Bronchoscopy
Conditions
Keywords
Remimazolam, midazolam, bronchoscopy, procedural sedation
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 bronchoscopy.
Interventions
DRUGRemimazolam
For induction and maintenance of sedation
DRUGPlacebo
Inactive control arm
DRUGMidazolam
For induction and maintenance of sedation
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
1. Male and female patients, aged ≥18 years, scheduled to undergo a diagnostic or therapeutic flexible bronchoscopy in the bronchoscopy suite (therapeutic bronchoscopies could include eg, lavage, biopsies, brushings, and foreign body extraction). 2. American Society of Anesthesiologists Physical Status Score (ASA PS) 1 through 3. 3. Body mass index (BMI) ≤ 45. 4. Peripheral blood oxygen saturation (measured by pulse oximetry: SpO2) ≥ 90% in ambient air or with no more than 2 L/min of oxygen support. 5. For all female patients, negative result of urine pregnancy test. Additionally, for women of child bearing potential only, use of birth control during the study period (from the time of consent until all specified observations were completed). 6. Patients voluntarily signed and dated an informed consent form that was approved by an IRB prior to the conduct of any study procedure, including screening procedures. 7. Patient was willing and able to comply with study requirements and available for a follow up phone call on Day Day 4 (+3/ 1 days) after the bronchoscopy.
Exclusion criteria
1. Patients with a known sensitivity to benzodiazepines, flumazenil, opioids, naloxone, or a medical condition such that these agents were contraindicated. 2. Bronchoscopy outside the bronchoscopy unit (eg, intensive care unit). 3. Patients on mechanical ventilation. 4. Tracheal stenosis. 5. Planned laser bronchoscopy, rigid scope bronchoscopy. 6. Use of unstable doses of benzodiazepines and opioids for any indication, eg, insomnia, anxiety, or spasticity. An unstable dose means dose changes of more than 50% of the previous dose within 30 days prior to Day of procedure. 7. Female patients with a positive pregnancy test at Screening or Baseline and lactating female patients. 8. Patients with positive drugs of abuse screen (unless explained by concomitant medication) or a positive ethanol test at baseline. 9. Patient with a history of drug or ethanol abuse within the past two years. 10. Patients in receipt of any investigational drug or use of investigational device within 30 days or less than 7 t½ (whichever was longer) before the start of the study or scheduled to receive one during the study period. 11. Participation in any previous clinical study with remimazolam. 12. 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 |
|---|---|---|
| Number of Participants With a Successful Procedure | From first dose of study drug to removal of bronchoscope (average time not known) | Success of Procedure measured by completion of bronchoscopy, no requirement for an alternative rescue sedative medication and no requirement for more than 5 doses 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 open-label midazolam arm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Start of Procedure | From first dose of study drug until insertion of the bronchoscope | The time from the first dose of study drug until bronchoscope insertion on Day 1 |
| Time to Fully Alert | From the last dose of study drug or rescue sedative AND from end of bronchoscopy until the patient has recovered to fully alert | The time to fully alert defined as time to first of 3 consecutive Modified Observer's Assessment of Alertness and Sedation (MOAA/S) scores after the end of the bronchoscopy procedure (bronchoscope out). MOAA/S scores: 5 = Responds readily to name spoken in normal tone \[alert\], 4 =Lethargic response to name spoken in normal tone, 3 = Responds only after name is called loudly and/or repeatedly, 2 = Responds only after mild prodding or shaking, 1 = Responds only after painful trapezius squeeze, 0 = Does not respond to painful trapezius squeeze. MOAA/S scores were assessed by the investigators. |
| Time to Ready for Discharge | After the last dose of study drug AND after the end of the bronchoscopy, until discharge | Time from the last dose of study drug or rescue sedative and from the end of bronchoscopy until discharge (defined as the ability to walk unassisted) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Remimazolam Remimazolam iv 5 mg for sedation induction, and 2.5 mg top-ups for sedation maintenance. | 303 |
| Placebo Placebo iv as inactive control arm | 59 |
| Midazolam Midazolam iv 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. | 69 |
| Total | 431 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Exclusion Criteria at Day of Procedure | 7 | 4 | 4 |
| Overall Study | Lost to Follow-up | 5 | 0 | 1 |
Baseline characteristics
| Characteristic | Remimazolam | Placebo | Midazolam | Total |
|---|---|---|---|---|
| Age, Continuous | 62.7 years STANDARD_DEVIATION 12.09 | 60.8 years STANDARD_DEVIATION 12.08 | 61.5 years STANDARD_DEVIATION 14.03 | 62.3 years STANDARD_DEVIATION 12.41 |
| Age, Customized <65 years | 154 Participants | 32 Participants | 36 Participants | 222 Participants |
| Age, Customized ≥65 years | 149 Participants | 27 Participants | 33 Participants | 209 Participants |
| Body Mass Index (BMI) | 28.4 kg/m^2 STANDARD_DEVIATION 6.39 | 27.9 kg/m^2 STANDARD_DEVIATION 7.09 | 28.0 kg/m^2 STANDARD_DEVIATION 5.79 | 28.3 kg/m^2 STANDARD_DEVIATION 6.39 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants | 0 Participants | 0 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 295 Participants | 59 Participants | 69 Participants | 423 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Height | 168.6 cm STANDARD_DEVIATION 9.5 | 167.1 cm STANDARD_DEVIATION 10 | 170.0 cm STANDARD_DEVIATION 9.87 | 168.6 cm STANDARD_DEVIATION 9.64 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 1 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 33 Participants | 10 Participants | 19 Participants | 62 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 2 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) White | 263 Participants | 46 Participants | 49 Participants | 358 Participants |
| Region of Enrollment United States | 303 participants | 59 participants | 69 participants | 431 participants |
| Sex: Female, Male Female | 164 Participants | 35 Participants | 34 Participants | 233 Participants |
| Sex: Female, Male Male | 139 Participants | 24 Participants | 35 Participants | 198 Participants |
| Weight | 80.9 kg STANDARD_DEVIATION 20.21 | 77.7 kg STANDARD_DEVIATION 21.17 | 83.0 kg STANDARD_DEVIATION 22.1 | 80.8 kg STANDARD_DEVIATION 20.66 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 303 | 0 / 59 | 0 / 69 |
| other Total, other adverse events | 268 / 303 | 52 / 59 | 63 / 69 |
| serious Total, serious adverse events | 17 / 303 | 4 / 59 | 0 / 69 |
Outcome results
Primary
Number of Participants With a Successful Procedure
Success of Procedure measured by completion of bronchoscopy, no requirement for an alternative rescue sedative medication and no requirement for more than 5 doses 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 open-label midazolam arm.
Time frame: From first dose of study drug to removal of bronchoscope (average time not known)
Population: All patients who were randomized and were analyzed as randomized.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Remimazolam | Number of Participants With a Successful Procedure | 250 Participants |
| Placebo | Number of Participants With a Successful Procedure | 3 Participants |
| Midazolam | Number of Participants With a Successful Procedure | 24 Participants |
p-value: <0.000195% CI: [0.6903, 0.8274]Cochran-Mantel-Haenszel
Secondary
Time to Fully Alert
The time to fully alert defined as time to first of 3 consecutive Modified Observer's Assessment of Alertness and Sedation (MOAA/S) scores after the end of the bronchoscopy procedure (bronchoscope out). MOAA/S scores: 5 = Responds readily to name spoken in normal tone \[alert\], 4 =Lethargic response to name spoken in normal tone, 3 = Responds only after name is called loudly and/or repeatedly, 2 = Responds only after mild prodding or shaking, 1 = Responds only after painful trapezius squeeze, 0 = Does not respond to painful trapezius squeeze. MOAA/S scores were assessed by the investigators.
Time frame: From the last dose of study drug or rescue sedative AND from end of bronchoscopy until the patient has recovered to fully alert
Population: Patients who do not reach the endpoint are censored at last MOAAS
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Remimazolam | Time to Fully Alert | After last dose of study drug or rescue sedative | 11.6 minutes |
| Remimazolam | Time to Fully Alert | After bronchoscope out | 6.0 minutes |
| Placebo | Time to Fully Alert | After last dose of study drug or rescue sedative | 20.0 minutes |
| Placebo | Time to Fully Alert | After bronchoscope out | 13.6 minutes |
| Midazolam | Time to Fully Alert | After last dose of study drug or rescue sedative | 18.0 minutes |
| Midazolam | Time to Fully Alert | After bronchoscope out | 12.0 minutes |
Secondary
Time to Ready for Discharge
Time from the last dose of study drug or rescue sedative and from the end of bronchoscopy until discharge (defined as the ability to walk unassisted)
Time frame: After the last dose of study drug AND after the end of the bronchoscopy, until discharge
Population: Patients who do not reach the endpoint are censored at last MOAAS
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Remimazolam | Time to Ready for Discharge | after last dose of study drug or rescue sedative | 64.8 minutes |
| Remimazolam | Time to Ready for Discharge | After bronchoscope out | 60.0 minutes |
| Placebo | Time to Ready for Discharge | after last dose of study drug or rescue sedative | 93.0 minutes |
| Placebo | Time to Ready for Discharge | After bronchoscope out | 81.0 minutes |
| Midazolam | Time to Ready for Discharge | after last dose of study drug or rescue sedative | 70.0 minutes |
| Midazolam | Time to Ready for Discharge | After bronchoscope out | 66.0 minutes |
Secondary
Time to Start of Procedure
The time from the first dose of study drug until bronchoscope insertion on Day 1
Time frame: From first dose of study drug until insertion of the bronchoscope
Population: All patients who were randomized and were analyzed as randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Remimazolam | Time to Start of Procedure | 4.1 minutes |
| Placebo | Time to Start of Procedure | 17.0 minutes |
| Midazolam | Time to Start of Procedure | 15.5 minutes |