Clinical Phase III study in patients undergoing surgery to confirm ability of remimazolam to induce hypnotic effect in comparison with propofol

• Register: EUCTR
• Last refreshed on: 27 July 2020
• Main ID: EUCTR2018-000174-29-FR
• Date of registration: 26/07/2018
• Prospective Registration: Yes
• Primary sponsor: PAION UK Limited
• Public title: Clinical Phase III study in patients undergoing surgery to confirm ability of remimazolam to induce hypnotic effect in comparison with propofol
• Scientific title: Phase III confirmatory efficacy and safety trial of remimazolam (CNS7056) compared with propofol for intravenous anaesthesia during elective surgery
• Date of first enrolment: 21/09/2018
• Target sample size: 500
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-000174-29
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: yes; Double blind: no; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: no; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, Denmark, France, Germany, Italy, Netherlands, Switzerland, United Kingdom

Contacts

• Name: Clinical Trial Information
• Affiliation: PAION Deutschland GmbH

• Name: Clinical Trial Information
• Affiliation: PAION Deutschland GmbH

Key inclusion & exclusion criteria

Inclusion criteria:
In order to be eligible to participate in this trial, an individual must meet all of the following criteria:
• Male or female ASA III / IV patients, at least 18 years old, scheduled for an elective surgical procedure of a minimum duration of approximately 90 minutes under GA and planned to be extubated immediately post-operatively
• Total intravenous GA with the requirement for mechanical ventilation via endotracheal tube and necessary invasive BP monitoring either due to severity of illness, severity of concomitant diseases, type of surgery or decisions of the anaesthesia staff.
• Patients scheduled to stay in the hospital long enough after the surgical procedure to perform all trial follow-up procedures (~1 day)
• For female patients of childbearing potential: Negative result of a urine pregnancy test taken shortly before the start of the administration of the IMP as well as consent to use highly effective birth control during the trial period (from the time of consent until the end of the trial follow-up procedures). Women who had their last menstruation at least two years ago or who underwent surgical interventions (surgical birth control, bilateral oophorectomy, hysterectomy, etc.) are regarded as having no childbearing potential.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 350
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 150

Exclusion criteria:
An individual who meets any of the following criteria will be excluded from participation in this trial:
- Patients scheduled for spinal anaesthesia, epidural anaesthesia (central neuroaxial anaesthesia) or regional anaesthesia. The placement of a peridural catheter with a test dose application (up to 3 mL) to verify correct positioning to achieve post-operative analgesia and the regional administration of local anaesthetic for post-operative analgesia after wound closure is accepted.
- Patients undergoing transplant surgery, cardiac surgery, intracranial neurosurgery, emergency surgery, or any surgical procedure with the need for or scheduled for post-operative ventilator support
- Patients undergoing surgical procedures that require keeping the BP at a high level, e.g. surgical procedures in beach chair position
- Patients with severe hypertension, i.e., one baseline result of systolic BP 200 mmHg or more and / or diastolic BP of 120 mmHg or more. Baseline is defined as the time after signature of ICF and before arrival in the OR suite.
- Patients with total bilirubin of =3.0 mg/dL or =3 times increase in aspartate aminotransferase or alanine aminotransferase than the institutional reference range in laboratory tests during screening.
- Patients with end-stage renal disease requiring scheduled dialysis
- Patients with known anaphylactic reactions to benzodiazepines, propofol, opioid analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), dextran, neuromuscular blocking agents, flumazenil, naloxone, or other anaesthetic agents, or a medical condition such that these agents are contraindicated (according to local label)
- Presence of acute alcoholic or illicit drug intoxication, shock or coma state
- Known current dependency on central nervous system depressant drugs or alcohol
- Patients with gastroparesis or delayed gastric emptying, gastric reflux or any other increased risk for gastric aspiration
- Patients with an anticipated (small mouth opening, impaired neck movement, goitre, head and neck tumours or any other anatomical reason) or known difficult airways, known difficulties in airway maintenance or mask ventilation.
- Patients in whom NCT may not provide results due to organic defect of the brain or forehead, or any neurologic disease interfering with the EEG monitoring
- Patients on treatment with valproate
- Any pregnant or breast-feeding patient
Patients who participated in any clinical trial within 30 days prior to the beginning of administration of the IMP.
- Any patient judged to lack the ability to give informed consent or perform the trial assessments (e.g., due to dementia)
- Any patient judged by the principal investigator (PI) or sub-investigator to be inappropriate for the trial for any other reason


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Induction and maintenance of general anaesthesia (GA)
MedDRA version: 20.0 Level: LLT Classification code 10018061 Term: General anesthesia System Organ Class: 100000004865
MedDRA version: 20.0 Level: LLT Classification code 10054434 Term: Induction and maintenance of anesthesia System Organ Class: 100000004865

Therapeutic area: Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Anesthesia and Analgesia [E03]

Intervention(s)

Product Name: Remimazolam
Product Code: CNS7056
Pharmaceutical Form: Lyophilisate for solution for injection
INN or Proposed INN: Remimazolam
Current Sponsor code: CNS7056
Other descriptive name: REMIMAZOLAM
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 2-

Trade Name: Propofol
Product Name: Propofol
Pharmaceutical Form: Emulsion for injection/infusion
INN or Proposed INN: PROPOFOL
Other descriptive name: PROPOFOL
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 20-

Primary Outcome(s)

Primary end point(s): The primary efficacy endpoint (PEP) is the anaesthetic effect of remimazolam and propofol assessed as percent (%) of time of Narcotrend (NCT) Index =60 during the maintenance phase of the GA defined as the time between the first skin incision and the completion of the last skin suture

Main Objective: This is a confirmatory trial to establish non-inferior efficacy of remimazolam compared with propofol for induction and maintenance of GA for the purpose of elective surgery.

Secondary Objective: This is a confirmatory trial to establish superior haemodynamic stability associated with the use of remimazolam compared with propofol for the induction and maintenance of GA for the purpose of elective surgery.

Timepoint(s) of evaluation of this end point: During the maintenance phase of the GA

Secondary Outcome(s)

Secondary end point(s): The key secondary endpoint (KSE) is haemodynamic instability defined as critical decrease(s) in mean arterial blood pressure (MAP) between start of IMP and 15 minutes after the first skin incision.
For this endpoint, each event from the following categories will be counted and summed up per patient:
• Incidence of MAP dropping below 65 mmHg for at least 1 minute duration
• Incidence of a MAP decrease of more than 20% below the calculated (mean) baseline MAP value for at least 1 minute duration
• Incidence of a MAP decrease of more than 30% below the calculated (mean) baseline MAP value for at least 1 minute duration
• Number of norepinephrine boluses (0.01 mg) required or, if an infusion is used to maintain MAP equal to or above 65 mmHg, then each time interval of 2 minutes duration of continuous norepinephrine infusion will be counted as one event.
The baseline MAP is calculated based on all blood pressure (BP) measurements that are taken after signing the informed consent form (ICF) and before arrival at the operation room (OR) suite.
This endpoint is a safety endpoint.
Other secondary endpoints for efficacy comprise
• Percentage of time of NCT index (NCI) =60 and =40 during the maintenance phase
• Percentage of time of NCI <40 during the maintenance phase
• Percentage of patients with NCI =60 and =40 during =90% of the maintenance phase
• Percentage of patients who were administered rescue sedative medication
• The occurrence of intra-operative awakening (explicit awareness)
• Time from start of IMP to first NCI =60
• Time from start of IMP to loss of palpebral reflex
• Time from start of IMP to loss of consciousness (LOC, i.e., modified observer’s assessment of alertness / sedation [MOAA/S] = 0)
• Time from stop of IMP to response to verbal command (MOAA/S =4)
• Time from stop of IMP to end of extubation
• Time from stop of IMP to orientation to time, place, person and situation
• Time from stop of IMP to Modified Aldrete Score = 10
• Investigator’s overall satisfaction with IMP

Timepoint(s) of evaluation of this end point: During the maintenance phase of the GA

Secondary ID(s)

CNS7056-022

2018-000174-29-DE

Source(s) of Monetary Support

PAION UK Limited

Ethics review

Status: Approved
Approval date: 20/11/2018
Contact: