Multiple Dose Safety and Efficacy Study Evaluating CNS 7056 Versus Midazolam in Patients Undergoing Colonoscopy

Study Overview
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Brief Summary
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The purpose of this dose-response study is to assess the safety and efficacy of CNS 7056 compared with midazolam to maintain suitable sedation levels in patients undergoing colonoscopy.

Detailed Description
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This is a double-blind, randomized, parallel group, dose-response study to assess the safety and efficacy of three dose levels of CNS 7056 compared with midazolam to maintain suitable sedation levels in patients undergoing colonoscopy. Safety assessment will include physical examinations, vital signs, ECGs, pulse oximetry measurements, capnography, clinical chemistry and hematology laboratory tests, routine drug and ethanol screening, urinalysis, pregnancy test, pain on injection using a verbal scale, and monitoring of adverse events.

Official Title
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A Phase IIb Study Evaluating the Safety and Efficacy of Multiple Doses of CNS 7056 Compared to Midazolam in Patients Undergoing Colonoscopy

Conditions
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Sedation

Intervention / Treatment
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* Drug: A. CNS 7056
* Drug: B. CNS 7056
* Drug: C. CNS 7056
* Drug: D. Midazolam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients, aged 18 to 70 years inclusive, scheduled to undergo a standard colonoscopy. American Society of Anesthesiologists Physical Status (ASA PS) Score I, II, or III. Weight range 55 to 130 kg inclusive. Body mass index (BMI) range 18 to 33 kg/m2 inclusive Patients of child-bearing potential and their partners must have been willing to use adequate contraception such as an intrauterine device, diaphragm or condom during the study and until 1 month after the last study drug administration. Childbearing potential was defined as all patients unless they were a female post menopausal for at least 2 years, or were surgically sterile. Patient voluntarily signed and dated an ICF that was approved by an IRB 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 (Day 4 ± 3 day) after the colonoscopy. Exclusion Criteria: Expected duration of colonoscopy > 30 minutes. Patients with a suspected or diagnosed pathology of the lower GI tract that would have added to the risk of colonoscopy, such as strictures, active inflammatory bowel disease. ASA III patients with history of sleep apnea. ASA III patients with obesity (BMI ≥ 30 kg/m2). Patients with evidence of uncontrolled renal, hepatic, central nervous system, respiratory, cardiovascular or metabolic dysfunction, or other clinically significant (CS) findings at screening that, in the investigator's or medical monitor's opinion, should have excluded them from the study. Patients with clinically significant abnormalities in 12 lead ECG recorded at screening. Female patients with a positive serum human chorionic gonadotropin (HCG) pregnancy test at screening or baseline. Lactating female patients. Patients with positive drugs of abuse screen at baseline. Patients with positive serum ethanol at baseline. Patient with a history of drug or ethanol abuse. Patients in receipt of any investigational drug within 30 days or less than 7 half lives (whichever was longer) before the start of the study, or scheduled to receive one during the study period. Patients with a known sensitivity to benzodiazepines, flumazenil, opioids, naloxone, or a medical condition such that these agents were contraindicated. Patients with an inability to communicate well with the investigator. Patients in whom management of airway was judged to be difficult due to, e.g., thyro-mental distance ≤ 4 cm (short neck), or Mallampati score of 4.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A. Remimazolam (CNS 7056)<br>Initial 8 mg iv for sedation induction, and 3 mg iv top-ups for sedation maintenance. Fentanyl pre-treatment: up to 100 μg (at the discretion of the investigator) and 25 μg top-up doses. | Drug: A. CNS 7056<br>* Initial low dose plus supplemental doses as necessary.<br>* Other names: Remimazolam;|
| Experimental: B. Remimazolam (CNS 7056)<br>Initial 7 mg iv for sedation induction, and 2 mg iv top-ups for sedation maintenance. Fentanyl pre-treatment: up to 100 μg (at the discretion of the investigator) and 25 μg top-up doses. | Drug: B. CNS 7056<br>* Initial intermediate dose plus supplemental doses as necessary.<br>* Other names: Remimazolam;|
| Experimental: C. Remimazolam (CNS 7056)<br>Initial 5 mg iv for sedation induction, and 3 mg iv top-ups for sedation maintenance. Fentanyl pre-treatment: up to 100 μg (at the discretion of the investigator) and 25 μg top-up doses. | Drug: C. CNS 7056<br>* Initial high dose plus supplemental doses as necessary.<br>* Other names: Remimazolam;|
| Active Comparator: D. Midazolam<br>Initial 2.5 mg iv for sedation induction, and 1 mg iv top-ups for sedation maintenance. Fentanyl pre-treatment: up to 100 μg (at the discretion of the investigator) and 25 μg top-up doses | Drug: D. Midazolam<br>* Initial standardized dose plus supplemental doses as necessary.<br>* Other names: CAS No. 59467-96-8;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Success Rates of the Procedure | Success of the procedure is a composite endpoint consisting of: Modified Observer's Assessment for Alertness/Sedation (MOAA/S) scores ≤4 on three consecutive measurements after administration of study drug AND completion of the endoscopy procedure AND no requirement for rescue sedative medication AND no requirement for manual or mechanical ventilation | From start of study drug injection to patient discharge | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Fully Alert | Time to first of 3 consecutive MOAA/S scores of 5 after the last injection of double-blind study medication | From last injection of double-blind study medication until fully alert criteria are reached | 
| Time to Ready for Discharge | Time of the first of 3 consecutive Aldrete scores ≥ 9 | After the Last Injection of Double-Blind Study Medication AND after end of colonoscopy until first of 3 consecutive Aldrete scores ≥ 9 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CNS 7056, Procedural Sedation, Colonoscopy