Clinical Trials Register

Summary
EudraCT Number:	2020-001322-54
Sponsor's Protocol Code Number:	CS/2018/6632
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2020-07-03
Trial 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

2020-001322-54

A.3

Full title of the trial

Carbon Dioxide Insufflation and Brain Protection During Open Heart Surgery: A Randomised Controlled Trial

A.3.1

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

The CO2 study: Carbon Dioxide Insufflation and Brain Protection During Open Heart Surgery

A.3.2

Name or abbreviated title of the trial where available

CO2 study

A.4.1

Sponsor's protocol code number

CS/2018/6632

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	University Hospitals Bristol and Weston NHS Foundation Trust
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	National Institute for Health Research - Efficacy and Mechanisam Evaluation Programme
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	Bristol Trials Centre, Clinical Trials and Evaluations Unit, University of Bristol
B.5.2	Functional name of contact point	Rachel Todd
B.5.3	Address:
B.5.3.1	Street Address	University of Bristol Level 7, Queen's Building
B.5.3.2	Town/ city	Bristol Royal Infirmary
B.5.3.3	Post code	BS2 8HW
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	0117 342 2374
B.5.6	E-mail	CO2-trial@bristol.ac.uk

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	Information not present in EudraCT
D.2.1.1.1	Trade name	Medical carbon dioxide
D.2.1.1.2	Name of the Marketing Authorisation holder	BOC ltd
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	Medical carbon dioxide
D.3.2	Product code	PL 0735/5006R
D.3.4	Pharmaceutical form	Medicinal gas, compressed
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Route of administration not applicable
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Carbon dioxide
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	% (V/V) percent volume/volume
D.3.10.2	Concentration type	not less then
D.3.10.3	Concentration number	99.5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
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	Yes
D.3.11.13.1	Other medicinal product type	Medical gas

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Medicinal gas, compressed
D.8.4	Route of administration of the placebo	Other use (Noncurrent)

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Brain injury during open heart valve surgery

E.1.1.1

Medical condition in easily understood language

Brain injury during open heart valve surgery

E.1.1.2

Therapeutic area

Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutic techniques [E02]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10067967
E.1.2	Term	Brain injury
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10048935
E.1.2	Term	Open heart surgery
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	10077808
E.1.2	Term	Mild neurocognitive disorder
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10001526
E.1.2	Term	Air embolism
E.1.2	System Organ Class	10047065 - Vascular disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The main aim is to evaluate the effectiveness and safety of carbon dioxide insufflation during open heart surgery compared to medical air in patients who are having open heart valve surgery.

The primary objective is the difference in incidence of acute clinical or radiographic ischemic brain injury, between 2 and 10 days post procedure, between the group that have carbon dioxide insufflation during surgery and the group that have medical air insufflation during surgery.

E.2.2

Secondary objectives of the trial

Secondary objectives are:
1. The difference between the carbon dioxide group and medical air group with respect to; clinical outcomes; brain MRI outcomes; adverse events; and patient-reported outcomes.

2. The association between the burden and location of new lesions demonstrating brain injury detected on the brain MRI and post-operative neurocognitive dysfunction assessed by standard neurocognitive function tests.

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

Mechanistic sub-study at Bristol centre only.
Objective: to determine whether there is a link between brain injury detected by MRI and:
1. The number and size of air bubbles detected by transcranial doppler ultrasound during surgery
2. The blood flow to the brain detected by transcranial doppler ultrasound during surgery
3. The amount of oxygen in the frontal lobes detected by near infrared spectrometry;
and whether these relationships differ between the CDI and medical air insufflation groups.

E.3

Principal inclusion criteria

1. Age ≥ 50 years
2. Planned left side aortic or mitral valve surgical repair or replacement (with or without another procedure, e.g. coronary artery bypass graft) via a partial or full sternotomy using central (i.e. aortic) or peripheral (i.e. femoral) perfusion cannulae

E.4

Principal exclusion criteria

1. Contraindication to medical carbon dioxide: acquired or genetic of acidosis (i.e. renal tubular acidosis)
2. Contraindication to MRI (e.g. known intolerance, permanent pacemaker in situ or expected implantation of a permanent pacemaker)
3. History of clinical stroke within 3 months prior to randomisation
4. Cardiac catheterisation within 3 days of the planned surgery
5. Cerebral and/or aortic arch arteriography or interventions within 3 days of the planned surgery
6. Active endocarditis at time of randomisation
7. Planned concomitant aortic procedure such as root replacement
8. Clinical signs of cardiogenic shock or treatment with IV inotropic therapy prior to randomisation
9. Participation in an interventional (drug or device) trial
10. Unable to provide written informed consent
11. Prisoners

E.5 End points

E.5.1

Primary end point(s)

The primary outcome is acute ischemic brain injury within 10 days post-surgery based on new brain lesions identified with diffusion weight magnetic resonance imaging of the brain or clinical evidence of permanent brain injury according to the updated definition of stroke for the 21st century: symptoms persisting ≥ 24 hours in the brain, spinal cord or/and retina; not including cases of global ischemia.

E.5.1.1

Timepoint(s) of evaluation of this end point

The primary outcome will be the time from start of surgery to hospital discharge.

E.5.2

Secondary end point(s)

1. Number and volume of DWI brain lesions
2. Objective quantification of the impairment caused by new ischemic brain injury assessed using the National Institutes of Health Stroke Scale (NIHSS)
3. Delirium assessed using the 3-minute diagnostic interview for Confusion Assessment Method (CAM)
4. Functional status assessed using the Barthel Index score
5. Neurocognitive function in 6 domains (verbal memory, visual memory, executive functioning, visuospatial or constructional praxis, attention, and information processing speed), assessed using the following tests:
a. Addenbrooke’s Cognitive Examination III
b. Trail making Tests A and B
6. Quality of life assessed using the physical and mental subscales of the 12-Item Short-Form Health Survey (SF-12)
7. Composite of all-cause mortality, clinical stroke, or acute kidney injury within 30 days of surgery
8. Serious adverse events (SAEs) to 3 months
9. Survival to 3 months

E.5.2.1

Timepoint(s) of evaluation of this end point

Secondary outcomes will be measured at baseline (before surgery), following surgery during the inpatient stay and at the three month follow up visit.

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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

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

Yes

E.6.13.1

Other scope of the trial description

Mechanistic

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

E.8.1.4

Double blind

Yes

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)

E.8.2.2

Placebo

Yes

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.8.5

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

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

The end of the trial for an individual patient is defined as completion of the three-month post-surgery follow-up assessments.

The end of the trial is the date when all patients have completed the three-month post-surgery follow-up, or are lost to follow-up, the database has been locked and all data queries have been resolved.

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