Phase III confirmatory efficacy and safety trial of remimazolam (CNS7056) compared with propofol for intravenous anaesthesia during elective surgery

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 results of 2
pregnancy tests, the first test taken at the start of Screening and the second
test taken shortly before the start of the administration of the IMP as well as
consent to use highly effective birth control from the last
menstrual cycle prior to the start of the IMP until the end of the trial
follow-up procedures. Highly effective methods of birth control include:
o Combined (estrogen and progestogen containing) hormonal contraception
associated with inhibition of ovulation:
- Oral / intravaginal / transdermal
o Progestogen-only hormonal contraception associated with inhibition of
ovulation:
- Oral / injectable / implantable
o Intrauterine device (IUD)
o Intrauterine hormone * releasing system (IUS)
o Bilateral tubal occlusion
o Vasectomised partner (provided that the partner is the sole sexual partner of
the female patient of childbearing potential and that the vasectomised partner
has received medical assessment of the surgical success).
o Sexual abstinence
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.

- Patients scheduled for spinal anaesthesia, epidural anaesthesia (central
neuroaxial anaesthesia) or regional anaesthesia. The placement of a peridural
catheter with a test dose application of a local anaesthetic drug (up to 5 mL)
to verify correct positioning to achieve post-operative analgesia and the
regional administration of local anaesthetic for postoperative analgesia after
wound closure (after the last skin suture) is accepted.
- Patients undergoing transplant surgery, cardiac surgery, or intracranial
neurosurgery, patients which have to be in prone position for surgery,
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 as per reference range in
laboratory tests which must be checked within the 7 days prior to start of IMP,
or any other laboratory results that make the patient unsuitable for the trial.
- 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) Patients with allergy/hypersensitivity to bovine
lactose, dextran or any other excipient in the remimazolam product.
- Presence of acute alcoholic or illicit drug intoxication, shock or coma state
- Known current dependency on or regular use of 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 airways
difficulties, 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 or 5 times the
half-life of the drug under investigation in any other clinical trial,
whichever is longer, prior to the beginning of administration of the IMP.
Exception: Non-interventional trials as defined in the European Clinical Trials
Directive 2001/20/EC: A trial where the medicinal product(s) is (are)
prescribed in the usual manner in accordance with the terms of the marketing
authorisation. The assignment of the patient to a particular therapeutic
strategy is not decided in advance by a trial protocol but falls within current
practice and the prescription of the medicine is clearly separated from the
decision to include the patient in the study. No additional diagnostic or
monitoring procedures shall be applied to the
patients and epidemiological methods should be used for the analysis of the
collected data.
- 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 subinvestigator to
be inappropriate for the trial for any other reason
- Planned use of forbidden concomitant medication