Trial Outcomes & Findings for A Phase III Study of Remimazolam in Patients Undergoing Bronchoscopy (NCT NCT02296892)

Last Updated: 2020-03-18

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

446 participants

Primary outcome timeframe

From first dose of study drug to removal of bronchoscope (average time not known)

Results posted on

2020-03-18

Participant Flow

Participant milestones

Participant milestones
Measure	Remimazolam Remimazolam iv 5 mg for sedation induction, and 2.5 mg top-ups for sedation maintenance.	Placebo Placebo iv as inactive control arm	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.
Overall Study STARTED	310	63	73
Overall Study Safety Population	303	59	69
Overall Study Complete Trial Treatment Period	303	59	69
Overall Study COMPLETED	298	59	68
Overall Study NOT COMPLETED	12	4	5

Reasons for withdrawal

Reasons for withdrawal
Measure	Remimazolam Remimazolam iv 5 mg for sedation induction, and 2.5 mg top-ups for sedation maintenance.	Placebo Placebo iv as inactive control arm	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.
Overall Study Exclusion Criteria at Day of Procedure	7	4	4
Overall Study Lost to Follow-up	5	0	1

Baseline Characteristics

A Phase III Study of Remimazolam in Patients Undergoing Bronchoscopy

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Remimazolam n=303 Participants Remimazolam iv 5 mg for sedation induction, and 2.5 mg top-ups for sedation maintenance.	Placebo n=59 Participants Placebo iv as inactive control arm	Midazolam n=69 Participants 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.	Total n=431 Participants Total of all reporting groups
Age, Continuous	62.7 years STANDARD_DEVIATION 12.09 • n=5 Participants	60.8 years STANDARD_DEVIATION 12.08 • n=7 Participants	61.5 years STANDARD_DEVIATION 14.03 • n=5 Participants	62.3 years STANDARD_DEVIATION 12.41 • n=4 Participants
Age, Customized <65 years	154 Participants n=5 Participants	32 Participants n=7 Participants	36 Participants n=5 Participants	222 Participants n=4 Participants
Age, Customized ≥65 years	149 Participants n=5 Participants	27 Participants n=7 Participants	33 Participants n=5 Participants	209 Participants n=4 Participants
Sex: Female, Male Female	164 Participants n=5 Participants	35 Participants n=7 Participants	34 Participants n=5 Participants	233 Participants n=4 Participants
Sex: Female, Male Male	139 Participants n=5 Participants	24 Participants n=7 Participants	35 Participants n=5 Participants	198 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	8 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	8 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	295 Participants n=5 Participants	59 Participants n=7 Participants	69 Participants n=5 Participants	423 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race (NIH/OMB) Asian	3 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	5 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	33 Participants n=5 Participants	10 Participants n=7 Participants	19 Participants n=5 Participants	62 Participants n=4 Participants
Race (NIH/OMB) White	263 Participants n=5 Participants	46 Participants n=7 Participants	49 Participants n=5 Participants	358 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	3 Participants n=5 Participants	2 Participants n=7 Participants	0 Participants n=5 Participants	5 Participants n=4 Participants
Region of Enrollment United States	303 participants n=5 Participants	59 participants n=7 Participants	69 participants n=5 Participants	431 participants n=4 Participants
Height	168.6 cm STANDARD_DEVIATION 9.5 • n=5 Participants	167.1 cm STANDARD_DEVIATION 10.0 • n=7 Participants	170.0 cm STANDARD_DEVIATION 9.87 • n=5 Participants	168.6 cm STANDARD_DEVIATION 9.64 • n=4 Participants
Weight	80.9 kg STANDARD_DEVIATION 20.21 • n=5 Participants	77.7 kg STANDARD_DEVIATION 21.17 • n=7 Participants	83.0 kg STANDARD_DEVIATION 22.10 • n=5 Participants	80.8 kg STANDARD_DEVIATION 20.66 • n=4 Participants
Body Mass Index (BMI)	28.4 kg/m^2 STANDARD_DEVIATION 6.39 • n=5 Participants	27.9 kg/m^2 STANDARD_DEVIATION 7.09 • n=7 Participants	28.0 kg/m^2 STANDARD_DEVIATION 5.79 • n=5 Participants	28.3 kg/m^2 STANDARD_DEVIATION 6.39 • n=4 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Remimazolam n=310 Participants Remimazolam iv 5 mg for sedation induction, and 2.5 mg top-ups for sedation maintenance.	Placebo n=63 Participants Placebo iv as inactive control arm	Midazolam n=73 Participants 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.
Number of Participants With a Successful Procedure	250 Participants	3 Participants	24 Participants

SECONDARY outcome

Timeframe: From first dose of study drug until insertion of the bronchoscope

Population: All patients who were randomized and were analyzed as randomized.

The time from the first dose of study drug until bronchoscope insertion on Day 1

Outcome measures

Outcome measures
Measure	Remimazolam n=310 Participants Remimazolam iv 5 mg for sedation induction, and 2.5 mg top-ups for sedation maintenance.	Placebo n=63 Participants Placebo iv as inactive control arm	Midazolam n=73 Participants 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.
Time to Start of Procedure	4.1 minutes Interval 4.0 to 4.8	17.0 minutes Interval 16.0 to 17.5	15.5 minutes Interval 13.8 to 16.7

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Remimazolam n=302 Participants Remimazolam iv 5 mg for sedation induction, and 2.5 mg top-ups for sedation maintenance.	Placebo n=60 Participants Placebo iv as inactive control arm	Midazolam n=68 Participants 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.
Time to Fully Alert After last dose of study drug or rescue sedative	11.6 minutes Interval 10.0 to 12.8	20.0 minutes Interval 15.3 to 31.0	18.0 minutes Interval 15.0 to 20.1
Time to Fully Alert After bronchoscope out	6.0 minutes Interval 5.2 to 7.1	13.6 minutes Interval 8.1 to 24.0	12.0 minutes Interval 5.0 to 15.0

SECONDARY outcome

Timeframe: 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

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)

Outcome measures

Outcome measures
Measure	Remimazolam n=302 Participants Remimazolam iv 5 mg for sedation induction, and 2.5 mg top-ups for sedation maintenance.	Placebo n=60 Participants Placebo iv as inactive control arm	Midazolam n=68 Participants 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.
Time to Ready for Discharge after last dose of study drug or rescue sedative	64.8 minutes Interval 62.0 to 68.5	93.0 minutes Interval 75.0 to 107.0	70.0 minutes Interval 67.0 to 87.0
Time to Ready for Discharge After bronchoscope out	60.0 minutes Interval 57.0 to 63.0	81.0 minutes Interval 70.0 to 100.0	66.0 minutes Interval 62.0 to 72.0

Adverse Events

Remimazolam

Serious events: 17 serious events

Other events: 268 other events

Deaths: 0 deaths

Placebo

Serious events: 4 serious events

Other events: 52 other events

Deaths: 0 deaths

Midazolam

Serious events: 0 serious events

Other events: 63 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Remimazolam n=303 participants at risk Remimazolam iv 5 mg for sedation induction, and 2.5 mg top-ups for sedation maintenance.	Placebo n=59 participants at risk Placebo iv as inactive control arm	Midazolam n=69 participants at risk 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.
Vascular disorders Hypotension	32.7% 99/303 • Treatment-emergent Adverse Events were collected from Day 1 until end of Follow-Up (Day 4 [+3/-1 days]). TEAEs were followed-up until events were resolved, became stable or could be explained by another known cause(s) Total number of participants affected with Other (Not Including Serious) Adverse Events represents any participant in the trial with a TEAE. The number of participants with Preferred Term (PT)TEAEs represents participants with non-serious TEAEs reported with a threshold of 5% in any of the arms	47.5% 28/59 • Treatment-emergent Adverse Events were collected from Day 1 until end of Follow-Up (Day 4 [+3/-1 days]). TEAEs were followed-up until events were resolved, became stable or could be explained by another known cause(s) Total number of participants affected with Other (Not Including Serious) Adverse Events represents any participant in the trial with a TEAE. The number of participants with Preferred Term (PT)TEAEs represents participants with non-serious TEAEs reported with a threshold of 5% in any of the arms	33.3% 23/69 • Treatment-emergent Adverse Events were collected from Day 1 until end of Follow-Up (Day 4 [+3/-1 days]). TEAEs were followed-up until events were resolved, became stable or could be explained by another known cause(s) Total number of participants affected with Other (Not Including Serious) Adverse Events represents any participant in the trial with a TEAE. The number of participants with Preferred Term (PT)TEAEs represents participants with non-serious TEAEs reported with a threshold of 5% in any of the arms
Vascular disorders Hypertension	28.1% 85/303 • Treatment-emergent Adverse Events were collected from Day 1 until end of Follow-Up (Day 4 [+3/-1 days]). TEAEs were followed-up until events were resolved, became stable or could be explained by another known cause(s) Total number of participants affected with Other (Not Including Serious) Adverse Events represents any participant in the trial with a TEAE. The number of participants with Preferred Term (PT)TEAEs represents participants with non-serious TEAEs reported with a threshold of 5% in any of the arms	15.3% 9/59 • Treatment-emergent Adverse Events were collected from Day 1 until end of Follow-Up (Day 4 [+3/-1 days]). TEAEs were followed-up until events were resolved, became stable or could be explained by another known cause(s) Total number of participants affected with Other (Not Including Serious) Adverse Events represents any participant in the trial with a TEAE. The number of participants with Preferred Term (PT)TEAEs represents participants with non-serious TEAEs reported with a threshold of 5% in any of the arms	27.5% 19/69 • Treatment-emergent Adverse Events were collected from Day 1 until end of Follow-Up (Day 4 [+3/-1 days]). TEAEs were followed-up until events were resolved, became stable or could be explained by another known cause(s) Total number of participants affected with Other (Not Including Serious) Adverse Events represents any participant in the trial with a TEAE. The number of participants with Preferred Term (PT)TEAEs represents participants with non-serious TEAEs reported with a threshold of 5% in any of the arms
Vascular disorders Diastolic hypertension	25.4% 77/303 • Treatment-emergent Adverse Events were collected from Day 1 until end of Follow-Up (Day 4 [+3/-1 days]). TEAEs were followed-up until events were resolved, became stable or could be explained by another known cause(s) Total number of participants affected with Other (Not Including Serious) Adverse Events represents any participant in the trial with a TEAE. The number of participants with Preferred Term (PT)TEAEs represents participants with non-serious TEAEs reported with a threshold of 5% in any of the arms	25.4% 15/59 • Treatment-emergent Adverse Events were collected from Day 1 until end of Follow-Up (Day 4 [+3/-1 days]). TEAEs were followed-up until events were resolved, became stable or could be explained by another known cause(s) Total number of participants affected with Other (Not Including Serious) Adverse Events represents any participant in the trial with a TEAE. The number of participants with Preferred Term (PT)TEAEs represents participants with non-serious TEAEs reported with a threshold of 5% in any of the arms	23.2% 16/69 • Treatment-emergent Adverse Events were collected from Day 1 until end of Follow-Up (Day 4 [+3/-1 days]). TEAEs were followed-up until events were resolved, became stable or could be explained by another known cause(s) Total number of participants affected with Other (Not Including Serious) Adverse Events represents any participant in the trial with a TEAE. The number of participants with Preferred Term (PT)TEAEs represents participants with non-serious TEAEs reported with a threshold of 5% in any of the arms
Vascular disorders Systolic hypertension	22.1% 67/303 • Treatment-emergent Adverse Events were collected from Day 1 until end of Follow-Up (Day 4 [+3/-1 days]). TEAEs were followed-up until events were resolved, became stable or could be explained by another known cause(s) Total number of participants affected with Other (Not Including Serious) Adverse Events represents any participant in the trial with a TEAE. The number of participants with Preferred Term (PT)TEAEs represents participants with non-serious TEAEs reported with a threshold of 5% in any of the arms	22.0% 13/59 • Treatment-emergent Adverse Events were collected from Day 1 until end of Follow-Up (Day 4 [+3/-1 days]). TEAEs were followed-up until events were resolved, became stable or could be explained by another known cause(s) Total number of participants affected with Other (Not Including Serious) Adverse Events represents any participant in the trial with a TEAE. The number of participants with Preferred Term (PT)TEAEs represents participants with non-serious TEAEs reported with a threshold of 5% in any of the arms	24.6% 17/69 • Treatment-emergent Adverse Events were collected from Day 1 until end of Follow-Up (Day 4 [+3/-1 days]). TEAEs were followed-up until events were resolved, became stable or could be explained by another known cause(s) Total number of participants affected with Other (Not Including Serious) Adverse Events represents any participant in the trial with a TEAE. The number of participants with Preferred Term (PT)TEAEs represents participants with non-serious TEAEs reported with a threshold of 5% in any of the arms
Vascular disorders Diastolic hypotension	13.5% 41/303 • Treatment-emergent Adverse Events were collected from Day 1 until end of Follow-Up (Day 4 [+3/-1 days]). TEAEs were followed-up until events were resolved, became stable or could be explained by another known cause(s) Total number of participants affected with Other (Not Including Serious) Adverse Events represents any participant in the trial with a TEAE. The number of participants with Preferred Term (PT)TEAEs represents participants with non-serious TEAEs reported with a threshold of 5% in any of the arms	28.8% 17/59 • Treatment-emergent Adverse Events were collected from Day 1 until end of Follow-Up (Day 4 [+3/-1 days]). TEAEs were followed-up until events were resolved, became stable or could be explained by another known cause(s) Total number of participants affected with Other (Not Including Serious) Adverse Events represents any participant in the trial with a TEAE. The number of participants with Preferred Term (PT)TEAEs represents participants with non-serious TEAEs reported with a threshold of 5% in any of the arms	23.2% 16/69 • Treatment-emergent Adverse Events were collected from Day 1 until end of Follow-Up (Day 4 [+3/-1 days]). TEAEs were followed-up until events were resolved, became stable or could be explained by another known cause(s) Total number of participants affected with Other (Not Including Serious) Adverse Events represents any participant in the trial with a TEAE. The number of participants with Preferred Term (PT)TEAEs represents participants with non-serious TEAEs reported with a threshold of 5% in any of the arms
Respiratory, thoracic and mediastinal disorders Hypoxia	21.1% 64/303 • Treatment-emergent Adverse Events were collected from Day 1 until end of Follow-Up (Day 4 [+3/-1 days]). TEAEs were followed-up until events were resolved, became stable or could be explained by another known cause(s) Total number of participants affected with Other (Not Including Serious) Adverse Events represents any participant in the trial with a TEAE. The number of participants with Preferred Term (PT)TEAEs represents participants with non-serious TEAEs reported with a threshold of 5% in any of the arms	18.6% 11/59 • Treatment-emergent Adverse Events were collected from Day 1 until end of Follow-Up (Day 4 [+3/-1 days]). TEAEs were followed-up until events were resolved, became stable or could be explained by another known cause(s) Total number of participants affected with Other (Not Including Serious) Adverse Events represents any participant in the trial with a TEAE. The number of participants with Preferred Term (PT)TEAEs represents participants with non-serious TEAEs reported with a threshold of 5% in any of the arms	18.8% 13/69 • Treatment-emergent Adverse Events were collected from Day 1 until end of Follow-Up (Day 4 [+3/-1 days]). TEAEs were followed-up until events were resolved, became stable or could be explained by another known cause(s) Total number of participants affected with Other (Not Including Serious) Adverse Events represents any participant in the trial with a TEAE. The number of participants with Preferred Term (PT)TEAEs represents participants with non-serious TEAEs reported with a threshold of 5% in any of the arms
Respiratory, thoracic and mediastinal disorders Tachypnoea	2.3% 7/303 • Treatment-emergent Adverse Events were collected from Day 1 until end of Follow-Up (Day 4 [+3/-1 days]). TEAEs were followed-up until events were resolved, became stable or could be explained by another known cause(s) Total number of participants affected with Other (Not Including Serious) Adverse Events represents any participant in the trial with a TEAE. The number of participants with Preferred Term (PT)TEAEs represents participants with non-serious TEAEs reported with a threshold of 5% in any of the arms	10.2% 6/59 • Treatment-emergent Adverse Events were collected from Day 1 until end of Follow-Up (Day 4 [+3/-1 days]). TEAEs were followed-up until events were resolved, became stable or could be explained by another known cause(s) Total number of participants affected with Other (Not Including Serious) Adverse Events represents any participant in the trial with a TEAE. The number of participants with Preferred Term (PT)TEAEs represents participants with non-serious TEAEs reported with a threshold of 5% in any of the arms	5.8% 4/69 • Treatment-emergent Adverse Events were collected from Day 1 until end of Follow-Up (Day 4 [+3/-1 days]). TEAEs were followed-up until events were resolved, became stable or could be explained by another known cause(s) Total number of participants affected with Other (Not Including Serious) Adverse Events represents any participant in the trial with a TEAE. The number of participants with Preferred Term (PT)TEAEs represents participants with non-serious TEAEs reported with a threshold of 5% in any of the arms
Investigations Respiratory rate increased	14.2% 43/303 • Treatment-emergent Adverse Events were collected from Day 1 until end of Follow-Up (Day 4 [+3/-1 days]). TEAEs were followed-up until events were resolved, became stable or could be explained by another known cause(s) Total number of participants affected with Other (Not Including Serious) Adverse Events represents any participant in the trial with a TEAE. The number of participants with Preferred Term (PT)TEAEs represents participants with non-serious TEAEs reported with a threshold of 5% in any of the arms	10.2% 6/59 • Treatment-emergent Adverse Events were collected from Day 1 until end of Follow-Up (Day 4 [+3/-1 days]). TEAEs were followed-up until events were resolved, became stable or could be explained by another known cause(s) Total number of participants affected with Other (Not Including Serious) Adverse Events represents any participant in the trial with a TEAE. The number of participants with Preferred Term (PT)TEAEs represents participants with non-serious TEAEs reported with a threshold of 5% in any of the arms	14.5% 10/69 • Treatment-emergent Adverse Events were collected from Day 1 until end of Follow-Up (Day 4 [+3/-1 days]). TEAEs were followed-up until events were resolved, became stable or could be explained by another known cause(s) Total number of participants affected with Other (Not Including Serious) Adverse Events represents any participant in the trial with a TEAE. The number of participants with Preferred Term (PT)TEAEs represents participants with non-serious TEAEs reported with a threshold of 5% in any of the arms
Respiratory, thoracic and mediastinal disorders Bradycardia	3.3% 10/303 • Treatment-emergent Adverse Events were collected from Day 1 until end of Follow-Up (Day 4 [+3/-1 days]). TEAEs were followed-up until events were resolved, became stable or could be explained by another known cause(s) Total number of participants affected with Other (Not Including Serious) Adverse Events represents any participant in the trial with a TEAE. The number of participants with Preferred Term (PT)TEAEs represents participants with non-serious TEAEs reported with a threshold of 5% in any of the arms	6.8% 4/59 • Treatment-emergent Adverse Events were collected from Day 1 until end of Follow-Up (Day 4 [+3/-1 days]). TEAEs were followed-up until events were resolved, became stable or could be explained by another known cause(s) Total number of participants affected with Other (Not Including Serious) Adverse Events represents any participant in the trial with a TEAE. The number of participants with Preferred Term (PT)TEAEs represents participants with non-serious TEAEs reported with a threshold of 5% in any of the arms	5.8% 4/69 • Treatment-emergent Adverse Events were collected from Day 1 until end of Follow-Up (Day 4 [+3/-1 days]). TEAEs were followed-up until events were resolved, became stable or could be explained by another known cause(s) Total number of participants affected with Other (Not Including Serious) Adverse Events represents any participant in the trial with a TEAE. The number of participants with Preferred Term (PT)TEAEs represents participants with non-serious TEAEs reported with a threshold of 5% in any of the arms

Additional Information

Trial Information

PAION UK Ltd

Phone: +49 2414453101

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee At least 30 days prior to submission of communications, sponsor shall review and comment on the communications. Sponsor shall have the right to require institution and investigator to remove specifically identified confidential information and to delay the proposed publication an additional 45 days to enable sponsor to seek patent protection.
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