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The goal of this clinical trial is to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of remimazolam (CNS 70754) in healthy adult participants. The main questions it aims to answer are:
What are the key pharmacokinetic parameters of remimazolam, including peak concentration (Cmax), time to peak concentration (Tmax), area under the curve (AUC), and elimination half-life (T1/2)? What is the effect of remimazolam on consciousness, as measured by the MOAA/S scale and Narcotrend monitoring during anesthesia? Researchers will compare the pharmacokinetic and pharmacodynamic effects of remimazolam to see if the drug provides consistent and predictable sedation without significant adverse effects.
Participants will:
Receive continuous Infusion of Remimazolam. Have blood samples taken at various time points to measure plasma concentrations and calculate PK parameters.
Be monitored for consciousness and sedation levels using the MOAA/S scale and Narcotrend.
Undergo safety assessments, including laboratory tests, vital signs monitoring, and physical examinations throughout the study.
This study will help determine the drug's behavior in the body and its impact on sedation, providing valuable information for its future clinical use in anesthesia and other medical applications.
Last updated on December 22, 2024
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| All enrolled participants receive Remimazolam Besylate via continuous IV infusion | Experimental | All enrolled participants receive a standardized Remimazolam Besylate-based anesthesia protocol for renal transplant surgery, as follows:
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Remimazolam Besylate | Drug | This is the first clinical trial evaluating Remimazolam's pharmacokinetics (PK), pharmacodynamics (PD), and safety in renal transplant recipients-a population with unique physiological alterations due to end-stage renal disease and graft reperfusion. Key differentiators include: Population-Specific Dosing Protocol: Induction: 6 mg/kg/h until MOAA/S ≤1 (vs. 5-12 mg/kg/h in general surgery). Maintenance: Titrated (0.5-2 mg/kg/h) to Narcotrend Index 27-60 (lower than typical BIS 40-60 targets), accounting for altered drug metabolism post-transplant. Transplant-Specific Context: Administered alongside standard immunosuppressants (methylprednisolone 750 mg + furosemide 60 mg at reperfusion) but prohibits common sedatives (midazolam/propofol) to isolate Remimazolam's effects. PK/PD sampling accounts for graft function dynamics (e.g., blood draws during reperfusion and post-op days 1-6). Exploratory Genetic Analysis: First study linking VDR/ |
| Measure | Description | Time Frame |
|---|---|---|
| Remimazolam Plasma Concentration | Blood concentration (ng/mL) of Remimazolam | During surgery: Pre-infusion, 2/5/10/20/30/45/60/120 minutes, hourly until infusion stop; Post-infusion: 0/5/15/30/60/90/120/240 minutes. |
| Remimazolam PK Parameters | Maximum Plasma Concentration | During surgery: Pre-infusion, 2/5/10/20/30/45/60/120 minutes, hourly until infusion stop; Post-infusion: 0/5/15/30/60/90/120/240 minutes. |
| Remimazolam PK Parameters | Area Under the Curve (0 to last measurable t) | During surgery: Pre-infusion, 2/5/10/20/30/45/60/120 minutes , hourly until infusion stop; Post-infusion: 0/5/15/30/60/90/120/240 minutes |
| Remimazolam PK Parameters | Area Under the Curve (0 to infinity) | During surgery: Pre-infusion, 2/5/10/20/30/45/60/120 minutes , hourly until infusion stop; Post-infusion: 0/5/15/30/60/90/120/240 minutes |
| Remimazolam PK Parameters | Time to Cmax | During surgery: Pre-infusion, 2/5/10/20/30/45/60/120 minutes , hourly until infusion stop; Post-infusion: 0/5/15/30/60/90/120/240 minutes |
| Remimazolam PK Parameters | Terminal Elimination Half-Life | During surgery: Pre-infusion, 2/5/10/20/30/45/60/120 minutes , hourly until infusion stop; Post-infusion: 0/5/15/30/60/90/120/240 minutes |
| Remimazolam PK Parameters |
| Measure | Description | Time Frame |
|---|---|---|
| Postoperative Urine Output | 24-hour urine volume | Postoperation Days 1 to 6 |
| Serum Creatinine Level | Blood creatinine concentration | Preoperation, Postoperation Days 1 to 6 |
| Measure | Description | Time Frame |
|---|---|---|
| VDR Genotype Effect on Remimazolam Maximum Plasma Concentration | Correlation of VDR polymorphisms with peak concentration | Pre-dose (Day 1) |
| CYP3A Genotype Effect on Remimazolam Area Under the Curve (0 to last measurable t) |
Inclusion Criteria Signed informed consent
Age ≥18 years and <65 years
Chronic renal failure scheduled for renal transplantation
Body mass index (BMI) 18-30 kg/m² (inclusive)
Weight ≥50 kg (males) or ≥45 kg (females)
ASA physical status classification III or IV
Exclusion Criteria Hepatic, psychiatric, or neurological disorders
Coagulopathy
Heart failure
Respiratory failure
Long-term sedative or antidepressant use
Pregnancy or lactation
Inability to communicate or cooperate
Participation in other drug/device trials within 3 months prior
Positive hepatitis B surface antigen (HBsAg)
Positive hepatitis C antibody (HCV-Ab)
Positive HIV antibody
Positive syphilis antibody
Use of hepatic enzyme inhibitors/inducers within 30 days prior (per Appendix 1)
Known hypersensitivity to ≥2 substances
Alcohol consumption >14 units/week within 6 months prior*
Drug abuse history within 3 months prior
Major infection/trauma within 1 month prior
Gastrointestinal surgery affecting drug absorption within 1 month prior
Vaccination within 1 month prior or planned during study
Blood loss/donation >400 mL within 3 months prior
Blood transfusion within 1 month prior
INR >1.5, PT >ULN+4 seconds, or APTT >15×ULN
Significant bleeding history within 3 months prior
Current anticoagulant therapy
Any condition deemed unsuitable by investigator
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| guanghan wu | Contact | +8618763995357 | guanghanwu2021@163.com |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Shandong First Medical University Hospital | Recruiting | Jinan | Shangdong | 250014 | China |
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| ID | Term |
|---|---|
| D051436 | Renal Insufficiency, Chronic |
| ID | Term |
|---|---|
| D051437 | Renal Insufficiency |
| D007674 | Kidney Diseases |
| D014570 | Urologic Diseases |
| D052776 | Female Urogenital Diseases |
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Total Body Clearance
| During surgery: Pre-infusion, 2/5/10/20/30/45/60/120 minutes , hourly until infusion stop; Post-infusion: 0/5/15/30/60/90/120/240 minutes |
| Remimazolam PK Parameters | Renal Clearance | During surgery: Pre-infusion, 2/5/10/20/30/45/60/120 minutes , hourly until infusion stop; Post-infusion: 0/5/15/30/60/90/120/240 minutes |
| Remimazolam PK Parameters | Apparent Volume of Distribution (Terminal) | During surgery: Pre-infusion, 2/5/10/20/30/45/60/120 minutes , hourly until infusion stop; Post-infusion: 0/5/15/30/60/90/120/240 minutes |
| Remimazolam PK Parameters | Mean Residence Time | During surgery: Pre-infusion, 2/5/10/20/30/45/60/120 minutes , hourly until infusion stop; Post-infusion: 0/5/15/30/60/90/120/240 minutes |
| Remimazolam PK Parameters | Percentage of AUC Extrapolated | Pre-infusion, 2/5/10/20/30/45/60/120 minutes , hourly until infusion stop; Post-infusion: 0/5/15/30/60/90/120/240 minutes |
| CNS 7054 (Metabolite) PK Parameters | Maximum Plasma Concentration | During surgery: Pre-infusion, 2/5/10/20/30/45/60/120 minutes, hourly until infusion stop; Post-infusion: 0/5/15/30/60/90/120/240 minutes. |
| CNS 7054 (Metabolite) PK Parameters | Area Under the Curve (0 to last measurable t) | During surgery: Pre-infusion, 2/5/10/20/30/45/60/120 minutes, hourly until infusion stop; Post-infusion: 0/5/15/30/60/90/120/240 minutes. |
| CNS 7054 (Metabolite) PK Parameters | Area Under the Curve (0 to infinity) | During surgery: Pre-infusion, 2/5/10/20/30/45/60/120 minutes, hourly until infusion stop; Post-infusion: 0/5/15/30/60/90/120/240 minutes. |
| CNS 7054 (Metabolite) PK Parameters | Time to Cmax | During surgery: Pre-infusion, 2/5/10/20/30/45/60/120 minutes, hourly until infusion stop; Post-infusion: 0/5/15/30/60/90/120/240 minutes. |
| CNS 7054 (Metabolite) PK Parameters | Terminal Elimination Half-Life | During surgery: Pre-infusion, 2/5/10/20/30/45/60/120 minutes, hourly until infusion stop; Post-infusion: 0/5/15/30/60/90/120/240 minutes. |
| CNS 7054 (Metabolite) PK Parameters | Mean Residence Time | During surgery: Pre-infusion, 2/5/10/20/30/45/60/120 minutes, hourly until infusion stop; Post-infusion: 0/5/15/30/60/90/120/240 minutes. |
| CNS 7054 (Metabolite) PK Parameters | Percentage of AUC Extrapolated | During surgery: Pre-infusion, 2/5/10/20/30/45/60/120 minutes, hourly until infusion stop; Post-infusion: 0/5/15/30/60/90/120/240 minutes. |
| Sedation Depth (PD) | MOAA/S score (0 to 5) + Narcotrend Index (NCI 0 to 100) | Induction: every 1minutes until MOAA/S≤1; Maintenance: every 10 minutes; Recovery: every 2 minutes until 3 consecutive MOAA/S=5. |
| Time to Loss of Consciousness (MOAA/S ≤1) | Time from infusion start to first MOAA/S score ≤1 | 0 to 10 minutes after infusion start |
| Time to Full Alertness (3 consecutive MOAA/S=5) | Time from infusion stop to sustained alertness | Time from infusion stop to sustained alertness |
| Narcotrend Index (NCI) Values | Anesthesia depth index (0-100 scale) | Continuous monitoring during infusion + 30 min post-stop |
| Estimated Glomerular Filtration Rate | Kidney filtration rate | Preoperation, Postoperation Days 1 to 6 |
| Intraoperative Hypotension Incidence | MAP <65 mmHg for >1 minute | Intra-operative period |
| Intraoperative Bradycardia Incidence | HR <45 bpm for >1 min | Intra-operative period |
| Injection Pain Incidence | Participant-reported pain during drug administration | During induction (0 to 10 minutes) |
| Postoperative Nausea/Vomiting Incidence | Postoperative Nausea/Vomiting occurrence | PACU admission to Postoperation Day 6 |
| Postoperative Agitation Incidence | RASS score ≥2 | PACU stay (0 to 2 hours) |
| Delayed Recovery Incidence | Extubation time >30 min post-surgery | End of surgery to PACU discharge |
| Intraoperative Awareness Incidence | Positive Brice questionnaire response | Upon PACU discharge (Day 1) |
Correlation of CYP3A polymorphisms with total exposure
| Pre-dose (Day 1) |
| POR Genotype Effect on Remimazolam Clearance | Correlation of POR polymorphisms with systemic clearance | Pre-dose (Day 1) |
| VDR Genotype Effect on CNS 7054 Terminal Elimination Half-Life | Correlation of VDR polymorphisms with metabolite half-life | Pre-dose (Day 1) |
| D005261 |
| Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |