A Phase III Study of Remimazolam in Patients Undergoing Bronchoscopy

A Phase III Study Evaluating the Efficacy and Safety of Remimazolam (CNS 7056) Compared to Placebo and Midazolam in Patients Undergoing Bronchoscopy

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.

Study Overview

• Status: Completed
• Conditions: Bronchoscopy
• Intervention / Treatment: Drug: Remimazolam; Drug: Placebo; Drug: Midazolam

• Study Type: Interventional
• Enrollment (Actual): 446
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Florida
    • Brandon, Florida, United States, 33511
      • PAB Clinical Research
    • Sun City Center, Florida, United States, 33573
      • Sun City Office
  • Indiana
    • Michigan City, Indiana, United States, 46360
      • LaPorte County Institute for Clinical Research
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • The Johns Hopkins Center for Interventional and Pulmonary Care
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine/Barnes-Jewish Hospital
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • Unc Division of Pulmonary and Critical Care
    • Durham, North Carolina, United States, 27710
      • Duke University
    • Pinehurst, North Carolina, United States, 28374
      • Pinehurst Medical Clinic
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest Baptist Health
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
    • Spartanburg, South Carolina, United States, 29303
      • S. Carolina Pharmaceutical Research
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University
    • Richmond, Virginia, United States, 23225
      • Pulmonary Associates of Richmond
  • Washington
    • Tacoma, Washington, United States, 98405
      • MultiCare Institute for Research & Innovation

Participation Criteria

Eligibility Criteria

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

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / 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 Names: 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 Names: Versed

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From first dose of study drug to removal of bronchoscope (average time not known)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Start of Procedure	The time from the first dose of study drug until bronchoscope insertion on Day 1	From first dose of study drug until insertion of the bronchoscope
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.	From the last dose of study drug or rescue sedative AND from end of bronchoscopy until the patient has recovered to fully alert
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)	After the last dose of study drug AND after the end of the bronchoscopy, until discharge

Collaborators and Investigators

• Sponsor: Paion UK Ltd.
• Collaborators: Premier Research Group plc
• Investigators: Principal Investigator: Gerard Silvestri, MD, Medical University of South Carolina, US

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2015
• Primary Completion (Actual): March 1, 2017
• Study Completion (Actual): March 13, 2017

Study Registration Dates

• First Submitted: November 11, 2014
• First Submitted That Met QC Criteria: November 20, 2014
• First Posted (Estimate): November 21, 2014

Study Record Updates

• Last Update Posted (Actual): March 18, 2020
• Last Update Submitted That Met QC Criteria: March 3, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: Remimazolam, midazolam, bronchoscopy, procedural sedation
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Midazolam
• Other Study ID Numbers: CNS7056-008

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No