alterations in terms of heart rate, arterial blood pressure (ABP), mean arterial pressure (MAP), stroke volume and cardiac output
Time frame: Through study completion, approximately 3 weeks
Exposure response models for respiratory depression
Time frame: Through study completion, approximately 3 weeks
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 11 Sep 2023.
- Background: PubMed 1588504Varvel JR, Donoho DL, Shafer SL. Measuring the predictive performance of computer-controlled infusion pumps. J Pharmacokinet Biopharm. 1992 Feb;20(1):63-94. doi: 10.1007/BF01143186.
- Derived from this study: PubMed 40067039Vellinga R, Koomen JV, Eleveld DJ, Stohr T, Pesic M, Struys MMRF, Colin PJ. Influence of Remifentanil on the Pharmacokinetics and Pharmacodynamics of Remimazolam in Healthy Volunteers. Anesthesiology. 2025 Apr 1;142(4):666-679. doi: 10.1097/ALN.0000000000005348. Epub 2025 Jan 15.
- Individual participant dataSharing planned: No
Related trials for Anesthesia
Not yet recruitingObservational study
"Comparison of Oxygen Reserve Index (ORI), End-Tidal Oxygen, and Time-Based Preoxygenation Targets With Arterial Blood Gas During Preoxygenation
Preoxygenation Adequacy Assessed by Oxygen Reserve Index, End-tidal Oxygen and Arterial Blood Gas
RecruitingObservational study
Comparison of Hemodynamic Responses During Anesthesia Induction Using Eleveld and Schnider
Spinal (Fusion) Surgery, Total Intravenous Anesthesia
Not yet recruiting
A Randomized Controlled SaCo-VLM Trial
General Anaesthesia Using Supraglotic Airway
Not yet recruiting
Bispectral Index-Guided Propofol Sedation During Endoscopic Retrograde Cholangiopancreatography
Deep Sedation, Endoscopic Retrograde Cholangiopancreatography
RecruitingPhase 4
Comparison of Hemodynamics and Respiratory Function Between Ciprofol and Propofol in Elderly Patients Undergoing Non-intubated General Anesthesia
Comparison of Hemodynamics and Respiratory Function Between Ciprofol and Propofol in Elderly Patients Undergoing Non-intubated General Anesthesia
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.
Remco Vellinga, MD principal investigator
University Medical Center Groningen (UMCG)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Remimazolam and Remifentanil in people with Anesthesia, run by Paion UK Ltd. at 1 site in Netherlands.
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 17 inclusion and 18 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 11 Sep 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. 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 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
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?
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. (time frame: Through study completion, approximately 3 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04670471, which also lists 2 linked publications.
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 11 Sep 2023.