Colonoscopy
Conditions
Brief summary
A prospective, double-blind, randomized, placebo and active controlled, multi-center, parallel group study comparing remimazolam to placebo, with an additional open-label arm for midazolam, in patients undergoing a colonoscopy for diagnostic or therapeutic reasons.
Interventions
DRUGRemimazolam
For induction and maintenance of sedation
DRUGMidazolam
For induction of maintenance and sedation
DRUGPlacebo
Inactive control arm
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 No maximum
Healthy volunteers
No
Inclusion criteria
* Male and female patients, aged ≥18, scheduled to undergo a diagnostic or therapeutic colonoscopy (therapeutic procedures could include hemostasis, resection, ablation decompression, foreign body extraction, for example). * American Society of Anesthesiologists Score 1 through 3 * Body mass index ≤40 kg/m2. * For female patients with child-bearing potential, negative result of pregnancy test (serum or urine) as well as use of birth control during the study period (from the time of consent until all specified observations were completed). * Patient voluntarily signed and dated an informed consent form that was approved by an Independent Review Board 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 on Day 4 (+3/-1 days) after the colonoscopy.
Exclusion criteria
* Patients with a known sensitivity to benzodiazepines, flumazenil, opioids, naloxone, or a medical condition such that these agents were contraindicated. * Chronic use of benzodiazepines for any indication (eg, insomnia, anxiety, spasticity). * Chronic use of opioids for any indication. * Female patients with a positive serum human chorionic gonadotropin pregnancy test at screening or baseline. * Lactating female patients. * Patients with positive drugs of abuse screen or a positive serum ethanol at baseline. * Patient with a history of drug or ethanol abuse within the past 2 years. * Patients in receipt of any investigational drug within 30 days or less than seven half-lives (whichever was longer) before screening, or scheduled to receive one during the study period. * Participation in any previous clinical trial with remimazolam. * Patients with an inability to communicate well in English with the investigator, or deemed unsuitable according to the investigator (in each case providing a reason).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Success Rates of the Procedure | From administration of the first dose of the study drug to the end of colonoscopy | Success of the Procedure is measured by completion of colonoscopy, no requirement for an alternative sedative and no requirement for more than 5 top-ups of study medication within any 15 minute period in the blinded arms (remimazolam/placebo) or no requirement for more than 3 doses within any 12 minute window in the midazolam arm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Start of Procedure | From first dose of study drug until insertion of the colonoscope | The time to the start of the procedure after administration of the first dose of randomized study drug |
| Time to Fully Alert | From the end of colonoscopy (colonoscope out) until the patient has recovered to fully alert and from the last injection of the study drug or rescue sedative medication until the patient has recovered to fully alert | The time to fully alert (time to first of three consecutive Modified Observer's Assessment of Alertness/Sedation \[MOAA/S\] scores of 5) after the end of colonoscopy procedure \[colonoscope out\], and after the last dose of study drug or rescue sedative medication |
| Time to Ready for Discharge | From the end of the colonoscopy until discharge (expected to be the same day). After the last dose of study drug or rescue sedative, until discharge (expected to be the same day). | The time after the end of colonoscopy procedure (colonoscope out) and after the last injection of study drug or rescue sedative medication, until discharge (defined as ability to walk unassisted). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Remimazolam Double-blind Remimazolam iv arm: 5 mg for sedation induction, and 2.5 mg top-ups for sedation maintenance. | 296 |
| Placebo Double-blind Placebo iv arm: inactive control arm | 60 |
| Midazolam Open-label Midazolam iv arm: 1.75 mg\* for sedation induction and 1.0 mg\* for sedation maintenance.
\*1.0 mg for induction and 0.5 mg for maintenance in adults over 60, debilitated or chronically ill | 102 |
| Total | 458 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Esophagogastroduodenoscopy was added | 1 | 0 | 0 |
| Overall Study | Nellcor device error | 1 | 0 | 0 |
| Overall Study | Protocol Violation | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Remimazolam | Placebo | Midazolam | Total |
|---|---|---|---|---|
| Age, Continuous | 54.4 years STANDARD_DEVIATION 10.12 | 56 years STANDARD_DEVIATION 9.51 | 55.6 years STANDARD_DEVIATION 10.15 | 54.9 years STANDARD_DEVIATION 10.05 |
| Age, Customized <65 years | 254 Participants | 53 Participants | 88 Participants | 395 Participants |
| Age, Customized ≥65 years | 42 Participants | 7 Participants | 14 Participants | 63 Participants |
| Body Max Index (BMI) | 28.9 kg/m2 STANDARD_DEVIATION 4.72 | 30 kg/m2 STANDARD_DEVIATION 5.31 | 28.8 kg/m2 STANDARD_DEVIATION 4.75 | 29 kg/m2 STANDARD_DEVIATION 4.81 |
| Height | 170.1 cm STANDARD_DEVIATION 10.36 | 167.8 cm STANDARD_DEVIATION 10.24 | 169.5 cm STANDARD_DEVIATION 11.15 | 169.6 cm STANDARD_DEVIATION 10.53 |
| Region of Enrollment United States | 296 participants | 60 participants | 102 participants | 458 participants |
| Sex: Female, Male Female | 149 Participants | 35 Participants | 56 Participants | 240 Participants |
| Sex: Female, Male Male | 147 Participants | 25 Participants | 46 Participants | 218 Participants |
| Weight | 83.2 Kg STANDARD_DEVIATION 17.39 | 84.6 Kg STANDARD_DEVIATION 19.9 | 81.9 Kg STANDARD_DEVIATION 16.24 | 83.1 Kg STANDARD_DEVIATION 17.47 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 296 | 0 / 60 | 0 / 102 |
| other Total, other adverse events | 218 / 296 | 47 / 60 | 93 / 102 |
| serious Total, serious adverse events | 0 / 296 | 0 / 60 | 0 / 102 |
Outcome results
Primary
Success Rates of the Procedure
Success of the Procedure is measured by completion of colonoscopy, no requirement for an alternative sedative and no requirement for more than 5 top-ups of study medication within any 15 minute period in the blinded arms (remimazolam/placebo) or no requirement for more than 3 doses within any 12 minute window in the midazolam arm.
Time frame: From administration of the first dose of the study drug to the end of colonoscopy
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Remimazolam | Success Rates of the Procedure | 272 Participants |
| Placebo | Success Rates of the Procedure | 1 Participants |
| Midazolam | Success Rates of the Procedure | 26 Participants |
p-value: <0.000195% CI: [0.8505, 0.9416]Cochran-Mantel-Haenszel
Secondary
Time to Fully Alert
The time to fully alert (time to first of three consecutive Modified Observer's Assessment of Alertness/Sedation \[MOAA/S\] scores of 5) after the end of colonoscopy procedure \[colonoscope out\], and after the last dose of study drug or rescue sedative medication
Time frame: From the end of colonoscopy (colonoscope out) until the patient has recovered to fully alert and from the last injection of the study drug or rescue sedative medication until the patient has recovered to fully alert
Population: Patients who do not reach the endpoint are censored at last MOAA/S
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Remimazolam | Time to Fully Alert | After the end of colonoscopy | 6 minutes |
| Remimazolam | Time to Fully Alert | After last dose of study drug or rescue sedative | 14 minutes |
| Placebo | Time to Fully Alert | After the end of colonoscopy | 15 minutes |
| Placebo | Time to Fully Alert | After last dose of study drug or rescue sedative | 28 minutes |
| Midazolam | Time to Fully Alert | After the end of colonoscopy | 13 minutes |
| Midazolam | Time to Fully Alert | After last dose of study drug or rescue sedative | 24 minutes |
Secondary
Time to Ready for Discharge
The time after the end of colonoscopy procedure (colonoscope out) and after the last injection of study drug or rescue sedative medication, until discharge (defined as ability to walk unassisted).
Time frame: From the end of the colonoscopy until discharge (expected to be the same day). After the last dose of study drug or rescue sedative, until discharge (expected to be the same day).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Remimazolam | Time to Ready for Discharge | After the end of colonoscopy procedure | 44 minutes |
| Remimazolam | Time to Ready for Discharge | After last dose of study drug or rescue sedative | 51 minutes |
| Placebo | Time to Ready for Discharge | After the end of colonoscopy procedure | 49 minutes |
| Placebo | Time to Ready for Discharge | After last dose of study drug or rescue sedative | 60.5 minutes |
| Midazolam | Time to Ready for Discharge | After the end of colonoscopy procedure | 48 minutes |
| Midazolam | Time to Ready for Discharge | After last dose of study drug or rescue sedative | 57 minutes |
Secondary
Time to Start of Procedure
The time to the start of the procedure after administration of the first dose of randomized study drug
Time frame: From first dose of study drug until insertion of the colonoscope
Population: Patients who do not reach the endpoint are excluded from the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Remimazolam | Time to Start of Procedure | 4 minutes |
| Placebo | Time to Start of Procedure | 19.5 minutes |
| Midazolam | Time to Start of Procedure | 19 minutes |
p-value: <0.000195% CI: [4.416, 8.517]Log Rank