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

• 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: Paion UK Ltd.
• Collaborator: Premier Research Group plc
• Information provided by (Responsible Party): Paion UK Ltd.

Tracking Information

• First Submitted Date: November 7, 2014
• First Posted Date: November 14, 2014
• Results First Submitted Date: October 10, 2018
• Results First Posted Date: November 9, 2018
• Last Update Posted Date: October 20, 2020
• Actual Study Start Date: March 30, 2015
• Actual Primary Completion Date: April 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 28, 2020)

Success Rates of the Procedure [ Time Frame: 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.

Original Primary Outcome Measures (submitted: November 11, 2014)

Success of Procedure [ Time Frame: From start to end of colonoscopy ]

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.

Current Secondary Outcome Measures (submitted: October 10, 2018)

• Time to Start of Procedure [ Time Frame: 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 [ 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 ]
  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 [ 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). ]
  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).

Original Secondary Outcome Measures (submitted: November 11, 2014)

• Time to Start of Procedure [ Time Frame: From first dose of study drug until insertion of the colonoscope ]
• Time to peak sedation [ Time Frame: From first dose of study drug until the lowest level of sedation, which has occurred during the colonoscopy procedure. ]
• Time to Ready for Discharge [ Time Frame: From the end of the colonoscopy and after the last dose of study drug, until discharge, expected to be the same day. ]
• Time to Fully Alert [ Time Frame: From the last dose of study drug, until the patient has recovered to fully alert. Expected to be the same day. ]
• Number of patients with adverse events [ Time Frame: From first dose of study drug until Day 4, or resolution of any ongoing adverse events. ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Phase III Study of the Efficacy and Safety of Remimazolam Compared to Placebo and Midazolam in Colonoscopy Patients
• Official Title: 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
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Colonoscopy

Intervention

• Drug: Remimazolam
  For induction and maintenance of sedation
  Other Name: Byfavo, CNS7056
• Drug: Midazolam
  For induction of maintenance and sedation
  Other Name: Versed
• Drug: Placebo
  Inactive control arm

Study Arms

• Experimental: Remimazolam

  Remimazolam iv 5 mg for sedation induction, and 2.5 mg top-ups for sedation maintenance.

  Fentanyl pre-treatment: 50 μg (or less for elderly/disabled subjects) and 25 μg top-up doses

  Intervention: Drug: Remimazolam
• Placebo Comparator: Placebo

  Inactive control arm

  Fentanyl pre-treatment: 50 μg (or less for elderly/disabled subjects) and 25 μg top-up doses

  Intervention: Drug: Placebo
• Active Comparator: 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

  Fentanyl pre-treatment: 50 μg (or less for elderly/disabled subjects) and 25 μg top-up doses

  Intervention: Drug: Midazolam

Publications *

• Antonik LJ, Goldwater DR, Kilpatrick GJ, Tilbrook GS, Borkett KM. A placebo- and midazolam-controlled phase I single ascending-dose study evaluating the safety, pharmacokinetics, and pharmacodynamics of remimazolam (CNS 7056): Part I. Safety, efficacy, and basic pharmacokinetics. Anesth Analg. 2012 Aug;115(2):274-83. doi: 10.1213/ANE.0b013e31823f0c28. Epub 2011 Dec 20.
• Wiltshire HR, Kilpatrick GJ, Tilbrook GS, Borkett KM. A placebo- and midazolam-controlled phase I single ascending-dose study evaluating the safety, pharmacokinetics, and pharmacodynamics of remimazolam (CNS 7056): Part II. Population pharmacokinetic and pharmacodynamic modeling and simulation. Anesth Analg. 2012 Aug;115(2):284-96. doi: 10.1213/ANE.0b013e318241f68a. Epub 2012 Jan 16.
• Worthington MT, Antonik LJ, Goldwater DR, Lees JP, Wilhelm-Ogunbiyi K, Borkett KM, Mitchell MC. A phase Ib, dose-finding study of multiple doses of remimazolam (CNS 7056) in volunteers undergoing colonoscopy. Anesth Analg. 2013 Nov;117(5):1093-100. doi: 10.1213/ANE.0b013e3182a705ae.
• Borkett KM, Riff DS, Schwartz HI, Winkle PJ, Pambianco DJ, Lees JP, Wilhelm-Ogunbiyi K. A Phase IIa, randomized, double-blind study of remimazolam (CNS 7056) versus midazolam for sedation in upper gastrointestinal endoscopy. Anesth Analg. 2015 Apr;120(4):771-80. doi: 10.1213/ANE.0000000000000548.
• Pambianco DJ, Borkett KM, Riff DS, Winkle PJ, Schwartz HI, Melson TI, Wilhelm-Ogunbiyi K. A phase IIb study comparing the safety and efficacy of remimazolam and midazolam in patients undergoing colonoscopy. Gastrointest Endosc. 2016 May;83(5):984-92. doi: 10.1016/j.gie.2015.08.062. Epub 2015 Sep 9.
• 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.
• Rex DK, Bhandari R, Desta T, DeMicco MP, Schaeffer C, Etzkorn K, Barish CF, Pruitt R, Cash BD, Quirk D, Tiongco F, Sullivan S, Bernstein D. A phase III study evaluating the efficacy and safety of remimazolam (CNS 7056) compared with placebo and midazolam in patients undergoing colonoscopy. Gastrointest Endosc. 2018 Sep;88(3):427-437.e6. doi: 10.1016/j.gie.2018.04.2351. Epub 2018 Apr 30.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 14, 2016): 461
• Original Estimated Enrollment (submitted: November 11, 2014): 460
• Actual Study Completion Date: April 19, 2016
• Actual Primary Completion Date: April 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

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).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02290873
• Other Study ID Numbers: CNS7056-006
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Responsible Party: Paion UK Ltd.
• Study Sponsor: Paion UK Ltd.
• Collaborators: Premier Research Group plc

Investigators

• Principal Investigator: Douglas K Rex, MD; Indiana University School of Medicine

• PRS Account: Paion UK Ltd.
• Verification Date: September 2020