A Phase III Study of Remimazolam in Patients Undergoing Bronchoscopy

• ClinicalTrials.gov Identifier: NCT02296892
• Recruitment Status: Completed
• First Posted: November 21, 2014
• Results First Posted: March 12, 2019
• Last Update Posted: March 18, 2020
• Sponsor: Paion UK Ltd.
• Collaborator: Premier Research Group plc
• Information provided by (Responsible Party): Paion UK Ltd.

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Bronchoscopy	Drug: Remimazolam; Drug: Placebo; Drug: Midazolam	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 446 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase III Study Evaluating the Efficacy and Safety of Remimazolam (CNS 7056) Compared to Placebo and Midazolam in Patients Undergoing Bronchoscopy
• Actual Study Start Date: April 2015
• Actual Primary Completion Date: March 2017
• Actual Study Completion Date: March 13, 2017

Arms and Interventions

Arm	Intervention/treatment
Experimental: Remimazolam; Double-blind Remimazolam arm: 5 mg iv for sedation induction, and 2.5 mg iv top-ups for sedation maintenance. Fentanyl pre-treatment: 25-50 μg (or less for elderly/disabled subjects), and 25 μg top-up doses	Drug: Remimazolam; For induction and maintenance of sedation; Other Name: CNS7056
Placebo Comparator: Placebo; Double-blind placebo arm as inactive control Fentanyl pre-treatment: 25-50 μg (or less for elderly/disabled subjects), and 25 μg top-up doses	Drug: Placebo; Inactive control arm
Active Comparator: Midazolam; Open-label Midazolam arm: 1.75 mg* iv for sedation induction and 1.0 mg* iv 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: 25-50 μg (or less for elderly/disabled subjects), and 25 μg top-up doses	Drug: Midazolam; For induction and maintenance of sedation; Other Name: Versed

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With a Successful Procedure [ Time Frame: 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 Outcome Measures :

1. Time to Start of Procedure [ Time Frame: 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
2. Time to Fully Alert [ 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 ]

   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.

3. Time to Ready for Discharge [ Time Frame: 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)

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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).

Contacts and Locations

Locations

United States, Florida

Pab Clinical Research

Brandon, Florida, United States, 33511

Sun City Office

Sun City Center, Florida, United States, 33573

United States, Indiana

Laporte County Institute For Clinical Research

Michigan City, Indiana, United States, 46360

United States, Maryland

The Johns Hopkins Center for Interventional and Pulmonary Care

Baltimore, Maryland, United States, 21287

United States, Missouri

Washington University School of Medicine/Barnes-Jewish Hospital

Saint Louis, Missouri, United States, 63110

United States, North Carolina

Unc Division of Pulmonary and Critical Care

Chapel Hill, North Carolina, United States, 27599

Duke University

Durham, North Carolina, United States, 27710

Pinehurst Medical Clinic

Pinehurst, North Carolina, United States, 28374

Wake Forest Baptist Health

Winston-Salem, North Carolina, United States, 27157

United States, South Carolina

Medical University of South Carolina

Charleston, South Carolina, United States, 29425

S. Carolina Pharmaceutical Research

Spartanburg, South Carolina, United States, 29303

United States, Virginia

Pulmonary Associates of Richmond

Richmond, Virginia, United States, 23225

Virginia Commonwealth University

Richmond, Virginia, United States, 23298

United States, Washington

Multicare Institute For Research & Innovation

Tacoma, Washington, United States, 98405

Sponsors and Collaborators

Paion UK Ltd.

Premier Research Group plc

Investigators

• Principal Investigator: Gerard Silvestri, MD; Medical University of South Carolina, US

  Study Documents (Full-Text)

Documents provided by Paion UK Ltd.:

Study Protocol  [PDF] March 3, 2016

Statistical Analysis Plan  [PDF] June 9, 2017

More Information

Publications of Results:

Pastis NJ, Yarmus LB, Schippers F, Ostroff R, Chen A, Akulian J, Wahidi M, Shojaee S, Tanner NT, Callahan SP, Feldman G, Lorch DG Jr, Ndukwu I, Pritchett MA, Silvestri GA; PAION Investigators. Safety and Efficacy of Remimazolam Compared With Placebo and Midazolam for Moderate Sedation During Bronchoscopy. Chest. 2019 Jan;155(1):137-146. doi: 10.1016/j.chest.2018.09.015. Epub 2018 Oct 4.

• Responsible Party: Paion UK Ltd.
• ClinicalTrials.gov Identifier: NCT02296892
• Other Study ID Numbers: CNS7056-008
• First Posted: November 21, 2014
• Results First Posted: March 12, 2019
• Last Update Posted: March 18, 2020
• Last Verified: March 2020

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

Keywords provided by Paion UK Ltd.:

Remimazolam, midazolam, bronchoscopy, procedural sedation

Additional relevant MeSH terms:

Midazolam; Adjuvants, Anesthesia; Hypnotics and Sedatives; Central Nervous System Depressants; Physiological Effects of Drugs; Anti-Anxiety Agents; Tranquilizing Agents; Psychotropic Drugs; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; GABA Modulators; GABA Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action