Clinical Trials Register

Summary
EudraCT Number:	2018-000174-29
Sponsor's Protocol Code Number:	CNS7056-022
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2018-05-14
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2018-000174-29

A.3

Full title of the trial

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

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

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

A.4.1

Sponsor's protocol code number

CNS7056-022

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	PAION UK Limited
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	PAION UK Limited
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	PAION Deutschland GmbH
B.5.2	Functional name of contact point	Clinical Trial Information
B.5.3	Address:
B.5.3.1	Street Address	Martinstrasse 10-12
B.5.3.2	Town/ city	Aachen
B.5.3.3	Post code	52062
B.5.3.4	Country	Germany
B.5.4	Telephone number	00492414453101
B.5.5	Fax number	00492414453100
B.5.6	E-mail	info@paion.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Remimazolam
D.3.2	Product code	CNS7056
D.3.4	Pharmaceutical form	Lyophilisate for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Remimazolam
D.3.9.2	Current sponsor code	CNS7056
D.3.9.3	Other descriptive name	REMIMAZOLAM
D.3.9.4	EV Substance Code	SUB119978
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Propofol
D.2.1.1.2	Name of the Marketing Authorisation holder	Fresenius Kabi Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Propofol
D.3.4	Pharmaceutical form	Emulsion for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PROPOFOL
D.3.9.3	Other descriptive name	PROPOFOL
D.3.9.4	EV Substance Code	SUB10116MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Induction and maintenance of general anaesthesia (GA)

E.1.1.1

Medical condition in easily understood language

Induction of hypnotic effect

E.1.1.2

Therapeutic area

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

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10018061
E.1.2	Term	General anesthesia
E.1.2	System Organ Class	100000004865

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10054434
E.1.2	Term	Induction and maintenance of anesthesia
E.1.2	System Organ Class	100000004865

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

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.

E.2.2

Secondary objectives of the trial

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.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Venous blood samples for bioanalysis and subsequent PK analysis will be obtained from a limited number of patients at selected sites (up to 100 patients) during general anesthesia (GA) induction, maintenance and after end of the infusion of the investigational medicinal product (IMP) at specified time points.

E.3

Principal 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 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 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.

E.4

Principal 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 local anaesthetic drug (up to 5 mL) to verify correct positioning to achieve post-operative analgesia and the regional administration of local anaesthetic for post-operative analgesia after wound closure (after the last skin suture) 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 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), 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 sub-investigator to be inappropriate for the trial for any other reason
- Planned use of forbidden concomitant medication

E.5 End points

E.5.1

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

E.5.1.1

Timepoint(s) of evaluation of this end point

During the maintenance phase of the GA

E.5.2

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 ≥ 27 during the maintenance phase
• Percentage of time of NCI < 27 during the maintenance phase
• Percentage of patients with NCI ≤60 and ≥ 27 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 ≥9
• Investigator’s overall satisfaction with IMP

E.5.2.1

Timepoint(s) of evaluation of this end point

During the maintenance phase of the GA

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

Yes

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Belgium

Denmark

France

Germany

Italy

Netherlands

Switzerland

United Kingdom

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LPLV

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

358

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

154

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

480

F.4.2.2

In the whole clinical trial

512

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-07-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-07-25

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2020-04-02

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