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Trial registered on ANZCTR


Registration number
ACTRN12616000562471
Ethics application status
Approved
Date submitted
16/03/2016
Date registered
2/05/2016
Date last updated
2/05/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
The Neuro-PROTECT Trial: Efficacy of two neuroprotection strategies for decreasing the incidence of neurological injury in patients undergoing Transcatheter aortic valve implantation (TAVI)
Scientific title
NEUROprotection with ischaemic PReconditioning Or TEmperature Control in Transcatheter aortic valve implantation (Neuro-PROTECT) Trial: Efficacy of ischaemic preconditioning and temperature control for decreasing the incidence of neurological injury in patients undergoing Transcatheter aortic valve implantation (TAVI)
Secondary ID [1] 288777 0
None
Universal Trial Number (UTN)
U1111-1180-8798
Trial acronym
Neuro-PROTECT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Aortic Stenosis 298040 0
Transcatheter Aortic Valve Implantation (TAVI) 298041 0
Perioperative Stroke 298042 0
Condition category
Condition code
Neurological 298200 298200 0 0
Other neurological disorders
Anaesthesiology 298201 298201 0 0
Other anaesthesiology
Cardiovascular 298202 298202 0 0
Diseases of the vasculature and circulation including the lymphatic system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants randomised to the intervention group will receive one of the following interventions:

1. Remote Ischaemic Preconditioning - Under standard conditions, two blood pressure cuffs will be placed, one on the left lower limb distal to the femoral cannulation site and one on the upper limb contralateral to the arterial line. Two to four cycles of transient ischaemia/reperfusion will follow induction of anaesthesia with completion prior to insertion of the delivery catheter. Each cycle will involve concurrent inflation of both upper and lower limb blood pressure cuffs to a pressure of greater than or equal to 200mmHg and at least 15mmHg greater than the systolic arterial pressure measured via the arterial line for 5 minutes, followed by 5 minutes of reperfusion (total 10 minutes). Patients will be sedated with intravenous propofol target controlled infusion and paralysed with intravenous rocuronium or cisatracurium. Doses will be initially calculated on a milligrams per kilogram basis at the induction of anaesthesia and titrated appropriately with ongoing administration for the duration of the procedure and extubation prior to transfer to the post anesthetic recovery unit. This intervention will be performed by dedicated research nurse or doctor with a minimum of 3 years clinical experience. All other researchers and clinicians will be blinded to randomization.

2. Targeted Temperature Management - Mild cerebral hypothermia, targeting a nasopharyngeal temperature of 34.5 degrees celsius, will be achieved as described below. Cerebral hypothermia will be induced following general anaesthetic induction and maintained until closure of the skin (last stage of the procedure). Continuous temperature monitoring will be performed and titrated using nasopharyngeal temperature probe. A urinary bladder temperature probe and intermittent tympanic measures will be used for comparison /analysis. Hypothermia will be achieved by withholding routine warming devices, administration of cooled fluids and with use of a cooling device (Cincinnati Sub-Zero Products Ltd, Cincinnati, OH, USA). Patients will be sedated with intravenous propofol target controlled infusion and paralysed with intravenous rocuronium or cisatracurium to prevent shivering. Doses will be initially calculated on a milligrams per kilogram basis at the induction of anaesthesia and titrated appropriately with ongoing administration for the duration of the procedure and in the intensive care unit, as required, until normothermia is achieved (36.5 degrees celsius to 37.5 degrees celsius). To avoid the deleterious effects of cerebral hyperthermia, slow re-warming, controlled at a rate of 0.5 degrees celsius/hour will occur in the intensive care unit, where required, following completion of the procedure until normothermia is attained, with ongoing monitoring to ensure the occurrence of rebound hyperpyrexia is managed rapidly. This will take approximately 4 hours if target temperature of 34.5 degrees celsius is achieved intraoperatively. This intervention will be performed by the treating anaesthetists, who will be the only person unblinded to randomisation.
Intervention code [1] 294223 0
Prevention
Comparator / control treatment
1. Sham remote ischaemic preconditioning
2. Sham targeted temperature management

The control groups will be prepared in an identical manner, including placement of equipment required to conduct the neuroprotective intervention. However, the intervention will not be delivered.
Control group
Placebo

Outcomes
Primary outcome [1] 297707 0
Technical success inducing and maintaining cerebral hypothermia to within 0.5 degrees celsius of the specified temperature (34.5) as measured by nasopharyngeal temperature probe.
Timepoint [1] 297707 0
From induction of anesthesia until prior to insertion of the TAVI delivery catheter.
Primary outcome [2] 297708 0
Technical success delivering the remote ischaemic preconditioning protocol as measured by completion of all cycles of cuff inflation prior to insertion of the delivery catheter.
Timepoint [2] 297708 0
From induction of anesthesia until prior to insertion of the TAVI delivery catheter.
Primary outcome [3] 297709 0
Adverse events occurring secondary to either of the two trial interventions as determined by medical record and patient assessment for the following potential adverse events:

1. Remote ischemic preconditioning: The limbs used to induce remote ischemic preconditioning will be assessed by researchers at completion of the TAVI procedure following removal of the tourniquets, and again at 72 hours post-procedure. This will involve a complete neurovascular and skin integrity examination.

2. Targeted Temperature Management: Patients and their records will be assessed by researchers to detect the following intraoperatively, following established normothermia and again at 72 hours:

a) Occurrence of arrhythmias or bradycardia < 40 beats per minute or requiring treatment. All patients will be monitored with telemetry intraoperatively and for 72 hours post-operatively.

b) Electrolyte (including magnesium, potassium and phosphate) and glucose abnormalities in the blood requiring pharmacologic intervention, measured intraoperatively, following established normothermia, and at 24, 48 and 72 hours postoperatively.

c) Requirement for blood product transfusion or intervention to reduce bleeding.

d) Occurrence of infection diagnosed by the treating clinicians, assessed by chart review at 72 hours.

e) Time to extubation, assessed by chart review.

f) Requirement for pharmacologic management of shivering, assessed by chart review.
Timepoint [3] 297709 0
Events occurring within the first 72 hours post-procedure.
Secondary outcome [1] 321929 0
Number of new diffusion weighted imaging positive lesions
Timepoint [1] 321929 0
Day 3 (+/-1) post-procedure.
Secondary outcome [2] 321930 0
Procedural complication including: 1) time to extubation; 2) respiratory tract infections; 3) Mortality (all cause and cardiovascular); 4) myocardial infarction; 5) clinically apparent stroke (minor, major); 6) bleeding (minor, major, life-threatening); 7) acute kidney injury (AKN classification); 8) vascular complications (major, minor, percutaneous closure device failure); 9) conduction disturbances and arrhythmias; 10) other (conversion to open surgery, unplanned cardiopulmonary bypass, ventricular septal perforation, mitral valve apparatus damage, cardiac tamponade, endocarditis, valve thrombosis, valve map-positioning, TAVI-in-TAVI requirement. These will be assessed by medical record review.
Timepoint [2] 321930 0
Assessed at 72 hours post-procedure for events occurring intra-operatively or within the first 72 hours post-procedure.
Secondary outcome [3] 321931 0
Early complications including: 1) time to extubation; 2) respiratory tract infections; 3) Mortality (all cause and cardiovascular); 4) myocardial infarction; 5) clinically apparent stroke (minor, major); 6) bleeding (minor, major, life-threatening); 7) acute kidney injury (AKN classification); 8) vascular complications (major, minor, percutaneous closure device failure); 9) conduction disturbances and arrhythmias; 10) other (conversion to open surgery, unplanned cardiopulmonary bypass, ventricular septal perforation, mitral valve apparatus damage, cardiac tamponade, endocarditis, valve thrombosis, valve map-positioning, TAVI-in-TAVI requirement. These will be assessed by medical record review.
Timepoint [3] 321931 0
Assessed at 6 weeks post-procedure for events occurring from 72 hours up to 6 weeks post-procedure.
Secondary outcome [4] 323240 0
Total volume of new diffusion weighted imaging positive lesions.
Timepoint [4] 323240 0
Day 3 (+/-1) post-procedure
Secondary outcome [5] 323263 0
Mean single lesion volume of diffusion weighted imaging positive lesions.
Timepoint [5] 323263 0
Day 3 (+/-1) post-procedure

Eligibility
Key inclusion criteria
1) Informed consent for participation; 2) severe aortic stenosis requiring management with isolated TAVI with an Edwards SAPIEN-XT prosthesis under general anaesthetic, as determined by the local 'heart team'; 3) Pre-procedural mini-mental state examination score greater than or equal to 24; 4) stable haemoglobin.
Minimum age
65 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) <65 years of age; 2) pre-existing neurological impairment including previous clinical cerebrovascular event or cognitive dysfunction; 3) contraindication to MRI (including incompatible prostheses / foreign body, inability to lie flat, claustrophobic requiring sedation); 4) contraindication to proposed neuroprotective intervention (e.g., previous thromboembolic disease, peripheral vascular disease etc.); 5) non- or poor english speaking (due to the unknown validity of neuropsychiatric battery in such a population); 6) chronic kidney or liver disease; 7) Patients with diabetes.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Every attempt will be made to ensure the patients, treating cardiologists / cardiothroacic surgeons, anaesthetists, intensive care staff, ward staff, and study investigators involved in the patient assessment and data analysis are blinded to allocation of study. The specific consideration and nature of both interventions requires that at least one investigator (who must deliver the intervention) is aware of allocation. Allocation will be delivered to the investigator responsible for intervention conduct in a sealed opaque envelope to ensure concealment.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Restricted randomisation will be determined by a computer random number generator to achieve random permuted blocking with randomly varies block sizes and a 1:1 allocation ratio between intervention and control.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Safety
Statistical methods / analysis
This study will use a convenience sample of at least 10, and up to 20 participants per cohort, or a minimum of 40 participants total. Multiple regression models will be used to adjust for potential confounders. Additionally, longitudinal analysis will be used to examine outcomes with repeated data. Following completion, power calculations will be performed to determine the number of subjects required by a subsequent efficacy study. Treatment failure will be considered on an intention to treat basis, with the aim of providing a more realistic estimate of the feasibility and efficacy of applying the neuroprotective strategies in this setting.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 5693 0
The Prince Charles Hospital - Chermside
Recruitment hospital [2] 5694 0
St Andrew's War Memorial Hospital - Brisbane
Recruitment postcode(s) [1] 13179 0
4032 - Chermside
Recruitment postcode(s) [2] 13180 0
4001 - Brisbane

Funding & Sponsors
Funding source category [1] 293145 0
Charities/Societies/Foundations
Name [1] 293145 0
Heart Foundation
Address [1] 293145 0
Level 12,
500 Collins Street,
Melbourne VIC 3000
Country [1] 293145 0
Australia
Primary sponsor type
Hospital
Name
The Prince Charles Hospital
Address
Rode Road
Chermside, QLD, 4032
Country
Australia
Secondary sponsor category [1] 291939 0
University
Name [1] 291939 0
The University of Queensland
Address [1] 291939 0
Mayne Medical School
288 Herston Road
Herston, QLD, 4006
Country [1] 291939 0
Australia
Secondary sponsor category [2] 292289 0
University
Name [2] 292289 0
St Andrew's War Memorial Hospital
Address [2] 292289 0
457 Wickham Terrace
Brisbane, QLD, 4001
Country [2] 292289 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294640 0
The Prince Charles Hospital, Metro North Hospital and Health Service HREC (EC00168)
Ethics committee address [1] 294640 0
Research, Ethics & Governance Unit
Metro North Hospital and Health Service
Building 14
The Prince Charles Hospital
Rode Road
Chermside, QLD, 4032
Ethics committee country [1] 294640 0
Australia
Date submitted for ethics approval [1] 294640 0
11/02/2016
Approval date [1] 294640 0
10/03/2016
Ethics approval number [1] 294640 0
HREC/16/QPCH/41
Ethics committee name [2] 294908 0
UnitingCare Health
Ethics committee address [2] 294908 0
Ground Floor Moorlands House,
The Wesley Hospital
451 Coronation Drive
Auchenflower, QLD, 4066
Ethics committee country [2] 294908 0
Australia
Date submitted for ethics approval [2] 294908 0
29/03/2016
Approval date [2] 294908 0
Ethics approval number [2] 294908 0
UCH HREC 1609

Summary
Brief summary
BACKGROUND:
Transcatheter aortic valve implantation (TAVI) is a minimally invasive management option available to select patients suffering from severe aortic stenosis (AS). However, the incidence of cerebrovascular events (CVEs), such as stroke, have raised concern and have the potential to dramatically mitigate any benefits associated with the procedure. We have identified two promising physiological neuroprotective strategies that warrant investigation in this setting: 1) remote ischemic preconditioning (RIPC); and, 2) targeted temperature management (TTM).

RATIONALE:
(1) RIPC is a protective mechanism whereby a non-lethal ischemic insult, occurring at a site remote from the target organ, activates adaptive mechanisms that blunt tissue injury on subsequent challenge. Laboratory and animal studies have demonstrated this to be one of the most powerful anti-ischaemic strategies known; and yet translation from theory to clinical practice remains a largely unmet medical need. One reason for this has been the unpredictable nature of the timing of stroke, precluding pre-treatment. Cardiovascular procedures, such as TAVI, provide a unique opportunity to apply this technique to a setting of predictably high risk for cerebrovascular events.

(2) TTM relies on the reduction in metabolic (e.g. oxygen and glucose) requirements of the brain that occurs with hypothermia. In addition to affecting oxygen consumption and glucose utilisation, hypothermia has other potential benefits including reducing waste products, inflammation, and preventing cell death.

HYPOTHESIS:
TTM and RIPC offer feasible neuroprotective strategies during TAVI and warrant further investigation.

METHODS:
This is a prospective, randomised, controlled pilot study. All patients planned to undergo TAVI at The Prince Charles Hospital and St. Andrew’s War Memorial Hospital will be considered. TAVI can be delivered in a number of ways including via blood vessels in the groin (transfemoral or TF approach) or directly through the chest wall (transaortic or TAo approach). Consecutive eligible participants undergoing implantation via a TAo approach will be randomised (1:1) to either control or TTM. Those for whom a Transfemoral (TF) approach is to be used will be randomised (1:1) to either control or RIPC.

ASSESSMENT & DATA COLLECTION:
A multi-disciplinary approach has been adopted to ensure that relevant experts address each assessment domain. Assessors will be blinded to treatment allocation.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 64450 0
Dr Jonathon P. Fanning
Address 64450 0
The Critical Care Research Group
Level 3, Clinical Sciences Building
The Prince Charles Hospital
Rode Road
Chermside, QLD, 4032
Country 64450 0
Australia
Phone 64450 0
+61 410408777
Fax 64450 0
Email 64450 0
jonathon_fanning@icloud.com
Contact person for public queries
Name 64451 0
Dr Jonathon P. Fanning
Address 64451 0
The Critical Care Research Group
Level 3, Clinical Sciences Building
The Prince Charles Hospital
Rode Road
Chermside, QLD, 4032
Country 64451 0
Australia
Phone 64451 0
+61 410408777
Fax 64451 0
Email 64451 0
jonathon_fanning@icloud.com
Contact person for scientific queries
Name 64452 0
Dr Jonathon P. Fanning
Address 64452 0
The Critical Care Research Group
Level 3, Clinical Sciences Building
The Prince Charles Hospital
Rode Road
Chermside, QLD, 4032
Country 64452 0
Australia
Phone 64452 0
+61 410408777
Fax 64452 0
Email 64452 0
jonathon_fanning@icloud.com

No information has been provided regarding IPD availability
Summary results
No Results