Sedation
Conditions
Keywords
CNS 7056, Procedural Sedation, Colonoscopy
Brief summary
The purpose of this dose-response study is to assess the safety and efficacy of CNS 7056 compared with midazolam to maintain suitable sedation levels in patients undergoing colonoscopy.
Detailed description
This is a double-blind, randomized, parallel group, dose-response study to assess the safety and efficacy of three dose levels of CNS 7056 compared with midazolam to maintain suitable sedation levels in patients undergoing colonoscopy. Safety assessment will include physical examinations, vital signs, ECGs, pulse oximetry measurements, capnography, clinical chemistry and hematology laboratory tests, routine drug and ethanol screening, urinalysis, pregnancy test, pain on injection using a verbal scale, and monitoring of adverse events.
Interventions
DRUGA. CNS 7056
Initial low dose plus supplemental doses as necessary.
DRUGB. CNS 7056
Initial intermediate dose plus supplemental doses as necessary.
DRUGC. CNS 7056
Initial high dose plus supplemental doses as necessary.
DRUGD. Midazolam
Initial standardized dose plus supplemental doses as necessary.
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 70 Years
Healthy volunteers
No
Inclusion criteria
* Male and female patients, aged 18 to 70 years inclusive, scheduled to undergo a standard colonoscopy. * American Society of Anesthesiologists Physical Status (ASA PS) Score I, II, or III. * Weight range 55 to 130 kg inclusive. * Body mass index (BMI) range 18 to 33 kg/m2 inclusive * Patients of child-bearing potential and their partners must have been willing to use adequate contraception such as an intrauterine device, diaphragm or condom during the study and until 1 month after the last study drug administration. Childbearing potential was defined as all patients unless they were a female post menopausal for at least 2 years, or were surgically sterile. * Patient voluntarily signed and dated an ICF that was approved by an IRB prior to the conduct of any study procedure. * Patient was willing and able to comply with study requirements and return for a Follow up Visit (Day 4 ± 3 day) after the colonoscopy.
Exclusion criteria
* Expected duration of colonoscopy \> 30 minutes. * Patients with a suspected or diagnosed pathology of the lower GI tract that would have added to the risk of colonoscopy, such as strictures, active inflammatory bowel disease. * ASA III patients with history of sleep apnea. * ASA III patients with obesity (BMI ≥ 30 kg/m2). * Patients with evidence of uncontrolled renal, hepatic, central nervous system, respiratory, cardiovascular or metabolic dysfunction, or other clinically significant (CS) findings at screening that, in the investigator's or medical monitor's opinion, should have excluded them from the study. * Patients with clinically significant abnormalities in 12 lead ECG recorded at screening. * Female patients with a positive serum human chorionic gonadotropin (HCG) pregnancy test at screening or baseline. * Lactating female patients. * Patients with positive drugs of abuse screen at baseline. * Patients with positive serum ethanol at baseline. * Patient with a history of drug or ethanol abuse. * Patients in receipt of any investigational drug within 30 days or less than 7 half lives (whichever was longer) before the start of the study, or scheduled to receive one during the study period. * Patients with a known sensitivity to benzodiazepines, flumazenil, opioids, naloxone, or a medical condition such that these agents were contraindicated. * Patients with an inability to communicate well with the investigator. * Patients in whom management of airway was judged to be difficult due to, e.g., thyro-mental distance ≤ 4 cm (short neck), or Mallampati score of 4.
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: Modified Observer's Assessment for Alertness/Sedation (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 last injection of double-blind study medication until fully alert criteria are reached | Time to first of 3 consecutive MOAA/S scores of 5 after the last injection of double-blind study medication |
| Time to Ready for Discharge | After the Last Injection of Double-Blind Study Medication AND after end of colonoscopy until first of 3 consecutive Aldrete scores ≥ 9 | Time of the first of 3 consecutive Aldrete scores ≥ 9 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Remimazolam 8.0/3.0 mg Double-blind Remimazolam iv arm: 8 mg for sedation induction, and 3 mg top-ups for sedation maintenance | 40 |
| Remimazolam 7.0/2.0 mg Double-blind Remimazolam iv arm: 7 mg for sedation induction, and 2 mg top-ups for sedation maintenance | 40 |
| Remimazolam 5.0/3.0 mg Double-blind Remimazolam iv arm: 5 mg for sedation induction, and 3 mg top-ups for sedation maintenance | 40 |
| Midazolam 2.5/1.0 Double-blind Midazolam iv arm: 2.5 mg for sedation induction, and 1 mg top-ups for sedation maintenance. | 41 |
| Total | 161 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Poor bowel preparation | 0 | 0 | 0 | 1 |
| Overall Study | Procedure not done (no anesthesiologist) | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Remimazolam 8.0/3.0 mg | Remimazolam 7.0/2.0 mg | Remimazolam 5.0/3.0 mg | Midazolam 2.5/1.0 | Total |
|---|---|---|---|---|---|
| Age, Continuous | 54.5 years STANDARD_DEVIATION 11.22 | 54.5 years STANDARD_DEVIATION 8.07 | 54.0 years STANDARD_DEVIATION 10.3 | 55.5 years STANDARD_DEVIATION 5.86 | 54.6 years STANDARD_DEVIATION 9.02 |
| Body Mass Index (BMI) | 27.79 Kg/m2 STANDARD_DEVIATION 3.451 | 27.02 Kg/m2 STANDARD_DEVIATION 4.042 | 26.73 Kg/m2 STANDARD_DEVIATION 3.063 | 26.58 Kg/m2 STANDARD_DEVIATION 3.515 | 27.03 Kg/m2 STANDARD_DEVIATION 3.533 |
| Height | 169.15 cm STANDARD_DEVIATION 11 | 168.18 cm STANDARD_DEVIATION 8.3 | 169.01 cm STANDARD_DEVIATION 11.3 | 169.87 cm STANDARD_DEVIATION 10.1 | 169.06 cm STANDARD_DEVIATION 10.2 |
| Region of Enrollment United States | 40 participants | 40 participants | 40 participants | 41 participants | 161 participants |
| Sex: Female, Male Female | 22 Participants | 25 Participants | 22 Participants | 20 Participants | 89 Participants |
| Sex: Female, Male Male | 18 Participants | 15 Participants | 18 Participants | 21 Participants | 72 Participants |
| Weight | 79.68 kg STANDARD_DEVIATION 13.4 | 76.23 kg STANDARD_DEVIATION 11.6 | 76.79 kg STANDARD_DEVIATION 14.5 | 76.95 kg STANDARD_DEVIATION 13.6 | 77.41 kg STANDARD_DEVIATION 13.3 |
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 / 40 | 0 / 40 | 0 / 40 | 0 / 41 |
| other Total, other adverse events | 10 / 40 | 8 / 40 | 9 / 40 | 6 / 41 |
| serious Total, serious adverse events | 0 / 40 | 0 / 40 | 0 / 40 | 0 / 41 |
Outcome results
Primary
Success Rates of the Procedure
Success of the procedure is a composite endpoint consisting of: Modified Observer's Assessment for Alertness/Sedation (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: Analysis Population is the ITT Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Remimazolam 8.0/3.0 mg | Success Rates of the Procedure | 37 Participants |
| Remimazolam 7.0/2.0 mg | Success Rates of the Procedure | 38 Participants |
| Remimazolam 5.0/3.0 mg | Success Rates of the Procedure | 39 Participants |
| Midazolam 2.5/1.0 | Success Rates of the Procedure | 30 Participants |
p-value: 0.007Fisher Exact
Secondary
Time to Fully Alert
Time to first of 3 consecutive MOAA/S scores of 5 after the last injection of double-blind study medication
Time frame: From last injection of double-blind study medication until fully alert criteria are reached
Population: Analysis Population is the ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Remimazolam 8.0/3.0 mg | Time to Fully Alert | 13.6 minutes | Standard Deviation 7.48 |
| Remimazolam 7.0/2.0 mg | Time to Fully Alert | 11.3 minutes | Standard Deviation 5.69 |
| Remimazolam 5.0/3.0 mg | Time to Fully Alert | 13.3 minutes | Standard Deviation 7.21 |
| Midazolam 2.5/1.0 | Time to Fully Alert | 15.2 minutes | Standard Deviation 7.43 |
Secondary
Time to Ready for Discharge
Time of the first of 3 consecutive Aldrete scores ≥ 9
Time frame: After the Last Injection of Double-Blind Study Medication AND after end of colonoscopy until first of 3 consecutive Aldrete scores ≥ 9
Population: Analysis Population is the ITT Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Remimazolam 8.0/3.0 mg | Time to Ready for Discharge | After last injection | 14.6 minutes | Standard Deviation 8.52 |
| Remimazolam 8.0/3.0 mg | Time to Ready for Discharge | After end of colonoscopy | 5.0 minutes | Standard Deviation 6.29 |
| Remimazolam 7.0/2.0 mg | Time to Ready for Discharge | After end of colonoscopy | 4.6 minutes | Standard Deviation 4.58 |
| Remimazolam 7.0/2.0 mg | Time to Ready for Discharge | After last injection | 12.4 minutes | Standard Deviation 6.72 |
| Remimazolam 5.0/3.0 mg | Time to Ready for Discharge | After last injection | 11.3 minutes | Standard Deviation 4.86 |
| Remimazolam 5.0/3.0 mg | Time to Ready for Discharge | After end of colonoscopy | 3.8 minutes | Standard Deviation 4.16 |
| Midazolam 2.5/1.0 | Time to Ready for Discharge | After last injection | 15.3 minutes | Standard Deviation 8.13 |
| Midazolam 2.5/1.0 | Time to Ready for Discharge | After end of colonoscopy | 5.5 minutes | Standard Deviation 6.59 |