Endoscopy, Procedural Sedation
Conditions
Keywords
CNS 7056, Procedural Sedation, Sedation, Endoscopy
Brief summary
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
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.
Interventions
DRUGCNS 7056
Administered as a single intravenous injection by a syringe driver over 1 minute
DRUGMidazolam
Administered as a single intravenous injection by a syringe driver over 1 minute
Sponsors
Premier Research
Paion UK Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Success Rates of the Procedure | From start of study drug injection to patient discharge | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Fully Alert | From study drug administration until fully alert criteria are reached | 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 |
| Time to Ready for Discharge | From the end of the endoscopy procedure up to 120 minutes or until 3 consecutive Aldrete scores of ≥9 are reached, whichever occurs first | Time to first of 3 consecutive Aldrete scores ≥9 after the end endoscopy procedure |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 1: CNS 7056 0.10 mg/kg CNS 7056: Administered as a single intravenous injection by a syringe driver over 1 minute | 25 |
| 2: CNS 7056 0.15 mg/kg CNS 7056: Administered as a single intravenous injection by a syringe driver over 1 minute | 25 |
| 3: CNS 7056 0.20 mg/kg CNS 7056: Administered as a single intravenous injection by a syringe driver over 1 minute | 25 |
| 4: Midazolam 0.075 mg/kg Midazolam: Administered as a single intravenous injection by a syringe driver over 1 minute | 25 |
| Total | 100 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Physician Decision | 1 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | 1: CNS 7056 0.10 mg/kg | 2: CNS 7056 0.15 mg/kg | 3: CNS 7056 0.20 mg/kg | 4: Midazolam 0.075 mg/kg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 37.7 years STANDARD_DEVIATION 13.33 | 38.8 years STANDARD_DEVIATION 14.08 | 43.2 years STANDARD_DEVIATION 13.95 | 44.6 years STANDARD_DEVIATION 13.64 | 41.1 years STANDARD_DEVIATION 13.86 |
| Body Mass Index (BMI) | 25.47 Kg/m2 STANDARD_DEVIATION 2.091 | 26.43 Kg/m2 STANDARD_DEVIATION 2.158 | 26.24 Kg/m2 STANDARD_DEVIATION 2.725 | 25.59 Kg/m2 STANDARD_DEVIATION 2.262 | 25.93 Kg/m2 STANDARD_DEVIATION 2.324 |
| Height | 169.33 cm STANDARD_DEVIATION 9.603 | 168.42 cm STANDARD_DEVIATION 10.283 | 168.97 cm STANDARD_DEVIATION 7.432 | 171.55 cm STANDARD_DEVIATION 9.65 | 169.57 cm STANDARD_DEVIATION 9.241 |
| Region of Enrollment United States | 25 participants | 25 participants | 25 participants | 25 participants | 100 participants |
| Sex: Female, Male Female | 13 Participants | 13 Participants | 16 Participants | 12 Participants | 54 Participants |
| Sex: Female, Male Male | 12 Participants | 12 Participants | 9 Participants | 13 Participants | 46 Participants |
| Weight | 73.22 kg STANDARD_DEVIATION 10.583 | 75.17 kg STANDARD_DEVIATION 10.869 | 75.13 kg STANDARD_DEVIATION 11.027 | 75.45 kg STANDARD_DEVIATION 10.099 | 74.74 kg STANDARD_DEVIATION 10.526 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 25 | 0 / 25 | 0 / 25 |
| other Total, other adverse events | 6 / 25 | 8 / 25 | 9 / 25 | 10 / 25 |
| serious Total, serious adverse events | 0 / 25 | 0 / 25 | 0 / 25 | 0 / 25 |
Outcome results
Primary
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
Time frame: From start of study drug injection to patient discharge
Population: All randomized patients who received a dose of study drug, underwent the endoscopy procedure, and had at least 1 efficacy assessment (Intent-to-treat population)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 1: CNS 7056 0.10 mg/kg | Success Rates of the Procedure | 8 Participants |
| 2: CNS 7056 0.15 mg/kg | Success Rates of the Procedure | 14 Participants |
| 3: CNS 7056 0.20 mg/kg | Success Rates of the Procedure | 16 Participants |
| 4: Midazolam 0.075 mg/kg | Success Rates of the Procedure | 11 Participants |
Secondary
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
Time frame: From study drug administration until fully alert criteria are reached
Population: All randomized patients who received a dose of study drug, underwent the endoscopy procedure, and had at least 1 efficacy assessment (Intent-to-treat population)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1: CNS 7056 0.10 mg/kg | Time to Fully Alert | 11 minutes | Standard Deviation 10.04 |
| 2: CNS 7056 0.15 mg/kg | Time to Fully Alert | 13.4 minutes | Standard Deviation 6.51 |
| 3: CNS 7056 0.20 mg/kg | Time to Fully Alert | 12.1 minutes | Standard Deviation 5.26 |
| 4: Midazolam 0.075 mg/kg | Time to Fully Alert | 17.2 minutes | Standard Deviation 16.71 |
Secondary
Time to Ready for Discharge
Time to first of 3 consecutive Aldrete scores ≥9 after the end endoscopy procedure
Time frame: From the end of the endoscopy procedure up to 120 minutes or until 3 consecutive Aldrete scores of ≥9 are reached, whichever occurs first
Population: All randomized patients who received a dose of study drug, underwent the endoscopy procedure, and had at least 1 efficacy assessment (Intent-to-treat population)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1: CNS 7056 0.10 mg/kg | Time to Ready for Discharge | 14 minutes | Standard Deviation 9.96 |
| 2: CNS 7056 0.15 mg/kg | Time to Ready for Discharge | 12.8 minutes | Standard Deviation 5.96 |
| 3: CNS 7056 0.20 mg/kg | Time to Ready for Discharge | 11.8 minutes | Standard Deviation 4.96 |
| 4: Midazolam 0.075 mg/kg | Time to Ready for Discharge | 17.2 minutes | Standard Deviation 12.81 |