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A Phase III Study of the Efficacy and Safety of Remimazolam Compared to Placebo and Midazolam in Colonoscopy Patients

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ClinicalTrials.gov Identifier: NCT02290873
Recruitment Status : Completed
First Posted : November 14, 2014
Results First Posted : November 9, 2018
Last Update Posted : October 20, 2020
Sponsor:
Collaborator:
Premier Research Group plc
Information provided by (Responsible Party):
Paion UK Ltd.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Colonoscopy
Interventions Drug: Remimazolam
Drug: Midazolam
Drug: Placebo
Enrollment 461
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Remimazolam Placebo Midazolam
Hide Arm/Group Description Double-blind Remimazolam iv arm: 5 mg for sedation induction, and 2.5 mg top-ups for sedation maintenance. Double-blind Placebo iv arm: as an inactive control

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

Period Title: Overall Study
Started 298 60 103
Modified Intention to Treat (mITT) [1] 296 60 102
Safety Population [2] 296 60 102
Completed 296 59 101
Not Completed 2 1 2
Reason Not Completed
Withdrawal by Subject             0             1             1
Nellcor device error             1             0             0
Esophagogastroduodenoscopy was added             1             0             0
Protocol Violation             0             0             1
[1]
All ITT population who received at least 1 complete dose of study medication
[2]
All randomized patients who received any amount of study drug and were analyzed as treated
Arm/Group Title Remimazolam Placebo Midazolam Total
Hide Arm/Group Description Double-blind Remimazolam iv arm: 5 mg for sedation induction, and 2.5 mg top-ups for sedation maintenance. Double-blind Placebo iv arm: inactive control arm

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

Total of all reporting groups
Overall Number of Baseline Participants 296 60 102 458
Hide Baseline Analysis Population Description
Baseline Analysis Population is the safety population
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 296 participants 60 participants 102 participants 458 participants
54.4  (10.12) 56  (9.51) 55.6  (10.15) 54.9  (10.05)
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 296 participants 60 participants 102 participants 458 participants
<65 years
254
  85.8%
53
  88.3%
88
  86.3%
395
  86.2%
≥65 years
42
  14.2%
7
  11.7%
14
  13.7%
63
  13.8%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 296 participants 60 participants 102 participants 458 participants
Female
149
  50.3%
35
  58.3%
56
  54.9%
240
  52.4%
Male
147
  49.7%
25
  41.7%
46
  45.1%
218
  47.6%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 296 participants 60 participants 102 participants 458 participants
296 60 102 458
Weight  
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 296 participants 60 participants 102 participants 458 participants
83.2  (17.39) 84.6  (19.9) 81.9  (16.24) 83.1  (17.47)
Height  
Mean (Standard Deviation)
Unit of measure:  Cm
Number Analyzed 296 participants 60 participants 102 participants 458 participants
170.1  (10.36) 167.8  (10.24) 169.5  (11.15) 169.6  (10.53)
Body Max Index (BMI)  
Mean (Standard Deviation)
Unit of measure:  Kg/m2
Number Analyzed 296 participants 60 participants 102 participants 458 participants
28.9  (4.72) 30  (5.31) 28.8  (4.75) 29  (4.81)
1.Primary Outcome
Title Success Rates of the Procedure
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Remimazolam Placebo Midazolam
Hide Arm/Group Description:
Double-blind Remimazolam iv arm: 5 mg for sedation induction, and 2.5 mg top-ups for sedation maintenance.
Double-blind Placebo iv arm: as an inactive control arm

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

Overall Number of Participants Analyzed 298 60 103
Measure Type: Count of Participants
Unit of Measure: Participants
272
  91.3%
1
   1.7%
26
  25.2%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Remimazolam, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments P-value calculated from a Cochran-Mantel-Haenszel test accounting for fentanyl strata.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Rates
Estimated Value 0.8961
Confidence Interval (2-Sided) 95%
0.8505 to 0.9416
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Time to Start of Procedure
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Patients who do not reach the endpoint are excluded from the analysis.
Arm/Group Title Remimazolam Placebo Midazolam
Hide Arm/Group Description:
Double-blind Remimazolam iv arm: 5 mg for sedation induction, and 2.5 mg top-ups for sedation maintenance.
Double-blind Placebo iv arm: as an inactive control arm

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

Overall Number of Participants Analyzed 296 60 102
Median (Inter-Quartile Range)
Unit of Measure: minutes
4
(3.0 to 6.0)
19.5
(17.0 to 23.0)
19
(12.0 to 21.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Remimazolam, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 6.133
Confidence Interval (2-Sided) 95%
4.416 to 8.517
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Time to Fully Alert
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Patients who do not reach the endpoint are censored at last MOAA/S
Arm/Group Title Remimazolam Placebo Midazolam
Hide Arm/Group Description:
Double-blind Remimazolam iv arm: 5 mg for sedation induction, and 2.5 mg top-ups for sedation maintenance.
Double-blind Placebo iv arm: as an inactive control

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

Overall Number of Participants Analyzed 296 60 102
Median (95% Confidence Interval)
Unit of Measure: minutes
After the end of colonoscopy Number Analyzed 293 participants 59 participants 101 participants
6
(5 to 7)
15
(13 to 21)
13
(11 to 16)
After last dose of study drug or rescue sedative Number Analyzed 296 participants 60 participants 102 participants
14
(13 to 14)
28
(24 to 32)
24
(22 to 26)
4.Secondary Outcome
Title Time to Ready for Discharge
Hide Description 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).
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Remimazolam Placebo Midazolam
Hide Arm/Group Description:
Double-blind Remimazolam iv arm: 5 mg for sedation induction, and 2.5 mg top-ups for sedation maintenance.
Double-blind Placebo iv arm: as an inactive control arm

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

Overall Number of Participants Analyzed 296 60 102
Median (95% Confidence Interval)
Unit of Measure: minutes
After the end of colonoscopy procedure
44
(42 to 46)
49
(44 to 54)
48
(41 to 51)
After last dose of study drug or rescue sedative
51
(49 to 54)
60.5
(55 to 67)
57
(53 to 61)
Time Frame From first dose of study drug until Day 4, or resolution of any ongoing adverse events
Adverse Event Reporting Description Total number of participants affected with Other (Not Including Serious) Adverse Events represents any participant in the trial with a non serious Treatment-emergent Adverse Event (TEAE). The listing of participants with Preferred Term (PT)TEAEs is reported with a threshold of 5% in any of the arms
 
Arm/Group Title Remimazolam Placebo Midazolam
Hide Arm/Group Description Double-blind Remimazolam iv arm: 5 mg for sedation induction, and 2.5 mg top-ups for sedation maintenance. Double-blind Placebo iv arm: as an inactive control

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

All-Cause Mortality
Remimazolam Placebo Midazolam
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/296 (0.00%)   0/60 (0.00%)   0/102 (0.00%) 
Hide Serious Adverse Events
Remimazolam Placebo Midazolam
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/296 (0.00%)   0/60 (0.00%)   0/102 (0.00%) 
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Remimazolam Placebo Midazolam
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   218/296 (73.65%)   47/60 (78.33%)   93/102 (91.18%) 
Cardiac disorders       
Bradycardia  1  33/296 (11.15%)  7/60 (11.67%)  16/102 (15.69%) 
Tachycardia  1  23/296 (7.77%)  7/60 (11.67%)  13/102 (12.75%) 
Gastrointestinal disorders       
Nausea * 1  5/296 (1.69%)  4/60 (6.67%)  2/102 (1.96%) 
Vascular disorders       
Hypotension  1  115/296 (38.85%)  25/60 (41.67%)  63/102 (61.76%) 
Hypertension * 1  59/296 (19.93%)  17/60 (28.33%)  18/102 (17.65%) 
Diastolic Hypertension * 1  29/296 (9.80%)  6/60 (10.00%)  9/102 (8.82%) 
Diastolic Hypotension  1  23/296 (7.77%)  4/60 (6.67%)  9/102 (8.82%) 
Systolic hypertension  1  16/296 (5.41%)  5/60 (8.33%)  6/102 (5.88%) 
1
Term from vocabulary, MedDRA (18.0)
Indicates events were collected by systematic assessment
*
Indicates events were collected by non-systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
At least 60 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 60 days to enable sponsor to seek patent protection.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Trial Information
Organization: PAION UK Ltd
Phone: +49 2414453101
EMail: reg_paion@paion.com
Publications of Results:
Douglas K. Rex, MD, MACG, Raj Bhandari, MD, Taddese Desta MD, Michael DeMicco MD, Cynthia Schaeffer MD, Kyle Etzkorn, Charles Barish MD, Ronald Pruitt MD, Brooks Cash MD, FACG, Daniel Quirk MD, Felix Tiongco MD, David Bernstein MD, FACG. REMIMAZOLAM IS A SAFE AND EFFECTIVE AGENT FOR SEDATION IN OUTPATIENT COLONOSCOPY: RESULTS OF A PHASE 3, MULTICENTER, RANDOMIZED, PLACEBO CONTROLLED TRIAL. Program No. ACG 2016 Annual Scientific Meeting Abstracts. Las Vegas, NV: American College of Gastroenterology.
Other Publications:
Layout table for additonal information
Responsible Party: Paion UK Ltd.
ClinicalTrials.gov Identifier: NCT02290873    
Other Study ID Numbers: CNS7056-006
First Submitted: November 7, 2014
First Posted: November 14, 2014
Results First Submitted: October 10, 2018
Results First Posted: November 9, 2018
Last Update Posted: October 20, 2020