Dose-Finding Safety Study Evaluating Remimazolam (CNS 7056) in Patients Undergoing Diagnostic Upper GI Endoscopy

Study Overview
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Brief Summary
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The purpose of this study was to assess the safety and efficacy of CNS 7056 as a procedural sedative at three dose levels compared to midazolam during a diagnostic upper GI endoscopy.

Detailed Description
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This was a randomized, double-blind, parallel-group, dose-finding study assessing the safety and efficacy of three dose levels of CNS 7056 compared with midazolam in patients undergoing diagnostic upper GI endoscopy. Patients who met all study entry criteria and completed screening procedures were randomly assigned to 1 of 4 treatment groups: CNS 7056 0.10 mg/kg,0.15 mg/kg, or 0.20 mg/kg; or midazolam 0.075 mg/kg. Patients received their assigned treatment administered as a single intravenous injection by a syringe driver over 1 minute. The endoscopy started when a Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score of ≤3 has been reached, but no earlier than 90 seconds after Time 0 (the start of study drug injection). Rescue with sedative medication (midazolam 1-2 mg) was be permitted at the discretion of the administering physician. Efficacy assessments consisted of the MOAA/S scores, Aldrete scores, and drowsiness measures using a Visual Analogue Scale (VAS). Cognitive function was assessed by the Hopkins Verbal Learning Test-Revised™ (HVLT-R™) and memory for the procedure by the Brice Questionnaire. Safety assessments included adverse events, physical examinations, vital signs, ECGs, pulse oximetry measurements, clinical laboratory tests, and pain on injection using a VAS.

Official Title
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A Phase IIa, Randomized, Controlled, Double-Blind, Dose-Finding Study Evaluating the Safety and Pharmacodynamics of CNS 7056 in Patients Undergoing Diagnostic Upper GI Endoscopy

Conditions
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Procedural Sedation, Endoscopy

Intervention / Treatment
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* Drug: CNS 7056
* Drug: Midazolam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients, aged 18 to 65 years inclusive, scheduled to undergo diagnostic upper GI endoscopy. American Society of Anesthesiologists Physical Status (ASA PS) Score I or II. Weight range 60 to 120 kg inclusive. Body mass index (BMI) 18 to < 30 kg/m2. Patients with no clinically significant abnormalities in 12 lead ECG recorded at Screening. Female with a negative serum human chorionic gonadotropin (hCG) pregnancy test result at Screening and negative urine hCG pregnancy test result on Day 1 before the endoscopy procedure. Patients with negative drugs of abuse serum result at Screening and negative drugs of abuse urine result on Day 1 before the endoscopy procedure. Patient has a negative serum ethanol test result at Screening and a negative ethanol saliva test result on Day 1 before the endoscopy procedure. Patient voluntarily signs and dates an informed consent form (ICF) that is approved by an investigational review board (IRB) prior to the conduct of any study procedure. Patient is willing and able to comply with study requirements and return for a Follow up Visit (Visit 3 ± 1 day) after the endoscopy procedure. Exclusion Criteria: Patients with a suspected upper GI bleed an conditions predisposing to hemorrhage at the discretion of the investigator. Has a known sensitivity to benzodiazepines, flumazenil, or anesthetic agents, or a medical condition such that these agents are contraindicated. Patients with evidence of uncontrolled renal, hepatic, central nervous system, respiratory, cardiovascular, or metabolic dysfunction, in the opinion of the investigator or medical monitor. Patients taking an agent that inhibits cytochrome P450 subtype 3A4 (CYP3A4) or patients who have taken such an agent within 14 days prior to study start or within the duration of 7 half lives of the drug, whichever is longer. Patients in receipt of any investigational drug within 30 days or less than 7 half lives (whichever is longer) before the start of the study, or scheduled to receive one during the study period. Chronic use of benzodiazepines for any indication (eg, insomnia, anxiety, spasticity). Has known or suspected history of alcoholism or drug abuse or misuse within 2 years of Screening or evidence of tolerance or physical dependence before dosing with study drug. Patients with clinically significant findings at Screening that, in the investigator's opinion, should exclude them from the study. Patients with a history of laboratory results that show the presence of hepatitis B surface antigen (HBs Ag), hepatitis C antibody (HCV Ab), or human immunodeficiency virus (HIV). Patients with an inability to communicate well in English with the investigator. Lactating female patients. Patients in whom management of airway is judged to be difficult due to: obesity (weight > 120 kg, or BMI ≥ 30 kg/m2), thyro mental distance ≤ 4 cm (short neck), or Mallampati score of 4 (Appendix IV).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1: Remimazolam (CNS 7056) 0.10 mg/kg<br>Remimazolam (CNS 7056) 0.10 mg/kg iv | Drug: CNS 7056<br>* Administered as a single intravenous injection by a syringe driver over 1 minute<br>* Other names: remimazolam;|
| Experimental: 2: Remimazolam (CNS 7056) 0.15 mg/kg<br>Remimazolam (CNS 7056) 0.15 mg/kg iv | Drug: CNS 7056<br>* Administered as a single intravenous injection by a syringe driver over 1 minute<br>* Other names: remimazolam;|
| Experimental: 3: Remimazolam (CNS 7056) 0.20 mg/kg<br>Remimazolam (CNS 7056) 0.20 mg/kg iv | Drug: CNS 7056<br>* Administered as a single intravenous injection by a syringe driver over 1 minute<br>* Other names: remimazolam;|
| Experimental: 4: Midazolam 0.075 mg/kg<br>Midazolam 0.075 mg/kg iv | Drug: Midazolam<br>* Administered as a single intravenous injection by a syringe driver over 1 minute<br>* Other names: Versed;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Success Rates of the Procedure | Success of the procedure is a composite endpoint consisting of: MOAA/S scores ≤4 on three consecutive measurements after administration of study drug AND completion of the endoscopy procedure AND no requirement for rescue sedative medication AND no requirement for manual or mechanical ventilation | From start of study drug injection to patient discharge | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Fully Alert | Time to first of 3 consecutive Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scores of 5 following study drug administration in patients who underwent the endoscopy procedure | From study drug administration until fully alert criteria are reached | 
| Time to Ready for Discharge | Time to first of 3 consecutive Aldrete scores ≥9 after the end endoscopy procedure | From the end of the endoscopy procedure up to 120 minutes or until 3 consecutive Aldrete scores of ≥9 are reached, whichever occurs first | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CNS 7056, Procedural Sedation, Sedation, Endoscopy