Clinical Trials Register

Summary
EudraCT Number:	2013-001113-32
Sponsor's Protocol Code Number:	CNS7056-010
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-04-26
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

Germany - BfArM

A.2

EudraCT number

2013-001113-32

A.3

Full title of the trial

A Randomized, Single-blind Phase II Study Evaluating the Efficacy, Safety and Pharmacokinetics of Remimazolam in General Anesthesia in Adult Patients Undergoing Cardiac Surgery, Including Follow-up Sedation in the Post-anesthesia Care Unit / Intensive Care Unit

A.3.1

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

Clinical phase II study of the sedative remimazolam in general narcosis in adult patients undergoing heart surgery, including subsequent care in the post-anaesthesia/intensive care unit, in order to evaluate the effects, tolerability, and metabolism of remimazolam

A.4.1

Sponsor's protocol code number

CNS7056-010

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 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	4924144530
B.5.5	Fax number	492414453 100
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 for Injection 25mg
D.3.2	Product code	CNS7056, ONO-2745
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.3.9.1	CAS number	1001415-66-2
D.3.9.2	Current sponsor code	CNS7056B
D.3.9.3	Other descriptive name	CNS 7056B, ONO-2745BS
D.3.9.4	EV Substance Code	SUB119978
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	26.25
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 1% MCT Fresenius
D.2.1.1.2	Name of the Marketing Authorisation holder	Fresenius Kabi Deutschland
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.4	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.3.9.1	CAS number	2078-54-8
D.3.9.2	Current sponsor code	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	10
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: 3
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	Sevofluran Baxter 100% Flüssigkeit zur Herstellung eines Dampfs zur Inhalation
D.2.1.1.2	Name of the Marketing Authorisation holder	Baxter Deutschland GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.4	Pharmaceutical form	Inhalation vapour, liquid
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Inhalation use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	sevoflurane
D.3.9.1	CAS number	28523-86-6
D.3.9.2	Current sponsor code	sevoflurane
D.3.9.3	Other descriptive name	SEVOFLURANE
D.3.9.4	EV Substance Code	SUB10506MIG
D.3.10	Strength
D.3.10.1	Concentration unit	% percent
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
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

Anaesthesia in adult patients undergoing cardiac surgery.

E.1.1.1

Medical condition in easily understood language

Sedation in adult patients undergoing cardiac surgery.

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	16.0
E.1.2	Level	LLT
E.1.2	Classification code	10021722
E.1.2	Term	Induction and maintenance anaesthesia
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

• to compare:
- 2 doses of remimazolam against each other and against propofol during induction of general anesthesia
and
- remimazolam versus the combination of propofol and sevoflurane during maintenance of general anesthesia
regarding efficacy and safety

E.2.2

Secondary objectives of the trial

• to collect data on pharmacokinetics to provide bridging to the PK data collected in Japanese subjects
• to support the design of a phase III study in general anesthesia
• to investigate pharmacoeconomic aspects

For more details please see Secondary endpoints in Section E.5.2.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Patients scheduled for major elective cardiac surgery, i.e. surgery assumed to require more than 2 hours of maintenance of general anesthesia and to require the use of extracorporeal circulation, including coronary bypass(es), valve replacement and surgery of the aortic arch
• Scheduled to receive mechanical ventilation via tracheal intubation (oropharyngeal or nasotracheal)
• Age at least 18 years
• Weight between 55 and 150 kg inclusive
• Body Mass Index (BMI) 18 to ≤ 35 kg/m2
• Willingness and ability to give informed consent, to understand, participate and comply with all study requirements
• For women with childbearing potential: negative pregnancy test

E.4

Principal exclusion criteria

• Thoraco-abdominal replacement of the aorta or other procedure expected to be accompanied by a massive hemorrhage (at least 15% of the circulating blood volume)
• History of or planned cooling below 34ºC
• History of or planned stop of circulation, e.g. due to repair of type A dissection of aorta or removal of thrombi from pulmonary artery
• Planned to receive epidural/spinal anesthesia together with general anesthesia
• Evidence of uncontrolled hepatic, central nervous system, respiratory, or metabolic dysfunction, or other clinically significant findings at screening that, in the investigator’s or medical monitor’s opinion, should exclude them from the study.
• Poorly controlled hypertension (e.g. systolic blood pressure ≥160 mmHg under antihypertensive medication)
• Severe renal insufficiency or end-stage renal disease (estimated glomerular filtration rate below 30 mL/min/1.73 m2)
• Clinically uncontrolled coagulation abnormalities, or coagulation abnormalities not under adequate treatment
• Total bilirubine ≥3.0 mg/dL or AST and/or ALT ≥2.5 x ULN during 7 days prior to starting administration of the investigational product
• Scheduled for heart or lung transplantation
• Infectious cardiac disorders (e.g. endocarditis, myocarditis)
• Sepsis
• Emergency surgery, status of shock or coma
• Ejection fraction of less than 20%
• Acute right heart failure
• Pre-operative use of phosphodiesterase 3 inhibitors
• History of resuscitation
• Known resistance to benzodiazepines or history of paradoxical effects after administration of benzodiazepines
• History of hypersensitivity to benzodiazepines, propofol, remifentanil hydrochloride, rocuronium bromide, flumazenil or other anesthetic agents
• Use of benzodiazepines within 5 times their half-life or 5 times the half-life of their active metabolites. Exception: Single dose pre-medication before the surgery according to local standards is allowed.
• Epilepsy
• Myasthenia gravis or myasthenic syndrome
• History of any severe allergy
• Dependence from alcohol or drugs or history of alcohol or drug abuse
• Acute alcoholic intoxication or ethanol intake within 48 hours prior to surgery
• Acute narrow-angle glaucoma
• Female patients of childbearing potential without acceptable method of birth control or not surgically sterile
• Pregnant or breast feeding female patients
• 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
• Administration of remimazolam in the past
• Unable to communicate well with the investigator
• Other reasons that, according to the investigator, exclude the patient from the trial

E.5 End points

E.5.1

Primary end point(s)

Efficacy: Proportion of patients with successful anesthesia, i.e. no use of rescue sedative.

E.5.1.1

Timepoint(s) of evaluation of this end point

Phase of general anaesthesia (Day 1).

E.5.2

Secondary end point(s)

Efficacy:
•Time to loss of consciousness
•Time to intubation completed
•Successful intubation
•Time with Narcotrend index ≤ 60
•Time to extubation
•Time to discharge from PACU / ICU
•Time on the IMC
•Time to transfer to normal ward
•Time to discharge from hospital
•Intra-operative awakening/memory
•Body motion
•Use of rescue medication

Safety:

During general anesthesia and recovery:
•Blood pressure, heart rate
•Blood gas analysis
•Bradycardia
•Low cardiac output syndrome
•Abnormalities in Narcotrend
•Use of vasopressors
•Duration of mechanical ventilation

During general anesthesia only:
•Ejection fraction
•Cardiac output index
•Cardiostability
•Parameters measured via PICCO catheter
•QTc prolongations

During recovery from general anesthesia only:
•Airway interventions
•Adverse events post general anesthesia
•Adverse events of special interest

After recovery:
•Post-operative admission to ICU when plan was to admit to PACU
•Re-admission to ICU after discharge from ICU or PACU
•Re-admission to the IMC
•Re-surgery after 6 – 8 hours

From screening through discharge
•Increase of troponin, myocardial infarctions
•Physical examination
•Adverse events
•General safety laboratory
•Electrocardiogram
•Cognitive function
•Quality of life

Pharmacokinetics, Pharmacoeconomics

E.5.2.1

Timepoint(s) of evaluation of this end point

Phase of general anaesthesia (Day 1), phase of recovery (Day 1 to Day N) including phase of intensive care unit (ICU) sedation depending on the medical condition of the patient, follow up phase I (48 hours post discharge form post-anasthesia care unit or ICU), follow up phase II (starts at the end of FU phase I and ends with the discharge from the hospital).

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

Yes

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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

LVLS

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

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:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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.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

2013-08-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-04-30

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-02-19

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